Oral dosage forms including ionically chargeable hydrogels for delivery of active agents - Patents.com

Abstract

The present disclosure provides, inter alia, pharma- ceutically acceptable oral dosage forms comprising an ionically chargeable hydrogel and a protective coating for delivery of an ionically chargeable active agent to an intestinal site, and methods of treatment using the pharma-ceutically acceptable oral dosage forms described herein.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 337,246, filed May 2, 2022, and U.S. Provisional Patent Application No. 63 / 394,107, filed August 1, 2022, the contents of which are incorporated herein by reference in their entireties.

[0002] FIELD OF THEINVENTION Aspects of the present invention relate to pharma- ceutically acceptable oral dosage forms for delivery of active agents to intestinal sites. [Background technology]

[0003] Oral administration of active agents is attractive for many reasons, including ease of administration and high patient compliance. However, for some active agents, such as poorly absorbed, sensitive (i.e., pH-sensitive, enzyme-sensitive, etc.) and / or high molecular weight active agents, oral administration may be less effective or ineffective in achieving sufficient blood levels of the active agent compared to other administration strategies. For example, active agents such as proteins and other macromolecules may be enzymatically degraded in the digestive tract and / or have limited transport across the intestinal epithelium.

[0004] One possible strategy to avoid the harsh environment of the gastrointestinal tract is the derivatization of drugs with polyethylene glycol to prevent environmental changes and / or enzymatic degradation by the use of protease inhibitors. Another possible strategy is to increase the permeability of tissues in the gastrointestinal tract so that drug absorption is increased. Drugs can be formulated with additives that, for example, open intestinal tight junctions to allow the drug to pass through the intestinal epithelium. A further approach to improve drug delivery in the gastrointestinal tract is to enterically coat the drug so that it is not exposed to the harsh pH conditions of the stomach and is instead released in the small intestine where absorption occurs more readily.

[0005] Another technique for drug delivery is to use hydrogel as part of drug delivery system.However, there is still a need for a drug delivery system that can provide improved delivery of drugs to the digestive tract, such as a form that allows active substances to be easily absorbed by intestinal tissue without excessive degradation.There is also still a need for a drug delivery system that can provide improved delivery of active substances to the intestinal tract. Summary of the Invention

[0006] According to one embodiment of the present disclosure, a medicamentically acceptable oral dosage form for delivering an active agent to an intestinal site is provided. The dosage form includes a delivery device and a protective coating over the delivery device. The delivery device includes a plurality of hydrogel particles comprising an ionically chargeable hydrogel material, the ionically chargeable hydrogel material comprising a crosslinked polymeric material having a swelling ratio of at least 5; and an ionically chargeable active agent having a net ionic charge of the same sign as the net ionic charge of the ionically chargeable hydrogel at an intestinal pH in the range of about 4 to about 8. Methods for treating disorders in a subject using such dosage forms are also provided. [Brief description of the drawings]

[0007] To facilitate further explanation of embodiments of the present disclosure, the following drawings are provided for illustrative purposes, not for limiting the scope of the disclosure.

[0008] [Figure 1] Figure 1 shows the schematic structure of hydrogel #3.02. The structures of the two components, AMPS and methylenebisacrylamide, are also shown.

[0009] [Diagram 2] Figures 2A-2B show the swelling results of hydrogels with various amounts of crosslinker in both DI water (A) and FASSIF at pH 7 (B).

[0010] [Diagram 3]Figures 3A-3B show the exclusion effect of hydrogels with various amounts of crosslinker in FASSIF at pH 7 (A, bar graph; B, individual points). 1 mg / mL of GG-427 was used as the drug. Error bars = 1 standard deviation. t-test comparing exclusion with standard hydrogel #3.02. There is no statistical difference in exclusion (all p-values ​​>0.05).

[0011] [Figure 4] FIG. 4 is a schematic diagram showing that the high negative charge of hydrogel #3.02 prevents the entry of negatively charged molecules.

[0012] [Diagram 5] 5A-5B show the concentration of GG-353 (A) in blood samples and its bioavailability ratio upon oral delivery to dogs with and without hydrogel (300 mg).

[0013] [Figure 6] FIG. 6 shows the concentration of atenolol in blood samples following oral delivery to dogs with and without hydrogel (300 mg).

[0014] [Figure 7] Figures 7A and 7B show the results of GG-353 (5 mg) oral bioavailability versus hydrogel content. All formulations contain one enteric gel cap (size 00), GG-353 (5 mg), atenolol (1 mg) and citric acid (0.25 mg), sodium caprate (200 mg), soybean trypsin inhibitor (50 mg), and hydrogel #3.02 (0-450 mg).

[0015] [Figure 8] FIG. 8 is a schematic diagram illustrating an exemplary peptide exclusion principle using an anionic hydrogel.

[0016] [Figure 9]FIG. 9 is a schematic diagram illustrating one embodiment of an oral dosage form comprising an ionically chargeable hydrogel and an ionically chargeable active agent.

[0017] [Figure 10] FIG. 10 shows the results of an oral bioavailability study using an ionically chargeable hydrogel and three different ionically chargeable peptides.

[0018] [Figure 11A] FIG. 11A is a schematic diagram of an embodiment showing a mixture of a protease and an ionically chargeable hydrogel and, optionally, an ionically chargeable peptide, which can be used to detect peptide levels in the bulk liquid outside the hydrogel (if an ionically chargeable peptide, such as peptide C, is added to the mixture) and can be used to detect protease activity in the bulk liquid outside the hydrogel (if an ionically chargeable peptide does not need to be added to the mixture).

[0019] [Figure 11B] FIG. 11B shows the results of ionically chargeable peptide levels detected for mixtures of peptides in liquid with protease and hydrogel, and mixtures of peptides in liquid with protease but without hydrogel (top left graph is peptide concentration in combination with chymotrypsin, top right graph is peptide concentration in combination with trypsin); and also shows the results of protease activity detected for mixtures of protease with hydrogel in liquid, protease without hydrogel in liquid, and protease with a hydrogel that has the same sign of net ionic charge as the protease in liquid (bottom left graph is chymotrypsin activity, bottom right graph is trypsin activity).

[0020] [Figure 12]Figure 12 shows the schematic structure of hydrogel #12.035, with the circled areas highlighting the differences from hydrogel #3.02. The structures of the three components, AMPS, methylenebisacrylamide and styrenesulfonate, are also shown.

[0021] [Figure 13] FIG. 13 shows the relative concentration of Evans Blue dye upon addition of various amounts of hydrogel #12.035 sufficient to absorb a specific fraction of the fluid present in simulated intestinal fluid at pH 7.

[0022] [Figure 14] FIG. 14 shows the concentration of Peptide C in blood samples (left) and its bioavailability (right) following oral delivery to dogs with and without hydrogel #12.035 (300 mg).

[0023] [Figure 15] FIG. 15 shows an in vitro study comparing hydrogel #12.035 and hydrogel #3.02 with peptide C.

[0024] Other aspects, embodiments and features of the inventive subject matter will become apparent from the following detailed description when considered in conjunction with the accompanying drawings, which are schematic and are not intended to be drawn to scale. For purposes of clarity, not every element or component is labeled in every figure, nor is every element or component of each embodiment of the inventive subject matter shown unless illustration is necessary to enable those skilled in the art to understand the inventive subject matter. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] (definition) As used herein, "drug" refers to any therapeutic agent that may be administered to a patient for the treatment and / or prevention of a disease and / or condition, and unless otherwise specified, includes, but is not limited to, pharmaceuticals, drugs, small molecule drugs, drug conjugates, prodrugs, antibodies or antibody fragments, nucleic acids, proteins, peptides, polysaccharides, small organic molecules (e.g., molecular weights of about 500 Da or less), metabolic activators (e.g., metabolites), nutrients, supplements, and the like.

[0026] As used herein, "biodegradable" refers to a material that, when introduced into the body of an individual, patient, or subject, is broken down by cellular mechanisms, chemical processes (e.g., hydrolysis), or physical processes (e.g., dissolution) into components (sometimes referred to as "degradation products") that the body can reuse or discard without significant toxic effects. In some instances, the degradation products may also be biocompatible.

[0027] As used herein, "mucoadhesive" refers to a composition that has the ability to bind to a mucosal surface.

[0028] As used herein, "hydrogel" refers to a hydrophilic crosslinked polymeric structure capable of absorbing liquids.

[0029] As used herein, "dry hydrogel" or "dry" hydrogel refers to a hydrogel material that has the same moisture content as a hydrogel material that has been dried for at least 18 hours in a convection oven set at 150°F at standard pressure.

[0030] As used herein, "swelling ratio" is a measure of the mass of liquid taken up by a hydrogel sample at a time after the liquid is introduced to the hydrogel sample, divided by the initial mass of the hydrogel sample. The swelling ratio can be expressed as follows: Q(swelling ratio)=(swollen mass-initial mass) / initial mass, or alternatively, as the ratio of the mass of liquid taken up by the hydrogel (Δliquid) to the initial mass of the hydrogel (i.e., before the liquid was introduced). The method used to determine the swelling ratio of a mass of a hydrogel, such as a hydrogel particle, is as follows (conducted at about standard temperature and pressure): a. Add 0.1 g of dry hydrogel (initial mass) to 15 mL of liquid. b. Soak for 15 minutes with gentle rocking. c. Drain non-absorbed liquid through a 500 μm mesh. d. Measure the mass of the non-absorbed liquid to obtain the mass of liquid absorbed by the hydrogel (Δliquid=initial mass of liquid-mass of non-absorbed liquid). The mass of liquid (initial or non-absorbed) can be obtained by weighing or by multiplying the volume of the liquid by its density. The liquid used in calculating the swelling ratio can be any suitable liquid, such as deionized water or fasting simulated intestinal fluid ("FASSIF"). For example, a typical FASSIF (e.g., 1 L) for use herein may be prepared by adding 961 g DI HO to 42 g FASSIF buffer concentrate (Biorelevant Media FASBUF, available from Biorelevant.com Ltd, Suite 4, Queen Mary Innovation Center, 42 New Road, London E1 2AX UK), adding 2.24 g FASSIF powder (Biorelevant Media FFF0, Biorelevant.com Ltd, Suite 4, Queen Mary Innovation Center, 42 New Road, London E1 2AX UK), stirring until dissolved, and adjusting to the desired pH (e.g., 6.5) with 1 M NaOH or HCl. The resulting FASSIF typically contains 3 mM taurocholic acid, 0.75 mM soy lecithin, 148 mM sodium, 106 mM chloride, and 29 mM phosphate.

[0031] As used herein, "swelling ratio percentage" refers to the percentage of the maximum swelling ratio to which the swelling ratio measured at a selected time interval corresponds. For example, if a hydrogel sample has a maximum swelling ratio of 100, then a swelling ratio of 50 measured at a 1 minute time interval would result in a swelling ratio percentage of 50%.

[0032] As used herein, "swelling rate" refers to the rate at which a hydrogel sample reaches a given swelling ratio. For example, a hydrogel sample may have a swelling rate that reaches at least a 30% swelling ratio in 1 minute, a 50% swelling ratio in 2 minutes, and a 100% swelling ratio in 10 minutes.

[0033] As used herein, "exclusion amount" refers to the amount of active agent that is excluded from the hydrogel material when the hydrogel material is introduced into fasting simulated intestinal fluid (FASSIF) (FASSIF medium at pH 6.5 as described above). The exclusion amount is calculated as follows: a. Use the swelling ratio of the hydrogel material to determine the mass of hydrogel material required to absorb 8 mL of FASSIF. b. Place the calculated amount of hydrogel into 10 mL of 1 mg / mL active agent in a 15 mL tube with gentle agitation (active solution). c. Place the calculated amount of hydrogel into 10 mL of FASSIF pH 7 in a 15 mL tube with gentle rocking (background solution). d. Extract 3 x 10 μL samples every 5 minutes for a total of 25 minutes and dilute into 190 μL deionized water in a 96-well UV plate. e. Also take 3 x 10 μL samples of 1 mg / mL active agent and pH 7 FASSIF stock solution. f. Upon completion, measure the absorbance of each sample at 230 nm and 265 nm (or another characteristic absorbance of the active substance). g. Background is subtracted from activity absorbance readings at each time point and compared to stock solutions to calculate the amount of clearance.

[0034] As used herein, "dry hydrogel" or "dry" hydrogel refers to a hydrogel material that has the same moisture content as a hydrogel material that has been dried for at least 18 hours in a convection oven set at 150°F at standard pressure.

[0035] As used herein, "ionically chargeable" means that the hydrogel material and / or active agent contain functional groups that can be in a charged form when provided in an aqueous medium, such as gastrointestinal fluids, deionized water, or FASSIF.

[0036] As used herein, "net ionic charge" refers to the sum of all ionic charges of the chargeable groups that are charged in an aqueous medium, such as a hydrogel containing ionically chargeable groups and / or an active agent having ionically chargeable groups, when provided in an aqueous medium, such as gastrointestinal fluid, deionized water or FASSIF. The sign of the net ionic charge of a material can be either positive, negative or neutral, depending on whether the material has more negatively charged groups, more positively charged groups or no charged groups at all when provided in an aqueous medium, and the magnitude of the charge of the charged groups. For example, a material that has ionically chargeable groups that are primarily negatively charged when provided in an aqueous medium can have a net negative ionic charge (the sign of the net ionic charge is negative), while a material that has ionically chargeable groups that are primarily positively charged when provided in an aqueous medium can have a net positive ionic charge (the sign of the net ionic charge is positive).

[0037] As used herein, the terms "individual," "patient," or "subject" are used interchangeably and refer to any animal, including mammals, preferably mice, rats, guinea pigs and other rodents; rabbits; dogs; cats; pigs; cows; sheep; horses; birds; reptiles; or primates, such as humans.

[0038] As used herein, a "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any solvents, dispersion media, coatings, isotonicity agents, absorption delaying agents, and the like that are biocompatible and suitable for administration to an individual.

[0039] As used herein, a "pharmaceutical composition" refers to a composition comprising at least one drug described herein formulated together with one or more pharma- ceutically acceptable carriers and / or excipients.

[0040] As used herein, "pharmacologically or pharmacologically acceptable" refers to molecular entities and compositions that are acceptable for administration to animals or humans, as appropriate, e.g., without producing excessive adverse, allergic or other untoward reactions.

[0041] As used herein, "treating" refers to any effect, eg, alleviation, reduction or modulation, that results in the improvement of a condition, disease, disorder, or the like.

[0042] As used herein, "protease activity assay" refers to an assay that determines protease activity in a given system, as will be understood by those skilled in the art. Two examples of such assays are chymotrypsin assay or trypsin assay. Protease activity of proteases, including chymotrypsin or trypsin, may be determined, for example, by a protease activity assay using either α-chymotrypsin, CAS:9004-07-3, or trypsin type 1, CAS:9002:07-7. According to one embodiment, a chymotrypsin activity assay kit, such as that available from Abcam, is used, which includes a coumarin substrate, a chymotrypsinogen activator, and a chymotrypsin assay buffer ("cTAB"). According to one embodiment, a trypsin activity assay kit, such as that available from Abcam, is used, which includes a p-NA substrate and a trypsin assay buffer ("TAB"). The materials for the assay may further include a Tris solution at pH 7.4 with 0.5 mM Ca.

[0043] In one embodiment, to prepare a chymotrypsin protease activity assay, the following steps are performed: weigh hydrogel (such as hydrogel #3.02 described in Example 1, with particle sizes ranging from 500-2000 μm) in 75 mg aliquots into labeled 15 mL tubes; label an additional 15 mL tube as a control; prepare aliquots of reaction solution by combining 46 μL of cTAB, 2 μL of coumarin substrate, and 2 μL of chymotrypsinogen activator in each aliquot (e.g., according to the Abcam assay kit instructions) (e.g., to provide four time points, all samples are n=3, in two tubes, so a total of 24 aliquots are needed, so the total solution is 1104 μL). 48 µL of cTAB, 48 µL of coumarin substrate, and 48 µL of chymotrypsinogen activator; vortex the reaction solution to mix; for one aliquot, prepare a sample background control (SBC) solution by combining 48 µL of cTab and 2 µL of chymotrypsinogen activator (e.g., according to the instructions of the Abcam assay kit) (e.g., to provide four time points, four aliquots are needed, so the total solution is 192 µL of cTab and 8 µL of chymotrypsinogen activator); vortex the solution to mix; and prepare a 10 µg / mL chymotrypsin solution in Tris buffer (e.g., 15 mL total solution for testing, 5 mL per tube). The procedure for the chymotrypsin activity assay involves adding 5 mL of chymotrypsin solution in Tris buffer to each of the sample tubes containing dried hydrogels and the empty control tube, starting a timer, and mixing with a spatula to break up the hydrogels as needed. The tubes are then incubated at 150 RPM and 39° C. Sampling from each tube is performed at each time point (5, 15, 30 and 60 minutes) by taking 10 μL from each tube and combining with 50 μL of the reaction solution above (n=3 tubes, total of 6 samples per time point).Samples are provided in wells of a UV-clear flat-bottom plate (e.g., a 96-well plate) and 50 μL of the SBC solution described above is provided in one well as a transfer background. Fluorescence readings are taken at 360 / 460 nm for each sample well at the time points. For each tube at each time point and incubation, the three readings for a single output are averaged and the SBC solution reading is subtracted from each average. For each average after subtracting the SBC solution reading, a calculation of activity is made for each incubation relative to the initial control reading.

[0044] In one embodiment, to prepare a trypsin protease activity assay, the following steps are performed: weigh hydrogel (such as hydrogel #3.02 described in Example 1, with particle sizes ranging from 500-2000 μm) in 75 mg aliquots into labeled 15 mL tubes; label an additional 15 mL tube as a control; prepare aliquots of reaction solution (e.g., according to the Abcam assay kit instructions) by combining 48 μL of TAB and 2 μL of p-NA substrate in each aliquot (e.g., to provide four time points, all samples are n=2, with 3 tubes, so a total of 26 aliquots are needed, so the total solution is 1248 μL of TAB and 52 μL of p-NA substrate); vortex the reaction solution to mix; and prepare a 150 μg / L trypsin solution in Tris (e.g., according to the Abcam assay kit instructions) (5 mL per tube, 15 mL total). The procedure for the trypsin activity assay involves adding 5 mL of trypsin solution in Tris buffer to each of the sample tubes containing dried hydrogels and the empty control tube, starting a timer and mixing with a spatula as necessary to break up the hydrogels. The tubes are then incubated at 150 RPM and 39°C. Two 50 μL reaction solution aliquots are placed into separate wells of the plate as background. Sampling from each tube is done at each time point (5, 15, 30, 60 minutes). 50 μL of each sample is placed into 450 μL of TAB and vortexed to mix. 10 μL of each solution is then taken from each tube and combined with the 50 μL reaction solution above. The samples are provided into wells of a UV-clear flat-bottom plate (e.g., a 96-well plate). Fluorescence readings are taken at 450 nm for each sample well at the time points. For each tube at each time point and incubation, the two readings for a single output are averaged and the average background reading of the reaction solutions is subtracted from all averages. For each average after background subtraction, a calculation of activity is made for each incubation relative to the initial control reading after background subtraction.

