Oral dosage forms containing ionically chargeable hydrogels for delivery of active agents

Abstract

The present disclosure provides, inter alia, a pharmaceutically acceptable oral dosage form comprising an ionically chargeable hydrogel and a protective coating for delivery of an ionically chargeable active agent to a site of the intestinal tract. Also provided are methods of treatment using the pharmaceutically acceptable oral dosage forms disclosed herein.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] 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 the above applications are incorporated herein by reference in their entirety. Technical Field

[0003] Aspects of the invention relate to pharmaceutically acceptable oral dosage forms for delivering active agents to intestinal sites.

[0004] background

[0005] Oral administration of active agents is attractive for a variety of 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 than other administration strategies for achieving adequate blood concentrations of the active agent. For example, active agents such as proteins and other macromolecules may be enzymatically degraded in the gastrointestinal tract and / or may be limited in transport across the intestinal epithelium.

[0006] One potential strategy to circumvent the adverse environment of the gastrointestinal tract is to change the environment by using protease inhibitors and / or using polyethylene glycol derivatized active agents to prevent enzymatic degradation. Another potential strategy is to increase the permeability of gastrointestinal tissues, thereby increasing the absorption of active agents. Active agents can be formulated with excipients that can, for example, open the tight junctions of the intestine so that the active agent passes through the intestinal epithelium. Another method to improve the delivery of drugs in the gastrointestinal tract is to apply an enteric coating to the active agent so that the drug is not exposed to the harsh pH conditions of the stomach, but is released in the small intestine where absorption is more likely to occur.

[0007] Another drug delivery technology is to use hydrogel as part of a drug delivery system. However, there is still a need for a drug delivery system that can provide improved drug delivery to the gastrointestinal tract, however, there is still a need for a drug delivery system that can provide better drug delivery to the gastrointestinal tract, such as in a form that allows the active agent to be easily absorbed by the intestinal tissue without excessive degradation. There is also a need for a drug delivery system that can provide improved delivery of active agents to the intestinal tract. SUMMARY OF THE INVENTION

[0009] According to one embodiment of the present invention, a pharmaceutically 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 covering the delivery device. The delivery device comprises: a plurality of hydrogel microparticles comprising an ionically chargeable hydrogel material, the ionically chargeable hydrogel material comprising a cross-linked polymer material having a swelling ratio of at least 5; and an ionically chargeable active agent, the ionically chargeable active agent having a net ionic charge, the sign of the net ionic charge being the same as the sign of the net ionic charge of the ionically chargeable hydrogel at an intestinal pH ranging from about 4 to about 8. Methods for treating disorders in individuals using such dosage forms are also provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] In order to facilitate further description of embodiments of the present disclosure, the following drawings are provided to illustrate but not to limit the scope of the present disclosure.

[0011] Figure 1 The schematic structure of hydrogel #3.02 is shown. The structures of the two components, AMPS and methylenebisacrylamide, are also shown.

[0012] Figure 2A-2B Shown are the swelling results of hydrogels with different amounts of cross-linker in DI water (A) and pH 7 FASSIF (B).

[0013] Figure 3A-3B The exclusion effect of hydrogels with different amounts of cross-linking agent in pH 7 FASSIF is shown (A, bar graph; B, single point graph). 1 mg / mL GG-427 was used as the active agent. Error bars = 1 standard deviation. T-tests compared the exclusion with standard hydrogel #3.02. There was no statistical difference in the exclusion (all p values>0.05).

[0014] Figure 4 Schematic diagram showing that highly negatively charged hydrogel #3.02 blocks the entry of negatively charged molecules.

[0015] Figure 5A-5B Shown are the GG-353 concentrations in blood samples (A) and their bioavailability ratios (B) following oral delivery to dogs, with and without hydrogel (300 mg).

[0016] Figure 6 Shown are atenolol concentrations in blood samples following oral delivery to dogs, with and without hydrogel (300 mg).

[0017] Fig. 7A and 7BResults are shown for oral bioavailability of GG-353 (5 mg) vs. hydrogel content. All formulations contained: enteric-coated capsules (1 x 00EL size), 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 to 450 mg).

[0018] Figure 8 is a schematic diagram showing an exemplary peptide exclusion principle of anionic hydrogels.

[0019] Fig. 9 is a schematic diagram showing an embodiment of an oral dosage form comprising an ionically chargeable hydrogel and an ionically chargeable active agent.

[0020] Fig.10 Results of oral bioavailability studies of the ionically chargeable hydrogel and three different ionically chargeable peptides are shown.

[0021] Fig.11A is a schematic diagram showing an embodiment of a mixture of a protease and an ionically chargeable hydrogel and, optionally, an ionically chargeable peptide, and the mixture can be used to detect peptide levels in the bulk fluid outside the hydrogel (in the case where an ionically chargeable peptide (e.g., peptide C) is added to the mixture), and can be used to detect protease activity in the bulk fluid outside the hydrogel (in this case, the ionically chargeable peptide does not need to be added to the mixture).

[0022] Fig. 11B The graph shows the results of the levels of ionically chargeable peptides detected in a mixture of peptides in a fluid containing a protease and a hydrogel, and a mixture of peptides in a fluid containing a protease but not a hydrogel (the upper left graph is the peptide concentration in combination with chymotrypsin, and the upper right graph is the peptide concentration in combination with trypsin); and shows the results of the protease activity detected in a mixture of a fluid containing a protease and a hydrogel, a mixture of a fluid containing a protease but not a hydrogel, and a mixture of a fluid containing a protease and a hydrogel with a net ionic charge (the sign of the net ionic charge of the protease in the fluid is the same as the sign of the net ionic charge of the protease) (the lower left graph is the chymotrypsin activity, and the lower right graph is the trypsin activity).

[0023] Fig.12 The schematic structure of hydrogel #12.035 is shown, with the circled portion highlighting the differences from hydrogel #3.02. The structures of the three components AMPS, methylene bisacrylamide, and styrene sulfonate are also shown.

[0024] Fig.13 Shown are the relative concentrations of Evans Blue dye present in simulated intestinal fluid at pH 7 when varying amounts of hydrogel #12.035 are added, sufficient to absorb a specific fraction of the fluid.

[0025] Fig.14 Shown are the concentration of peptide C in blood samples after oral delivery to dogs with and without hydrogel #12.035 (300 mg) (left) and its bioavailability (right).

[0026] Fig.15 An in vitro study using peptide C comparing hydrogel #12.035 and hydrogel #3.02 is shown.

[0027] 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. The accompanying drawings are schematic and are not drawn to scale. For clarity, not every element or component is identified in every figure, nor is every element or component of every embodiment of the inventive subject matter shown where such illustration is not necessary for one of ordinary skill in the art to understand the inventive subject matter.

[0028] definition

[0029] As used herein, "active agent" refers to any therapeutic agent that can be administered to a patient for the treatment and / or prevention of a disease and / or condition, including but not limited to pharmaceutically active agents, drugs, small molecule drugs, drug conjugates, prodrugs, antibodies or antibody fragments, nucleic acids, proteins, peptides, polysaccharides, small organic molecules (e.g., having a molecular weight of about 500 Da or less), metabolically active agents (e.g., metabolites), nutrients, supplements, etc., unless otherwise indicated.

[0030] As used herein, "biodegradable" means that when a material enters the body of an individual, patient or subject, it 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 can be reused or removed by the human body without producing significant toxic effects. In some cases, degradation products may also be biocompatible.

[0031] As used herein, "mucoadhesive agent" refers to a composition that has the ability to bind to a mucosal surface.

[0032] As used herein, "hydrogel" refers to a hydrophilic cross-linked polymeric structure capable of absorbing liquids.

[0033] As used herein, "dried hydrogel" or hydrogel in a "dried state" refers to a hydrogel material having the same water content as a hydrogel material dried in a convection oven set at 150° F. for at least 18 hours at standard pressure.

[0034] As used herein, "swelling ratio" is a measure of the mass of liquid absorbed by a hydrogel sample at a certain point in time after the liquid is introduced into the hydrogel sample divided by the initial mass of the hydrogel sample. The swelling ratio can be expressed as follows: Q (swelling ratio) = (swelling mass - initial mass) / initial mass, or in other words, expressed as the ratio of the mass of liquid absorbed by the hydrogel (Δ liquid) to the initial mass of the hydrogel (i.e., before the introduction of the liquid). The method for determining the swelling ratio of a hydrogel mass (e.g., hydrogel microparticles) is as follows (performed at about standard temperature and pressure):

[0035] a. Add 0.1 g of dry hydrogel (initial mass) to 15 mL of liquid;

[0036] b. Soak for 15 minutes, shaking gently;

[0037] c. draining the unabsorbed liquid through a 500 μm mesh; and

[0038] d. Measure the mass of unabsorbed liquid to obtain the mass of liquid absorbed by the hydrogel (ΔLiquid = initial mass of liquid - mass of unabsorbed liquid). The mass of liquid (initial or unabsorbed) can be obtained by weighing or multiplying the volume of the liquid by its density. The liquid used to calculate the swelling ratio can be any suitable liquid, such as deionized water or fasting state simulated intestinal fluid ("FASSIF"). For example, conventional FASSIF (e.g., 1 L) used herein can be prepared by the following method: 961 g DI H2O is added 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), 2.24 g FASSIF powder (Biorelevant Media FFF02, available from Biorelevant.com Ltd, Suite 4, Queen Mary Innovation Center, 42 New Road, London E1 2AX UK), stirred until dissolved, and adjusted to the desired pH (e.g., 6.5) using 1 M NaOH or HCI. The resulting FASSIF typically contains: 3 mM taurocholate, 0.75 mM soy lecithin, 148 mM sodium, 106 mM chloride, and 29 mM phosphate.

[0039] As used herein, "percentage of swelling ratio" refers to the percentage of the swelling ratio corresponding to the maximum swelling ratio measured within a selected time interval. For example, for a hydrogel sample with a maximum swelling ratio of 100, a swelling ratio of 50 measured at a time interval of 1 minute corresponds to a swelling ratio percentage of 50%.

[0040] As used herein, "swelling rate" refers to the speed at which a hydrogel sample reaches a predetermined swelling ratio percentage. For example, a hydrogel sample may have a swelling rate that reaches a swelling ratio percentage of at least 30% within 1 minute, a swelling ratio percentage of 50% within 2 minutes, and a swelling ratio percentage of 100% within 10 minutes.

[0041] As used herein, "excretion" refers to the amount of active agent excreted from a hydrogel material when the hydrogel material is introduced into fasting state simulated intestinal fluid (FASSIF) (the above-mentioned FASSIF medium, pH 6.5). The calculation method of the excretion is as follows:

[0042] a. Using the swelling ratio of the hydrogel material, determine the mass of hydrogel material required to absorb 8 mL of FASSIF;

[0043] b. Place the calculated amount of hydrogel into 10 mL of active agent at a concentration of 1 mg / mL in a 15 mL tube and shake gently (active solution).

[0044] c. Place the calculated amount of hydrogel into 10 mL pH 7 FASSIF in a 15 mL tube and shake gently (background solution).

[0045] d. Every 5 minutes for 25 minutes, extract 3 x 10 μL samples and dilute into 190 μL deionized water in a 96-well UV plate.

[0046] e. Also take 3 x 10 μL samples of 1 mg / mL active and pH 7 FASSIF stock solution.

[0047] f. Upon completion, measure the absorbance of each sample at 230 nm and 265 nm (or another absorbance characteristic of the active agent).

[0048] g. Subtract the background from the activity absorbance readings at each time point and compare to the stock solution to calculate the output.

[0049] As used herein, "dried hydrogel" or hydrogel in a "dried state" refers to a hydrogel material having the same water content as a hydrogel material dried in a convection oven set at 150°F at standard pressure for at least 18 hours.

[0050] As used herein, "ionically chargeable" refers to hydrogel materials and / or active agents that contain functional groups that are capable of forming a charged form when the material / agent is present in an aqueous medium (eg, gastrointestinal fluid, deionized water, or FASSIF).

[0051] As used herein, "net ionic charge" refers to an ionic chargeable material provided in an aqueous medium (e.g., gastrointestinal fluid, deionized water, or FASSIF), such as a hydrogel comprising ionic chargeable groups and / or an active agent having ionic chargeable groups, and refers to the sum of all ionic charges of chargeable groups that present a charged state in an aqueous medium. The sign of the net ionic charge of a material can be positive, negative, or neutral, depending on whether the material has more negatively charged groups, more positively charged groups, or no charged groups when provided in an aqueous medium, and the charge amount of any charged groups. For example, a material having mainly negatively charged ionic chargeable groups may carry a net negative ionic charge (the sign of the net ionic charge is negative) when provided in an aqueous medium, while a material having mainly positively charged ionic chargeable groups may carry a net positive ionic charge (the sign of the net ionic charge is positive) when provided in an aqueous medium.

[0052] As used herein, "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.

[0053] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like that are biocompatible and suitable for administration to a human.

[0054] As used herein, a "pharmaceutical composition" refers to a composition comprising at least one active agent disclosed herein formulated together with one or more pharmaceutically acceptable carriers and / or excipients.

[0055] As used herein, "pharmaceutically or pharmacologically acceptable" refers to molecular entities and compositions that are acceptable for administration to animals or humans, for example, without producing excessive adverse reactions, allergic reactions or other untoward reactions.

[0056] As used herein, "treat" or "treating" refers to any effect resulting in an improvement in a condition, disease, disorder, etc., such as an effect of alleviating, reducing, or regulating.

[0057] As understood by those of ordinary skill in the art, "protease activity assay" as used herein refers to an assay for determining protease activity in a given system. Examples of two such assays are chymotrypsin assays or trypsin assays. For example, using α-chymotrypsin, CAS: 9004-07-3 or type 1 trypsin, CAS: 9002: 07-7, the protease activity of a protease comprising chymotrypsin or trypsin can be determined by a protease activity assay. According to one embodiment, a chymotrypsin activity assay kit is used, such as a kit available from Abcam, 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 a kit available from Abcam, includes a p-NA substrate and a trypsin assay buffer ("TAB"). The material used for the assay may also include a Tris solution having a pH of 7.4 and containing 0.5 mM Ca.