[0045] As used herein, "active agent concentration assay" includes any assay known to one of skill in the art that is suitable for determining the concentration of an active agent (e.g., peptide concentration) in a liquid sample. For example, an assay suitable for determining the concentration of an active agent in a liquid when provided in combination with an ion-chargeable hydrogel may include mixing the ion-chargeable hydrogel material and the active agent in a liquid (e.g., water), optionally mixed with other compounds of interest such as proteases. The ion-chargeable hydrogel material may be allowed to settle to the bottom of the mixture (e.g., the bottom of a test tube containing the mixture), and the liquid on top of the mixture above the hydrogel may be sampled. The concentration of the active agent present in such a sample may be determined by standard methods, such as liquid chromatography mass spectrometry (LCMS).

[0046] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise.

[0047] The terms "comprising," "comprise," "including," and "includes" should be construed as referring to elements, components, or steps in a non-exclusive manner and indicate that a referenced element, component, or step may be present, utilized, or combined with other elements, components, or steps that are not expressly referenced.

[0048] (Detailed Description) SUMMARY OF THE DISCLOSURE

[0002] Aspects of the present disclosure relate to dosage forms, systems and methods for oral, enteral and / or transmucosal delivery of an active agent. In particular, aspects of the present disclosure relate to a medicamentously acceptable oral dosage form for delivering an active agent to an intestinal site, comprising a delivery device and a protective coating over the delivery device. The delivery device comprises a plurality of hydrogel particles comprising an ionically chargeable hydrogel material, the ionically chargeable hydrogel material comprising a crosslinked polymeric material having a swelling ratio of at least 5; and an ionically chargeable active agent having a net ionic charge of the same sign as the sign of the net ionic charge of the ionically chargeable hydrogel at an intestinal pH in the range of about 4 to about 8. Aspects of the present disclosure also relate to dosage forms comprising the ionically chargeable hydrogel in a form having physical properties that enable superior active agent delivery characteristics at the intestinal site, such as swelling ratio, swelling rate, compressive strength and radial strength. Further aspects of the present disclosure provide methods of making a dosage form having a delivery structure comprising an ionically chargeable hydrogel, and methods of administering an active agent using the dosage form.

[0049] Without being limited to any theory, it is believed that the dosage form embodiment herein may be capable of providing improved bioavailability of the active agent delivered by the dosage form.For example, the dosage form may provide a highly swellable body that can expand rapidly at intestinal site, so that at least a portion of the outer surface of the hydrogel body is pressed into contact with adjacent intestinal tissue at the intestinal site.By contacting the outer surface of the hydrogel body with intestinal tissue, the active agent on the outer surface may be placed in physical contact with and / or in close proximity to the intestinal tissue, which allows the intestinal tissue to more easily absorb the active agent, improving the bioavailability of the active agent.

[0050] Yet another advantage of the embodiments of the dosage forms and / or delivery methods described herein is that drugs that need to be systemically available (i.e., enter the bloodstream) can reduce the amount of active agent required to be effective. For example, a drug that has only 40% bioavailability in standard oral dosage forms can have higher bioavailability when administered according to the embodiments described herein. Higher oral bioavailability has the potential to reduce the cost of the active agent, reduce side effects caused by the active agent in the GI tract, and reduce the possibility of side effects occurring due to active agent remaining in the GI tract. Furthermore, increasing the oral bioavailability of oral antibiotics has the potential to reduce the occurrence of antibiotic drug resistance due to unabsorbed drug in the small intestine and colon.

[0051] Furthermore, without being limited to any one theory, it is believed that the improvement of the bioavailability of the active agent may be enhanced by the liquid incorporation of the hydrogel at the intestinal site, which may increase the effective local concentration of the active agent and provide a greater driving force to transport the active agent through the intestinal wall. Further potential benefits to bioavailability that may be imparted by the liquid incorporation of the hydrogel and / or the presentation of the active agent near the mucosal surface may include the active agent being required to diffuse from the dosage form to the mucosal surface, thus increasing its potential absorption rate, and also shortening the exposure of the active agent to the harsh and potentially degrading environment of the GI tract.

[0052] Furthermore, without being limited to any one theory, it is believed that the ionically chargeable hydrogels of the present invention may increase the oral bioavailability of drugs (e.g., ionically chargeable peptides) that have a net ionic charge of the same sign as that of the hydrogel. For example, when an anionic drug and an anionic hydrogel are released in the small intestine, the hydrogel will absorb water and reduce the amount of free fluid present in the localized area of ​​the patient's small intestine. As the hydrogel swells, it may also absorb some drug, but the drug concentration in the water inside the hydrogel is lower than in the water outside the hydrogel. There are at least two possible mechanisms for the selective uptake of water relative to the drug. The first mechanism of drug exclusion from hydrogels is through ionic interactions and is known in the literature as Donnan equilibrium or Donnan exclusion effect. Briefly, the constrained negative charges on the hydrogel tend to prevent free negatively charged species (e.g., anionic drugs) from entering the hydrogel. The second mechanism of drug exclusion from non-porous hydrogels is generally related to the fast diffusion of water, whereas the diffusion of larger molecules is much slower. As a result, when a nonporous hydrogel is first contacted with a liquid containing both water and a drug, diffusion of water into the hydrogel is expected to be faster than the diffusion of large drug molecules. For example, given the known diffusion coefficient of water (~2.9 × 10 -9 m 2 / sec) and the reported diffusion coefficient for peptides of similar size (i.e., 4.5–5 kDa) (0.074 × 10 -9 m 2Using a 100 Hz / sec (100 Hz / s) NMR spectrum, the average time for water to diffuse 0.5 mm (and thus to the center of a 1 mm particle) is approximately 0.7 minutes, whereas a peptide drug takes 28 minutes to diffuse the same distance. As a result, the deep interior of the hydrogel particle is predicted to be substantially rich in water compared to the drug when it is initially swollen. For at least these two reasons, the drug concentration is higher in the free fluid remaining after swelling of the hydrogel than it would be in the absence of the hydrogel in the formulation. Since peptide drug uptake is driven by diffusion, and the rate of diffusion is directly related to the concentration by Fick's law, an increase in the drug concentration outside the hydrogel is predicted to increase the rate of drug uptake. For example, in one embodiment of the present disclosure, when the crosslinked polymeric material is exposed to an aqueous solution containing an ionically chargeable active agent (e.g., via an active agent concentration assay), the ratio of the percentage of the ionically chargeable active agent incorporated into the crosslinked polymeric material to the percentage of water incorporated into the crosslinked polymer is less than 0.1:1.

[0053] Provided below is a detailed description of embodiments of oral dosage forms that can enhance absorption and bioavailability of active agents.

[0054] (target tissue) In one embodiment, oral dosage form is configured to provide active substance delivery to target tissue in the digestive tract, such as upper digestive tract or lower digestive tract (i.e. small intestine or large intestine).For example, in one embodiment, the delivery site of active substance can be the mucosa of small intestine (e.g. duodenum, jejunum or ileum) and / or large intestine (e.g. ascending colon, right flexure, transverse colon, transverse mesocolon, left flexure, descending colon, sigmoid colon and rectum).In one embodiment, oral dosage form is configured to provide active substance delivery to tissue in the ileum of small intestine.

[0055] According to one embodiment, delivery to a particular region of the digestive tract, e.g., a site in the small intestine, can be achieved by selecting the make-up and composition of the oral dosage form. For example, a protective coating, such as an enteric coating, can be provided that at least partially protects the dosage form during passage through the stomach and / or other regions of the upper digestive tract until it reaches a predetermined location in the lower digestive tract. Further description of protective coatings and / or enteric coated dosage forms and / or other forms capable of delivering active substances to a predetermined location in the digestive tract is provided in more detail below.

[0056] (Ion-chargeable particulate hydrogel) According to embodiments of the present disclosure, a pharma- ceutically acceptable oral dosage form for delivery of an active agent to an intestinal site may be capable of providing the active agent in intimate contact and / or proximity with intestinal tissue at a target intestinal site, increasing the local drug concentration and facilitating uptake of the active agent at the target site. As discussed above, one potential mechanism of drug exclusion from the hydrogel is by ionic interactions via Donnan equilibrium or Donnan exclusion effect. For example, to maintain a negative charge inside the hydrogel for drug delivery, a chemical moiety may be provided that retains a negative charge when the hydrogel is in the small intestine. According to some embodiments, the pharma- ceutically acceptable oral dosage form may be suitable for an intestinal pH ranging from about 4 to about 8. Also, since the pH of the small intestine may typically range from pH 5 to pH 8, according to certain embodiments, it is desirable to use functional groups that have a pKa in the intestinal environment well below this range. Carboxylic acids, such as those derived from crosslinked sodium polyacrylate, have some negative charge at pH 5 to 8. However, the pKa of carboxylic acids is slightly lower than 5 (4.76 for acetic acid), so not all of them are in a charged state at pH 5 or 6.

[0057] Also, the pKa value inside the hydrogel (relative to the surface) may be shifted to somewhat higher pKa values ​​due to charge-charge repulsion inside the hydrogel, making it more difficult to collect large numbers of charges. This effect has been observed for other hydrogels, such as crosslinked polyallylamine, where the pKa of the amine (pKa ~9) shifts by about 1-2 pH units in the hydrogel compared to typical dissolved primary amines before polymerization (propylamine pKa ~10.7).

[0058] For this reason, in certain embodiments, it may be desirable for the pKa of the acid groups in the hydrogel to be well below pKa 5 in the intestinal environment. Functional groups that fit this criteria include sulfonates and sulfates, which in certain embodiments have pKa values ​​ranging from -5 to +2. Published values ​​indicate that the pKa of these moieties are methanesulfonic acid (-1.92), ethanesulfonic acid (-1.68), benzenesulfonic acid (-2.8), and methanesulfate (-3.4). Thus, sulfonates and sulfates are preferred functional groups for anionic hydrogels designed to eliminate anionic drugs in the small intestine. For practical purposes, the pKa of the functional groups described herein are those measured in deionized water, and the pKa of such functional groups in intestinal fluid or simulated intestinal fluid (e.g., FASSIF) is expected to be very similar and substantially the same as the pKa measured in deionized water.

[0059] According to certain embodiments, it may be preferred to generate negative charges in the hydrogel because chargeable moieties that include sulfates or sulfonates tend to bind less strongly with calcium or magnesium from the small intestine fluids than chargeable moieties that include carboxylates, essentially reducing the net negative charge inside the hydrogel. According to certain embodiments, for similar reasons of providing a low pKa, it may be desirable to use phosphonates or phosphates to generate negative charges in the hydrogel, since certain phosphonates and / or phosphates may have pKa values ​​less than 2. According to yet other embodiments, carboxylates may be provided and / or different chargeable moieties may be provided, such as sulfates and / or sulfonates in combination with carboxylates.

[0060] Examples of suitable anionic hydrogels include monomers including acrylic acid, methacrylic acid, vinyl sulfonic acid, polyvinyl sulfate, itaconic acid, vinyl phosphoric acid, styrene sulfonic acid, carboxymethyl cellulose, carboxymethyl starch, alginic acid, aspartic acid, glutamic acid, and pharma- ceutically acceptable salts thereof.

[0061] Examples of suitable anionic hydrogels include polyacrylic acid, sodium polyacrylate, potassium polyacrylate, mixed sodium and potassium polyacrylate, polymethacrylic acid, sodium polymethacrylate, sodium polyvinylsulfonate, sodium polyvinylsulfate, sodium polyitaconate, sodium polyvinylphosphate, sodium polystyrenesulfonate, sodium carboxymethylcellulose, carboxymethylcellulose, sodium carboxymethylstarch, sodium alginate, sodium polyaspartate, polyaspartic acid, sodium polyglutamate, polyglutamic acid, and copolymers thereof.

[0062] In some embodiments, it is preferred to have the polymer contain as many negative charges as possible to better eliminate negatively charged drug molecules. Examples of polymers with chargeable moieties that have very high negative charges in the pH range of 5-8 include sodium polyacrylate, sodium polyvinylsulfonate, and sodium polyvinylsulfate. Sodium polyvinylsulfonate and sodium polyvinylsulfate are the most preferred in this regard, since the pKa of the acidic moieties (sulfonate and sulfate groups) is very low, ensuring that as many groups as possible are in the charged form at the required pH of 5-8.

[0063] In some embodiments, it is preferred that the polymer is net neutral with respect to the delivery and excretion of sodium and potassium.For example, a polymer administered to a patient as sodium polyacrylate and excreted as a mixture of sodium polyacrylate and potassium polyacrylate may cause a net excretion of potassium, which may be undesirable.A particular ratio of sodium and potassium in the administered polymer does not result in substantial excretion of either sodium or potassium.

[0064] In some embodiments, the crosslinked polymeric material that comprises the ion-chargeable hydrogel can absorb a significant amount of liquid in the intestine, and improve the delivery of active substances.For example, in certain embodiments, the crosslinked polymeric material that comprises the ion-chargeable hydrogel has a swelling ratio of at least 5, at least 10, at least 20, at least 25, at least 30, at least 40, at least 50, at least 60, at least 75, at least 85, at least 100, at least 110, at least 120, or even up to 200 or more, measured in deionized water.In other embodiments, the crosslinked polymeric material that comprises the ion-chargeable hydrogel has a swelling ratio of at least 5, at least 10, at least 20, at least 25, at least 30, at least 35, at least 40, or even up to 100 or more, measured in FASSIF. In some embodiments, the crosslinked polymeric material swells in deionized water by at least 100%, at least 200%, at least 500%, at least 1000%, at least 2000%, at least 3000%, at least 4000%, at least 5000%, at least 8000%, at least 10,000%, and / or at least 15,000% by weight. In some embodiments, the crosslinked polymeric material swells in FASSIF by at least 100%, at least 200%, at least 500%, at least 1000%, at least 2000%, at least 3000%, at least 4000%, at least 5000%, at least 8000%, at least 10,000%, and / or at least 15,000%. For example, in certain embodiments, the crosslinked polymeric material absorbs at least 2 mL, at least 3 mL, at least 4 mL, at least 5 mL, at least 8 mL, at least 10 mL, at least 15 mL, at least 20 mL, at least 50 mL, at least 100 mL, at least 125 mL, at least 150 mL, at least 175 mL, and / or at least 200 mL of deionized water.

[0065] In some embodiments, the ionically chargeable hydrogel material comprises a plurality of ionically chargeable functional groups. In certain embodiments, the plurality of ionically chargeable functional groups can have either a net cationic charge or a net anionic charge at intestinal pH. Exemplary ionically chargeable functional groups can be selected from the group consisting of, but not limited to, sulfonate groups, sulfate groups, carboxylate groups, phosphate groups, and combinations thereof.

[0066] To formulate the dosage form described herein, in some embodiments, the dosage form can contain at least 50mg, at least 100mg, at least 200mg, at least 300mg, or at least 450mg of crosslinked polymeric material, and less than 1g of crosslinked polymeric material.In certain embodiments, the crosslinked polymeric material comprises at least 10% by weight, at least 20% by weight, at least 30% by weight, at least 40% by weight, at least 50% by weight, at least 60% by weight, at least 70% by weight, or at least 90% by weight of the dosage form.In some embodiments, the ratio of the mass of the crosslinked polymeric material to the mass of the ionically chargeable active agent in the dosage form is at least 2:1, at least 4:1, at least 8:1, at least 10:1, at least 20:1, at least 50:1, or at least 100:1.

[0067] In one embodiment, the crosslinked polymeric material comprises at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers that comprise the polymer that are ionically chargeable.In certain embodiments, the crosslinked polymeric material comprises at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers that comprise the polymer that are negatively chargeable.In certain embodiments, the crosslinked polymeric material comprises at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers that comprise the polymer that are positively chargeable. For example, in one embodiment, the crosslinked polymeric material comprises carboxylate moieties in at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers comprising the polymer. In another embodiment, the crosslinked polymeric material comprises phosphate moieties in at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers comprising the polymer. In yet another embodiment, the crosslinked polymeric material comprises sulfonate or sulfate moieties in at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers comprising the polymer. In further embodiments, sulfur atoms comprise at least 2%, at least 4%, at least 8%, at least 10%, or at least 16% of the dry weight of the crosslinked polymer.

[0068] In some embodiments, the crosslinked polymer is formed from residues that contain one or more vinyl-substituted amide moieties, such as residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharma- ceutically acceptable salt thereof, residues of 4-vinylbenzenesulfonic acid or a pharma- ceutically acceptable salt thereof (e.g., styrenesulfonate), and / or residues of methylenebisacrylamide or a pharma- ceutically acceptable salt thereof. In some embodiments, at least 10% by weight, at least 15% by weight, at least 20% by weight, at least 30% by weight, at least 45% by weight, at least 50% by weight, at least 60% by weight, at least 75% by weight, or at least 80% by weight of the crosslinked polymer comprises residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharma- ceutically acceptable salt thereof. In some embodiments, no more than 90% by weight, 80% by weight, 70% by weight, 60% by weight, 55% by weight, 50% by weight, 45% by weight, 30% by weight, or 20% by weight of the crosslinked polymer material comprises residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharma- ceutically acceptable salt thereof. In some embodiments, at least 10%, at least 15%, at least 20%, at least 30%, at least 45%, at least 50%, at least 60%, at least 75%, or at least 80% by weight of the crosslinked polymeric material comprises residues of 4-vinylbenzenesulfonic acid or a pharma- ceutically acceptable salt thereof. In some embodiments, no more than 90%, 80%, 70%, 60%, 55%, 50%, 45%, 30%, or 20% by weight of the crosslinked polymeric material comprises residues of 4-vinylbenzenesulfonate or a pharma- ceutically acceptable salt thereof. In some embodiments, 0.2% to 20% by weight of the crosslinked polymer comprises residues of methylenebisacrylamide or a pharma- ceutically acceptable salt thereof. In some embodiments, 1% to 5% by weight of the crosslinked polymer comprises residues of methylenebisacrylamide or a pharma- ceutically acceptable salt thereof. In certain embodiments, 2% by weight of the crosslinked polymer comprises residues of methylenebisacrylamide or a pharma- ceutically acceptable salt thereof.In certain embodiments, the pharma- ceutically acceptable salts may be sodium salts, such as sodium styrenesulfonate and sodium 2-acrylamido-2-methylpropanesulfonate, although other pharma- ceutically acceptable salt forms may be provided.

[0069] According to certain embodiments of the present disclosure, there is provided a hydrogel comprising an ionically chargeable crosslinked polymeric material comprising a crosslinker comprising (i) residues of 4-vinylbenzenesulfonate or a pharma- ceutically acceptable salt thereof, (ii) residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharma- ceutically acceptable salt thereof, and (iii) residues of methylenebisacrylamide or a pharma- ceutically acceptable salt thereof. According to certain embodiments, the weight ratio of the residues of 4-vinylbenzenesulfonate or a pharma- ceutically acceptable salt thereof to the residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharma- ceutically acceptable salt thereof in the ionically chargeable crosslinked polymer is within the range of 0.25:1 to 1:0.25, such as within the range of 0.5:1 to 1:0.5 and / or 0.75:1 to 1:0.75. In certain embodiments, the hydrogel may be in the form of hydrogel particles.

[0070] In some embodiments, the ionically chargeable crosslinked polymer comprises carboxylate and / or carboxylic acid groups. In some embodiments, the hydrogel particles contain less than 10% by weight of the ionically chargeable active agent within the internal dosage form volume occupied by the hydrogel particles prior to administration to a patient. In certain embodiments, the hydrogel particles have a mesh size ranging from 0.05 mm to 2 mm, and / or 0.5 mm to 2 mm. According to one embodiment, the hydrogel particles have a mesh size ranging from 0.05 mm to 2 mm, and / or 0.5 mm to 2 mm.

[0071] In some embodiments, the crosslinked polymeric material comprises negatively chargeable functional groups having a pKa of less than 5 in deionized water at a pH of about 7. In some embodiments, the crosslinked polymeric material comprises negatively chargeable functional groups having a pKa of less than 3 in deionized water at a pH of about 7. In some embodiments, at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers of the crosslinked polymeric material comprise negatively chargeable functional groups having a pKa of less than 5 in deionized water at a pH of about 7. In some embodiments, at least 10%%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers of the crosslinked polymeric material comprise negatively chargeable functional groups having a pKa of less than 3 in deionized water at a pH of about 7.

[0072] (active substance) The oral dosage forms according to the embodiments of the present disclosure are adapted to deliver any of a wide range of active agents to a tissue site. Thus, for example, the oral dosage forms can be adapted to deliver a single active agent or multiple active agents (e.g., two, three or more active agents, either sequentially or simultaneously) to a tissue site. Furthermore, the active agents can be in any of a wide range of alternative forms, such as pharma- ceutically acceptable salt forms, free acid forms, free base forms, and hydrates.

[0073] In general, the active substance may be in the form of particles, liquid or gel, and may comprise any of a variety of compositions with biological relevance, such as metals, metal oxides, peptides, peptides structurally designed to resist enzymatic degradation, antibodies, hormones, enzymes, growth factors, small organic molecules, ligands, or other pharmaceuticals, nutraceuticals, or biologics.In some embodiments, the drug may comprise one or more large molecules (e.g., proteins and / or protein conjugates) and / or one or more small molecules (e.g., small organic molecules and / or small peptides) as the drug.In one exemplary embodiment, the active substance comprises at least one polypeptide and / or small molecule that has therapeutic effect. Examples of active agents that may be delivered by oral dosage forms include insulin, vasopressin, calcitonin (including salmon calcitonin), oxytocin, adrenocorticotropic hormone (ACTH), leuprorelin, octreotide, ixazomib, adryxin, abaloparatide, angiotensin II, etelcalcetide, macimorelin, plecanatide, semaglutide and other GLP-1 analogues (GLP-1 agonists), 177 Lu DOTA-TATE (Lutathera®), 68Ga DOTA-TOC, Afamelanotide, Bremelanotide, Enfortumab vedotin-Ejfv, Polatuzumab vedotin-Piiq, Cetomelanotide, Brevirtide, P consensus, Laminin-derived peptides, Nucleosomal peptides, DWEYS peptides, Glatiramer acetate, Thymopentin-5, Peptide P140, AMG623, Bivalirudin, Buserelin, Corticotropin, Cosyntropin, Enfuvirtide, Eptifibatide, Gramicidin D, Lepirudin, Leuprolide, Lucinactant, Nesiritide, Oxytocin, Pramlintide, Secretin, Sermorelin, Teduglutide, Thymalfasi, Rs-ARF2, Iturin, Histatin 5, Aureobasidin, Echinocandin, Pneumocandin, Acreasin (AD, F), Mulundukyangin, WF11899(A,B,C), WmKT, cilofungin, anidulafungin, FOL-005, teriparatide, ZPGG-72, ZP3022, MOD-6030, ZP2929, HM12525A, VSR859, NN9926, TTP273 / TTP054, ZYOG1, MAR709, TT401, HM11260C , PB1023, ITCA, parathyroid hormone (PTH), teriparatide (recombinant form of PTH), peptide agonists of GLP-1, such as exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, GLP-1 / GIP coagonists, such as tirzepatide, GLP-2 agonists, and peptide GPCR agonists. Further examples of active substances include antibiotics, such as azithromycin, vancomycin, dalbavancin (Dalvans), micafungin (Mycamine), brilicidin, avidocin, purocin, and arenicin. Active substances can also include antimycobacterial drugs such as clofazimine, ethionamide, paraaminosalicylic acid, and amikacin.

[0074] In yet another embodiment, the active agent may include other large molecules and / or other structures other than those specifically listed above, such as one or more of antibodies (monoclonal and polyclonal) or antibody fragments, polysaccharides, carbohydrates, nanoparticles, vaccines, biologics, nucleic acids, cells and cell therapies, DNA, RNA, siRNA, blood factors, gene therapy, thrombolytic agents (tissue plasminogen activator), growth factors (erythropoietin), interferons, interleukin-based molecules, fusion proteins, recombinant proteins, therapeutic enzymes, and others. The active agent may additionally and / or alternatively include at least one of small molecule drugs, drug conjugates, prodrugs, small organic molecules (e.g., molecular weights of about 500 Da or less), metabolic activators (e.g., metabolites), nutrients, supplements, and the like.

[0075] According to one embodiment, the oral dosage form disclosed herein may provide improved bioavailability when delivering active substances that may not otherwise be fully absorbed in the intestine. For example, the oral dosage form disclosed herein may surprisingly be capable of improving the bioavailability of relatively large molecular weight polypeptides and / or other small molecules that may otherwise be difficult to administer effectively due to their relatively large size. Examples of such active substances may include polypeptides and / or small molecules having a size of at least about 450 Da. However, according to one embodiment, the molecular weight of the active substance may still be less than about 200,000 Da to allow good delivery / absorption of the active substance in the intestine. According to one example, in one embodiment, the active substance has a molecular weight of at least about 2000 Da. As a further example, in one embodiment, the active substance has a molecular weight of at least about 5000 Da. As yet another example, in one embodiment, the active substance has a molecular weight of at least about 10,000 Da. The active agent according to one embodiment, as described above, generally has a molecular weight of less than about 600,000 Da, but in one example, the molecular weight may be less than about 200,000 Da, such as less than about 100,000 Da. For example, the active agent provided as part of the oral dosage form may, in one embodiment, have a molecular weight in the range of about 450 Da to about 500,000 Da, such as about 450 Da to about 25,000 Da, or even 450 Da to 10,000 Da, such as about 450 Da to about 6000 Da. For example, in one embodiment, the active agent may have a molecular weight of about 1000 Da to about 25,000 Da, or even about 1,000 Da to about 10,000 Da, such as about 1000 Da to 5000 Da. As described above, the oral dosage form may include two or more drugs independently selected from molecules having molecular weights within the ranges described herein.

[0076] As mentioned above, to enhance ionic interaction, the active agent can be ionically charged in the intestinal environment.For example, in one embodiment, the ionically chargeable active agent comprises multiple ionically chargeable groups, for example, at least one, at least two, at least three, at least four, at least five, or even many ionically chargeable groups that are expected to be negatively or positively charged at intestinal pH (e.g., pH 5-8).To maximize repulsion, in some embodiments, both the ionically chargeable hydrogel material and the ionically chargeable active agent have a net cationic charge at intestinal pH.Alternatively, in other embodiments, both the ionically chargeable hydrogel material and the ionically chargeable active agent have a net anionic charge at intestinal pH.

[0077] In another embodiment, the ionically chargeable active agent is at least one of a peptide or modified peptide and a polynucleotide having a molecular weight of at least 500 g / mol, at least 1000 g / mol, at least 2000 g / mol, at least 4000 g / mol, at least 500 g / mol, and / or up to 10,000 g / mol.

[0078] The dosage forms described herein can significantly increase the local concentration of drug.For example, in one embodiment, when the dosage form is dispersed in water, the concentration of ion-chargeable active agent after 10 minutes of dispersion in water is at least 20% higher than when the same dosage form without cross-linked polymer is dispersed in water for the same time.In another embodiment, when the dosage form is dispersed in water, the concentration of ion-chargeable active agent after 30 minutes of dispersion in water is at least 50% higher than when the same dosage form without cross-linked polymer is dispersed in water for the same time.In yet another embodiment, when the dosage form is dispersed in water, the concentration of ion-chargeable active agent after 60 minutes of dispersion in water is at least 100% higher than when the same dosage form without cross-linked polymer is dispersed in water for the same time.In yet another embodiment, when the dosage form is dispersed in water, the concentration of ion-chargeable active agent after 90 minutes of dispersion in water is at least 200% higher than when the same dosage form without cross-linked polymer is dispersed in water for the same time. In a further embodiment, when the dosage form is dispersed in water, the concentration of the ionically chargeable active agent after 120 minutes of dispersion in water is up to 30% higher than when the same dosage form without the crosslinked polymer is dispersed in water for the same period of time.

[0079] Considering the different acidity in different parts of the GI tract, it is beneficial for the ionically chargeable hydrogel and the ionically chargeable active agent to have the same sign of net ionic charge at different pH.In some embodiments, the cross-linked polymeric material and the ionically chargeable active agent have the same sign of net ionic charge (e.g., both net negative or both net positive) at pH 2.In some embodiments, the cross-linked polymeric material and the ionically chargeable active agent have the same sign of net ionic charge at pH 5.In some embodiments, the cross-linked polymeric material and the ionically chargeable active agent have the same sign of net ionic charge at pH 6.In some embodiments, the cross-linked polymeric material and the ionically chargeable active agent have the same sign of net ionic charge at pH 7.

[0080] (Penetration enhancer) In yet another embodiment, the oral dosage form comprises at least one permeation enhancer to improve the permeation of the active substance into intestinal tissue. In some embodiments, the permeation enhancer may be capable of opening the tight junction between cells (e.g., intestinal cells or epithelial cells). The permeation enhancer may, in some instances, promote the uptake of the drug into epithelial cells. Representative classes of permeation enhancers include, but are not limited to, fatty acids, medium chain glycerides, surfactants, steroid surfactants, acylcarnitines, lauroylcarnitines, palmitoylcarnitines, alkanoylcholines, N-acetylated amino acids, esters, salts, bile salts, sodium salts, nitrogen-containing rings, derivatives thereof, and combinations thereof. The permeation enhancer may be anionic, cationic, zwitterionic, or nonionic. Anionic permeation enhancers include, but are not limited to, sodium lauryl sulfate, sodium decyl sulfate, sodium octyl sulfate, N-lauryl sarcosinate, and sodium carbamate. Cationic penetration enhancers include, but are not limited to, cetyltrimethylammonium bromide, decyltrimethylammonium bromide, benzyldimethyldodecylammonium chloride, myristyltrimethylammonium chloride and dodecylpyridinium chloride. Zwitterionic penetration enhancers include, but are not limited to, N-dodecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate, 3-(N,N-dimethylpalmitylammonio)propanesulfonate. Fatty acids include, but are not limited to, butyric acid, caproic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, oleic acid, linoleic acid, linoleic acid, salts thereof, derivatives thereof, and combinations thereof. In some embodiments, fatty acids can be modified as esters, such as glycerides, monoglycerides, diglycerides, or triglycerides.Bile acids or salts, including conjugated or unconjugated bile acid penetration enhancers, include, but are not limited to, cholic acid, deoxycholic acid, taurocholic acid, glycocholic acid, taurodeoxycholic acid, ursodeoxycholic acid, tauroursodeoxycholic acid, chenodeoxycholic acid, their derivatives, their salts, and their combinations.In some embodiments, the penetration enhancer comprises a metal chelator, such as EDTA or EGTA, a surfactant, such as sodium dodecyl sulfate, polyethylene ether or ester, polyethylene glycol-12 lauryl ether, polysorbate 80 salicylate, nonylphenoxypolyoxyethylene, sodium dioctyl sulfosuccinate, saponin, palmitoyl carnitine, lauroyl-l-carnitine, dodecyl maltoside, acyl carnitine, alkanoylthioline, and their combinations. Other penetration enhancers include, but are not limited to, 3-nitrobenzoic acid, Zounula occludens toxin, fatty acid esters of lactate, glycyrrhizinate, hydroxyl β-cyclodextrin, N-acetylated amino acids such as sodium N-[8-(2-hydroxybenzoyl)amino]caprylate and chitosan, micelle formers, channel formers, substances that modify micelle formers, substances that modify channel formers, salts thereof, derivatives thereof, and combinations thereof. In some embodiments, the micelle formers include bile salts. In some embodiments, the channel formers include antimicrobial peptides. In some embodiments, the substances that modify micelle formers include substances that change the critical micelle concentration of the micelle formers. An exemplary penetration enhancer is 1% by weight 3-(N,N-dimethylpalmitylammonio)propanesulfonate. Penetration enhancers are also described in patent application publication US2013 / 0274352, the contents of which are incorporated herein by reference in their entirety. In one embodiment, the penetration enhancer may include at least one of EDTA, palmitoylcarnitine, lauroylcarnitine, dimethylpalmitoylammoniopropanesulfonate (PPS), and sodium caprate.

[0081] In one embodiment, the permeation enhancer selected for oral dosage form can be selected based on one or more of the main permeation mechanism and hydrophilicity and / or hydrophobicity of the permeation enhancer.For example, permeation enhancers that are fatty acid esters and / or have nitrogen-containing rings can show more paracellular transport activity, while cationic and zwitterionic permeation enhancers can show more intercellular activity, as described, for example, in the article by Whitehead and Mitragotri entitled "Mechanistic Analysis of Chemical Permeation Enhancers for Oral Drug Delivery" (Pharmaceutical Research, Vol. 25, No. 6, June 2008, pages 1412-1419), which is incorporated herein by reference in its entirety.Furthermore, for permeation enhancers that have intercellular transport mechanism, increasing the hydrophobicity of the permeation enhancer can improve this mechanism, while for permeation enhancers that have more paracellular transport activity, greater improvement can be seen for more hydrophilic permeation enhancers (e.g., by interacting with the hydrophilic components of tight junctions). In one embodiment, the relative hydrophobicity / hydrophilicity of an enhancer can be determined by its logP value, where P is the octanol / water partition coefficient of the compound.For example, in one embodiment, to improve paracellular transport, the penetration enhancer can have a logP value of at least 2, such as at least 4, or even at least 6. Conversely, to improve paracellular transport activity, in one embodiment, the penetration enhancer can have a logP value of less than about 4, such as less than 2, or even less than 0.

[0082] In one embodiment, the content of the penetration enhancer in the oral dosage form is at least about 0.01% by weight, for example at least about 0.1% by weight, and can be less than about 80% by weight, or even less than about 30% by weight.For example, in one embodiment, the content of the penetration enhancer in the oral dosage form can be at least about 0.01% by weight, for example at least about 0.1% by weight, for example at least about 1% by weight, for example at least about 5% by weight, or even at least about 10% by weight, for example at least about 30% by weight, or even at least about 50% by weight, for example at least about 70% by weight.For example, in one embodiment, the content of the penetration enhancer can be in the range of 0.1% by weight to 70% by weight, for example about 0.1% by weight to about 20% by weight, or even about 1% by weight to about 10% by weight.

[0083] As mentioned above, in certain embodiments, ionic interactions (repulsion) can play an important role in the dosage forms disclosed herein. In certain embodiments, the same theory is relevant to the permeation enhancer used. Anionic permeation enhancers (e.g., sodium caprate) and anionic micelles of such enhancers may be excluded from the hydrogel for the same reasons as mentioned above (anionic charge and size / diffusion coefficient). Zwitterionic permeation enhancers, such as dimethyl palmitoyl ammonio propane sulfonate (PPS), may also be excluded by size / diffusion coefficient effects and by charge effects if they form micelles in which the outermost surface of the micelle is anionic. As with ionically chargeable hydrogels and active agents, the permeation enhancers may be ionically charged, for example, by having one or more ionically chargeable groups. In some embodiments, the crosslinked polymeric material, the ionically chargeable active agent, and the permeation enhancer all have a net ionic charge of the same sign at an intestinal pH range of 4-8. In certain embodiments, the crosslinked polymeric material, the ionically chargeable active agent, and the permeation enhancer all have a net negative charge at an intestinal pH ranging from 4 to 8. In some embodiments, the crosslinked polymeric material, the ionically chargeable active agent, and the permeation enhancer all have a net negative charge in an aqueous solution at a pH of about 7. In some embodiments, the crosslinked polymeric material, the ionically chargeable active agent, and the permeation enhancer all have a net negative charge in an aqueous solution at a pH of about 5.

[0084] (Other additives) The oral dosage form may contain further additives in addition to the active agent, the particulate hydrogel and any permeation enhancers.