[0058] In one embodiment, to prepare a protease activity assay for chymotrypsin, the following steps are performed: aliquots of 75 mg of the hydrogel (e.g., hydrogel #3.02 described in Example 1, which has a particle size in the range of 500 to 2000 microns) are loaded into labeled 15 mL tubes; an additional 15 mL tube is labeled as a control; aliquots of the reaction solution are generated by combining 46 microliters of cTAB, 2 microliters of coumarin substrate, and 2 microliters of chymotrypsinogen activator (e.g., according to the instructions of the Abcam assay kit) in each aliquot (e.g., to provide 4 time points, n=3, all samples, 2 tubes = 24 aliquots are required in total, so the total solution is 1104 10 μg / mL chymotrypsin solution in tris buffer containing 0.5 mM calcium (e.g., 15 mL total solution for testing, 5 mL per tube). The method for the chymotrypsin activity assay includes adding 5 mL of chymotrypsin solution in tris buffer containing calcium to each sample tube containing dry hydrogel and an empty control tube, starting a timer and mixing with a spatula to break up any hydrogel as needed. The tubes were then incubated at 150RPM and 39°C. Samples were taken from each tube at each time point (5, 15, 30 and 60 minutes) by the following steps: 10 microliters were taken from each tube and merged into 50 microliters of the above reaction solution, n=3 tubes, 6 samples for each time point. The samples were provided in the wells of a UV transparent flat bottom plate (such as a 96-well plate), and 50 microliters of the above SBC solution were provided in a single well as a moving background. The fluorescence readings at 380 / 460nm in each sample well were read at each time point. For each time point and each tube incubated, the three readings of a single output were averaged, and the SBC solution readings were subtracted from each average. For each average after subtracting the SBC solution readings, the activity of each incubation relative to the initial control readings was calculated.

[0059] In one embodiment, to prepare a protease activity assay for trypsin, the following steps are performed: load the hydrogel (e.g., hydrogel #3.02 described in Example 1, which has a particle size ranging from 500 to 2000 microns) into labeled 15 mL tubes in 75 mg aliquots; label an additional 15 mL tube as a control; produce aliquots of the reaction solution by combining 48 microliters of TAB and 2 microliters of p-NA substrate (e.g., according to the Abcam assay kit) in each aliquot (e.g., to provide 4 time points, n=2, all samples, 3 tubes = a total of 26 aliquots are required, so the total solution is 1248 microliters of TAB and 52 microliters of p-NA substrate); vortex the reaction solution to mix; and produce a solution of 150 micrograms of trypsin per milliliter in tris (e.g., according to the instructions of the Abcam assay kit), 5 mL per tube, totaling 15 mL. The method of trypsin activity assay method comprises adding 5mL of trypsin solution in tris buffer to each sample tube containing dry hydrogel and empty control tube, then starting the timer and mixing with a spatula to break any hydrogel as needed. Then the tube is incubated at 150RPM and 39°C. Two 60 microliters of reaction solution aliquots are placed in the individual wells of the plate as background. Samples are taken from each tube at each time point (5, 15, 30, 60 minutes). 50 microliter samples are each placed in 450 microliters of TAB and vortexed to mix. Then 10 microliters of solution are taken out from each tube, and merged into 50 microliters of the above-mentioned reaction solution. Samples are provided in the holes of UV transparent flat bottom plates (e.g., 96-well plates). The fluorescence readings of 405nm in each sample well are read at each time point. For each time point and each tube incubated, two readings of a single output are averaged, and the average value of the reaction solution background readings is subtracted from all average values. For each background-subtracted mean, the activity of each incubation was calculated relative to the initial background-subtracted control reading.

[0060] As used herein, "active agent concentration assay" includes any assay known to those skilled in the art that is suitable for determining the concentration of active agents (e.g., peptide concentration) in a liquid sample. For example, when provided in combination with an ionically chargeable hydrogel, a suitable assay for determining the concentration of active agents in a liquid may include mixing the ionically chargeable hydrogel material with an active agent in a liquid (e.g., water), optionally with any other such compound, such as a protease, etc. The ionically chargeable hydrogel material may be precipitated to the bottom of the mixture (e.g., the bottom of a test tube containing the mixture), and the liquid at the top of the mixture above the hydrogel may be sampled. The concentration of active agents present in such samples may be determined by standard methods such as liquid chromatography-mass spectrometry (LCMS).

[0061] As used herein, the singular form "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0062] The terms "includes," "comprising," and "containing" should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, used, or combined with other elements, components, or steps not explicitly referenced.

[0063] Detailed description

[0064] Various aspects of the present disclosure relate to dosage forms, systems and methods for oral, enteral and / or transmucosal delivery of active agents. In particular, various aspects of the present disclosure relate to pharmaceutically acceptable oral dosage forms for delivering active agents to intestinal sites, the oral dosage forms comprising a delivery device and a protective coating covering the delivery device. The delivery device comprises: a plurality of hydrogel microparticles comprising an ionically chargeable hydrogel material, the ionically chargeable hydrogel material comprising a cross-linked polymer material having a swelling ratio of at least 5; and an ionically chargeable active agent, the ionically chargeable active agent having a net ionic charge, the sign of the net ionic charge being the same as the sign of the net ionic charge of the ionically chargeable hydrogel at an intestinal pH ranging from about 4 to about 8. Various aspects of the present disclosure also relate to dosage forms comprising an ionically chargeable hydrogel, the form of the ionically chargeable hydrogel having physical properties that allow excellent active agent delivery characteristics to be achieved in intestinal sites, such as swelling ratio, swelling rate, compressive strength and radial strength. Additional aspects of the present disclosure provide methods of preparing dosage forms having delivery structures comprising ionically chargeable hydrogels, and methods of administering active agents using the dosage forms.

[0065] Without being limited by any theory, it is believed that various aspects of the dosage forms herein can provide enhanced bioavailability of an active agent delivered by the dosage form. For example, the dosage form can provide a highly swellable body that can expand rapidly in the intestinal tract, 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 tract. By contacting the outer surface of the hydrogel body with the intestinal tissue, the active agent at the outer surface can be in physical contact with the intestinal tissue and / or be placed in a position close to the intestinal tissue, thereby making it easier for the intestinal tissue to absorb the active agent to provide enhanced bioavailability of the active agent.

[0066] Another advantage of the embodiments of the dosage forms and / or delivery methods described herein is that for active agents that need to be systemically available (i.e., enter the bloodstream) to be effective, the amount of active agent required can be reduced. For example, an active agent with a bioavailability of only 40% in a standard oral dosage form may have a higher bioavailability when administered as described in the embodiments disclosed herein. Higher oral bioavailability is likely to reduce the cost of the active agent, reduce side effects caused by the active agent in the gastrointestinal tract, and reduce the possibility of side effects due to the active agent remaining in the gastrointestinal tract. In addition, improving the oral bioavailability of oral antibiotics is likely to reduce the occurrence of antibiotic resistance due to unabsorbed drugs in the small intestine and colon.

[0067] In addition, without being limited to any one theory, it is believed that the improved bioavailability of the active agent can be enhanced by the liquid absorption of the hydrogel at the intestinal site, which can increase the effective local concentration of the active agent, providing a greater driving force to transport the active agent across the intestinal wall. Additional potential benefits that the absorption of the hydrogel liquid and / or the presence of the active agent near the mucosal surface may confer on bioavailability may include the fact that the distance required for the active agent to diffuse from the dosage form to the mucosal surface is smaller, thereby increasing its potential absorption rate, and also providing a shorter exposure time of the active agent in the harsh and potentially degradative environment of the gastrointestinal tract.

[0068] In addition, without being limited by any one theory, it is believed that the ionically chargeable hydrogels of the present invention can increase the oral bioavailability of drugs (e.g., ionically chargeable peptides) having a net ionic charge of the same sign as the hydrogel. For example, when anionic drugs and anionic hydrogels are released in the small intestine, the hydrogel absorbs water and reduces the amount of free fluid present in the local area of ​​the patient's small intestine. When the hydrogel swells, it may also absorb some drugs, but the drug concentration in the water inside the hydrogel is lower than the drug concentration in the water outside the hydrogel. There are at least two possible mechanisms for selective uptake of water relative to the drug. The first mechanism for drug excretion from the hydrogel is through ionic interactions, which is called Donnan Equilibrium or Donnan Exclusion Effect in the literature. In short, the bound negative charges on the hydrogel tend to repel free negatively charged species (e.g., anionic drugs) from entering the hydrogel. The second mechanism for drug excretion from non-porous hydrogels involves faster diffusion relative to water, and the diffusion of larger molecules is generally much slower. Therefore, when a nonporous hydrogel is first exposed to a liquid containing both water and drug, the diffusion of water into the hydrogel is expected to be faster than the diffusion of large drug molecules. For example, using the known water diffusion coefficient (~2.9 x 10 -9 m 2 / sec) and the reported diffusion coefficient for peptides of similar size (i.e., 4.5 to 5 kDa) (0.074 x 10 -9 m 2 / second), the average time for water to diffuse 0.5mm (and thus diffuse to the center of a 1mm particle size) is ~0.7 minutes, while a peptide drug will take 28 minutes to diffuse to the same distance. Therefore, when the hydrogel microparticles initially swell, it is expected that the deep interior thereof will be significantly enriched with water relative to the drug. Due to at least these two possible reasons, the drug concentration in the free liquid remaining after the hydrogel swells is higher than the drug concentration when there is no hydrogel in the formulation. Since the absorption of peptide drugs is driven by diffusion, and according to Fick's Law, the diffusion rate is directly related to the concentration, an increase in the drug concentration outside the hydrogel is expected to increase the absorption rate of the drug. For example, in one embodiment of the present disclosure, when the cross-linked polymer material is exposed to an aqueous liquid containing an ionically chargeable active agent (e.g., as measured by the active agent concentration), the ratio of the fraction of ionically chargeable active agent absorbed in the cross-linked polymer material to the fraction of water absorbed in the cross-linked polymer is 0.1:1 to 0.7:1.

[0069] Provided below is a detailed discussion of embodiments of oral dosage forms that can enhance the absorption and bioavailability of an active agent.

[0070] Target Organization

[0071] In one embodiment, the oral dosage form is configured to provide delivery of the active agent to a target tissue in the gastrointestinal tract, such as the upper gastrointestinal tract or the lower gastrointestinal tract (i.e., the small intestine or the large intestine). For example, in one embodiment, the delivery site of the active agent can be the mucosa of the small intestine (e.g., the duodenum, jejunum, or ileum) and / or the large intestine (e.g., the ascending colon, the right colic flexure, the transverse colon, the transverse mesocolon, the left colic flexure, the descending colon, the sigmoid colon, and the rectum). In one embodiment, the oral dosage form is configured to provide delivery of the active agent to tissues in the ileum of the small intestine.

[0072] According to one embodiment, by selecting the configuration and composition of the oral dosage form, delivery to a specific region of the gastrointestinal tract (e.g., a certain position in the small intestine) can be achieved. For example, a protective coating such as an enteric coating can be provided, which at least partially protects (shields) the dosage form during passage through the stomach and / or other regions of the upper gastrointestinal tract until reaching a predetermined position in the lower gastrointestinal tract. Further discussion of embodiments of protective coatings and / or enteric coatings and / or other forms of embodiments capable of delivering active agents to predetermined positions in the gastrointestinal tract will also be provided in detail below.

[0073] Ion-chargeable microparticle hydrogel

[0074] According to embodiments of the present disclosure, a pharmaceutically acceptable oral dosage form for delivering an active agent to an intestinal site can provide the active agent in close contact with and / or near the intestinal tissue of the target intestinal site and increase the local drug concentration to promote the absorption of the active agent at the target site. As described above, one potential mechanism for drug excretion from a hydrogel is through ionic interactions, via Donnan equilibrium or Donnan exclusion effects. For example, in order to maintain a negative charge inside a hydrogel for drug delivery, a chemical moiety that retains a negative charge when the hydrogel is located in the small intestine can be provided. According to some embodiments, a pharmaceutically acceptable oral dosage form can be an oral dosage form suitable for an intestinal pH ranging from about 4 to about 8. In addition, since the pH of the small intestine is generally in the range of pH 5 to pH 8, according to certain embodiments, it is desirable to use functional groups with a pKa far below this range in the intestinal environment. Carboxylic acids, such as those obtained from cross-linked sodium polyacrylate, carry some negative charge at pH 5-8. However, since the pKa of carboxylic acids is slightly lower than 5 (4.76 for acetic acid), they may not all form a charged form at pH 5 or 6.

[0075] In addition, due to charge-charge repulsion within the hydrogel, the pKa value of the hydrogel interior (relative to the surface) may shift to a higher pKa value, making it more difficult to accumulate large charges. This effect has also been observed in other hydrogels, for example, cross-linked polyallylamine, where the pKa of the amine in the hydrogel (pKa ~9) is shifted by about 1-2 pH units compared to the normally dissolved primary amine (propylamine pKa ~10.7) before polymerization.

[0076] For this reason, in certain embodiments, it may be desirable for the acidic groups in the hydrogel to have a pKa much lower than the pKa5 in the intestinal environment. In certain embodiments, functional groups that meet this criterion include sulfonate and sulfate, whose pKa values ​​range from -5 to +2. Published values ​​show that the pKas of these parts are: methanesulfonic acid (-1.92), ethanesulfonic acid (-1.68), benzenesulfonic acid (-2.8) and methanesulfuric acid (methanesulfate) (-3.4). Therefore, sulfonate and sulfate are preferred functional groups for anionic hydrogels for excreting anionic drugs in the small intestine. For implementation purposes, the pKa of the functional groups described herein is measured in deionized water, because 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.

[0077] According to certain embodiments, in terms of generating negative charge in the hydrogel, chargeable moieties comprising sulfate or sulfonate may be preferred over chargeable moieties comprising carboxylate, because the chargeable moieties comprising carboxylate have a reduced tendency to strongly bind to calcium or magnesium in the intestinal fluid, thereby substantially reducing the net negative charge within the hydrogel. According to certain embodiments, for similar reasons of providing a low pKa, it may be desirable to use phosphonate or phosphate to generate negative charge in the hydrogel, because the pKa values ​​of certain phosphonates and / or phosphates may be lower than 2. According to yet another embodiment, carboxylates may be provided, and / or combinations of different chargeable moieties may be provided, such as a combination of sulfate and / or sulfonate with carboxylates.

[0078] Examples of suitable anionic hydrogels include those containing the monomers acrylic acid, methacrylic acid, vinyl sulfonic acid, vinyl sulfuric acid, itaconic acid, vinyl phosphoric acid, styrene sulfonic acid, carboxymethyl cellulose, carboxymethyl starch, alginic acid, aspartic acid, glutamic acid, and pharmaceutically acceptable salts thereof.

[0079] Examples of suitable anionic hydrogels include poly(acrylic acid), sodium polyacrylate, potassium polyacrylate, mixed sodium and potassium polyacrylates, polymethacrylic acid, sodium polymethacrylate, sodium polyethylene sulfonate, sodium poly(vinyl sulfate), sodium poly(itaconate), sodium polyphosphate, sodium polystyrene sulfonate, sodium carboxymethylcellulose, carboxymethylcellulose, sodium carboxymethyl starch, sodium alginate, sodium polyaspartate, polyaspartic acid, sodium polyglutamate, polyglutamic acid, and copolymers thereof.

[0080] In some embodiments, it is preferred to make the polymer contain as much negative charge as possible to better exclude negatively charged drug molecules. Examples of polymers with very high negatively charged charged moieties in the pH 5-8 range include sodium polyacrylate, sodium polyvinyl sulfonate, and sodium polyvinyl sulfate. Sodium polyvinyl sulfonate and sodium polyvinyl sulfate are most preferred in this regard because the pKa of their acidic moieties (sulfonate and sulfate groups) is very low, which ensures that as many groups as possible are in charged form at the desired pH 5-8.

[0081] In some embodiments, it is preferred that the polymer be net neutral with respect to the delivery and excretion of sodium and potassium. For example, if the polymer administered to a patient is sodium polyacrylate, excretion as a mixture of sodium polyacrylate and potassium polyacrylate may result in a net excretion of potassium, which may be undesirable. A certain ratio of sodium and potassium in the administered polymer will result in no significant excretion of sodium or potassium.

[0082] In some embodiments, the cross-linked polymer material comprising the ion chargeable hydrogel is capable of absorbing a large amount of liquid in the intestinal tract to enhance the delivery of the active agent. For example, in certain embodiments, the swelling ratio of the cross-linked polymer material contained in the ion chargeable hydrogel measured in deionized water is 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, even up to 200 or higher. In other embodiments, the swelling ratio of the cross-linked polymer material contained in the ion chargeable hydrogel measured in FASSIF is at least 5, at least 10, at least 20, at least 25, at least 30, at least 35, at least 40, even up to 100 or higher. In some embodiments, the cross-linked polymer material swells 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 deionized water. In some embodiments, the cross-linked polymer material swells 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% in FASSIF. For example, in certain embodiments, the cross-linked 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 in a FASSIF.

[0083] 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 may carry a net cationic charge or a net anionic charge at intestinal pH. Exemplary ionically chargeable functional groups may be selected from, but are not limited to, sulfonate groups, sulfate groups, carboxylate groups, phosphate groups, and combinations thereof.

[0084] To formulate the dosage forms described herein, in some embodiments, the dosage forms may include at least 50 mg, at least 100 mg, at least 200 mg, at least 300 mg, or at least 450 mg of cross-linked polymer material, and less than 1 g of cross-linked polymer material. In certain embodiments, the cross-linked polymer material accounts for 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% of the weight of the dosage form. In some embodiments, the ratio of the mass of cross-linked polymer material in the dosage form to the mass of the ionically chargeable active agent 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.

[0085] In one embodiment, the cross-linked polymer material contains ionically chargeable moieties on 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 99.9% of the monomers that make up the polymer. In certain embodiments, the cross-linked polymer material contains negatively chargeable moieties on 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 99.9% of the monomers that make up the polymer. In certain embodiments, the cross-linked polymer material contains positively chargeable moieties on 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 99.9% of the monomers that make up the polymer. For example, in one embodiment, the crosslinked polymer material contains carboxylate moieties on 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 99.9% of the monomers that make up the polymer. In another embodiment, the crosslinked polymer material contains phosphate moieties on 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 99.9% of the monomers that make up the polymer. In yet another embodiment, the crosslinked polymer material contains sulfonate moieties or sulfate moieties on 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 99.9% of the monomers that make up the polymer. In further embodiments, the 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.

[0086] In some embodiments, the cross-linked polymer is formed by the residue of the amide part that comprises one or more vinyl substitutions, such as the residue of 2-acrylamide-2-methylpropanesulfonic acid or its pharmaceutically acceptable salt, the residue of 4-vinylbenzenesulfonic acid or its pharmaceutically acceptable salt (such as styrene sulfonate), and / or the residue of methylenebisacrylamide or its pharmaceutically acceptable salt. 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% of the cross-linked polymer comprises the residue of 2-acrylamide-2-methylpropanesulfonic acid or its pharmaceutically acceptable salt by weight. In some embodiments, no more than 90%, 80%, 70%, 60%, 55%, 50%, 45%, 30% or 20% of the cross-linked polymer material comprises the residue of 2-acrylamide-2-methylpropanesulfonic acid or its pharmaceutically acceptable salt by weight. 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% of the cross-linked polymer material by weight comprises the residue of 4-vinylbenzenesulfonic acid or its pharmaceutically acceptable salt. In some embodiments, no more than 90%, 80%, 70%, 60%, 55%, 50%, 45%, 30% or 20% of the cross-linked polymer material by weight comprises the residue of 4-vinylbenzenesulfonic acid (vinyl benzenesulfonate) or its pharmaceutically acceptable salt. In some embodiments, 0.2% to 20% by weight of the cross-linked polymer comprises a cross-linking agent, and the cross-linking agent comprises the residue of methylenebisacrylamide or its pharmaceutically acceptable salt. In some embodiments, 1% to 5% by weight of the cross-linked polymer comprises the residue of methylenebisacrylamide or its pharmaceutically acceptable salt. In certain embodiments, 2% by weight of the cross-linked polymer comprises the residue of methylenebisacrylamide or its pharmaceutically acceptable salt. In certain embodiments, the pharmaceutically acceptable salt may be a sodium salt, such as sodium styrene sulfonate and sodium 2-acrylamido-2-methylpropane sulfonate, although other pharmaceutically acceptable salt forms may also be provided.

[0087] According to certain embodiments of the present disclosure, a hydrogel comprising an ionically chargeable crosslinked polymer material is provided, wherein the ionically chargeable crosslinked polymer material comprises (i) residues of 4-vinylbenzenesulfonic acid or a pharmaceutically acceptable salt thereof, (i) residues of 2-acrylamide-2-methylpropanesulfonic acid or a pharmaceutically acceptable salt thereof, and (iii) a crosslinker comprising residues of methylenebisacrylamide or a pharmaceutically acceptable salt thereof. According to certain embodiments, the weight ratio of the residues of 4-vinylbenzenesulfonic acid or a pharmaceutically acceptable salt thereof to the residues of 2-acrylamide-2-methylpropanesulfonic acid or a pharmaceutically acceptable salt thereof in the ionically chargeable crosslinked polymer is in the range of 0.25:1 to 1:0.25, for example, in 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 microparticles.

[0088] In some embodiments, the ionically chargeable cross-linked polymer comprises carboxylates and / or carboxylic acid groups. In some embodiments, prior to administration to a patient, the hydrogel microparticles contain less than 10% by weight of the ionically chargeable active agent in the internal dosage form volume occupied by the hydrogel microparticles. In certain embodiments, the mesh size of the hydrogel microparticles ranges from 0.05 mm to 2 mm, and / or 0.5 mm to 2 mm. According to one embodiment, the mesh size of the hydrogel microparticles ranges from 0.05 mm to 2 mm, and / or 0.5 mm to 2 mm.

[0089] In some embodiments, the crosslinked polymeric material comprises negatively charged 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 charged 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 99.9% of the monomers of the crosslinked polymeric material comprise negatively charged 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 99.9% of the monomers of the crosslinked polymeric material comprise negatively charged functional groups having a pKa of less than 3 in deionized water at a pH of about 7.

[0090] Active Agent

[0091] The oral dosage form according to the embodiment of the present disclosure is suitable for delivering any of a variety of active agents to a tissue site. Therefore, for example, the oral dosage form can be suitable for delivering a single active agent or a variety of active agents (e.g., two, three or more active agents, sequentially or simultaneously) to a tissue site. In addition, the active agent can be a variety of alternative forms, such as any of a pharmaceutically acceptable salt form, a free acid form, a free base form, and a hydrate.

[0092] Typically, the active agent can be in the form of a particle, liquid or gel, and can include any of a variety of compositions with biological relevance, such as metals, metal oxides, peptides, peptides structurally modified to resist enzymatic degradation, antibodies, hormones, enzymes, growth factors, small organic molecules, ligands or other drugs, nutrients or biological agents. In some embodiments, the active agent can include one or more macromolecules (e.g., proteins and / or protein conjugates) as active agents, and / or one or more small molecules (e.g., small organic molecules and / or small peptides). In an exemplary embodiment, the active agent includes at least one polypeptide and / or small molecule with a therapeutic effect. Examples of active agents that can be delivered via the oral dosage form may include at least one of the following active agents: Insulin, Vasopressin, Calcitonin (including salmon calcitonin), Oxytocin, Adrenocorticotropic Hormone (ACTH), Leuprorelin, Octreotide, Ixazomib, Adlyxin, Abaloparatide, Abaloparatide, Angiotensin II, Etelcalcetide, Macimorelin, Plecanatide, Semaglutide and other GLP-1 analogs (GLP-1 agonists), 177 Lu DOTA-TATE 68GaDOTA-TOC, Afamelanotide, Bremelanotide, Enfortumab Vedotin-Ejfv, Polatuzumab Vedotin-Piiq, Setmelanotide, BULEVIRTIDE, PConsensus, laminin-derived peptide, nucleosomal peptides, DWEYS peptide, glatiramer acetate, thymopentin-5, peptide P140, AMG623, Bivalirudin, Buserelin, Corticotropin, Cosyntropin, Enfuvirtide, Eptifibatide, Gramicidin D D), Lepirudin, Leuprorelin, Lucinactant, Nesiritide, Oxytocin, Pramlintide, Secretin, Sermorelin, Teduglutide, Thymalfasi, Rs-ARF2, Iturins, Histatin 5, Aureobasidins, Echinocandins, Pneumocandins, Aculeacins (AD, F), Mulundocandins, WF11899 (A, B, and 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,For example, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, GLP-1 / GIP co-agonists, such as tirzepatide, GLP-2 agonists, and peptide GPCR agonists. Other examples of active agents include antibiotics, such as azithromycin, vancomycin, dalbavancin, mycamine, brilicidin, avidocin, purocin, and arenicin. Active agents may also include antimycobacterial active agents clofazimine, ethionamide, para-aminosalicylic acid, and amikacin. ,

[0093] In yet another embodiment, the active agent may comprise other macromolecules and / or other structures other than those specifically listed above, such as any one or more of the following: antibodies (monoclonal and polyclonal) or antibody fragments, polysaccharides, carbohydrates, nanoparticles, vaccines, biologics, nucleic acids, cells and cell therapy, 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, etc. The active agent may also and / or alternatively include at least one of a small molecule drug, a drug conjugate, a prodrug, an organic small molecule (e.g., having a molecular weight of about 500 Da or less), a metabolically active agent (e.g., a metabolite), a nutrient, a supplement, etc.

[0094] According to one embodiment, oral dosage forms disclosed herein can provide improved bioavailability when delivering an active agent that may be incompletely absorbed in the intestinal tract. For example, oral dosage forms disclosed herein can provide surprisingly improved bioavailability for polypeptides and / or other small molecules with relatively high molecular weight, and these active agents may be difficult to effectively apply due to their relatively large size. Examples of such active agents can include polypeptides and / or small molecules, which have a size of at least about 450Da. However, according to one embodiment, the molecular weight of the active agent can still be less than about 200,000Da, so that the active agent is well delivered / absorbed in the intestinal tract. According to an example, in one embodiment, the molecular weight of the active agent is at least about 2000Da. By another example, in one embodiment, the molecular weight of the active agent is at least about 5000Da. By another example, in one embodiment, the molecular weight of the active agent is at least about 10,000Da. At the same time, according to one embodiment, the molecular weight of the active agent is generally less than about 600,000Da, as described above, in one example, the molecular weight can also be less than about 200,000Da, such as less than about 100,000Da. For example, in one embodiment, the molecular weight range of the active agent provided as part of the oral dosage form can be about 450Da to about 500,000Da, such as about 450Da to about 25,000Da, or even 450Da to 10,000Da, such as about 450Da to about 6000Da. For example, in one embodiment, the molecular weight range of the active agent can be about 1000Da to about 25,000Da, or even about 1,000Da to about 10,000Da, such as about 1000Da to 5000Da. As previously described, the oral dosage form can contain two or more active agents independently selected from molecules with molecular weights in the ranges described herein.

[0095] As described above, in order to enhance ionic interactions, the active agent can be an ionically chargeable active agent in the intestinal environment. For example, in one embodiment, the ionically chargeable active agent comprises a plurality of ionically chargeable groups, such as at least one, at least two, at least three, at least four, at least five, or even more ionically chargeable groups, which are expected to be negatively or positively charged at intestinal pH (e.g., pH 5-8). In order to maximize repulsion, in some embodiments, the ionically chargeable hydrogel material and the ionically chargeable active agent are both charged with a net cationic charge at intestinal pH. Alternatively, in other embodiments, the ionically chargeable hydrogel material and the ionically chargeable active agent are both charged with a net anionic charge at intestinal pH.