[0085] In one embodiment, the oral dosage form may include an osmagent that aids in the delivery of active substances. Without being limited to any one theory, it is believed that the osmagent may assist in the evacuation of active substances from the oral dosage form by absorbing water and pushing the active substances out of the oral dosage form, and / or may help open the tight junctions in the intestine by drawing water out of the intestine. In one embodiment, the hydratable osmagent may include water-soluble salts, carbohydrates, small molecules, amino acids, and combinations thereof. Exemplary water-soluble salts may include, but are not limited to, magnesium chloride, magnesium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium sulfate, sodium sulfate, potassium sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, sodium ascorbate, etc., and combinations thereof. Exemplary carbohydrates may include sugars, such as arabinose, ribose, xylose, glucose, fructose, galactose, mannose, sucrose, maltose, lactose, raffinose, and combinations thereof. Exemplary amino acids may include glycine, leucine, alanine, methionine, and the like, and combinations thereof. In one embodiment, the osmotic agent provided in the oral dosage form includes at least one of sucrose, mannitol, fructose, and polyethylene glycol. In one embodiment, the content of the osmotic agent in the oral dosage form may be at least about 1% by weight and less than about 60% by weight, such as about 10% by weight to about 50% by weight, or even about 20% by weight to about 40% by weight.

[0086] In another embodiment, the oral dosage form may contain a protease inhibitor. As used herein, "protease inhibitor" or "antiprotease" refers to a molecule (usually a protein) that inhibits the function of proteases (enzymes that help break down proteins). In the present disclosure, a protease inhibitor is one that inhibits the breakdown of active substance peptides, for example during delivery in the intestine. Exemplary protease inhibitors include aspartic protease inhibitors, cysteine ​​protease inhibitors, metalloprotease inhibitors, serine protease inhibitors, threonine protease inhibitors, and trypsin inhibitors. In one embodiment of the present disclosure, the oral dosage form contains soybean trypsin inhibitor.

[0087] Other additives and / or additives that may be provided as part of the oral dosage form may include one or more of stabilizers, glidants, bulking agents, anti-adhesive agents, mucoadhesives, binders, adsorbents, preservatives, cryoprotectants, hydrating agents, enzyme inhibitors, mucus modifiers (such as mucus drying agents), pH adjusters, solubilizers, plasticizers, crystallization inhibitors, bulking excipients, bioavailability enhancers, and combinations thereof. In some embodiments, the additives and / or additives may include polyethylene glycol, polyethylene oxide, humectants, vegetable oils, medium chain mono-, di-, and tri-glycerides, lecithin, waxes, hydrogenated vegetable oils, colloidal silicon dioxide, polyvinylpyrrolidone (PVP) ("povidone"), cellulose, CARBOPOL® polymers (Lubrizol Advanced Materials, Inc.) (i.e., cross-linked acrylic acid-based polymers), acrylate polymers, pectins, sugars, magnesium sulfate, or other hydrogel-forming polymers.

[0088] (Protective Coating) The oral dosage form according to one embodiment further comprises a protective coating that at least partially protects the oral dosage form from the acidic environment in the stomach and delivers the active agent to the intestinal region. In one embodiment, the protective coating may form an outer coating of the oral dosage form that protects the active agent and / or particulate hydrogel or other additives in the oral dosage form. In one embodiment, the protective coating completely covers the outer surface of the delivery structure including the hydrogel particles and active agent of the dosage form, although the protective coating may be designed to cover only a portion of the outer surface of the delivery structure, if desired. The protective coating may comprise only a single coating layer or may be configured as multiple coating layers. For example, in one embodiment, the protective coating comprises a capsule form. In another embodiment, the protective coating comprises a tablet form. In yet another embodiment, the protective coating comprises an enteric coating for releasing the ionically chargeable active agent in the small intestine. In yet another embodiment, the protective coating comprises a sustained release coating. In a further embodiment, the protective coating comprises a capsule coated with an enteric coating.

[0089] According to one embodiment, the protective coating can be an enteric coating, which is a pH-dependent coating, with an enteric material that is a polymer that is substantially insoluble in the acidic environment of the stomach, but has increased solubility in intestinal fluids at higher pH. That is, the enteric coating can be preferentially dissolved and / or at least partially permeable in the intestine as opposed to in the stomach. Thus, in one embodiment, the protective coating comprises an enteric coating for releasing the ionically chargeable active agent in the small intestine. For example, the enteric coating can be formed from an enteric material that is substantially insoluble at a pH of less than about 5, for example, in the acidic environment of the stomach, but becomes soluble at a higher pH, for example, at a pH of at least about 5.5 in the duodenum, at a pH of at least about 6.5 in the jejunum, at a pH of at least about 7.0 in the ileum, for example, at a pH of at least about 7.5 (the duodenum, jejunum, and ileum are parts of the small intestine). That is, enteric coating can be selected to be insoluble at lower pH but soluble at higher pH, so that when it reaches the environment of the digestive system with pH where the material of enteric coating is soluble, enteric coating can dissolve and / or become at least partially permeable and release the contents of oral dosage form.Therefore, in one embodiment, the enteric material suitable for forming enteric coating is not soluble until it reaches pH of at least about 5.5, for example pH of at least about 6.0.In one embodiment, the enteric material suitable for forming enteric coating is not soluble until it reaches pH of at least about 6.5, for example pH of at least about 7.0, or even pH of at least about 7.5.Examples of enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymers of methyl methacrylic acid and methyl methacrylate, copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (Gantrez). ES series), ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymers, poly(vinyl alcohol), natural resins such as zein, shellac and copalcohol, and some commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, Kollicoat MAE 100P and Aquateric). For example, in one embodiment, the enteric material used to form the enteric coating can include at least one of Eudragit S100 (poly(methacrylic acid-co-methyl methacrylate) 1:2), Eudragit L100 (poly(methacrylic acid-co-methyl methacrylate) 1:1), and Kollicoat MAE 100P (methacrylic acid ethyl acrylate copolymer 1:1). The solubility of each of the above materials at a particular pH is known or can be easily determined in vitro. For example, while the above is a list of possible materials, those skilled in the art who have the benefit of this disclosure will recognize that the above list is not comprehensive and there are other enteric materials that can be used. In yet another embodiment, the protective coating can be one that dissolves and / or becomes partially permeable due to changes in the environment that are unrelated to pH.In yet another embodiment, the protective coating and / or enteric coating may dissolve at a predetermined rate and / or become at least partially permeable as it passes through the gastrointestinal system, providing a controlled and / or timed release of the active agent in a predetermined region of the intestine.

[0090] In one embodiment, the protective coating comprises at least a portion that is permeable and / or dissolving under predetermined conditions, such as at a predetermined pH (e.g., pH at a target site in the intestine) or after exposure to liquids for a predetermined time (e.g., controlled release after administration at a predetermined time point). In one embodiment, the protective coating comprises substantially the entire coating of material that is permeable and / or dissolving under predetermined conditions.

[0091] In one embodiment, by providing a protective coating having a permeable and / or dissolving portion surrounding a majority of the surface of the dosage form, the contents of the dosage form can be released effectively and in multiple directions without unnecessarily retaining the contents inside the dosage form. In yet another embodiment, by providing a permeable and / or dissolving portion around at least a majority of the surface of the area of ​​the dosage form that contains the active agent delivery area, good release of the particulate hydrogel and the active agent delivery area from a relatively large surface area of ​​the dosage form can be provided.

[0092] The protective coating is formed on the surface of the delivery structure according to a suitable method. In one embodiment, the protective coating is formed by spray coating a material, such as an enteric material, on the surface of the delivery structure until a coating having a thickness within a predetermined range is formed. In one embodiment, the protective material is sprayed relatively uniformly on the delivery structure to provide a protective coating having a uniform thickness on the surface of the oral dosage form. In another embodiment, the protective coating can be sprayed non-uniformly depending on the composition of the oral dosage form and the desired release characteristics. In yet another embodiment, the protective coating can be formed on the surface of the delivery structure by a dip-coating method, in which the surface of the oral dosage form is immersed or otherwise immersed in a liquid containing a protective coating material, such as an enteric coating material, to form a coating of the protective material on the surface.

[0093] In some embodiments, the oral dosage form may be configured to provide a controlled release (time release) of the active agent in the intestinal region, for example, by providing a protective coating corresponding to an enteric coating that provides a controlled release at a given pH and / or pH range. Additionally and / or alternatively, other ingredients and / or additives may be provided in the oral dosage form to provide a controlled release of the active agent and particulate hydrogel.

[0094] According to one embodiment, the oral dosage form is provided in a size that provides good delivery of the active agent in the intestinal tract without excessive obstruction or blocking of the intestinal tract. For example, the longest dimension of the oral dosage form may be less than about 3 cm, such as less than about 2 cm, or even less than about 1.5 cm. Typically, the longest dimension of the oral dosage form ranges from about 0.5 cm to about 3 cm, such as from about 1 cm to about 3 cm, or even from about 1 cm to about 2 cm. Suitable capsule sizes are, for example, sizes 1, 0, 00, and 000, including "EL" versions of any of these sizes.

[0095] (Treatment Method) In some embodiments, the oral dosage form may be administered to an individual, patient, or subject. In some instances, the oral dosage form may be administered as a single dose. In other embodiments, multiple oral dosage forms may be administered to provide multiple doses over time. Alternatively, the oral dosage form described herein may be administered to a subject in need thereof without food or under fasting conditions. For example, the oral dosage form may be administered at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, about 3 hours to about 12 hours, about 4 hours to about 12 hours, about 4 hours to about 10 hours, about 4 hours to about 8 hours, or about 4 hours to about 6 hours after ingestion of a meal by the subject.

[0096] Alternatively, the oral dosage forms described herein may be administered to a subject in need thereof under conditions of liquid restriction. This restriction means that the subject may consume less than 16 ounces of liquid, less than 8 ounces of liquid, less than 4 ounces of liquid, less than 2 ounces of liquid, or less than 1 ounce of liquid over a specified period of time. For example, the subject may be restricted from consuming liquids for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 8 hours, about 1 hour to about 2 hours, or about 1 hour to about 4 hours before being administered the oral dosage form. Additionally, the subject may be restricted from consuming liquids for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 8 hours, about 1 hour to about 2 hours, or about 1 hour to about 4 hours after being administered the oral dosage form.

[0097] Treatment may continue for a long or short period of time, as required. Oral dosage forms may be administered, for example, in a regimen of one to four or more times per day. Suitable treatment periods may be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about one year, or indefinitely. Treatment periods may end when desired results are achieved. Treatment regimes may include, for example, a corrective phase during which a dose sufficient to relieve symptoms is administered, and a maintenance phase during which a lower dose sufficient to maintain the relieved symptoms is administered. Suitable maintenance doses are likely to be found in the lower portion of the dose ranges provided herein, but corrective and maintenance doses may be readily established for individual subjects by those skilled in the art without undue experimentation based on the disclosure herein.

[0098] In certain embodiments, the oral dosage form can be used to deliver a drug (e.g., octreotide) to a subject in need thereof. In some embodiments, the oral dosage form can deliver insulin to a patient in need thereof, such as a person suffering from diabetes. In certain embodiments, the oral dosage form can be used to deliver a drug (e.g., calcitonin) to a subject in need thereof. For example, the oral dosage form can be used to treat hypercalcemia. In another example, the oral dosage form can be used to treat bone disease, such as osteoporosis. In yet another embodiment, the oral dosage form can be used to treat psychiatric disorders, such as bipolar disorder or mania. In yet another embodiment, the oral dosage form can deliver an active agent, such as a GLP-1 agonist and / or a GIP / GLP1 coagonist, to treat disorders such as type II diabetes and / or obesity in a patient in need thereof. In yet another embodiment, the oral dosage form can deliver an active agent, such as an enzyme-resistant peptide, to treat disorders such as metabolic disorders in a patient in need thereof.

[0099] For example, in one embodiment of the present disclosure, a method for treating or ameliorating the effects of a condition in a subject is provided.The method comprises administering to the subject an effective amount of a dosage form described herein.In some embodiments, the condition is selected from type 2 diabetes, obesity, and combinations thereof.In some embodiments, the ionically chargeable active agent in the dosage form comprises a peptide with GIP-1 agonist activity or GIP / GLP1 coagonist activity.Such peptides can be selected from, for example, semaglutide, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, tirzepatide, and combinations thereof.

[0100] The oral dosage forms described herein may be used to administer drugs to patients (e.g., animals and / or humans) in need of such treatment at dosages that provide optimal pharmaceutical efficacy. It is understood that the number and / or type of oral dosage forms required for use in a particular application will vary from patient to patient, depending not only on the particular drug selected, but also on the concentration of the drug in the oral dosage form, the nature of the condition being treated, the age and condition of the patient, any concurrent medications or special diets the patient is following, and other factors that one of skill in the art will recognize, and that the appropriate dosage is ultimately at the discretion of the attending physician.

[0101] 9 is a schematic diagram illustrating one embodiment of an oral dosage form comprising an ionically chargeable hydrogel and an ionically chargeable active agent. The oral dosage form 100 includes a delivery device 101, such as a capsule, tablet, or other structure capable of providing an ionically chargeable hydrogel. The delivery device 101 is at least partially covered with a protective coating 102, such as an enteric coating. The delivery device further includes a plurality of hydrogel particles 103 comprising the ionically chargeable hydrogel, and an active agent 104, and optionally, a permeation enhancer 105 is further provided. Other embodiments of the oral dosage form may also be provided.

[0102] According to certain embodiments, without being limited to any theory, it is believed that the designed hydrogel particles according to the aspects herein selectively absorb water relative to the active agent, increasing the local active agent and / or permeation concentration outside the hydrogel, and subsequently resulting in the absorption of the active agent. According to certain embodiments, the ionically chargeable hydrogel is immiscible with the ionically chargeable active agent and / or permeation enhancer (e.g., according to Donnan equilibrium). According to further embodiments, without being limited to any theory, it is believed that the relative lack of macroscopic channels in the hydrogel particles limits the diffusion of larger molecules through the polymer network, restricting the entry of larger active agents, such as certain peptides, into the hydrogel polymer network. According to yet another embodiment, without being limited to any theory, it is believed that the hydrogel particles may reduce protease activity, such as by sequestration and / or self-inactivation of proteases, including those found in the intestine.

[0103] According to one embodiment, the dosage form or method herein comprises an ionically chargeable hydrogel material that reduces the activity of a protease at an intestinal site. For example, a protease that exhibits reduced activity in the presence of an ionically chargeable hydrogel material may have a net ionic charge of the opposite sign to the net ionic charge of the ionically chargeable hydrogel material at an intestinal pH range of about 4 to about 8. Thus, in certain embodiments, a dosage form comprising an ionically chargeable hydrogel material may comprise an ionically chargeable hydrogel material having a net ionic charge of the opposite sign to the net ionic charge of the protease at an intestinal pH range of about 4 to about 8 to reduce the activity of one or more proteases and inhibit degradation of the active agent for improved delivery thereof. A method of delivering an active agent using an ionically chargeable hydrogel material as part of a dosage form may, in certain embodiments, comprise providing an ionically chargeable hydrogel material that can reduce the activity of proteases that tend to degrade the active agent in the intestine. According to one embodiment, the dosage form or method provides a delivery device using an ionically chargeable hydrogel material that reduces the activity of any of the proteases chymotrypsin and trypsin, such as α-chymotrypsin and trypsin type 1, or a combination thereof. According to one embodiment, the dosage form comprising the ionically chargeable hydrogel material can reduce the activity of one or more proteases by at least 15%, at least 20%, at least 25%, at least 30%, at least 45%, at least 50% at 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 60 minutes, as determined by a protease activity assay. According to a further embodiment, the dosage form comprises an ionically chargeable hydrogel material that reduces the activity of one or more proteases and comprises an active agent that is a peptide. According to yet another embodiment, the active agent has GIP-1 agonist activity or GIP / GLP1 co-agonist activity. In yet another embodiment, the active agent peptide is selected from semaglutide, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, tirzepatide, and any combination thereof.

[0104] According to another embodiment, the dosage form comprising a delivery device with ion-chargeable hydrogel material and the method therewith maintain or increase the concentration of the active agent at the intestinal site in the presence of a protease, as compared to a delivery device without an ion-chargeable hydrogel material. According to one embodiment, the dosage form comprising an ion-chargeable hydrogel material maintains or increases the concentration of the active agent in an active agent concentration assay in the presence of a protease for a time period of at least 20 minutes, at least 40 minutes, or at least 60 minutes. According to another embodiment, the concentration of the active agent provided by the delivery device comprising an ion-chargeable hydrogel material is higher than the concentration of the active agent provided by the delivery device without an ion-chargeable hydrogel material, as determined by an active agent concentration assay, for a time period of at least 20 minutes, at least 40 minutes, or at least 60 minutes. According to one embodiment, the concentration of the active agent is maintained or increased in the presence of a protease, including chymotrypsin (e.g., α-chymotrypsin), trypsin (e.g., trypsin type 1), or a combination of both. According to one embodiment, the dosage form and methods therewith include an active agent that is susceptible to degradation by proteases at the intestinal site. For example, the dosage form may be capable of inhibiting protease activity so as to maintain or increase the level of an active agent that is otherwise susceptible to degradation at the intestinal site.

[0105] The following examples are provided to further illustrate the methods of the present disclosure. These examples are illustrative only and are not intended to limit the scope of the present disclosure in any way. EXAMPLES

[0106] Specific examples herein show results with the anionically charged peptides GG-353 and GG-427 (see, e.g., Examples 2 and 4 and Table 13), which are described in U.S. Patent Application Publication No. 2020 / 0024322 (hereby incorporated by reference in its entirety) and act as GIP / GLP1 co-agonists (see, e.g., Tables 1 and 10). According to the published description, GG-353 has a molecular weight of about 4928 g / mol and GG-427 has a molecular weight of about 4926 g / mol. Both structures contain multiple carboxyl groups that are expected to be negatively charged at pH 5-8.

[0107] Example 1 This example provides the formulation, manufacturing procedures and testing criteria for a representative particulate hydrogel according to the present disclosure. The representative hydrogel, designated Hydrogel #3.02, contains the following components: [Table 1] (1) AMPS = 2-acrylamido-2-methylpropanesulfonic acid; (2) BIS = methylenebisacrylamide 2% (crosslinker); (3) AP = ammonium persulfate; (4) TEMED = tetraethylenediamine

[0108] To obtain hydrogel #3.02, the dry ingredients were added to the liquid and completely dissolved. Ammonium persulfate was then added and stirred well. TEMED was then added and stirred, and the mixture was allowed to polymerize and harden overnight. The hardened gel was broken into approximately 1 cm chunks and added to 2 L of DI water under stirring. After immersion for 30 minutes, the pH of the mixture was measured. Then, 1N HCl was added until the pH was adjusted to 7 (±0.2). The mixture was allowed to soak for an additional 30 minutes under stirring. The liquid was drained and replaced with an additional 2 L of DI water. The conductivity of the liquid was measured to determine the purity. The mixture was then allowed to soak for an additional 30 minutes under stirring. The liquid was drained and replaced with 400 mL of isopropyl alcohol, and the mixture was allowed to dehydrate for 1 hour. The liquid was drained and the gel was poured into a tray and dried in a 158°F oven overnight. The dried gel was crushed into particles of 500 μm to 2000 μm.