[0096] 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.

[0097] The dosage forms disclosed herein can significantly increase the local concentration of the drug, for example, in one embodiment, when the dosage form is dispersed in water, the concentration of the ionically chargeable active agent after 10 minutes of dispersion in water is at least 20% higher than the same dosage form without a cross-linked polymer after dispersion in water for the same time. In another embodiment, when the dosage form is dispersed in water, the concentration of the ionically chargeable active agent after 30 minutes of dispersion in water is at least 50% higher than the same dosage form without a cross-linked polymer after dispersion in water for the same time. In yet another embodiment, when the dosage form is dispersed in water, the concentration of the ionically chargeable active agent after 60 minutes of dispersion in water is at least 100% higher than the same dosage form without a cross-linked polymer after dispersion in water for the same time. In yet another embodiment, when the dosage form is dispersed in water, the concentration of the ionically chargeable active agent after 90 minutes of dispersion in water is at least 200% higher than the same dosage form without a cross-linked polymer after dispersion 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 300% higher than the same dosage form without the crosslinked polymer after dispersion in water for the same period of time.

[0098] In view of the different acidity of different parts of the gastrointestinal tract, it is advantageous for the ionically chargeable hydrogel and the ionically chargeable active agent to have a net ionic charge of the same sign at different pH. In some embodiments, the cross-linked polymer material and the ionically chargeable active agent have a net ionic charge of the same sign at pH 2 (e.g., both carry a net negative charge or both carry a net positive charge). In some embodiments, the cross-linked polymer material and the ionically chargeable active agent have a net ionic charge of the same sign at pH 5. In some embodiments, the cross-linked polymer material and the ionically chargeable active agent have a net ionic charge of the same sign at pH 6. In some embodiments, the cross-linked polymer material and the ionically chargeable active agent have a net ionic charge of the same sign at pH 7.

[0099] Penetration enhancers

[0100] In another embodiment, the oral dosage form includes at least one penetration enhancer to enhance the penetration of the active agent through the intestinal tissue. In some embodiments, the penetration enhancer can open the tight connection between cells (such as intestinal cells or epithelial cells). In some cases, the penetration enhancer can promote the entry of drugs into epithelial cells. The representative categories of penetration enhancers include but are not limited to fatty acids, medium-chain glycerides, surfactants, steroid detergents, acylcarnitines, lauroylcarnitine, palmitoylcarnitine, alkanoylcholine, N-acetylated amino acids, esters, salts, bile salts, sodium salts, nitrogen-containing rings, derivatives thereof, and combinations thereof. The penetration enhancer can be anionic, cationic, zwitterionic or nonionic. Anionic penetration enhancers include but are not limited to sodium lauryl sulfate, sodium decyl sulfate, sodium octyl sulfate, sodium N-dodecyl sarcosine and sodium decanoate. Cationic penetration enhancers include but are not limited to hexadecyl trimethyl ammonium bromide, decyl trimethyl ammonium bromide, benzyl dimethyl dodecyl ammonium chloride, tetradecyl trimethyl ammonium chloride and dodecyl pyridinium chloride. Zwitterionic penetration enhancers include, but are not limited to, N-dodecyl-N, N-dimethyl-3-ammonio-1-propanesulfonate, 3-(N,N-dimethyl palmitamide ammonium) propanesulfonate. Fatty acids include, but are not limited to, butyric acid, caproic acid, caprylic acid, nonanoic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, oleic acid, linoleic acid and linolenic acid, salts thereof, derivatives thereof, and combinations thereof. In some embodiments, fatty acids may be modified to esters, such as glycerides, monoglycerides, diglycerides or triglycerides. Bile acid or salt (including conjugated or unconjugated bile acid) penetration enhancers include, but are not limited to, cholate, deoxycholate, taurocholate, glycocholate, taurodexycholate, ursodeoxycholate, tauroursodeoxycholate, chenodeoxycholate, derivatives thereof, salts thereof, and combinations thereof. In some embodiments, penetration enhancers include metal chelators (e.g., EDTA or EGTA), surfactants (e.g., sodium lauryl sulfate, polyethylene ethers or esters, polyethylene glycol-12 lauryl ether, polysorbate 80 salicylate, nonylphenoxy polyoxyethylene, dioctyl sodium sulfosuccinate, saponins, palmitoyl carnitine, lauroyl-l-carnitine, dodecyl maltoside, acyl carnitines, alkanoyl cjolline, and combinations thereof.Other penetration enhancers include, but are not limited to, 3-nitrobenzoate, zoonulaocculden toxin, fatty acid esters of lactate, glycyrrhizinate, hydroxy-β-cyclodextrin, N-acetylated amino acids such as sodium N-[8-(2-hydroxybenzoyl)amino]octanoate and chitosan, micelle formers, channel formers, active agents of modified micelle formers, active agents of modified channel formers, salts thereof, derivatives thereof, and combinations thereof. In some embodiments, micelle formers include bile salts. In some embodiments, channel formers include antimicrobial peptides. In some embodiments, active agents of modified micelle formers include active agents that change the critical micelle concentration of micelle formers. An exemplary penetration enhancer is 1% by weight of 3-(N,N-dimethylpalmitoyl ammonium) propane sulfonate. Penetration enhancers are also described in patent application publication US2013 / 0274352, the contents of which are incorporated herein as a whole. In one embodiment, the penetration enhancer may include at least one of EDTA, palmitoyl carnitine, lauroyl carnitine, dimethyl palmitoylammonium propane sulfonate (PPS), and sodium caprate.

[0101] In one embodiment, the selection of the penetration enhancer for oral dosage form can be based on one or more of the hydrophilicity and / or hydrophobicity of the main penetration mechanism and the penetration enhancer. For example, fatty ester penetration enhancers and / or penetration enhancers with nitrogenous rings may show more paracellular transport activity, and cation and zwitterion penetration enhancers may show more transcellular activity, such as Whitehead and Mitragotri in " Pharmaceutical Research ", volume 25, the 6th phase, June, 2008, described in the article entitled " Mechanism Analysis of Chemical Permeation Enhancers for Oral Drug Delivery " published on page 1412-1419, which is incorporated herein by reference in its entirety. In addition, for penetration enhancers with transcellular mechanism, the increase of the hydrophobicity of the penetration enhancer can enhance the mechanism, and for penetration enhancers with more paracellular transport activity, the stronger hydrophilic penetration enhancer (for example, by interacting with the hydrophilic component tightly connected) can be observed to have a larger enhancement. In one embodiment, the relative hydrophobicity / hydrophilicity of the 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 enhance transcellular transport, the permeation enhancer may have a logP value of at least 2, such as at least 4, or even at least 6. Conversely, to enhance paracellular transport, in one embodiment, the permeation enhancer may have a logP of less than about 4, such as less than 2, or even less than 0.

[0102] In one embodiment, the content of the penetration enhancer in the oral dosage form can be at least about 0.01 weight %, for example, at least about 0.1 weight %, and be no more than about 80 weight %, and can even be less than about 30 weight %. For example, in one embodiment, the content of the penetration enhancer in the oral dosage form can be at least about 0.01 weight %, for example, at least about 0.1 weight %, including at least about 1 weight %, for example, at least about 5 weight %, even at least about 10 weight %, for example, at least about 30 weight %, or even at least about 50 weight %, for example, at least about 70 weight %. For example, in one embodiment, the scope of the penetration enhancer content can be 0.1 weight % to 70 weight %, for example, about 0.1 weight % to about 20 weight %, even about 1 weight % to about 10 weight %.

[0103] As described above, in certain embodiments, ionic interactions (repulsive forces) can play an important role in the dosage forms disclosed herein. In certain embodiments, the same theory relates to the penetration enhancers used. Anionic penetration enhancers (such as sodium decanoate) and anionic micelles of such enhancers may be discharged from the hydrogel for the same reasons as above (anionic charge and size / diffusion coefficient). Zwitterionic penetration enhancers, such as dimethyl palmitamide propane sulfonate (PPS), may also be discharged due to size / diffusion coefficient effects, and if they form micelles whose outermost surface is anionic, they are discharged due to charge effects. Like ionically chargeable hydrogels and active agents, penetration enhancers can also be ionically charged by having, for example, one or more ionically chargeable groups. In some embodiments, crosslinked polymer materials, ionically chargeable active agents, and penetration enhancers all have the same net ionic charge at intestinal pHs ranging from 4 to 8. In certain embodiments, crosslinked polymer materials, ionically chargeable active agents, and penetration enhancers all carry a net negative charge at intestinal pHs 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 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 aqueous solution at a pH of about 5.

[0104] Other additives

[0105] In addition to the active agent, microparticle hydrogel, and optional penetration enhancers, oral dosage forms may contain other additives.

[0106] In one embodiment, the oral dosage form may include an osmotic agent that helps deliver the active agent. Without being limited by any theory, it is believed that the osmotic agent can help expel the active agent from the oral dosage form by absorbing moisture and pushing the active agent out of the oral dosage form, and / or can help open tight junctions in the intestine by extracting moisture from the intestine. In one embodiment, the osmotic agent that can be hydrated can include water-soluble salts, carbohydrates, small molecules, amino acids, and combinations thereof. Exemplary water-soluble salts can 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 can include sugars, such as arabinose, ribose, xylose, glucose, fructose, galactose, mannose, sucrose, maltose, lactose, raffinose, etc., and combinations thereof. Exemplary amino acids can include glycine, leucine, alanine, methionine, etc., 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 can 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, and even about 20% by weight to about 40% by weight.

[0107] In another embodiment, the oral dosage form may include a protease inhibitor. "Protease inhibitor" or "antiprotease" as used herein refers to a molecule (usually a protein) that inhibits the function of a protease (an enzyme that contributes to protein breakdown). In the present disclosure, protease inhibitors are used to inhibit the decomposition of active agent peptides, such as their decomposition during intestinal delivery. Exemplary protease inhibitors include aspartic acid protease inhibitors, cysteine ​​protease inhibitors, metalloproteinase inhibitors, serine protease inhibitors, threonine protease inhibitors and trypsin inhibitors. In one embodiment of the present disclosure, the oral dosage form includes a soybean trypsin inhibitor.

[0108] Other additives and / or excipients that can be provided as part of the oral dosage form can include one or more of the following: stabilizers, glidants, bulking agents, anti-adherents, mucoadhesives, adhesives, adsorbents, preservatives, cryoprotectants, hydrating agents, enzyme inhibitors, mucus modifiers (e.g., mucus drying agents, etc.), pH modifiers, solubilizers, plasticizers, crystallization inhibitors, bulk filling agents, bioavailability enhancers, and combinations thereof. In some embodiments, the additives and / or excipients can include polyethylene glycol, polyethylene oxide, humectants, vegetable oils, medium chain monoglycerides, medium chain diglycerides and medium chain triglycerides, lecithin, waxes, hydrogenated vegetable oils, colloidal silicon dioxide, polyvinyl pyrrolidone (PVP) ("povidone"), cellulose, polymer (Lubrizol Advanced Materials, Inc.) (ie, a cross-linked acrylic acid-based polymer), acrylate polymer, pectin, sugar, magnesium sulfate or other hydrogel-forming polymers.

[0109] Protective coating

[0110] According to one embodiment, the oral dosage form further comprises a protective coating that at least partially protects the oral dosage form from the acidic environment in the stomach to deliver the active agent to the intestinal region. In one embodiment, the protective coating can form an outer coating of the oral dosage form to protect the active agent and / or microparticle hydrogel, or other additives in the oral dosage form. Although in one embodiment, the protective coating completely covers the outer surface of the delivery structure containing the hydrogel microparticles and active agent of the dosage form, the protective coating can also be optionally designed to cover only a portion of the outer surface of the delivery structure. The protective coating can also include only a single layer coating, or can be configured as a multilayer coating. For example, in one embodiment, the protective coating includes a capsule form. In another embodiment, the protective coating includes a tablet form. In yet another embodiment, the protective coating includes an enteric coating to release an ionically chargeable active agent in the small intestine. In yet another embodiment, the protective coating includes a sustained-release coating. In a further embodiment, the protective coating includes a capsule coated with an enteric coating.

[0111] According to one embodiment, the protective coating can be an enteric coating, which is a pH-dependent coating, having an enteric material that is a polymer, which is substantially insoluble in the acidic environment of the stomach, but increases solubility in the intestinal fluid where the pH is higher. That is, the enteric coating may preferentially dissolve and / or at least partially penetrate in the intestinal tract rather than in the stomach. Therefore, in one embodiment, the protective coating comprises an enteric coating to release an ion-chargeable active agent in the small intestine. For example, the enteric coating can be formed by such an enteric material, which is substantially insoluble in the pH lower than about 5, for example in the acidic environment of the stomach, but becomes soluble at a higher pH, for example, the pH of at least about 5.5 in the duodenum, the pH of at least about 6.5 in the jejunum, and the pH of at least about 7.0, for example, at least about 7.5 in the ileum (the duodenum, the jejunum and the ileum are a part of the small intestine). That is, an enteric coating that is insoluble at a lower pH but soluble at a higher pH can be selected so that once the gastrointestinal system environment reaches a pH at which the enteric coating material is soluble, the enteric coating can dissolve and / or become at least partially permeable and release the contents of the oral dosage form. Therefore, in one embodiment, a suitable enteric material for forming an enteric coating is an enteric material that is soluble until a pH of at least about 5.5 (e.g., a pH of at least about 6.0) is reached. In one embodiment, a suitable enteric material for forming an enteric coating is an enteric material that is soluble until a pH of at least about 6.5, such as a pH of at least about 7.0, or even a pH of at least about 7.5 is reached. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (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, copolymer of methylmethacrylic acid and methyl methacrylate, methyl acrylate, copolymer of methyl methacrylate and methacrylic acid,methylmethacrylate and methacrylic acid), copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, polyvinyl alcohol, natural resins such as zein, shellac and copal collophorium, and several 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 may 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 specific pH is known or can be easily determined in vitro. For example, the foregoing is a list of possible materials, but those skilled in the art who have the benefit of the present disclosure will recognize that the foregoing list is not exhaustive and that there are other enteric materials that can be used. In yet another embodiment, the protective coating can be a coating that dissolves and / or becomes partially permeable due to environmental changes that are not related to pH. In addition, in another embodiment, the protective coating and / or the enteric coating can be a coating that dissolves and / or becomes at least partially permeable at a predetermined rate when passing through the gastrointestinal system, thereby providing controlled and / or timed release of the active agent in a predetermined area of ​​the intestine. ,

[0112] In one embodiment, the protective coating comprises a protective coating at least a portion of which becomes permeable and / or soluble under predetermined conditions, such as at a predetermined pH (e.g., the pH at a target location in the intestinal tract), or after exposure to a liquid for a predetermined period of time (e.g., controlled release at a predetermined time point after administration). In one embodiment, the protective coating comprises a coating of material that becomes permeable and / or soluble under predetermined conditions.