[0109] Standard hydrogel #3.02 contains two monomers: 98% AMPS (2-acrylamido-2-methylpropanesulfonic acid) and 2% BIS (methylenebisacrylamide) (as crosslinker) (Figure 1). To understand the consistency of production of hydrogel #3.02, and how changes in the amount of crosslinker may affect its key properties, tests were performed to determine the swelling of the generated hydrogel and the displacement of sample material. For testing purposes, three samples (A, B and C) were generated for each of the following hydrogel variants: (1) using +20% crosslinker (0.24 g BIS); (2) using +10% crosslinker (0.22 g BIS); (3) using the standard amount of crosslinker (0.20 g BIS); (4) using -10% crosslinker (0.18 g BIS) and; (5) using -20% crosslinker (0.16 g BIS).

[0110] Swelling of the hydrogel was performed in both DI water and FASSIF (fasting artificial intestinal fluid) at pH 7 by adding 0.1 g of dry hydrogel to 15 mL of liquid; soaking for 15 min under gentle rocking; draining the non-absorbed liquid through a 500 μm mesh; measuring the non-absorbed liquid and calculating the swelling. The results are shown in the following table and in Figures 2A-2B. [Table 2]

[0111] Exclusion tests were performed in FASSIF pH 7 with GG427 as the sample material. The swelling results in FASSIF from the table above were used to calculate the amount of gel required to absorb 8 mL of FASSIF. The calculated amount of gel was then placed in 10 mL of 1 mg / mL GG427 in a 15 mL tube under gentle rocking (active group). The same amount of gel was also placed in 10 mL of FASSIF pH 7 in a 15 mL tube under gentle rocking (background group). Every 5 minutes for 25 minutes, 3 x 10 μL samples were extracted and diluted in 190 μL of DI water in a 96-well UV plate. Also, 3 x 10 μL samples of 1 mg / mL GG427 and FASSIF pH 7 stock solutions were taken as controls. Upon completion, the absorbance was measured at 230 nm and 265 nm. Background was subtracted from the active absorbance readings at each time point and compared to the stock solution to calculate the exclusion effect. The results are shown in Figures 3A-3B. A consistent concentration effect of 1.4-fold was observed after 25 minutes, indicating 80% fluid uptake into the hydrogel; i.e., the drug concentration in the remaining free 20% fluid is 1.4-fold higher than the starting concentration.

[0112] Example 2A This example illustrates an in vivo procedure for the particulate hydrogels disclosed herein.

[0113] (Oral capsule administration) Beagle dogs (same animals as those given subcutaneously, n=4 or 8) were fasted overnight (approximately 12 hours) prior to dosing. To stimulate gastric secretion, each animal received a single 6 μg / kg intramuscular injection of pentagastrin approximately 30 minutes prior to dosing. Food was restored after 6 hours of sampling. Oral administration of the capsules was followed by a 10 ml saline flush. Blood samples were taken pre-dose and 0.25, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours after dosing. Blood samples were collected by cephalic vein puncture into tubes (1.3 mL K3EDTA) containing 3 μL of a commercial aprotinin solution and 1.3 μL of a commercial dipeptidyl peptidase 4 (DPP IV) inhibitor. After addition of the whole blood sample, the blood tubes were vortex mixed. Sample tubes were stored on wet ice until processed to plasma by centrifugation (3500 rpm, 10 min at 5° C.) within 30 min of collection. Plasma samples were transferred to matrix tubes and stored at nominal −70° C. until shipped to a contract laboratory for analysis of proprietary peptides present.

[0114] The capsules were size 00 or 000 gelatin capsules with an enteric coating (Eudragit S100) designed to open in the small intestine. The drug formulation consisted of 5-24 mg of peptide drug, 200-500 mg of sodium caprate, 0 or 125 mg of soybean trypsin inhibitor (125 mg was used for GG-353 and 0 mg was used for GG-427), and 0 or 300 mg of hydrogel.

[0115] (Subcutaneous administration allowing for oral bioavailability calculations) Beagle dogs (same animals as capsule dosing, n=4 or 8) were fasted overnight (approximately 12 hours) prior to dosing. Food was returned after 6 hours of sampling. Subcutaneous dosing solutions were prepared at 0.5 mg / mL with the proprietary peptide to be tested in 40 mM Tris buffer, pH 8. Dosing formulations were prepared by adding pre-weighed drug to the appropriate amount of vehicle to obtain the desired dosing concentration. Vehicles used in the formulations were pre-filtered prior to use. All dosing syringes were weighed before and after dosing to determine the amount of formulation administered gravimetrically, and approximately 0.02 mL / kg was administered for a final drug dose of 0.01 mg / kg.

[0116] Blood samples were collected pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours post-dose. Blood samples were collected by cephalic vein puncture into tubes (1.3 mL K3EDTA) containing 3 μL of commercial aprotinin solution and 1.3 μL of commercial dipeptidyl peptidase 4 (DPP IV) inhibitor. After addition of the whole blood sample, the blood tubes were vortex mixed. Sample tubes were stored on wet ice until processed to plasma by centrifugation (3500 rpm, 10 min at 5°C) within 30 min of collection. Plasma samples were transferred to matrix tubes and stored at nominal -70°C until shipped to a contract laboratory for analysis of the proprietary peptides present.

[0117] (Bioavailability calculation) Oral bioavailability was calculated by determining the area under the drug concentration curve (AUC) for both oral and subcutaneous dosing up to 24 hours after dosing. Percent bioavailability was calculated by determining the ratio of oral to subcutaneous AUC, corrected for mg / kg of drug administered to each animal by each route of administration, and multiplied by 100%.

[0118] (result) Hydrogel 1

[0119] Experiment 1. Oral bioavailability in dogs (n=8 per group) Peptide 1 without hydrogel had a subcutaneous bioavailability of 2.9%, CV (coefficient of variation) = 1.37. Peptide 2 with 300 mg of hydrogel had a subcutaneous bioavailability of 10.8%, CV (coefficient of variation) = 1.32.

[0120] Experiment 2. Oral bioavailability in dogs (n=8 per group), with pentagastrin to acidify the stomach. Peptide 1 without hydrogel had a subcutaneous bioavailability of 2.5%, CV (coefficient of variation) = 1.03. Peptide 2 with 300 mg of hydrogel had a subcutaneous bioavailability of 6.3%, CV (coefficient of variation) = 0.79.

[0121] Experiment 3. Oral bioavailability in dogs with pentagastrin to acidify the stomach. Peptide 2 without hydrogel (n=7) had a subcutaneous bioavailability of 2.6%, CV (coefficient of variation)=0.75. Peptide 2 (n=4) with 300 mg of hydrogel had a subcutaneous bioavailability of 6.6%, CV (coefficient of variation) = 0.43.

[0122] Hydrogel 2 (less crosslinker content than Hydrogel 1)

[0123] Experiment 3. Oral bioavailability in dogs, with pentagastrin to acidify the stomach Peptide 2 without hydrogel (n=7) had a subcutaneous bioavailability of 2.6%, CV (coefficient of variation)=0.75. Peptide 2 (n=4) with 300 mg of hydrogel had a subcutaneous bioavailability of 5.4%, CV (coefficient of variation)=1.04.

[0124] Studies were performed with GG-353 (referred to as "Peptide A"), GG-427 (referred to as "Peptide B"), and a large molecule hormone analogue (referred to as "Peptide C") that contains multiple chargeable carboxyl groups and is ionically chargeable at pH 4-8 with a molecular weight of 4000-5000 g / mol. These studies used #3.02 hydrogel particles sieved through a 63 μm sleeve and bioavailability was determined according to the procedure described above. In "Study 1" with GG-353 (Peptide A), the dose of GG-353 was divided equally among 5 capsules. In "Study 2" with GG-353 (Peptide A), the entire dose was provided in a single large capsule. In "Study 1" and "Study 2" with GG-427 (Peptide B), bioavailability was compared with (Study 2) or without (Study 1) administration of pentagastrin to animals. Administration of pentagastrin was performed to ensure that the gastric pH of the administered animals was equivalent to that of humans (pentagastrin lowers gastric pH). Administration of pentagastrin was performed by intramuscular injection of 5 mg of pentagastrin 30 minutes prior to capsule administration.

[0125] The bioavailability results of each peptide for samples containing hydrogel and samples without any hydrogel are shown in Figure 10. The results show that samples with hydrogel significantly and significantly increased the uptake and bioavailability of the peptide.

[0126] Example 2B In this example, an in vivo evaluation of a representative dosage form described herein is provided. The representative dosage form is a regular enteric coated capsule or tablet (size 0), containing GG-353 (active agent), sodium caprate (permeation enhancer), soybean trypsin inhibitor, and hydrogel #3.02 particles (approximately 1 mm each). 3The mechanisms of action are as follows: the capsule dissolves in the small intestine; the hydrogel selectively absorbs water, leaving behind higher concentrations of other ingredients; higher concentrations of permeation enhancers open tight junctions more; higher concentrations of SBTI inhibit pancreatic enzymes more; and higher drug concentrations allow for faster uptake through tight junctions.

[0127] Hydrogel #3.02 is non-porous and has a high anionic charge (through bound sulfonate groups). It is lightly cross-linked, resulting in high swelling in aqueous solutions. GG-353 has many negatively charged carboxylate groups. Caprates and caprate micelles are also negatively charged. As shown in Figure 4, the high negative charge of hydrogel #3.02 blocks the entry of negatively charged molecules (known as Donnan equilibrium). On the other hand, the lack of channels through the gel results in size exclusion: SBTI (181 amino acids / 20 kDa) is too large to penetrate the gel, and the peptide penetrates the swollen hydrogel by diffusion much more slowly than water, which results in excess water in the interior compared to near the surface region. In vivo results are shown in Figures 5A-5B and 6. Comparing oral bioavailability versus hydrogel content across all samples shows that 300 mg of hydrogel results in 2.5-fold increased bioavailability compared to no hydrogel, as shown in FIG. 7A (FIG. 7B provides another visualization of the same data in the form of a line graph with error bars and includes data points for 450 mg of hydrogel).

[0128] Example 2C This example shows the results of several representative drugs with different ionic charges. Using hydrogel #3.02 as an example, because this hydrogel has a net anionic charge, drugs with a net anionic charge can be effectively excluded from the swollen hydrogel, while drugs with a net cationic charge are more likely to be trapped inside (Figure 8).

[0129] (anionic drugs) Exenatide Exenatide (exenatide acetate) is an FDA-approved therapeutic peptide with a molecular weight of 4,187 g / mol and a net negative charge at pH above 5 (isoelectric point of exenatide = 4.86). Exenatide (5 mg) was dissolved in 5 mL of modified FASSIF buffer at pH 7. Hydrogel #3.02 (300 mg) was added and absorbed approximately 80% of the liquid over 25 min. In multiple replicates, the concentration of exenatide in the external solution was determined by UV absorbance to be 1.75-2 mg / mL after 25 min, indicating partial exclusion of the peptide from the hydrogel.

[0130] Sodium Caprate Sodium caprate (sodium decanoate) is a known intestinal permeation enhancer that has a negative charge (negative charge on caprate). Sodium caprate (280 mg) was dissolved in 5 mL of modified FASSIF buffer at pH 7. Hydrogel #3.02 (300 mg) was added and absorbed approximately 80% of the liquid. In multiple replicates, the concentration of caprate in the external solution was determined by UV absorbance to be approximately 1.4 times the initial concentration before addition of the hydrogel, indicating partial expulsion of caprate from the hydrogel.

[0131] Exenatide + Sodium Caprate Similar to the above experiment, exenatide (5 mg) was dissolved in 5 mL of modified FASSIF buffer at pH 7. The intestinal permeation enhancer sodium caprate (280 mg) was added. Hydrogel #3.02 (300 mg) was added and absorbed approximately 80% of the liquid. In multiple replicates, the concentration of exenatide in the external solution was determined by UV absorbance to be 1.6 mg / mL, indicating partial exclusion of the peptide from the hydrogel in the presence of sodium caprate.

[0132] (Cationic Drugs) Octreotide Octreotide (as octreotide acetate) is an FDA-approved therapeutic peptide with a molecular weight of 1019 g / mol and a net positive charge at pH <8 (isoelectric point of octreotide = 8.5). Octreotide (5 mg) was dissolved in 5 mL of modified FASSIF buffer at pH 7 (yielding a starting concentration of 1 mg / mL). Hydrogel #3.02 (300 mg) was added and absorbed approximately 80% of the liquid. In multiple replicates, the concentration of octreotide in the external solution was determined by UV absorbance to be less than 0.8 mg / mL after 10 minutes, indicating binding (not exclusion) of the peptide to the hydrogel.

[0133] Lanreotide (in FASSIF) Lanreotide is an FDA-approved therapeutic peptide with a molecular weight of 1096 g / mol and a net positive charge at pH <8. Lanreotide (5 mg) was dissolved in 5 mL of modified FASSIF buffer at pH 7. Hydrogel #3.02 (300 mg) was added and allowed to absorb approximately 80% of the liquid over 25 min. In multiple replicates, the concentration of lanreotide in the external solution was determined by UV absorbance to be approximately 0.3 mg / mL after 25 min, indicating binding (not exclusion) of the peptide to the hydrogel.

[0134] Lanreotide (in DI water) Lanreotide is an FDA-approved therapeutic peptide with a molecular weight of 1096 g / mol and a net positive charge at pH <8. Lanreotide (5 mg) was dissolved in 5 mL of deionized water. Hydrogel #3.02 (300 mg) was added and allowed to absorb approximately 80% of the liquid over 25 min. In multiple replicates, the concentration of lanreotide in the external solution was determined by UV absorbance to be less than 0.05 mg / mL after 25 min, indicating binding (not exclusion) of the peptide to the hydrogel.

[0135] Example 3 This example provides data on the levels of peptides present on the outside of the hydrogel when the protease is combined with the hydrogel in a liquid such as water, and the measured activity of the proteases (chymotrypsin, trypsin) when combined with the hydrogel.

[0136] Protease activity assays were used to determine the levels of proteases. Protease activity of proteases including chymotrypsin or trypsin was determined by using either α-chymotrypsin, CAS:9004-07-3 or trypsin type 1, CAS:9002:07-7. A chymotrypsin activity assay kit available from Abcam was used, containing coumarin substrate, chymotrypsinogen activator and chymotrypsin assay buffer ("cTAB"). A trypsin activity assay kit available from Abcam was used, containing p-NA substrate and trypsin assay buffer ("TAB"). The assay materials further included a Tris solution at pH 7.4 with 0.5 mM Ca.

[0137] To prepare the chymotrypsin protease activity assay, the following steps were performed: Hydrogel (such as hydrogel #3.02 described in Example 1) was weighed in 75 mg aliquots into labeled 15 mL tubes; an additional 15 mL tube was labeled as a control; aliquots of reaction solution were prepared (following the Abcam assay kit instructions) by combining 46 μL cTAB, 2 μL coumarin substrate, and 2 μL chymotrypsinogen activator in each aliquot (e.g., to provide 4 time points, all samples are n=3, 2 tubes, so a total of 24 aliquots are needed, so the total solution is 1104 μL cTAB, 48 μL coumarin substrate, and 2 μL chymotrypsinogen activator). The reaction solution was vortexed to mix; for one aliquot, a sample background control (SBC) solution was prepared by combining 48 μL of cTab and 2 μL of chymotrypsinogen activator (following the instructions in the Abcam assay kit) (e.g., to provide four time points, four aliquots are needed, so the total solution was 192 μL of cTab and 8 μL of chymotrypsinogen activator); the solution was vortexed to mix; and a 10 μg / mL chymotrypsin solution in Tris buffer was prepared (e.g., 15 mL total solution for testing, 5 mL per tube). The procedure for the chymotrypsin activity assay included adding 5 mL of chymotrypsin solution in Tris buffer to each of the sample tubes containing dried hydrogels and the empty control tube, starting a timer, and mixing with a spatula as necessary to break up the hydrogels. The tubes were then incubated at 150 RPM and 39 °C. Sampling from each tube was performed at each time point (5, 15, 30 and 60 min) by taking 10 μL from each tube and combining with 50 μL of the reaction solution above (n=3 tubes, total of 6 samples per time point). Samples were provided in wells of a UV-clear flat-bottom plate (e.g., a 96-well plate) and 50 μL of the SBC solution above was provided in one well as a migration background.Fluorescence readings were taken at 360 / 460 nm for each sample well at the time points. For each tube at each time point and incubation, the three readings for a single output were averaged and the SBC solution reading was subtracted from each average. For each average, a calculation of activity relative to the initial control reading was made for each incubation.

[0138] To prepare the trypsin protease activity assay, the following steps were performed: hydrogel (such as hydrogel #3.02 described in Example 1) was weighed in 75 mg aliquots into labeled 15 mL tubes; an additional 15 mL tube was labeled as a control; aliquots of reaction solution were prepared (according to the Abcam assay kit instructions) by combining 48 μL of TAB and 2 μL of p-NA substrate in each aliquot (e.g., to provide 4 time points, all samples are n=2, 3 tubes, so a total of 26 aliquots are needed, so the total solution was 1248 μL of TAB and 52 μL of p-NA substrate); the reaction solution was vortexed to mix; and a 150 μg / L trypsin solution in Tris (e.g., according to the Abcam assay kit instructions) was prepared (5 mL per tube, 15 mL total). The procedure for the trypsin activity assay included adding 5 mL of trypsin solution in Tris buffer to each of the sample tubes containing dried hydrogels and the empty control tube, starting a timer and mixing with a spatula as necessary to break up the hydrogels. The tubes were then incubated at 150 RPM and 39°C. Two 50 μL reaction solution aliquots were placed into separate wells of the plate as background. Sampling from each tube was done at each time point (5, 15, 30, 60 minutes). 50 μL of each sample was placed into 450 μL of TAB and vortexed to mix. 10 μL of each solution was then taken from each tube and combined with the 50 μL reaction solution above. The samples were provided to wells of a UV-clear flat-bottom plate (e.g., a 96-well plate). Fluorescence readings were taken at 450 nm for each sample well at the time points. For each tube at each time point and incubation, the two readings for a single output were averaged and the average background reading of the reaction solution was subtracted from all averages. For each average after background subtraction, a calculation of activity was made for each incubation relative to the initial control reading after background subtraction.