[0113] In one embodiment, by providing a protective coating having a permeable and / or soluble portion surrounding a majority of the surface of the dosage form, the protective coating having a permeable and / or soluble portion, the contents of the dosage form can be effectively released in a multi-directional manner without unnecessarily retaining the contents inside the dosage form. In addition, in yet another embodiment, by providing a permeable and / or soluble portion around at least a majority of the surface of the dosage form region containing the active agent delivery region, good release of the particulate hydrogel and the active agent delivery region from a relatively large surface area of ​​the dosage form can be provided.

[0114] A 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 spraying a coating material such as an enteric material onto the surface of the delivery structure until a coating with a thickness of a predetermined range is formed. In one embodiment, the protective material can be sprayed relatively evenly on the delivery structure to provide a protective coating with uniform thickness on the surface of the oral dosage form. In another embodiment, the protective coating can also be sprayed unevenly depending on the configuration of the oral dosage form and the desired release characteristics. In yet another embodiment, a protective coating can be formed on the surface of the delivery structure by a dip coating method, wherein the surface of the oral dosage form is immersed or otherwise immersed in a liquid containing a protective coating material (e.g., an enteric coating material) to form a protective material coating on the surface.

[0115] In some embodiments, the oral dosage form can be configured for controlled release (timed release) of the active agent in the intestinal region, for example by providing a protective coating corresponding to an enteric coating to provide controlled release at a predetermined pH and / or pH range. Additionally and / or alternatively, other ingredients and / or excipients can be provided in the oral dosage form to provide controlled release of the active agent and the microparticle hydrogel.

[0116] According to one embodiment, the oral dosage form is provided with a size that can deliver the active agent well to the intestinal tract without excessive obstruction or obstruction of the intestinal tract. For example, the longest dimension (dimension) of the oral dosage form can be less than about 3 cm, for example, 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, for example, from about 1 cm to about 3 cm, or even from about 1 cm to about 2 cm. Suitable capsule sizes can be, for example, No. 1, 0, 00, and 000, including "EL" versions of any of these sizes.

[0117] Treatment

[0118] In some embodiments, oral dosage forms can be applied to individuals, patients or objects. In some cases, oral dosage forms can be applied in single doses. In other embodiments, multiple oral dosage forms can be applied to provide multiple doses over time. Alternatively, in the absence of food or fasting, oral dosage forms as described herein can be applied to individuals in need. For example, oral dosage forms can be applied 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, between about 3 hours to about 12 hours, between about 4 hours to about 12 hours, between about 4 hours to about 10 hours, between about 4 hours to about 8 hours, or between about 4 hours to about 6 hours after individual intake (consumption) food.

[0119] Alternatively, oral dosage forms as described herein can be applied to individuals in need under the condition of liquid restriction. The restriction means that within the prescribed time, the liquid that an individual can take in is less than 16 ounces, less than 8 ounces, less than 4 ounces, less than 2 ounces or less than 1 ounce. For example, 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, between about 1 hour to about 2 hours, between about 1 hour to about 4 hours before applying the oral dosage form, the liquid intake of the individual can be restricted. In addition, 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, between about 1 hour to about 2 hours, between about 1 hour to about 4 hours after applying the oral dosage form, the liquid intake of the individual can be restricted.

[0120] Treatment can last for a longer or shorter time as needed. Oral dosage forms can be administered according to a regimen of, for example, one to four times a day or more. A suitable treatment cycle can 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. When the desired results are achieved, the treatment cycle can be terminated. The treatment regimen can include a correction phase, during which a dose sufficient to alleviate the symptoms is administered, and a maintenance phase can be subsequently performed, during which a lower dose sufficient to maintain the symptoms of the alleviation is administered. A suitable maintenance dose may be in the lower portion of the dosage range provided herein, but based on the disclosure herein, those skilled in the art can easily determine the correction dose and maintenance dose for a single individual without excessive experimentation.

[0121] In certain embodiments, oral dosage forms can be used to deliver active agents (e.g., octreotide) to individuals in need. In some embodiments, oral dosage forms are capable of delivering insulin to patients in need, such as people with diabetes. In certain embodiments, oral dosage forms can be used to deliver active agents (e.g., calcitonin) to individuals in need. For example, oral dosage forms can be used to treat hypercalcemia. In another example, oral dosage forms can be used to treat bone diseases, such as osteoporosis. In yet another embodiment, oral dosage forms can be used to treat mental disorders, such as bipolar disorder or mania. In yet another embodiment, oral dosage forms can deliver active agents, such as GLP-1 agonists and / or GIP / GLP1 co-agonists, to patients in need to treat disorders, such as type II diabetes and / or obesity. In yet another embodiment, oral dosage forms can deliver active agents, such as enzyme-resistant peptides to patients in need to treat diseases, such as metabolic disorders.

[0122] For example, in one embodiment of the present disclosure, a method for treating or improving the effects of an individual's illness is provided. The method comprises administering an effective amount of a dosage form disclosed herein to an individual. In some embodiments, the illness is selected from type 2 diabetes, obesity, and a combination thereof. In some embodiments, the ion-chargeable active agent in the dosage form comprises a peptide having GIP-1 agonist activity or GIP / GLP1 co-agonist activity. Such peptides may be selected from, for example, semaglutide, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, tirpotide, and a combination thereof.

[0123] The oral dosage forms described herein can be used to administer active agents to patients (e.g., animals and / or humans) in need of such treatment at dosages that provide optimal drug efficacy. It should be understood that the number and / or type of oral dosage forms required to be used in any particular application will vary from patient to patient, not only in relation to the specific active agent selected, but also in relation to the concentration of the active agent in the oral dosage form, the nature of the condition being treated, the age and condition of the patient, the concomitant medications or special diets that the patient subsequently follows, and other factors that will be recognized by those skilled in the art, and ultimately the appropriate dosage is determined by the attending physician.

[0124] Fig. 9 is a schematic diagram showing an embodiment of an oral dosage form comprising an ionically chargeable hydrogel and an ionically chargeable active agent. The oral dosage form 100 comprises 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 by a protective coating 102, such as an enteric coating. The delivery device also contains a plurality of hydrogel microparticles 103 comprising an ionically chargeable hydrogel, and an active agent 104, and optionally a permeation enhancer 105 is provided. Other embodiments of the oral dosage form may also be provided.

[0125] According to certain embodiments, and without being limited by any theory, it is believed that the engineered hydrogel microparticles according to various aspects of the present invention selectively absorb water relative to the active agent, increase the concentration of the local active agent and / or permeate outside the hydrogel, which then leads to increased absorption of the active agent. According to certain embodiments, the ionically chargeable hydrogel repels ionically chargeable active agents and / or permeation enhancers (e.g., according to Donnan equilibrium). According to other embodiments, and without being limited by any theory, it is believed that the relative lack of macroscopic channels in the hydrogel microparticles limits the diffusion of larger molecules through the polymer network, thereby limiting the entry of larger active agents (e.g., certain peptides) into the hydrogel polymer network. According to yet another embodiment, and without being limited by any theory, it is believed that the hydrogel microparticles can reduce protease activity, such as by sequestration and / or self-inactivation of proteases (including proteases found in the intestine).

[0126] According to one embodiment, the dosage form or method herein comprises an ionically chargeable hydrogel material that reduces the activity of the protease in the intestinal tract. For example, the protease that exhibits reduced activity in the presence of the ionically chargeable hydrogel material can be those proteases with a net ionic charge of a sign opposite 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. Therefore, in certain embodiments, the dosage form comprising the ionically chargeable hydrogel material can be comprised of an ionically chargeable hydrogel material with a net ionic charge of a sign opposite to the sign of the net ionic charge of the protease at an intestinal pH in the range of about 4 to about 8, to reduce the activity of one or more proteases and inhibit the degradation of the active agent to enhance its delivery. In certain embodiments, the method of delivering an active agent using an ionically chargeable hydrogel material as part of the dosage form can include providing an ionically chargeable hydrogel material that can reduce the activity of the protease that causes the active agent to degrade in the intestinal tract. According to one embodiment, the dosage form or method provides a delivery device having an ionically chargeable hydrogel material that can reduce the activity of any protease chymotrypsin and trypsin (e.g., α-chymotrypsin and type 1 trypsin, or a combination thereof). According to one embodiment, the dosage form comprising an ionically chargeable hydrogel material is capable of reducing 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% over a time interval of 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 60 minutes, as determined by a protease activity assay. According to another embodiment, the dosage form comprises an ionically chargeable hydrogel material that reduces the activity of one or more proteases, and includes 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. According to yet another embodiment, the active agent peptide is selected from any one of the following: semaglutide, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, telpotide, and combinations thereof.

[0127] According to another embodiment, a dosage form and method thereof comprising a delivery device containing an ionically chargeable hydrogel material maintains or increases the concentration of an active agent in an intestinal site in the presence of a protease relative to a delivery device that does not contain an ionically chargeable hydrogel material. According to one embodiment, a dosage form 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 time interval of at least 20 minutes, at least 40 minutes, or at least 60 minutes. According to another embodiment, the concentration of an active agent provided by a delivery device having an ionically chargeable hydrogel material is higher than the concentration of an active agent provided by a delivery device that does not have an ionically chargeable hydrogel material, as determined by an active agent concentration assay. According to one embodiment, in the presence of a protease comprising chymotrypsin (e.g., α-chymotrypsin), trypsin (e.g., type 1 trypsin), or a combination of both, the concentration of an active agent is maintained or increased. According to one embodiment, the dosage form and method thereof comprise an active agent that is easily degraded by a protease in an intestinal site. For example, the dosage form can inhibit protease activity, thereby maintaining or increasing the level of an active agent that would otherwise be susceptible to degradation in the intestinal tract.

[0128] The following examples are provided to further illustrate the methods of the present disclosure. These examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure in any way. Example

[0129] Certain examples herein demonstrate the results of using anionically chargeable peptides GG-353 and GG-427, which are described in U.S. Patent Application Publication No. 2020 / 0024322 (see, e.g., Examples 2 and 4 and Table 13), which are incorporated herein by reference in their entirety, and which act as GIP / GLP1 co-agonists (see, e.g., Table 1 and Table 10). According to the disclosed description, the molecular weight of GG-353 is about 4928 g / mol, and the molecular weight of GG-427 is about 4926 g / mol. Both structures contain a large number of carboxyl groups and are expected to be negatively charged at pH 5-8.

[0130] Example 1

[0131] This example provides the formulation, preparation method and testing standards of a representative microparticle hydrogel according to the present disclosure. The representative hydrogel is named hydrogel #3.02 and contains the following ingredients:

[0132] Amount (g) <![CDATA[DI H2O]]> 40 <![CDATA[AMPS 1 ]]> 10 <![CDATA[BIS 2 ]]> 0.2 NaOH 2.1 <![CDATA[20%AP 3 ]]> 0.4 <![CDATA[20%TEMED 4 ]]> 0.4 sum 53.1

[0133] (1) AMPS = 2-acrylamide-2-methylpropanesulfonic acid; (2) BIS = methylenebisacrylamide 2% (crosslinker); (3) AP = ammonium persulfate; (4) TEMED = N,N,N',N'-tetramethylenediamine

[0134] To obtain hydrogel #3.02, the dry ingredients were added to the liquid and dissolved completely. Then ammonium persulfate was added and stirred. Next, TEMED was added and stirred, and the mixture was polymerized and cured overnight. The cured gel was broken into ~1 cm chunks and added to 2L of DI water under stirring. After soaking 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 soaked for another 30 minutes under stirring. The liquid was drained and replaced with another 2L of DI water. The conductivity of the liquid was measured to determine the purity. The mixture was then soaked for another 30 minutes under stirring. The liquid was drained and replaced with 400mL of isopropanol, and the mixture was then dehydrated for 1 hour. The liquid was drained, the gel was poured into a tray, and placed in an oven at 158°F to dry overnight. The dry gel was ground into particles of 500μm to 2000μm.

[0135] Standard hydrogel #3.02 contains two monomers: 98% AMPS (2-acrylamide-2-methylpropanesulfonic acid) and 2% BIS (methylenebisacrylamide) (as a crosslinker) ( Figure 1 ). In order to understand the consistency of preparation of hydrogel #3.02 and how different amounts of cross-linker affect its key properties, tests were conducted to measure the swelling of the produced hydrogels and the excretion of sample active agents. For the tests, three samples (A, B, and C) were produced for each of the following hydrogel variants: (1) using +20% cross-linker (0.24g BIS); (2) using +10% cross-linker (0.22g BIS); (3) using standard amount of cross-linker (0.20g BIS); (4) using -10% cross-linker (0.18g BIS); (5) using -20% cross-linker (0.16g BIS).

[0136] The swelling of the hydrogel was carried out in DI water and pH 7 FASSIF (fasting state simulated intestinal fluid) as follows: 0.1g dry hydrogel was added to 15mL liquid; soaked for 15 minutes with gentle shaking; unabsorbed liquid was drained through a 500μm mesh; unabsorbed liquid was measured and swelling was calculated. The results are shown in the following table and Figure 2A-2B shown.