[0139] To determine the level of active agent present in the bulk liquid when combined with the hydrogel, 30 mg / mL of Peptide C (a polymeric hormone analog with multiple COH groups and a molecular weight of 4000-5000 g / mol, ionically chargeable at pH 4-8) was combined with 1 mg / mL of an ionically chargeable hydrogel (hydrogel #3.02 as described in Example 1) and a protease (chymotrypsin or trypsin) in a buffer solution. The amount of Peptide C in the liquid (i.e., outside the hydrogel) was determined by liquid chromatography-mass spectrometry at the first data point, and 30 and 60 minutes after the first data point.

[0140] 11A-11B, in vitro assays demonstrated that combinations of hydrogels and peptide C, where the hydrogel has a net ionic charge of the same sign as that of the net ionic charge of peptide C, maintained or even increased the concentration of the peptide over time, despite being in the presence of proteases that tend to degrade peptide C (see top graph in FIG. 11B, trypsin on the right, chymotrypsin on the left). This is in comparison to solutions containing peptide C and proteases but no hydrogel, which show a significant decrease in peptide levels over time.

[0141] Furthermore, the combination of peptide C with hydrogel results in a decrease in overall protease activity (chymotrypsin and trypsin), as shown in Figure 11B. While trypsin and chymotrypsin activity levels remained relatively stable and even increased over time without hydrogel, activity was significantly decreased in the presence of hydrogel (see bottom graph in Figure 11B, trypsin on the right, chymotrypsin on the left). Also, testing of an ionically chargeable hydrogel with the same net charge and overall sign of net charge as that of trypsin showed that this hydrogel had little effect on trypsin activity, indicating that the effect of reducing protease activity may be due, at least in part, to the reverse charge effect of the ionically chargeable hydrogel, which has a net ionic charge of the opposite sign to that of the protease (see bottom graph in Figure 11B, trypsin on the right, labeled "wrong charge").

[0142] Example 4A This example illustrates the formulation, manufacturing procedures, and testing criteria for another representative particulate hydrogel according to the present disclosure, designated Hydrogel #12.035. As shown in FIG. 12, Hydrogel #12.035 is a cross-linked copolymer containing two monomers (AMPS and styrene sulfonate) and a cross-linker (methylene bisacrylamide). The circled area in FIG. 12 highlights the difference from Hydrogel 3.02. Without being limited to a particular theory, the addition of styrene sulfonate (also called vinylbenzene sulfonic acid) was provided to optimize the binding of chymotrypsin to the hydrogel by providing a hydrophobic moiety on the benzene ring to interact with the hydrophobic moiety of the chymotrypsin enzyme, thereby reducing the interaction of chymotrypsin with the active agent and inhibiting its degradation.

[0143] Preparation of Hydrogel 12.035 In a 200 mL glass beaker, 5 g of 2-acrylamido-2-methylpropanesulfonic acid (AMPS), 5 g of 4-vinylbenzenesulfonate (4-VBS), 1 g of sodium hydroxide (NaOH), and 0.35 g of methylene bis(acrylamide) (BIS) were added to 40 g of deionized water (DI) under stirring at room temperature.

[0144] The solution was stirred until it became clear and the material was completely dissolved. While the material was being stirred, an initiator solution was prepared containing ammonium persulfate (20% by weight ammonium persulfate in 80% by weight DI) and tetramethylethylenediamine (TEMED) (20% by weight TEMED in 80% by weight DI).

[0145] Once all the solution was clear and completely dissolved, a nitrogen (N2) line was inserted into the hydrogel solution and N2 gas was bubbled into 200 mL of hydrogel solution for 2 minutes. After 2 minutes, with the N2 line still in place, 400 μL of ammonium persulfate solution was added to the beaker, followed immediately by 400 μL of TEMED solution. The N2 line was turned off and the beaker was capped. The solution was allowed to polymerize and harden overnight.

[0146] After overnight curing, the hydrogel was removed from the beaker and broken into chunks less than 1 cm in size. The chunks were placed in a 2 L beaker and stirred with 1800 mL of DI water at room temperature. After 15 minutes, the pH of the mixture was measured. 1N HCl was added in small increments until the pH of the mixture was approximately 7.0 (± approximately 0.1). It is estimated that approximately 1.0-1.5 mL of HCl will be required. After the final HCl addition, the mixture was stirred for an additional 30 minutes. After 30 minutes, the excess DI water was drained from the swollen gel and replaced with 1800 mL of fresh DI water. The mixture was stirred for 30 minutes, then drained and the liquid was replaced. This process was repeated until a total of six washes were completed. After the final DI water wash, all excess water was drained and 500 mL of 100% isopropanol (IPA) was poured into the beaker containing the gel. The mixture was stirred for 30 minutes. After 30 minutes, the IPA was drained and the hydrated gel mass was placed in a tray and the tray was placed in a 160F oven overnight or until completely dry. Once the gel was completely dry, the gel particles were ground using a particle mill or coffee grinder. The particles were repeatedly sieved through a 63μm sieve and particles larger than 63μm were re-ground.

[0147] Evans Blue Exclusion Procedure Commercially available Evans Blue dye was used as a surrogate marker for anionic drugs in hydrogel testing. It has a molecular weight of 961.8 g / mol and has four negative charges at pH 7 due to four sulfonate groups in its structure. Visible light absorbance at 605 nm provides a simple way to monitor the concentration of the dye when exposed to hydrogels in solution.

[0148] FASSIF buffer was prepared by adding 41.65 g of FASSIF buffer concentrate (Biorelevant Media, code FaSSIF) to 961.1 g of DI water and stirring until thoroughly mixed. Evans Blue solution was prepared by adding Evans Blue to approximately half of the FASSIF solution such that the final concentration in the media was 0.125 mg Evans Blue / mL.

[0149] 5 mL of Evans Blue solution was added to a 15 mL centrifuge tube (EB tube). 5 mL of FASSIF buffer (without Evans Blue) was added to another 15 mL tube (background tube). 200 mg of 63 μm or less hydrogel #12.035 was added to both tubes. The tubes were vortexed until thoroughly mixed and both tubes were placed on a rocker plate for 15 minutes. After 15 minutes, both tubes were centrifuged at 3000 g for 1 minute (N=3). 20 μL of sample was extracted from the supernatant of both tubes and diluted in 180 μL of DI water in a 96-well UV transparent plate (N=3). Samples (20 μL) of 0.125 mg / mL Evans Blue solution (EB stock) and FASSIF buffer (FASSIF stock) were also added to 180 μL of DI water in the same plate. The plate was read at 605 nm absorbance.

[0150] The absorbance readings for each group of samples were averaged. The concentration factor was calculated using the following formula:

number

[0151] The results are shown in Figure 13, which shows the relative concentration of dye when hydrogel #12.035 is added in various amounts sufficient to absorb a particular fraction of the liquid present in FASSIF buffer at pH 7. For example, 200 mg absorbed approximately 80% of the liquid present in a 5 ml test. Figure 13 clearly shows that the concentration of dye increases with the addition of more hydrogel. Each data point (40, 60, 80 and 90% liquid uptake) was tested multiple times and was statistically significant at p<0.001 compared to the no hydrogel control using a two-tailed Student's t-test. Error bars shown are standard error of the mean.

[0152] Example 4B This example illustrates the in vivo procedure for hydrogel #12.035, using essentially the same procedure as described in Example 2A above.

[0153] (Oral capsule administration) Beagle dogs (same animals as those given subcutaneously, n=8) were fasted overnight (approximately 12 hours) prior to dosing. To stimulate gastric secretion, each animal received a single 6 μg / kg intramuscular injection of pentagastrin approximately 30 minutes prior to dosing. Food was restored after 6 hours of sampling. Oral administration of the capsules was followed by a 10 ml saline flush. Blood samples were collected pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours post-dose. Blood samples were collected by cephalic vein puncture into tubes (1.3 mL K3EDTA) containing 3 μL of a commercial aprotinin solution and 1.3 μL of a commercial dipeptidyl peptidase 4 (DPP IV) inhibitor. After addition of the whole blood sample, the blood tubes were vortex mixed. Sample tubes were stored on wet ice until processed to plasma by centrifugation (3500 rpm, 10 min at 5° C.) within 30 min of collection. Plasma samples were transferred to matrix tubes and stored at nominal −70° C. until shipped to a contract laboratory for analysis of proprietary peptides present.

[0154] The capsules were size 00 gelatin capsules with an enteric coating (00EL) designed to open in the small intestine. The drug formulation consisted of 20 mg Peptide C, 280 mg sodium caprate, and 0 or 300 mg hydrogel #12.035.

[0155] (Subcutaneous administration allowing for oral bioavailability calculations) Beagle dogs (same animals as capsule dosing, n=8) were fasted overnight (approximately 12 hours) prior to dosing. Food was returned after 6 hours of sampling. Subcutaneous dosing solutions were prepared at 0.5 mg / mL with the proprietary peptide to be tested in 40 mM Tris buffer, pH 8. Dosing formulations were prepared by adding pre-weighed amounts of drug to the appropriate amount of vehicle to obtain the desired dosing concentration. Vehicles used in the formulations were pre-filtered prior to use. All dosing syringes were weighed before and after dosing to determine the amount of formulation administered gravimetrically, and approximately 0.02 mL / kg was administered for a final drug dose of 0.01 mg / kg.

[0156] Blood samples were collected pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours post-dose. Blood samples were collected by cephalic vein puncture into tubes (1.3 mL K3EDTA) containing 3 μL of commercial aprotinin solution and 1.3 μL of commercial dipeptidyl peptidase 4 (DPP IV) inhibitor. After addition of the whole blood sample, the blood tubes were vortex mixed. Sample tubes were stored on wet ice until processed to plasma by centrifugation (3500 rpm, 10 min at 5°C) within 30 min of collection. Plasma samples were transferred to matrix tubes and stored at nominal -70°C until shipped to a contract laboratory for analysis of the proprietary peptides present.

[0157] (Bioavailability calculation) Oral bioavailability was calculated by determining the area under the drug concentration curve (AUC) for both oral and subcutaneous dosing up to 24 hours after dosing. Percent bioavailability was calculated by determining the ratio of oral to subcutaneous AUC, corrected for mg / kg of drug administered to each animal by each route of administration, and multiplied by 100%.

[0158] (result) As shown in Figure 14, the oral bioavailability of this hydrogel formulation was better than the control with p=0.03 in a two-tailed Student's t-test. Error bars shown are standard error of the mean.

[0159] Example 5 This example provides a direct comparison between two hydrogels disclosed herein, Hydrogel #12.035 and Hydrogel #3.02. The experimental procedure for this in vitro study is summarized below:

[0160] (Summary of concentration in 5mL total test solution) Peptide C 1mg / mL Alpha-chymotrypsin type II from bovine pancreas, freeze-dried powder (Sigma) 10 μg / mL Hydrogel #12.035 or 3.02, 40 mg / mL (accounting for approximately 80% of the liquid)

[0161] (Incubation Composition) 200 mg of hydrogel (0 mg of hydrogel for control) 1.67mL of buffer 1.67mL drug stock 1.67mL chymotrypsin stock

[0162] (Stock solution) Buffer: Tris-Ca Tris-buffered saline + 0.5 mM calcium chloride Peptide C 1mg / mL in Tris-Ca Chymotrypsin 30μg / mL in Tris-Ca Stop solution: 0.1 mg / mL soybean trypsin inhibitor (Sigma) Tris-Ca

[0163] (Detailed Method) Each solution was preheated to 45°C (the chymotrypsin solution was kept at room temperature) and placed into a separate 15 mL centrifuge tube.

[0164] The solution was mixed by hand with a spatula to break up the hydrogel and vortexed.

[0165] The tubes were placed in an incubator at 150 RPM and 45° C. 45 was chosen because the majority of the time was outside the incubator for sampling, which kept the sample temperature fairly close to 37°.

[0166] Sampling procedure for each time point: The tubes were pulsed in a centrifuge to 3000G; A 20 μL sample was removed from each tube and diluted with 480 μL of stop solution; Each diluted sample had 20 μL of sample diluted in an additional 480 μL of stop solution; After each time point, the first sample tube was discarded and the second sample tube (from the second dilution step) was placed in a −80°C freezer; The tubes were mixed by hand with a spatula, vortexed, and then returned to the incubator; Analytical measurements of peptide C in thawed samples were performed by HPLC-MS. Values ​​shown for peptide C represent concentrations detected in the final stop solution samples (FIG. 15). In vitro data indicates better therapeutic potential for hydrogel #12.035 compared to hydrogel #3.02.

[0167] The embodiments listed below are provided to illustrate aspects of the present disclosure, however, the embodiments are not intended to be limiting and other aspects and / or embodiments may be provided.

[0168] Embodiment 1: A pharma- ceutically acceptable oral dosage form for delivering an active agent to an intestinal site, the dosage form comprising: 1. A delivery device comprising: a plurality of hydrogel particles comprising an ionically chargeable hydrogel material, the ionically chargeable hydrogel material comprising a crosslinked polymeric material having a swelling ratio in deionized water of at least 5; and an ionically chargeable active agent having a net ionic charge of the same sign as the net ionic charge of the ionically chargeable hydrogel at an intestinal pH in the range of about 4 to about 8; a delivery device comprising: A protective coating over the delivery device A dosage form comprising:

[0169] Embodiment 2: The dosage form of embodiment 1, wherein the crosslinked polymeric material has a swelling ratio, measured in deionized water, of at least 10, at least 20, at least 25, at least 30, at least 40, at least 50, at least 60, at least 75, at least 85, at least 100, at least 110, at least 120, and / or 200 or more.

[0170] Embodiment 3: The dosage form of any of the preceding embodiments, wherein the crosslinked polymeric material has a swelling ratio, as measured in fasting simulated intestinal fluid (FASSIF), of at least 5, at least 10, at least 20, at least 25, at least 30, at least 35, at least 40, and / or greater than 100.

[0171] Embodiment 4: A dosage form according to any of the preceding embodiments, wherein the ionically chargeable hydrogel material comprises a plurality of ionically chargeable functional groups.

[0172] Embodiment 5: A dosage form according to any of the preceding embodiments, wherein the ionically chargeable hydrogel material comprises a plurality of ionically chargeable functional groups having a net cationic charge at intestinal pH.

[0173] Embodiment 6: A dosage form described in any of embodiments 1 to 4, wherein the ionically chargeable hydrogel material comprises a plurality of ionically chargeable functional groups having a net anionic charge at intestinal pH.

[0174] Embodiment 7: The dosage form of embodiment 6, wherein the ionically chargeable hydrogel material comprises a plurality of ionically chargeable functional groups selected from the group consisting of sulfonate groups, sulfate groups, carboxylate groups, phosphate groups, and combinations thereof.

[0175] Embodiment 8: A dosage form according to any of embodiments 1 to 5, wherein both the ionically chargeable hydrogel material and the ionically chargeable active agent have a net cationic charge at intestinal pH.

[0176] Embodiment 9: A dosage form according to any of embodiments 1-4, 6 and 7, wherein both the ionically chargeable hydrogel material and the ionically chargeable active agent have a net anionic charge at intestinal pH.

[0177] Embodiment 10: The dosage form of any of the preceding embodiments, wherein the ionically chargeable active agent comprises a plurality of ionically chargeable groups.

[0178] Embodiment 11: The dosage form according to any of the preceding embodiments, wherein the ionically chargeable active agent is at least one of a peptide or modified peptide and a polynucleotide having a molecular weight of at least 500 g / mol, at least 1000 g / mol, at least 2000 g / mol, at least 4000 g / mol, at least 5000 g / mol, and / or up to 10,000 g / mol.

[0179] Embodiment 12: A dosage form according to any of the preceding embodiments, wherein when the dosage form is dispersed in water, the concentration of the ionically chargeable active agent 10 minutes after dispersion in water is at least 20% higher than when the same dosage form not containing the crosslinked polymer is dispersed in water for the same period of time.

[0180] Embodiment 13: A dosage form according to any of the preceding embodiments, wherein when the dosage form is dispersed in water, the concentration of the ionically chargeable active agent 30 minutes after dispersion in water is at least 50% higher than when the same dosage form not containing the crosslinked polymer is dispersed in water for the same period of time.

[0181] Embodiment 14: A dosage form according to any of the preceding embodiments, wherein when the dosage form is dispersed in water, the concentration of the ionically chargeable active agent 60 minutes after dispersion in water is at least 100% greater than when the same dosage form not containing the crosslinked polymer is dispersed in water for the same period of time.

[0182] Embodiment 15: A dosage form according to any of the preceding embodiments, wherein when the dosage form is dispersed in water, the concentration of the ionically chargeable active agent 90 minutes after dispersion in water is at least 200% greater than when the same dosage form not containing the crosslinked polymer is dispersed in water for the same period of time.

[0183] Embodiment 16: A dosage form according to any of the preceding embodiments, wherein when the dosage form is dispersed in water, the concentration of the ionically chargeable active agent 120 minutes after dispersion in water is up to 300% higher than when the same dosage form not containing the crosslinked polymer is dispersed in water for the same period of time.

[0184] Embodiment 17: The dosage form of any of the preceding embodiments, wherein the crosslinked polymeric material swells in deionized water by at least 100%, at least 200%, at least 500%, at least 1000%, at least 2000%, at least 3000%, at least 4000%, at least 5000%, at least 8000%, at least 10,000% and / or at least 15,000% by weight.

[0185] Embodiment 18: The dosage form of any of the preceding embodiments, wherein the crosslinked polymeric material swells in FASSIF by at least 100% by weight, at least 200% by weight, at least 500% by weight, at least 1000% by weight, at least 2000% by weight, at least 3000% by weight, at least 4000% by weight, at least 5000% by weight, at least 8000% by weight, at least 10,000% by weight and / or at least 15,000% by weight.

[0186] Embodiment 19: The dosage form of any of the preceding embodiments, wherein the crosslinked polymer material absorbs at least 2 mL, at least 3 mL, at least 4 mL, at least 5 mL, at least 8 mL, at least 10 mL, at least 15 mL, at least 20 mL, at least 50 mL, at least 100 mL, at least 125 mL, at least 150 mL, at least 175 mL, and / or at least 200 mL of deionized water.