[0137]

[0138]

[0139] Expulsion tests were performed in FASSIF at pH 7 using GG427 as the sample active agent. The amount of gel required to absorb 8 mL of FASSIF was calculated using the swelling results for FASSIF in the table above. The calculated amount of gel was then placed into 10 mL of 1 mg / mL GG427 in a 15 mL tube and gently shaken (active group). An equal amount of gel was placed into 10 mL of pH 7 FASSIF in a 15 mL tube and gently shaken (background group). This continued for 25 minutes, extracting 3x 10 μL samples every 5 minutes and diluting them into 190 μL of DI water in a 96-well UV plate. In addition, 3x 10 μL samples of 1 mg / mL GG427 and pH 7 FASSIF stock solutions were taken as controls. Upon completion, the absorbance at 230 nm and 265 nm was measured. The background was subtracted from the active absorbance readings at each time point and compared to the stock solution to calculate the expulsion effect (expulsion amount). The results are shown in Figure 2. Figure 3A-3B A consistent concentration effect of 1.4-fold was observed after 25 minutes, indicating that 80% of the fluid was absorbed into the hydrogel. That is, the drug concentration in the remaining 20% ​​of free fluid was 1.4-fold higher than the starting concentration.

[0140] Example 2A

[0141] This example illustrates an in vivo protocol for the microparticle hydrogels disclosed herein.

[0142] Oral capsule administration

[0143] Beagle dogs (same animals as for subcutaneous administration; n=4 or 8) were fasted overnight (~12 hours) before dosing. To stimulate gastric secretion, each animal received an intramuscular injection of 6 μg / kg pentagastrin approximately 30 minutes before dosing. After 6 hours of sample collection, feeding was resumed. Oral administration of capsules was followed by 10 mL saline rinse. Blood samples were collected before dosing 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 commercial aprotinin solution and 1.3 μL of commercial dipeptidyl peptidase 4 (DPP IV) inhibitor. After adding the whole blood sample, the blood tube was vortexed to mix. The sample tubes were stored on wet ice until processed into plasma by centrifugation (3500 rpm, 5°C, 10 minutes) within 30 minutes after collection. Plasma samples were transferred into matrix tubes and stored at a nominal temperature of −70°C until shipped to a contract laboratory for analysis of the presence of proprietary peptides.

[0144] The capsules are 00EL or 000 size gelatin capsules with an enteric coating (Eudragit S100) designed to open in the small intestine. The drug formulation consists of 5-24 mg peptide drug, 200-500 mg sodium caprate, 0 or 125 mg soybean trypsin inhibitor (125 mg for GG-353 and 0 mg for GG-427), and 0 or 300 mg hydrogel.

[0145] Subcutaneous administration to calculate oral bioavailability

[0146] Beagles (same animals as for capsule administration; n=4 or 8) were fasted overnight (~12 hours) prior to dosing. After 6 hours of sample collection, feeding was resumed. A 0.5 mg / mL subcutaneous dosing solution was prepared in 40 mM Tris buffer at pH 8 using the proprietary peptide under study. The dosing formulation was prepared by adding pre-weighed drug to an appropriate amount of vehicle to achieve the specified dose concentration. The vehicle used for the formulation was pre-filtered prior to use. All dosing syringes were weighed before and after dosing to determine the amount of formulation administered by gravimetric analysis, delivering ~0.02 mL / kg, with a final drug dose of 0.01 mg / kg.

[0147] Blood samples were collected before dosing and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 and 24 hours after dosing. Blood samples were collected by cephalic venipuncture 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 adding the whole blood sample, the blood tube was vortexed to mix. The sample tubes were stored on wet ice until processed into plasma by centrifugation (3500 rpm, 5°C, 10 minutes) within 30 minutes of collection. The plasma samples were transferred to matrix tubes and stored at a nominal temperature of -70°C until shipped to the contract laboratory for analysis of the presence of proprietary peptides.

[0148] Bioavailability calculation

[0149] Oral bioavailability was calculated by measuring the area under the drug concentration curve (AUC) from the time of administration to 24 hours after administration for oral and subcutaneous administration. The percent bioavailability was calculated by determining the ratio of the oral AUC to the subcutaneous AUC, corrected for the mg / kg dose per animal per route of administration, and then multiplied by 100%.

[0150] result

[0151] Hydrogel 1

[0152] Experiment 1. Oral bioavailability in dogs (n=8 per group)

[0153] The bioavailability of peptide 1 without hydrogel compared with subcutaneous administration was 2.9%, with a CV (coefficient of variation) = 1.37.

[0154] The bioavailability of peptide 1 containing 300 mg of hydrogel compared to subcutaneous administration was 10.8%, CV (coefficient of variation) = 1.32.

[0155] Experiment 2. Oral bioavailability in dogs (n=8 per group) using pentagastrin to acidify the stomach.

[0156] The bioavailability of peptide 1 without hydrogel compared with subcutaneous administration was 2.5%, with a CV (coefficient of variation) = 1.03.

[0157] The bioavailability of peptide 1 containing 300 mg of hydrogel compared to subcutaneous administration was 6.3%, CV (coefficient of variation) = 0.79.

[0158] Experiment 3. Oral bioavailability in dogs using pentagastrin to acidify the stomach.

[0159] The bioavailability of peptide 2 without hydrogel (n=7) compared with subcutaneous administration was 2.6%, CV (coefficient of variation) = 0.75.

[0160] The bioavailability of peptide 2 (n=4) containing 300 mg of hydrogel compared to subcutaneous administration was 6.6%, CV (coefficient of variation) = 0.43.

[0161] Hydrogel 2 (lower cross-linking amount than hydrogel 1)

[0162] Experiment 3. Oral bioavailability in dogs using pentagastrin to acidify the stomach

[0163] The bioavailability of peptide 2 without hydrogel (n=7) compared with subcutaneous administration was 2.6%, CV (coefficient of variation) = 0.75.

[0164] The bioavailability of peptide 2 (n=4) containing 300 mg of hydrogel compared to subcutaneous administration was 5.4%, CV (coefficient of variation) = 1.04.

[0165] GG-353 (referred to as "peptide A"), GG-427 (referred to as "peptide B"), and macromolecular hormone analogs (referred to as "peptide C") that are ionically chargeable at pH 4 to 8 and contain multiple chargeable carboxyl groups and have a molecular weight between 4000-5000 g / mol were also studied. These studies used #3.02 hydrogel microparticles screened by a 63 micron sleeve, and the bioavailability was determined according to the above method. For "Study 1" using GG-353 ("peptide A"), the dose of GG-353 was evenly divided into 5 capsules. For "Study 2" using GG-353 ("peptide A"), the complete dose was filled in a larger capsule. For "Study 1" and "Study 2" using GG-427 ("peptide B"), the bioavailability of pentagastrin was compared with animals administered ("Study 2") and not administered ("Study 1"). Administration of pentagastrin was performed to ensure that the gastric pH of the animals being administered was similar to that of humans (pentagastrin can lower gastric pH). Administration of pentagastrin was performed by intramuscular injection of 5 mg of pentagastrin 30 minutes before capsule administration.

[0166] Fig.10 Results for bioavailability in samples containing hydrogels and samples without any hydrogels are shown for each peptide. The results show that samples containing hydrogels significantly increased the absorption and bioavailability of the peptides.

[0167] Example 2B

[0168] In this example, an in vivo evaluation of a representative dosage form described herein is provided. The representative dosage form comprises: a regular enteric-coated capsule or tablet (size 0), GG-353 (active agent), sodium caprate (permeation enhancer), soybean trypsin inhibitor, and hydrogel #3.02 microparticles (each 1 mm 3 The mechanism of action is as follows: the capsule dissolves in the small intestine; the hydrogel selectively absorbs water, resulting in a higher concentration of the remaining ingredients; a higher permeation enhancer concentration opens the tight junctions more; a higher SBTI concentration inhibits pancreatic enzymes more strongly; and a higher drug concentration results in faster absorption of the drug across the tight junctions.

[0169] Hydrogel #3.02 is nonporous and has a high anionic charge (via attached sulfonate groups). It is lightly cross-linked, resulting in high swelling in aqueous solution. GG-353 has many negatively charged carboxylate groups. Caprate and caprate micelles are also negatively charged. Figure 4As shown, the high negative charge of hydrogel #3.02 prevents the entry of negatively charged molecules (known as Donnan equilibrium). At the same time, the lack of channels in the gel leads to exclusion by size: SBTI (181 amino acids / 20 kDa) is too large to penetrate the gel, while peptides penetrate the swollen hydrogel much more slowly than water by diffusion, which results in excess water in the interior relative to the near-surface area. In vivo results are shown in Figure 5A-5B and 6. The oral bioavailability of all samples was compared with the hydrogel content, and the results showed that the bioavailability of 300 mg hydrogel was increased by 2.5 times compared with that of the anhydrous gel, as shown in Fig. 7A As shown ( Figure 7B Another visualization of the same data is provided as a line graph with error bars, including a data point for 450 mg of hydrogel).

[0170] Example 2C

[0171] This example illustrates the results for some representative active agents with different ionic charges. Taking hydrogel #3.02 as an example, since the hydrogel has a net anionic charge, drugs with a net anionic charge can be effectively expelled from the swollen hydrogel, while drugs with a net cationic charge are likely to be trapped inside ( Figure 8 ).

[0172] Anionic surfactant

[0173] Exenatide

[0174] Exenatide (exenadine acetate) is an FDA-approved therapeutic peptide with a molecular weight of 4,187 g / mol and a net negative charge above pH 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 about 80% of the liquid was absorbed after 25 minutes. After multiple repetitions, the exenatide concentration in the external liquid was 1.75-2 mg / mL after 25 minutes as determined by UV absorbance, indicating that some of the peptide was expelled from the hydrogel.

[0175] Sodium Decanoate

[0176] Sodium decanoate (sodium salt of decanoic acid) is a known intestinal permeation enhancer with a negative charge (negative charge on the decanoate salt). Sodium decanoate (280 mg) was dissolved in 5 mL of modified FASSIF buffer at pH 7. Hydrogel #3.02 (300 mg) was added and about 80% of the liquid was absorbed. After multiple repetitions, the concentration of decanoate in the external liquid was determined by UV absorbance to be 1.4 times the initial concentration before the addition of the hydrogel, indicating that some decanoate was expelled from the hydrogel.

[0177] Exenatide plus sodium decanoate

[0178] Similar to the above experiment, exenatide (5 mg) was dissolved in 5 mL of modified FASSIF buffer at pH 7. Sodium decanoate (280 mg), an intestinal permeation enhancer, was added. Hydrogel #3.02 (300 mg) was added and absorbed about 80% of the liquid. After multiple repetitions, the exenatide concentration in the external liquid was determined by UV absorbance to be 1.6 mg / mL, demonstrating that part of the peptide was expelled from the hydrogel in the presence of sodium decanoate.

[0179] Cationic surfactant

[0180] Octreotide

[0181] Octreotide (octreotide acetate) is an FDA-approved therapeutic peptide with a molecular weight of 1019 g / mol and a net positive charge below pH 8 (isoelectric point of octreotide = 8.5). Octreotide (5 mg) was dissolved in 5 mL of modified FASSIF buffer at pH 7 (initial concentration was 1 mg / mL). Hydrogel #3.02 (300 mg) was added and approximately 80% of the liquid was absorbed. After multiple repetitions, the octreotide concentration in the external liquid measured by UV absorbance after 10 minutes was less than 0.8 mg / mL, indicating that the peptide was bound to the hydrogel (rather than expelled).

[0182] Lanreotide (in FASSIF)

[0183] Lanreotide is an FDA-approved therapeutic peptide with a molecular weight of 1096 g / mol and a net positive charge below 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 about 80% of the liquid was absorbed after 25 minutes. After multiple repetitions, the lanreotide concentration in the external liquid was determined by UV absorbance after 25 minutes to be ~0.3 mg / mL, indicating that the peptide was bound to the hydrogel (rather than expelled).

[0184] Lanreotide (in DI water)

[0185] Lanreotide is an FDA-approved therapeutic peptide with a molecular weight of 1096 g / mol and a net positive charge at pH below 8. Lanreotide (5 mg) was dissolved in 5 mL of deionized water. Hydrogel #3.02 (300 mg) was added and approximately 80% of the liquid was absorbed within 25 minutes. After multiple repetitions, the lanreotide concentration in the external liquid was less than 0.05 mg / mL after 25 minutes as measured by UV absorbance, indicating that the peptide was bound to the hydrogel (rather than expelled).

[0186] Example 3

[0187] This example provides data on the levels of peptides present on the outside of a hydrogel when combined with a protease and hydrogel in a liquid such as water, as well as the measured activity of the proteases (chymotrypsin, trypsin) when bound to the hydrogel.

[0188] The level of protease was determined using a protease activity assay. The protease activity of proteases comprising chymotrypsin or trypsin was determined using α-chymotrypsin (CAS: 9004-07-3) or type 1 trypsin (CAS: 9002: 07-7). A chymotrypsin activity assay kit available from Abcam was used, which included a coumarin substrate, a chymotrypsinogen activator, and a chymotrypsin assay buffer ("cTAB"). A trypsin activity assay kit available from Abcam was also used, which included a p-NA substrate and a trypsin assay buffer ("TAB"). The material used for the assay also included a Tris solution at pH 7.4 and containing 0.5 mM Ca.