[0187] Embodiment 20: The dosage form of any of the preceding embodiments, wherein the crosslinked polymeric material and the ionically chargeable active agent have a net ionic charge of the same sign at pH 2.

[0188] Embodiment 21: The dosage form of any of the preceding embodiments, wherein the crosslinked polymeric material and the ionically chargeable active agent have a net ionic charge of the same sign at pH 5.

[0189] Embodiment 22: The dosage form of any of the preceding embodiments, wherein the crosslinked polymeric material and the ionically chargeable active agent have net ionic charges of the same sign at pH 6.

[0190] Embodiment 23: The dosage form of any of the preceding embodiments, wherein the crosslinked polymeric material and the ionically chargeable active agent have a net ionic charge of the same sign at pH 7.

[0191] Embodiment 24: The dosage form of any of the preceding embodiments, wherein when the crosslinked polymer material is exposed to an aqueous solution containing an ionically chargeable active agent, the ratio of the percentage of the ionically chargeable active agent incorporated into the crosslinked polymer material to the percentage of water incorporated into the crosslinked polymer is less than 0.1:1.

[0192] Embodiment 25: The dosage form of any of the preceding embodiments, further comprising a penetration enhancer.

[0193] Embodiment 26: The dosage form of embodiment 25, wherein the permeation enhancer has one or more ionically chargeable groups, and the crosslinked polymeric material, the ionically chargeable active agent and the permeation enhancer all have a net ionic charge of the same sign at an intestinal pH in the range of 4 to 8.

[0194] Embodiment 27: A dosage form according to any of embodiments 25-26, wherein the crosslinked polymeric material, the ionically chargeable active agent and the permeation enhancer all have a net negative charge at an intestinal pH in the range of 4-8.

[0195] Embodiment 28: A dosage form described in any of embodiments 25-26, wherein the crosslinked polymeric material, the ionically chargeable active agent and the permeation enhancer all have a net negative charge in aqueous solution at a pH of about 7.

[0196] Embodiment 29: A dosage form described in any of embodiments 25-26, wherein the crosslinked polymeric material, the ionically chargeable active agent and the permeation enhancer all have a net negative charge in aqueous solution at a pH of about 5.

[0197] Embodiment 30: The dosage form of any of the preceding embodiments, comprising at least 50 mg, at least 100 mg, at least 200 mg, at least 300 mg, or at least 450 mg of crosslinked polymeric material, and less than 1 g of crosslinked polymeric material.

[0198] Embodiment 31: The dosage form of any of the preceding embodiments, wherein the crosslinked polymeric material constitutes at least 10% by weight, at least 20% by weight, at least 30% by weight, at least 40% by weight, at least 50% by weight, at least 60% by weight, at least 70% by weight, or at least 90% by weight of the dosage form.

[0199] Embodiment 32: A dosage form according to any of the preceding embodiments, wherein the ratio of the mass of the crosslinked polymeric material to the mass of the ionically chargeable active agent in the dosage form is at least 2:1, at least 4:1, at least 8:1, at least 10:1, at least 20:1, at least 50:1, or at least 100:1.

[0200] Embodiment 33: The dosage form of any of the preceding embodiments, wherein the crosslinked polymeric material comprises at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers comprising the polymer are ionically chargeable moieties.

[0201] Embodiment 34: The dosage form of any of the preceding embodiments, wherein the crosslinked polymeric material comprises at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers comprising the polymer are negatively chargeable moieties.

[0202] Embodiment 35: A dosage form described in any of embodiments 1 to 33, wherein the crosslinked polymer material comprises at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers comprising the polymer that are positively chargeable.

[0203] Embodiment 36: The dosage form of embodiment 34, wherein the crosslinked polymer material contains carboxylate moieties in at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers comprising the polymer.

[0204] Embodiment 37: The dosage form of embodiment 34, wherein the crosslinked polymer material contains phosphate moieties in at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers comprising the polymer.

[0205] Embodiment 38: The dosage form of embodiment 34, wherein the crosslinked polymeric material contains sulfonate or sulfate moieties in at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers comprising the polymer.

[0206] Embodiment 39: The dosage form of embodiment 38, wherein sulfur atoms constitute at least 2%, at least 4%, at least 8%, at least 10%, or at least 16% of the dry weight of the crosslinked polymer.

[0207] Embodiment 40: A dosage form according to any of the preceding embodiments, wherein the crosslinked polymeric material comprises residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharma-ceutically acceptable salt thereof.

[0208] Embodiment 41: The dosage form of embodiment 40, wherein at least 10% by weight, at least 15% by weight, at least 20% by weight, at least 30% by weight, at least 45% by weight, at least 50% by weight, at least 60% by weight, at least 75% by weight, or at least 80% by weight of the crosslinked polymeric material comprises residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharma-ceutically acceptable salt thereof.

[0209] Embodiment 42: The dosage form of any of the preceding embodiments, wherein the crosslinked polymer comprises a crosslinker comprising residues of methylenebisacrylamide or a pharma- ceutically acceptable salt thereof.

[0210] Embodiment 43: The dosage form of embodiment 42, wherein 0.2% to 20% by weight of the crosslinked polymeric material comprises residues of methylenebisacrylamide or pharma- ceutically acceptable salts thereof.

[0211] Embodiment 44: The dosage form of embodiment 43, wherein 1% to 5% by weight of the crosslinked polymeric material comprises residues of methylenebisacrylamide or pharma- ceutically acceptable salts thereof.

[0212] Embodiment 45: The dosage form of any of the preceding embodiments, wherein the crosslinked polymeric material comprises a residue of 4-vinylbenzenesulfonate, or a pharma- ceutically acceptable salt thereof.

[0213] Embodiment 46: The dosage form of embodiment 45, wherein at least 10% by weight, at least 15% by weight, at least 20% by weight, at least 30% by weight, at least 45% by weight, at least 50% by weight, at least 60% by weight, at least 75% by weight, or at least 80% by weight of the crosslinked polymeric material comprises residues of 4-vinylbenzenesulfonate or a pharma- ceutical acceptable salt thereof.

[0214] Embodiment 47: The dosage form of any of the preceding embodiments, wherein the crosslinked polymeric material comprises residues of 4-vinylbenzenesulfonate, or a pharma- ceutically acceptable salt thereof, and residues of 2-acrylamido-2-methylpropanesulfonic acid, or a pharma- ceutically acceptable salt thereof, in a weight ratio within the range of 0.25:1 to 1:0.25, 0.5:1 to 1:0.5, or 0.75:1 to 1:0.75.

[0215] Embodiment 48: A dosage form according to any of the preceding embodiments, wherein the ionically chargeable crosslinked polymeric material comprises carboxylate and / or carboxylic acid groups.

[0216] Embodiment 49: A dosage form according to any of the preceding embodiments, wherein the hydrogel particles contain less than 10% by weight of an ionically chargeable active agent within the internal dosage form volume occupied by the hydrogel particles prior to administration to a patient.

[0217] Embodiment 50: A dosage form according to any of the preceding embodiments, comprising a capsule dosage form.

[0218] Embodiment 51: The dosage form according to any of the preceding embodiments, comprising a tablet form.

[0219] Embodiment 52: A dosage form according to any of the preceding embodiments, wherein the protective coating comprises an enteric coating for releasing the ionically chargeable active agent in the small intestine.

[0220] Embodiment 53: The dosage form of any of the preceding embodiments, wherein the protective coating comprises a sustained release coating.

[0221] Embodiment 54: A dosage form according to any of the preceding embodiments, comprising a capsule coated with an enteric coating.

[0222] Embodiment 55: A dosage form according to any of the preceding embodiments, wherein the crosslinked polymeric material comprises a negatively chargeable functional group having a pKa of less than 5 in deionized water at a pH of about 7.

[0223] Embodiment 56: A dosage form according to any of the preceding embodiments, wherein the crosslinked polymeric material comprises a negatively chargeable functional group having a pKa of less than 3 in deionized water at a pH of about 7.

[0224] Embodiment 57: The dosage form of any of the preceding embodiments, wherein at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers of the crosslinked polymeric material contain negatively chargeable functional groups having a pKa of less than 5 in deionized water at a pH of about 7.

[0225] Embodiment 58: The dosage form of any of the preceding embodiments, wherein at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers of the crosslinked polymeric material contain negatively chargeable functional groups having a pKa of less than 3 in deionized water at a pH of about 7.

[0226] Embodiment 59: A method for treating or ameliorating the effects of a condition in a subject, comprising administering to the subject an effective amount of a dosage form according to any of the preceding embodiments.

[0227] Embodiment 60: A dosage form or method according to any of the preceding embodiments, wherein the ionically chargeable hydrogel material reduces the activity of one or more proteases at the intestinal site.

[0228] Embodiment 61: The dosage form or method of any of the preceding embodiments, wherein the one or more proteases have a net ionic charge of opposite sign to the sign of the net ionic charge of the ionically chargeable hydrogel material at an intestinal pH in the range of about 4 to about 8.

[0229] Embodiment 62: The dosage form or method of any of the preceding embodiments, wherein the ionically chargeable hydrogel material reduces the activity of one or more proteases by at least 15%, at least 20%, at least 25%, at least 30%, at least 45%, or at least 50% at 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, or 60 minutes as determined by a protease activity assay.

[0230] Embodiment 63: A dosage form or method according to any of the preceding embodiments, wherein a delivery device comprising an ionically chargeable hydrogel material maintains or increases the concentration of an active agent at an intestinal site in the presence of a protease compared to a delivery device not comprising an ionically chargeable hydrogel material.

[0231] Embodiment 64: A dosage form or method according to any of the preceding embodiments, wherein the delivery device comprising an ionically chargeable hydrogel material maintains or increases the concentration of an active agent in an active agent concentration assay in the presence of a protease for a period of at least 20 minutes, at least 40 minutes, or at least 60 minutes.

[0232] Embodiment 65: The dosage form or method of any of the preceding embodiments, wherein the concentration of active agent provided by a delivery device comprising an ionically chargeable hydrogel material is greater than the concentration of active agent provided by a delivery device not comprising an ionically chargeable hydrogel material for a period of at least 20 minutes, at least 40 minutes, or at least 60 minutes, as determined by an active agent concentration assay.

[0233] Embodiment 66: A dosage form or method described in embodiment 64, wherein the protease is alpha-chymotrypsin, trypsin type 1, or a combination thereof.

[0234] Embodiment 67: A dosage form or method described in any of the preceding embodiments, wherein the hydrogel particles have a mesh size in the range of 0.05 mm to 2 mm, and / or 0.5 mm to 2 mm.

[0235] Embodiment 68: A dosage form or method described in any of the preceding embodiments, wherein the hydrogel particles are capable of passing through a 63 μm sieve.

[0236] Embodiment 69: A dosage form or method according to any of the preceding embodiments, wherein the dosage form comprises an active agent that is susceptible to degradation in the intestinal region.

[0237] Embodiment 70: A hydrogel comprising an ionically chargeable crosslinked polymeric material comprising: (i) at least 10% by weight of residues of 4-vinylbenzenesulfonate, or a pharma- ceutically acceptable salt thereof; (ii) at least 10% by weight of residues of 2-acrylamido-2-methylpropanesulfonic acid, or a pharma- ceutically acceptable salt thereof; and (iii) 0.2% to 20% by weight of a crosslinker comprising residues of methylenebisacrylamide, or a pharma- ceutically acceptable salt thereof, wherein the weight ratio of the residues of 4-vinylbenzenesulfonate, or a pharma- ceutically acceptable salt thereof to the residues of 2-acrylamido-2-methylpropanesulfonic acid, or a pharma- ceutically acceptable salt thereof, is within the range of 0.25:1 to 1:0.25.

[0238] Embodiment 71: The hydrogel described in embodiment 70, wherein at least 15% by weight, at least 20% by weight, at least 30% by weight, at least 45% by weight, or at least 50% by weight of the crosslinked polymeric material comprises residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharma-ceutically acceptable salt thereof.

[0239] Embodiment 72: A hydrogel described in any of embodiments 70 to 71, wherein 90% by weight, 80% by weight, 70% by weight, 60% by weight, 55% by weight, 50% by weight, 45% by weight, 30% by weight or less of the crosslinked polymeric material comprises residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharma-ceutically acceptable salt thereof.

[0240] Embodiment 73: A hydrogel described in any of embodiments 70 to 72, wherein 0.2% by weight to 20% by weight of the crosslinked polymeric material comprises residues of methylenebisacrylamide or pharma- ceutically acceptable salts thereof.

[0241] Embodiment 74: A hydrogel described in any of embodiments 70 to 73, wherein 1% by weight to 5% by weight of the crosslinked polymeric material comprises residues of methylenebisacrylamide or pharma- ceutically acceptable salts thereof.

[0242] Embodiment 75: A hydrogel described in any of embodiments 70 to 74, wherein at least 15% by weight, at least 20% by weight, at least 30% by weight, at least 45% by weight, or at least 50% by weight of the crosslinked polymeric material comprises residues of 4-vinylbenzenesulfonate or a pharma-ceutical acceptable salt thereof.

[0243] Embodiment 76: A hydrogel described in any of embodiments 70 to 75, wherein 90% by weight, 80% by weight, 70% by weight, 60% by weight, 55% by weight, 50% by weight, 45% by weight, 30% by weight or less of the crosslinked polymeric material comprises residues of 4-vinylbenzenesulfonate or a pharma-ceutical acceptable salt thereof.

[0244] Embodiment 77: A hydrogel described in any of embodiments 70 to 76, wherein the crosslinked polymer material comprises residues of 4-vinylbenzenesulfonate or a pharma- ceutically acceptable salt thereof and residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharma- ceutically acceptable salt thereof, in a weight ratio ranging from 0.5:1 to 1:0.5, or from 0.75:1 to 1:0.75.

[0245] Embodiment 78: A hydrogel described in any of embodiments 70 to 77, wherein the crosslinked polymeric material has a swelling ratio, measured in deionized water, of at least 10, at least 20, at least 25, at least 30, at least 40, at least 50, at least 60, at least 75, at least 85, at least 100, at least 110, at least 120, and / or 200 or more.

[0246] Embodiment 79: A hydrogel described in any of embodiments 70 to 78, wherein the crosslinked polymer material has a swelling ratio, measured in fasting simulated intestinal fluid (FASSIF), of at least 5, at least 10, at least 20, at least 25, at least 30, at least 35, at least 40, and / or 100 or more.

[0247] Embodiment 80: A hydrogel described in any of embodiments 70 to 79, wherein the ionically chargeable hydrogel material comprises a plurality of ionically chargeable functional groups having a net anionic charge at intestinal pH.

[0248] Embodiment 81: A hydrogel described in any of embodiments 70 to 80, wherein the crosslinked polymer material swells in deionized water by at least 100%, at least 200%, at least 500%, at least 1000%, at least 2000%, at least 3000%, at least 4000%, at least 5000%, at least 8000%, at least 10,000% and / or at least 15,000% by weight.

[0249] Embodiment 82: A hydrogel described in any of embodiments 70 to 81, wherein the crosslinked polymeric material swells in FASSIF by at least 100%, at least 200%, at least 500%, at least 1000%, at least 2000%, at least 3000%, at least 4000%, at least 5000%, at least 8000%, at least 10,000% and / or at least 15,000% by weight.

[0250] Embodiment 83: A hydrogel described in any of embodiments 70 to 82, wherein the crosslinked polymer material absorbs at least 2 mL, at least 3 mL, at least 4 mL, at least 5 mL, at least 8 mL, at least 10 mL, at least 15 mL, at least 20 mL, at least 50 mL, at least 100 mL, at least 125 mL, at least 150 mL, at least 175 mL, and / or at least 200 mL of deionized water.

[0251] Embodiment 84: A hydrogel described in any of embodiments 70 to 83, wherein the crosslinked polymer material has a net negative ionic charge at pH 2.

[0252] Embodiment 85: A hydrogel described in any of embodiments 70 to 84, wherein the crosslinked polymer material has a net negative ionic charge at pH 5.

[0253] Embodiment 86: A hydrogel described in any of embodiments 70 to 85, wherein the crosslinked polymer material has a net negative ionic charge at pH 6.

[0254] Embodiment 87: A hydrogel described in any of embodiments 70 to 86, wherein the crosslinked polymeric material has a net anionic charge at pH 7.

[0255] Embodiment 88: A hydrogel described in any of embodiments 70 to 87, wherein the crosslinked polymer material comprises at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers comprising the polymer that can be negatively charged.

[0256] Embodiment 89: A hydrogel described in any of embodiments 70 to 88, wherein the crosslinked polymer material contains sulfonate or sulfate moieties in at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers comprising the polymer.

[0257] Embodiment 90: A hydrogel described in any of embodiments 70 to 89, wherein sulfur atoms constitute at least 2%, at least 4%, at least 8%, at least 10%, or at least 16% of the dry weight of the crosslinked polymer.

[0258] Embodiment 91: A hydrogel described in any of embodiments 70 to 90, wherein the ionically chargeable crosslinked polymer is in the form of hydrogel particles having a mesh size in the range of 0.05 mm to 2 mm, and / or 0.5 mm to 2 mm.

[0259] Embodiment 92: A hydrogel described in any of embodiments 70 to 91, wherein at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers of the crosslinked polymeric material contain negatively chargeable functional groups having a pKa of less than 5 in deionized water at a pH of about 7.

[0260] Embodiment 93: A hydrogel described in any of embodiments 70 to 92, wherein at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers of the crosslinked polymeric material contain negatively chargeable functional groups having a pKa of less than 3 in deionized water at a pH of about 7.

[0261] Embodiment 94: A hydrogel described in any of embodiments 70 to 93, wherein the ionically chargeable hydrogel material reduces the activity of one or more proteases by at least 15%, at least 20%, at least 25%, at least 30%, at least 45%, or at least 50% in 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, or 60 minutes, as determined by a protease activity assay.

[0262] Embodiment 95: A hydrogel described in any of embodiments 70 to 94, wherein the ionically chargeable hydrogel material maintains or increases the concentration of an active agent in an active agent concentration assay in the presence of a protease for a period of at least 20 minutes, at least 40 minutes, or at least 60 minutes.

[0263] Embodiment 96: A hydrogel described in any of embodiments 70 to 95, wherein the hydrogel is in the form of hydrogel particles capable of passing through a 63 μm sieve.

[0264] Embodiment 97: A dosage form according to any of embodiments 1 to 69, comprising a hydrogel according to any of embodiments 70 to 96.