[0189] To prepare for the protease activity assay of chymotrypsin, the following steps were performed: aliquots of 75 mg of hydrogel (e.g., hydrogel #3.02 described in Example 1) were loaded into labeled 15 mL tubes; an additional 15 mL tube was labeled as a control; aliquots of the reaction solution were generated by combining 46 μl of cTAB, 2 μl of coumarin substrate, and 2 μl of chymotrypsinogen activator (according to the instructions of the Abcam assay kit) in each aliquot (e.g., to provide 4 time points, n=3, all samples, 2 tubes = 24 aliquots were required in total, so the total solution was 1104 μl of cTAB, 48 μl of coumarin substrate, and 2 μl of chymotrypsinogen activator). and 48 microliters of chymotrypsinogen activator); vortex the reaction solution to mix; for one aliquot, generate a sample background control (SBC) solution by combining 48 microliters of cTab and 2 microliters of chymotrypsinogen activator (e.g., according to the instructions of the Abcam assay kit) (e.g., 4 time points are provided = 4 aliquots are required, so the total solution is 192 microliters of cTab and 8 microliters of chymotrypsinogen activator); vortex the solution to mix; and generate a 10 μg / mL chymotrypsin solution in tris buffer containing 0.5 mM calcium (e.g., 15 mL total solution for testing, 5 mL per tube). The method of the chymotrypsin activity assay includes adding 5 mL of chymotrypsin solution in tris buffer containing calcium to each sample tube containing dry hydrogel and an empty control tube, starting a timer and mixing with a spatula to break up any hydrogel as needed. The tubes are then incubated at 150 RPM and 39°C. Samples were taken from each test tube at each time point (5, 15, 30 and 60 minutes) by the following steps: 10 microliters were taken from each test tube and mixed into 50 microliters of the above reaction solution, n=3 tubes, 6 samples for each time point. The samples were provided in the wells of a UV transparent flat bottom plate (such as a 96-well plate), and 50 microliters of the above SBC solution were provided in a single well as a mobile background. Fluorescence readings at 380 / 460nm were read in each sample well at each time point. For each time point and each tube of incubation, the three readings of a single output were averaged, and the SBC solution reading was subtracted from each average. For each average after subtracting the SBC solution reading, the activity of each incubation relative to the initial control reading was calculated.

[0190] To prepare for the protease activity assay of trypsin, the following steps were performed: the hydrogel (e.g., hydrogel #3.02 described in Example 1) was loaded into a 75 mg aliquot into a labeled 15 mL tube; an additional 15 mL tube was labeled as a control; aliquots of the reaction solution were generated by combining 48 microliters of TAB and 2 microliters of p-NA substrate (e.g., according to the Abcam assay kit) in each aliquot (e.g., to provide 4 time points, n=2, all samples, 3 tubes = a total of 26 aliquots are required, so the total solution is 1248 microliters of TAB and 52 microliters of p-NA substrate); the reaction solution was vortexed to mix; and a solution of 150 micrograms of trypsin per milliliter in tris was generated (e.g., according to the instructions of the Abcam assay kit), 5 mL per tube, a total of 15 mL. The method for the trypsin activity assay includes adding 5 mL of a trypsin solution in tris buffer to each sample tube containing dry hydrogel and an empty control tube, then starting a timer and mixing with a spatula to break up any hydrogel as needed. Then the tube is incubated at 150RPM and 39°C. Two 60 microlitre reaction solutions are placed in the individual wells of the plate as background. Samples are taken from each tube at each time point (5, 15, 30, 60 minutes). 50 microlitre samples are placed in 450 microlitre TABs and vortexed to mix. Then 10 microlitre solutions are taken out from each tube, and mixed into 50 microlitre above-mentioned reaction solutions. Samples are provided in the holes of UV transparent flat-bottom plates (e.g., 96-well plates). Fluorescence readings of 405nm in each sample well are read at each time point. For each time point and each tube of incubation, two readings of a single output are averaged, and the average value of the reaction solution background readings is subtracted from each average value. For each average value after subtracting background, the activity of each incubation relative to the initial control reading after subtracting background is calculated.

[0191] To determine the level of active agent present in the bulk of the liquid when combined with the hydrogel, 1 mg / mL of peptide C (a macromolecular hormone analog with multiple CO2H groups and a molecular weight between 4000-5000 g / mol, which is ionically chargeable at pH 4 to 8) was combined with 30 mg / mL of ionically chargeable hydrogel (hydrogel #3.02 described in Example 1) and a protease (chymotrypsin or trypsin) in a buffered liquid. The amount of peptide C in the liquid (i.e., outside the hydrogel) was determined by liquid chromatography-mass spectrometry at the initial data point and 30 minutes and 60 minutes after the initial data point.

[0192] like Figures 11A-11BAs shown, in vitro assays indicate that for combinations of hydrogels and peptide C, combinations of hydrogels and peptide C (where the hydrogel has a net ionic charge of the same sign as that of peptide C) maintain or even increase the concentration of the peptide over time, despite the presence of proteases that cause degradation of peptide C (see Fig. 11B (top panel, trypsin on the right and chymotrypsin on the left). Compared to the solution containing peptide C and protease but without hydrogel, the peptide levels showed a clear decrease over time.

[0193] In addition, if Fig. 11B As shown, the combination of peptide C with the hydrogel resulted in a decrease in overall protease activity (chymotrypsin and trypsin). In the absence of hydrogel, the activity levels of trypsin and chymotrypsin were relatively stable and even increased over time, but in the presence of the hydrogel, their activities were significantly reduced (see Fig. 11B Similarly, the results of testing ionically chargeable hydrogels with the same overall sign of net charge as trypsin showed that the hydrogels had less effect on trypsin activity, suggesting that the effect of reducing protease activity may be at least partially due to the opposite charge effect of ionically chargeable hydrogels with net ionic charge of opposite sign to the net ionic charge of the protease (see Fig. 11B (bottom image in Figure 2, trypsin on the right, labeled “wrongly charged”).

[0194] Example 4A

[0195] This example provides the formulation, preparation method and testing standards of another representative microparticle hydrogel (named hydrogel #12.035) according to the present invention. Fig.12 As shown, hydrogel #12.035 is a cross-linked copolymer containing two monomers (AMPS and styrene sulfonate) and a cross-linker (methylene bisacrylamide). Fig.12 The circled portion in the middle highlights the difference from hydrogel 3.02. Without being bound by any particular theory, the addition of styrene sulfonate (also known as vinylbenzene sulfonate) is intended to optimize the binding of chymotrypsin to the hydrogel by providing a hydrophobic region on the benzene ring to interact with the hydrophobic portion of chymotrypsin, thereby reducing the interaction of the active agent with chymotrypsin to inhibit its degradation.

[0196] Preparation of hydrogel 12.035

[0197] In a 200 mL glass beaker, the following were added to 40 g of deionized water (DI) at room temperature with stirring: 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 methylenebis(acrylamide) (BIS).

[0198] The solution was stirred until clear and the material was completely dissolved. While the material was stirred, an initiator solution containing the following ingredients was produced: ammonium persulfate (20% ammonium persulfate by mass in 80% DI) and N,N,N',N'-tetramethylethylenediamine (TEMED) (20% TEMED by mass in 80% DI).

[0199] After all solutions were clear and completely dissolved, a nitrogen (N2) tube was placed in the hydrogel solution and N2 was bubbled into 200 mL of the hydrogel solution for two minutes. After two minutes, with the N2 tube still present, 400 μL of ammonium persulfate solution was added to the beaker, followed by 400 μL of TEMED solution. The N2 tube was removed and the beaker was covered. The solution was polymerized and cured overnight.

[0200] After overnight curing, the hydrogel was removed from the beaker and broken into pieces less than 1 cm (sub-1 cm). The pieces were placed in a 2L beaker and 1800 mL of deionized water was added at room temperature with stirring. After 15 minutes, the pH of the mixture was measured. 1N HCI was added in small increments until the pH of the mixture reached about 7.0 (+ / -~0.1). It is expected that about 1.0-1.5 mL of HCl will be required. After the last HCl is added, the mixture is stirred for another 30 minutes. After 30 minutes, the excess deionized water in the swollen gel is drained and replaced with 1800 mL of fresh deionized water. The mixture is stirred for 30 minutes, then the liquid is drained and replaced. This process is repeated until a total of six washes are completed. After the last DI water wash, all excess water is drained and 500 mL of 100% isopropyl alcohol (IPA) is poured into the beaker containing the gel. The mixture is stirred for 30 minutes. After 30 minutes, drain the IPA, place the hydrated gel pieces in a tray, and place the tray in a 160°F oven overnight or until completely dry. Once the gel is completely dry, grind the gel microparticles using a microparticle mill or coffee grinder. Using a 63μm mesh screen, repeatedly screen the microparticles and re-grind any microparticles larger than 63μm.

[0201] Evans blue excretion method

[0202] 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 the presence of four sulfonate groups in its structure. Its visible light absorbance at 605 nm provides a simple way to monitor the concentration of the dye when exposed to hydrogels in solution.

[0203] FASSIF buffer was produced by adding 41.65 g of FASSIF buffer concentrate (Biorelevant Media, codenamed FaSSIF) to 961.1 g of DI water and stirring until thoroughly mixed. Evans blue solution was produced by adding Evans blue to approximately half of the FASSIF solution, resulting in a final concentration of 0.125 mg / mL Evans blue in the media.

[0204] 5mL Evans blue solution was added to a 15mL centrifuge tube (EB tube). 5mL FASSIF buffer (without Evans blue) was added to another 15mL tube (background tube). 200mg of hydrogel #12.035 with a particle size less than 63μm was added to two tubes. The tubes were vortexed until completely mixed, and then the two tubes were placed on a shaking plate for 15 minutes. After 15 minutes, the two tubes were centrifuged at 3000g for 1 minute. 20μL samples (N=3) were extracted from the supernatant of the two tubes and diluted to 180μL DI water in a 96-well UV transparent plate. Samples (20μL) (N=3) of 0.125mg / mL Evans blue solution (EB stock solution) and FASSIF buffer (FASSIF stock solution) were also added to 180μL DI water in the same plate. The absorbance of the plate was read at 605nm.

[0205] Average the absorbance readings for each set of samples. Calculate the concentration factor using the following formula:

[0206]

[0207] Fig.13 Results are provided showing the relative concentration of dye present in FASSIF buffer at pH 7 when varying amounts of hydrogel #12.035 are added sufficient to absorb a specific fraction of the liquid. For example, 200 mg absorbed approximately 80% of the liquid in 5 mL of the test liquid. Fig.13 It is clearly shown that as more hydrogel is added, the dye concentration increases. Each data point (40%, 60%, 80% and 90% liquid absorption) was tested multiple times and was statistically significant relative to the no hydrogel control (0% liquid absorption) using a two-tailed student t-test, p<0.001. The error bars shown are the standard error of the mean.

[0208] Example 4B

[0209] This example describes an in vivo protocol for hydrogel #12.035 and uses essentially the same methods as described above in Example 2A.

[0210] Oral capsule administration

[0211] Beagle dogs (same animals as for subcutaneous administration; n=8) were fasted overnight (~12 hours) before dosing. To stimulate gastric secretion, each animal received an intramuscular injection of 6 μg / kg pentagastrin approximately 30 minutes before dosing. After 6 hours of sample collection, feeding was resumed. Oral administration of capsules was followed by 10 mL saline rinse. Blood samples were collected before dosing 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 commercial aprotinin solution and 1.3 μL of commercial dipeptidyl peptidase 4 (DPP IV) inhibitor. After adding the whole blood sample, the blood tube was vortexed to mix. The sample tubes were stored on wet ice until processed into plasma by centrifugation (3500 rpm, 5°C, 10 minutes) within 30 minutes after collection. Plasma samples were transferred into matrix tubes and stored at a nominal temperature of −70°C until shipped to a contract laboratory for analysis of the presence of proprietary peptides.

[0212] The capsules were 00EL size gelatin capsules with an enteric coating 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.

[0213] Subcutaneous administration to calculate oral bioavailability

[0214] Beagles (same animals as for capsule administration; n=8) were fasted overnight (~12 hours) prior to dosing. After 6 hours of sample collection, feeding was resumed. A 0.5 mg / mL subcutaneous dosing solution was prepared in 40 mM Tris buffer at pH 8 using the proprietary peptide under study. The dosing formulation was prepared by adding pre-weighed drug to an appropriate amount of vehicle to achieve the specified dose concentration. The vehicle used for the formulation was pre-filtered prior to use. All dosing syringes were weighed before and after dosing to determine the amount of formulation administered by gravimetric analysis, delivering ~0.02 mL / kg, with a final drug dose of 0.01 mg / kg.

[0215] Blood samples were collected before dosing and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 and 24 hours after dosing. Blood samples were collected by cephalic venipuncture 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 adding the whole blood sample, the blood tube was vortexed to mix. The sample tubes were stored on wet ice until processed into plasma by centrifugation (3500 rpm, 5°C, 10 minutes) within 30 minutes of collection. The plasma samples were transferred to matrix tubes and stored at a nominal temperature of -70°C until shipped to the contract laboratory for analysis of the presence of proprietary peptides.

[0216] Bioavailability calculation

[0217] Oral bioavailability was calculated by measuring the area under the drug concentration curve (AUC) from the time of administration to 24 hours after administration for oral and subcutaneous administration. The percent bioavailability was calculated by determining the ratio of the oral AUC to the subcutaneous AUC, corrected for the mg / kg dose per animal per route of administration, and then multiplied by 100%.

[0218] result

[0219] like Fig.14 As shown, the oral bioavailability of the hydrogel formulation was superior to the control, p = 0.03 in a two-tailed student t-test. The error bars shown are the standard error of the mean.

[0220] Example 5

[0221] This example directly compares two hydrogels disclosed herein: hydrogel #12.035 and hydrogel #3.02. The experimental protocol for this in vitro test is summarized as follows: Concentrations in a total volume of 5 mL of test fluid are summarized

[0222] Peptide C 3mg / mL

[0223] Type II bovine pancreatic α-chymotrypsin lyophilized powder (Sigma) 10 μg / mL

[0224] Hydrogel #12.035 or 3.02, 40 mg / mL (~80% of liquid)

[0225] Incubation composition

[0226] 200 mg hydrogel (0 mg hydrogel in control)

[0227] 1.67 mL buffer

[0228] 1.67mL drug stock solution

[0229] 1.67 mL Chymotrypsin stock solution

[0230] Stock solution

[0231] Buffer: Tris-Ca tris-buffered saline + 0.5 mM calcium chloride

[0232] Peptide C 3 mg / mL in Tris-Ca

[0233] Chymotrypsin 30 μg / mL in Tris-Ca

[0234] Stop solution 0.1 mg / mL soybean trypsin inhibitor (Sigma) in Tris-Ca

[0235] Detailed Methods

[0236] Each solution was preheated to 45°C (chymotrypsin solution was kept at room temperature) and placed in separate 15 mL centrifuge tubes.