[0265] Embodiment 98: A method of treatment according to any of embodiments 59 to 69, comprising administering a dosage form according to any of embodiments 1 to 69 and 97, comprising a hydrogel according to any of embodiments 70 to 96.

[0266] (Incorporated by reference) All patents and published patent applications referred to herein are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent and / or published patent application was specifically and individually indicated to be incorporated by reference. In the case of conflict, the present application, including any definitions herein, will control.

[0267] (Equivalent) While specific embodiments have been described, the above specification is illustrative and not restrictive. Many variations will become apparent to those skilled in the art upon review of this specification. The full scope of the embodiments should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

1. 1. A pharma- ceutically acceptable oral dosage form for delivery of an active agent to an intestinal site, the dosage form comprising:

1. A delivery device comprising: a plurality of hydrogel particles comprising an ionically chargeable hydrogel material, the ionically chargeable hydrogel material comprising a crosslinked polymeric material having a swelling ratio in deionized water of at least 5; and an ionically chargeable active agent having a net ionic charge of the same sign as the net ionic charge of the ionically chargeable hydrogel at an intestinal pH in the range of about 4 to about 8; A delivery device comprising: A protective coating over the delivery device A dosage form comprising:

2. 2. The dosage form of claim 1, wherein the crosslinked polymeric material has a swelling ratio, measured in deionized water, of at least 10, at least 20, at least 25, at least 30, at least 40, at least 50, at least 60, at least 75, at least 85, at least 100, at least 110, at least 120, and / or greater than 200.

3. 3. The dosage form of claim 1 or 2, wherein the crosslinked polymeric material has a swelling ratio, measured in fasting simulated intestinal fluid (FASSIF), of at least 5, at least 10, at least 20, at least 25, at least 30, at least 35, at least 40, and / or greater than or equal to 100.

4. 4. The dosage form of any one of claims 1 to 3, wherein the ionically chargeable hydrogel material comprises a plurality of ionically chargeable functional groups.

5. 5. The dosage form of any one of claims 1 to 4, wherein the ionically chargeable hydrogel material comprises a plurality of ionically chargeable functional groups having a net cationic charge at intestinal pH.

6. 5. The dosage form of any one of claims 1 to 4, wherein the ionically chargeable hydrogel material comprises a plurality of ionically chargeable functional groups having a net anionic charge at intestinal pH.

7. 7. The dosage form of claim 6, wherein the ionically chargeable hydrogel material comprises a plurality of ionically chargeable functional groups selected from the group consisting of sulfonate groups, sulfate groups, carboxylate groups, phosphate groups, and combinations thereof.

8. 6. The dosage form of any one of claims 1 to 5, wherein both the ionically chargeable hydrogel material and the ionically chargeable active agent have a net cationic charge at intestinal pH.

9. The dosage form of any one of claims 1 to 4, 6 and 7, wherein both the ionically chargeable hydrogel material and the ionically chargeable active agent have a net anionic charge at intestinal pH.

10. 10. The dosage form of any one of claims 1 to 9, wherein the ionically chargeable active agent comprises a plurality of ionically chargeable groups.

11. 11. The dosage form of any one of claims 1 to 10, wherein the ionically chargeable active agent is at least one of a peptide or modified peptide and a polynucleotide having a molecular weight of at least 500 g / mol, at least 1000 g / mol, at least 2000 g / mol, at least 4000 g / mol, at least 5000 g / mol, and / or up to 10,000 g / mol.

12. 12. The dosage form of any one of claims 1 to 11, wherein when the dosage form is dispersed in water, the concentration of the ionically chargeable active agent 10 minutes after dispersion in water is at least 20% greater than when the same dosage form does not contain the cross-linked polymer is dispersed in water for the same period of time.

13. 12. The dosage form of any one of claims 1 to 11, wherein when the dosage form is dispersed in water, the concentration of the ionically chargeable active agent 30 minutes after dispersion in water is at least 50% greater than when the same dosage form does not contain the cross-linked polymer is dispersed in water for the same period of time.

14. 12. The dosage form of any one of claims 1 to 11, wherein when the dosage form is dispersed in water, the concentration of the ionically chargeable active agent 60 minutes after dispersion in water is at least 100% greater than when the same dosage form does not contain the cross-linked polymer is dispersed in water for the same period of time.

15. 12. The dosage form of any one of claims 1 to 11, wherein when the dosage form is dispersed in water, the concentration of the ionically chargeable active agent 90 minutes after dispersion in water is at least 200% greater than when the same dosage form does not contain the cross-linked polymer is dispersed in water for the same period of time.

16. 12. The dosage form of any one of claims 1 to 11, wherein when the dosage form is dispersed in water, the concentration of the ionically chargeable active agent after 120 minutes of dispersion in water is up to 300% higher than when the same dosage form does not contain the cross-linked polymer is dispersed in water for the same period of time.

17. 17. The dosage form of any one of claims 1 to 16, wherein the crosslinked polymeric material swells in deionized water at least 100%, at least 200%, at least 500%, at least 1000%, at least 2000%, at least 3000%, at least 4000%, at least 5000%, at least 8000%, at least 10,000% and / or at least 15,000% by weight.

18. 17. The dosage form of any one of claims 1 to 16, wherein the crosslinked polymeric material swells in FASSIF by at least 100%, at least 200%, at least 500%, at least 1000%, at least 2000%, at least 3000%, at least 4000%, at least 5000%, at least 8000%, at least 10,000% and / or at least 15,000% by weight.

19. 19. The dosage form of any one of claims 1 to 18, wherein the crosslinked polymeric material absorbs at least 2 mL, at least 3 mL, at least 4 mL, at least 5 mL, at least 8 mL, at least 10 mL, at least 15 mL, at least 20 mL, at least 50 mL, at least 100 mL, at least 125 mL, at least 150 mL, at least 175 mL, and / or at least 200 mL of deionized water.

20. 20. The dosage form of any one of claims 1 to 19, wherein the crosslinked polymeric material and the ionically chargeable active agent have net ionic charges of the same sign at pH 2.

21. 20. The dosage form of any one of claims 1 to 19, wherein the crosslinked polymeric material and the ionically chargeable active agent have net ionic charges of the same sign at pH 5.

22. 20. The dosage form of any one of claims 1 to 19, wherein the crosslinked polymeric material and the ionically chargeable active agent have net ionic charges of the same sign at pH 6.

23. 20. The dosage form of any one of claims 1 to 19, wherein the crosslinked polymeric material and the ionically chargeable active agent have net ionic charges of the same sign at pH 7.

24. 24. The dosage form of any one of claims 1 to 23, wherein when the crosslinked polymeric material is exposed to an aqueous solution containing an ionically chargeable active agent, the ratio of the percentage of ionically chargeable active agent incorporated into the crosslinked polymeric material to the percentage of water incorporated into the crosslinked polymer is less than 0.1:

1.

25. 25. The dosage form of any one of claims 1 to 24, further comprising a penetration enhancer.

26. 26. The dosage form of claim 25, wherein the permeation enhancer has one or more ionically chargeable groups, and the crosslinked polymeric material, the ionically chargeable active agent and the permeation enhancer all have a net ionic charge of the same sign at an intestinal pH in the range of 4 to 8.

27. 27. The dosage form of claim 25 or 26, wherein the crosslinked polymeric material, the ionically chargeable active agent and the permeation enhancer all have a net negative charge at an intestinal pH in the range of 4 to 8.

28. 27. The dosage form of claim 25 or 26, wherein the crosslinked polymeric material, the ionically chargeable active agent and the permeation enhancer all have a net negative charge in aqueous solution at a pH of about 7.

29. 27. The dosage form of claim 25 or 26, wherein the crosslinked polymeric material, the ionically chargeable active agent and the permeation enhancer all have a net negative charge in aqueous solution at a pH of about 5.

30. 30. The dosage form of any one of claims 1 to 29, comprising at least 50 mg, at least 100 mg, at least 200 mg, at least 300 mg, or at least 450 mg of crosslinked polymeric material and less than 1 g of crosslinked polymeric material.

31. 31. The dosage form of any one of claims 1 to 30, wherein the crosslinked polymeric material constitutes at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 90% by weight of the dosage form.

32. 32. The dosage form of any one of claims 1 to 31, wherein the ratio of the mass of crosslinked polymeric material to the mass of ionically chargeable active agent in the dosage form is at least 2:1, at least 4:1, at least 8:1, at least 10:1, at least 20:1, at least 50:1, or at least 100:

1.

33. 33. The dosage form of any one of claims 1-32, wherein the crosslinked polymeric material comprises at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers comprising the polymer are ionically chargeable moieties.

34. 34. The dosage form of any one of claims 1 to 33, wherein the crosslinked polymeric material comprises at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers comprising the polymer are negatively chargeable moieties.

35. 34. The dosage form of any one of claims 1 to 33, wherein the crosslinked polymeric material comprises at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers comprising the polymer are positively chargeable moieties.

36. 35. The dosage form of claim 34, wherein the crosslinked polymeric material comprises carboxylate moieties in at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers that comprise the polymer.

37. 35. The dosage form of claim 34, wherein the crosslinked polymeric material comprises phosphate moieties in at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers that comprise the polymer.

38. 35. The dosage form of claim 34, wherein the crosslinked polymeric material contains sulfonate or sulfate moieties in at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers that comprise the polymer.

39. 39. The dosage form of claim 38, wherein sulfur atoms comprise at least 2%, at least 4%, at least 8%, at least 10%, or at least 16% of the dry weight of the crosslinked polymer.

40. 40. The dosage form of any one of claims 1 to 39, wherein the crosslinked polymeric material comprises residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharma- ceutically acceptable salt thereof.

41. 41. The dosage form of claim 40, wherein at least 10%, at least 15%, at least 20%, at least 30%, at least 45%, at least 50%, at least 60%, at least 75%, or at least 80% by weight of the crosslinked polymeric material comprises residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharma-ceutically acceptable salt thereof.

42. 42. The dosage form of any one of claims 1 to 41, wherein the crosslinked polymer comprises a crosslinker comprising residues of methylenebisacrylamide or a pharma- ceutically acceptable salt thereof.

43. 43. The dosage form of claim 42, wherein 0.2% to 20% by weight of the crosslinked polymeric material comprises residues of methylenebisacrylamide or pharma- ceutically acceptable salts thereof.

44. 44. The dosage form of claim 43, wherein 1% to 5% by weight of the crosslinked polymeric material comprises residues of methylenebisacrylamide or pharma- ceutically acceptable salts thereof.

45. 45. The dosage form of any one of claims 1 to 44, wherein the crosslinked polymeric material comprises residues of 4-vinylbenzenesulfonic acid or a pharma- ceutically acceptable salt thereof.

46. 46. ​​The dosage form of claim 45, wherein at least 10%, at least 15%, at least 20%, at least 30%, at least 45%, at least 50%, at least 60%, at least 75%, or at least 80% by weight of the crosslinked polymeric material comprises residues of 4-vinylbenzenesulfonic acid or a pharma-ceutically acceptable salt thereof.

47. 47. The dosage form of any one of claims 1 to 46, wherein the crosslinked polymeric material comprises residues of 4-vinylbenzenesulfonic acid, or a pharma- ceutically acceptable salt thereof, and residues of 2-acrylamido-2-methylpropanesulfonic acid, or a pharma- ceutically acceptable salt thereof, in a weight ratio within the range of 0.25:1 to 1:0.25, 0.5:1 to 1:0.5, or 0.75:1 to 1:0.

75.

48. 48. The dosage form of any one of claims 1 to 47, wherein the ionically chargeable crosslinked polymeric material comprises carboxylate and / or carboxylic acid groups.

49. 49. The dosage form of any one of claims 1 to 48, wherein the hydrogel particles contain less than 10% by weight of the ionically chargeable active agent within the internal dosage form volume occupied by the hydrogel particles prior to administration to a patient.

50. 41. The dosage form of claim 40, wherein the hydrogel particles have a mesh size in the range of 0.05 mm to 2 mm, and / or 0.5 mm to 2 mm.

51. 51. The dosage form of any one of claims 1 to 50, including a capsule dosage form.

52. 52. The dosage form of any one of claims 1 to 51, comprising a tablet form.

53. 53. The dosage form of any one of claims 1 to 52, wherein the protective coating comprises an enteric coating for release of the ionically chargeable active agent in the small intestine.

54. 54. The dosage form of any one of claims 1 to 53, wherein the protective coating comprises a sustained release coating.

55. 55. The dosage form of any one of claims 1 to 54, comprising a capsule coated with an enteric coating.

56. 56. The dosage form of any one of claims 1-55, wherein the crosslinked polymeric material comprises negatively chargeable functional groups having a pKa of less than 5 in deionized water at a pH of about 7.

57. 57. The dosage form of any one of claims 1-56, wherein the crosslinked polymeric material comprises negatively chargeable functional groups having a pKa of less than 3 in deionized water at a pH of about 7.

58. 52. The dosage form of claim 51, wherein at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers of the crosslinked polymeric material contain negatively chargeable functional groups having a pKa of less than 5 in deionized water at a pH of about 7.

59. 53. The dosage form of claim 52, wherein at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or up to 99% of the monomers of the crosslinked polymeric material contain negatively chargeable functional groups having a pKa of less than 3 in deionized water at a pH of about 7.

60. 13. A method for treating or ameliorating the effects of a condition in a subject, comprising administering to the subject an effective amount of the dosage form of claim 1.

61. 61. The dosage form or method of any one of claims 1 to 60, wherein the ionically chargeable hydrogel material reduces the activity of one or more proteases at the intestinal site.

62. 62. The dosage form or method of any one of claims 1-61, wherein the one or more proteases have a net ionic charge of opposite sign to the net ionic charge of the ionically chargeable hydrogel material at an intestinal pH in the range of about 4 to about 8.

63. 63. The dosage form or method of any one of claims 1-62, wherein the ionically chargeable hydrogel material reduces the activity of one or more proteases by at least 15%, at least 20%, at least 25%, at least 30%, at least 45%, or at least 50% at 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, and 60 minutes as determined by a protease activity assay.

64. 64. The dosage form or method of any one of claims 1 to 63, wherein a delivery device comprising an ionically chargeable hydrogel material maintains or increases the concentration of the active agent at an intestinal site in the presence of a protease compared to a delivery device not comprising an ionically chargeable hydrogel material.

65. 66. The dosage form or method of claim 65, wherein the delivery device comprising the ionically chargeable hydrogel material maintains or increases the concentration of the active agent in an active agent concentration assay in the presence of a protease for a period of at least 20 minutes, at least 40 minutes, or at least 60 minutes.

66. 67. The dosage form or method of claim 66, wherein the concentration of active agent provided by a delivery device comprising an ionically chargeable hydrogel material is greater than the concentration of active agent provided by a delivery device not comprising an ionically chargeable hydrogel material for a period of at least 20 minutes, at least 40 minutes, or at least 60 minutes, as determined by an active agent concentration assay.

67. 67. The dosage form or method of claim 66, wherein the protease is alpha-chymotrypsin, trypsin type 1, or a combination thereof.

68. 68. The dosage form or method of any one of the preceding claims, wherein the hydrogel particles have a mesh size in the range of 0.05mm to 2mm, and / or 0.5mm to 2mm.

69. 69. The dosage form or method of any one of claims 1 to 68, wherein the hydrogel particles are capable of passing a 63 μm sieve.

70. 70. The dosage form or method of any one of claims 1 to 69, wherein the dosage form comprises an active agent that is susceptible to degradation in the intestinal region.

71. 71. The dosage form or method of claim 70, wherein the protease comprises alpha-chymotrypsin, trypsin type 1, or a combination thereof.

72. 1. A hydrogel comprising an ionically chargeable crosslinked polymeric material comprising: (i) at least 10% by weight of residues of 4-vinylbenzenesulfonic acid, or a pharma- ceutical acceptable salt thereof; (ii) at least 10% by weight of residues of 2-acrylamido-2-methylpropanesulfonic acid, or a pharma-ceutical acceptable salt thereof; and (iii) 0.2% to 20% by weight of a crosslinker comprising residues of methylenebisacrylamide, or a pharma-ceutical acceptable salt thereof, wherein the weight ratio of the residues of 4-vinylbenzenesulfonic acid, or a pharma-ceutical acceptable salt thereof to the residues of 2-acrylamido-2-methylpropanesulfonic acid, or a pharma-ceutical acceptable salt thereof, is within the range of 0.25:1 to 1:0.

25.

73. 73. The hydrogel of claim 72, wherein at least 15%, at least 20%, at least 30%, at least 45%, or at least 50% by weight of the crosslinked polymeric material comprises residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharma-ceutically acceptable salt thereof.

74. 74. The hydrogel of claim 72 or 73, wherein no more than 90%, 80%, 70%, 60%, 55%, 50%, 45%, 30% or 20% by weight of the crosslinked polymeric material comprises residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharma-ceutically acceptable salt thereof.

75. 75. The hydrogel of any one of claims 72-74, wherein 0.2% to 20% by weight of the crosslinked polymeric material comprises residues of methylenebisacrylamide or pharma- ceutically acceptable salts thereof.

76. 76. The hydrogel of any one of claims 72-75, wherein 1% to 5% by weight of the crosslinked polymeric material comprises residues of methylenebisacrylamide or pharma- ceutically acceptable salts thereof.

77. 77. The hydrogel of any one of claims 72-76, wherein at least 15%, at least 20%, at least 30%, at least 45%, or at least 50% by weight of the crosslinked polymeric material comprises residues of 4-vinylbenzenesulfonic acid or pharma-ceutical acceptable salts thereof.

78. 78. The hydrogel of any one of claims 72-77, wherein no more than 90%, 80%, 70%, 60%, 55%, 50%, 45%, 30% or 20% by weight of the crosslinked polymeric material comprises residues of 4-vinylbenzenesulfonic acid or pharma-ceutical acceptable salts thereof.

79. 79. The hydrogel of any one of claims 72-78, wherein the crosslinked polymeric material comprises residues of 4-vinylbenzenesulfonic acid, or a pharma-ceutically acceptable salt thereof, and residues of 2-acrylamido-2-methylpropanesulfonic acid, or a pharma-ceutically acceptable salt thereof, in a weight ratio in the range of 0.5:1 to 1:0.5, or 0.75:1 to 1:0.

75.

80. 80. The dosage form of any one of claims 1 to 71, comprising a hydrogel as claimed in any one of claims 72 to 79.

81. A method of treatment according to any one of claims 60 to 71, comprising administering a dosage form according to any one of claims 1 to 71 comprising a hydrogel according to any one of claims 72 to 79.

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