[0237] The solution was mixed manually with a spatula to break up the hydrogel and vortexed.

[0238] The tubes were placed in an incubator at 150 RPM and 45° C. 45° C was chosen because the sampling time outside the incubator was relatively long, which would keep the sample temperature fairly close to 37° C.

[0239] Sampling methods at each time point:

[0240] The tube was centrifuged and pulsed to 3000 G;

[0241] Take 20 μL of sample from each tube and dilute it with 480 μL of stop solution;

[0242] Take 20 μL of each diluted sample and dilute it in another 480 μL of stop solution;

[0243] 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;

[0244] The tubes were manually mixed and vortexed using a spatula and returned to the incubator;

[0245] Peptide C in thawed samples was analyzed by HPLC-MS. The values ​​shown for peptide C represent the concentration detected in the final stop solution sample ( Fig.15 ). In vitro data showed that hydrogel #12.035 had better therapeutic potential than hydrogel #3.02.

[0246] The embodiments listed below are provided to illustrate various aspects of the present disclosure, but the embodiments are not intended to be limiting, and other aspects and / or embodiments may also be provided.

[0247] Embodiment 1: A pharmaceutically acceptable oral dosage form for delivering an active agent to an intestinal site, the dosage form comprising:

[0248] A delivery device, the delivery device comprising:

[0249] a plurality of hydrogel microparticles comprising an ionically chargeable hydrogel material comprising a cross-linked polymer material having a swelling ratio of at least 5 in deionized water; and

[0250] an ionically chargeable active agent having a net ionic charge having 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; and

[0251] A protective coating covers the delivery device.

[0252] Embodiment 2: The dosage form according to embodiment 1, wherein the cross-linked polymer material has a swelling ratio 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 measured in deionized water.

[0253] Embodiment 3: A dosage form according to any of the preceding embodiments, wherein the cross-linked polymer material 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 and / or 100 or more measured in fasting state simulated intestinal fluid (FASSIF).

[0254] Embodiment 4: The dosage form according to any one of the preceding embodiments, wherein the ionically chargeable hydrogel material comprises a plurality of ionically chargeable functional groups.

[0255] Embodiment 5: The dosage form according to any one 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.

[0256] Embodiment 6: The dosage form according to any one of embodiments 1-4, wherein the ionically chargeable hydrogel material comprises a plurality of ionically chargeable functional groups having a net anionic charge at intestinal pH.

[0257] Embodiment 7: The dosage form according to 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.

[0258] Embodiment 8: The dosage form according to any one of embodiments 1-5, wherein the ionically chargeable hydrogel material and the ionically chargeable active agent both have a net cationic charge at intestinal pH.

[0259] Embodiment 9: The dosage form according to any one of embodiments 1-4, 6 and 7, wherein the ionically chargeable hydrogel material and the ionically chargeable active agent both have a net anionic charge at intestinal pH.

[0260] Embodiment 10: The dosage form according to any one of the preceding embodiments, wherein the ionically chargeable active agent comprises a plurality of ionically chargeable groups.

[0261] Embodiment 11: A 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.

[0262] Embodiment 12: The 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 after 10 minutes of dispersion in water is at least 20% higher than the same dosage form without the crosslinked polymer after dispersion in water for the same period of time.

[0263] Embodiment 13: The 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 after 30 minutes of dispersion in water is at least 50% higher than the same dosage form without the crosslinked polymer after the same time of dispersion in water.

[0264] Embodiment 14: The 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 after 60 minutes of dispersion in water is at least 100% higher than the same dosage form without the crosslinked polymer after dispersion in water for the same period of time.

[0265] Embodiment 15: The 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 after 90 minutes of dispersion in water is at least 200% higher than the same dosage form without the crosslinked polymer after dispersion in water for the same period of time.

[0266] Embodiment 16: The 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 after 120 minutes of dispersion in water is up to 300% higher than the same dosage form without the crosslinked polymer after dispersion in water for the same period of time.

[0267] Embodiment 17: A dosage form according to any of the preceding embodiments, wherein the cross-linked 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.

[0268] Embodiment 18: The dosage form according to any of the preceding embodiments, wherein the cross-linked polymer 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.

[0269] Embodiment 19: A dosage form according to any of the preceding embodiments, wherein the cross-linked 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.

[0270] Embodiment 20: The dosage form according to any one of the preceding embodiments, wherein the crosslinked polymer material and the ionically chargeable active agent have a net ionic charge of the same sign at pH 2.

[0271] Embodiment 21: The dosage form according to any one of the preceding embodiments, wherein the crosslinked polymer material and the ionically chargeable active agent have a net ionic charge of the same sign at pH 5.

[0272] Embodiment 22: The dosage form according to any one of the preceding embodiments, wherein the crosslinked polymer material and the ionically chargeable active agent have a net ionic charge of the same sign at pH 6.

[0273] Embodiment 23: The dosage form according to any one of the preceding embodiments, wherein the crosslinked polymer material and the ionically chargeable active agent have a net ionic charge of the same sign at pH 7.

[0274] Embodiment 24: A dosage form according to any of the preceding embodiments, wherein when the cross-linked polymer material is exposed to an aqueous liquid containing an ionically chargeable active agent, the ratio of the fraction of ionically chargeable active agent absorbed in the cross-linked polymer material to the fraction of water absorbed in the cross-linked polymer is from 0.1:1 to 0.7:1.

[0275] Embodiment 25: The dosage form according to any one of the preceding embodiments, further comprising a penetration enhancer.

[0276] Embodiment 26: The dosage form according to embodiment 25, wherein the permeation enhancer has one or more ionically chargeable groups, and wherein the cross-linked 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 ranging from 4 to 8.

[0277] Embodiment 27: The dosage form according to any one of embodiments 25-26, wherein the cross-linked polymer 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.

[0278] Embodiment 28: The dosage form according to any one of embodiments 25-26, wherein the cross-linked polymer 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.

[0279] Embodiment 29: The dosage form according to any one of embodiments 25-26, wherein the cross-linked polymer 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.

[0280] Embodiment 30: The dosage form according to any one 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 the cross-linked polymer material and less than 1 g of the cross-linked polymer material.

[0281] Embodiment 31: A dosage form according to any of the preceding embodiments, wherein the cross-linked polymer material accounts for 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% of the weight of the dosage form.

[0282] Embodiment 32: A dosage form according to any of the preceding embodiments, wherein the ratio of the mass of cross-linked polymer 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.

[0283] Embodiment 33: A dosage form according to any of the preceding embodiments, wherein the cross-linked polymer material contains ionically chargeable moieties on 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 99.9% of the monomers comprising the polymer.

[0284] Embodiment 34: A dosage form according to any of the preceding embodiments, wherein the cross-linked polymer material contains negatively chargeable moieties on 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 99.9% of the monomers comprising the polymer.

[0285] Embodiment 35: A dosage form according to any one of embodiments 1-33, wherein the cross-linked polymer material contains positively chargeable moieties on 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 99.9% of the monomers comprising the polymer.

[0286] Embodiment 36: A dosage form according to embodiment 34, wherein the cross-linked polymer material contains carboxylate structural moieties on 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 99.9% of the monomers comprising the polymer.

[0287] Embodiment 37: A dosage form according to embodiment 34, wherein the cross-linked polymer material contains phosphate structural moieties on 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 99.9% of the monomers comprising the polymer.

[0288] Embodiment 38: A dosage form according to embodiment 34, wherein the cross-linked polymer material contains sulfonate structural moieties or sulfate structural moieties on 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 99.9% of the monomers comprising the polymer.

[0289] Embodiment 39: The dosage form according to embodiment 38, wherein the 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 cross-linked polymer material.

[0290] Embodiment 40: A dosage form according to any preceding claim, wherein the cross-linked polymer material comprises a residue of 2-acrylamido-2-methylpropanesulfonic acid or a pharmaceutically acceptable salt thereof.

[0291] Embodiment 41: The dosage form according to embodiment 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 cross-linked polymer material comprises residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharmaceutically acceptable salt thereof.

[0292] Embodiment 42: The dosage form according to any one of the preceding embodiments, wherein the cross-linked polymer comprises a cross-linking agent comprising a residue of methylenebisacrylamide or a pharmaceutically acceptable salt thereof.

[0293] Embodiment 43: The dosage form according to embodiment 42, wherein 0.2 wt% to 20 wt% of the cross-linked polymeric material comprises a residue of methylenebisacrylamide or a pharmaceutically acceptable salt thereof.

[0294] Embodiment 44: The dosage form according to embodiment 43, wherein 1 wt% to 5 wt% of the cross-linked polymeric material comprises a residue of methylenebisacrylamide or a pharmaceutically acceptable salt thereof.

[0295] Embodiment 45: The dosage form according to any one of the preceding embodiments, wherein the cross-linked polymer material comprises a residue of 4-vinylbenzenesulfonic acid or a pharmaceutically acceptable salt thereof.

[0296] Embodiment 46: A dosage form according to embodiment 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 cross-linked polymer material comprises residues of 4-vinylbenzenesulfonic acid or a pharmaceutically acceptable salt thereof.

[0297] Embodiment 47: A dosage form according to any one of the preceding embodiments, wherein the cross-linked polymer material comprises residues of 4-vinylbenzenesulfonic acid or a pharmaceutically acceptable salt thereof and residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharmaceutically acceptable salt thereof in a weight ratio ranging from 0.25:1 to 1:0.25, 0.5:1 to 1:0.5 or 0.75:1 to 1:0.75.

[0298] Embodiment 48: The dosage form according to any one of the preceding embodiments, wherein the ionically chargeable cross-linked polymer material comprises carboxylate and / or carboxylic acid groups.

[0299] Embodiment 49: The dosage form according to any of the preceding embodiments, wherein prior to administration to a patient, the hydrogel microparticles contain less than 10% by weight of ionically chargeable active agent in the interior dosage form volume occupied by the hydrogel microparticles.

[0300] Embodiment 50: The dosage form according to any one of the preceding embodiments, comprising a capsule form.

[0301] Embodiment 51: The dosage form according to any one of the preceding embodiments, comprising a tablet form.

[0302] Embodiment 52: The dosage form according to any one of the preceding embodiments, wherein the protective coating comprises an enteric coating to release the ionically chargeable active agent in the small intestine.

[0303] Embodiment 53: The dosage form according to any one of the preceding embodiments, wherein the protective coating comprises a sustained release coating.

[0304] Embodiment 54: The dosage form according to any one of the preceding embodiments, comprising a capsule coated with an enteric coating.

[0305] Embodiment 55: The dosage form according to any one of the preceding embodiments, wherein the cross-linked polymer material comprises negatively chargeable functional groups having a pKa of less than 5 in deionized water at a pH of about 7.

[0306] Embodiment 56: The dosage form according to any one of the preceding embodiments, wherein the cross-linked polymer material comprises negatively chargeable functional groups having a pKa of less than 3 in deionized water at a pH of about 7.

[0307] Embodiment 57: A dosage form according to 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 99.9% of the monomers of the cross-linked polymer material contain negatively chargeable functional groups having a pKa of less than 5 in deionized water at a pH of about 7.

[0308] Embodiment 58: A dosage form according to 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 99.9% of the monomers of the cross-linked polymer material comprise negatively chargeable functional groups having a pKa of less than 3 in deionized water at a pH of about 7.

[0309] Embodiment 59: A method for treating or ameliorating the effects of a disorder in a subject, comprising administering to the subject an effective amount of a dosage form according to any one of the preceding embodiments.

[0310] Embodiment 60: A dosage form or method according to any one of the preceding embodiments, wherein the ionically chargeable hydrogel material reduces the activity of one or more proteases in a region of the intestinal tract.

[0311] Embodiment 61: A dosage form or method according to any of the preceding embodiments, wherein the one or more proteases carry a net ionic charge, the sign of which is opposite 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.

[0312] Embodiment 62: 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 by at least 15%, at least 20%, at least 25%, at least 30%, at least 45%, at least 50% over a time interval of 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 60 minutes, as determined by a protease activity assay.

[0313] Embodiment 63: A dosage form or method according to any one of the preceding embodiments, wherein the delivery device comprising the ionically chargeable hydrogel material maintains or increases the concentration of the active agent at the intestinal site in the presence of a protease relative to a delivery device not containing the ionically chargeable hydrogel material.

[0314] Embodiment 64: The 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 active agent concentration in an active agent concentration assay in the presence of a protease over a time interval of at least 20 minutes, at least 40 minutes, or at least 60 minutes.

[0315] Embodiment 65: A dosage form or method according to any of the preceding embodiments, wherein over a time interval of at least 20 minutes, at least 40 minutes, or at least 60 minutes, the concentration of the active agent provided by a delivery device having an ionically chargeable hydrogel material is higher than the concentration of the active agent provided by a delivery device not having an ionically chargeable hydrogel material, as determined by an active agent concentration assay.

[0316] Embodiment 66: The dosage form or method of Embodiment 64, wherein the protease is alpha-chymotrypsin, type 1 trypsin, or a combination thereof.

[0317] Embodiment 67: A dosage form or method according to any one of the preceding embodiments, wherein the hydrogel microparticles have a mesh size ranging from 0.05 mm to 2 mm, and / or from 0.5 mm to 2 mm.

[0318] Embodiment 68: A dosage form or method according to any one of the preceding embodiments, wherein the hydrogel microparticles are capable of passing through a 63 micron mesh.

[0319] Embodiment 69: The dosage form or method of any one of the preceding embodiments, wherein the dosage form comprises an active agent that is susceptible to degradation by proteases in the intestinal tract.

[0320] Embodiment 70: A hydrogel comprising an ionically chargeable cross-linked polymer material, wherein the cross-linked polymer material comprises (i) at least 10 weight percent of residues of 4-vinylbenzenesulfonic acid or a pharmaceutically acceptable salt thereof, (ii) at least 10 weight percent of residues of 2-acrylamide-2-methylpropanesulfonic acid or a pharmaceutically acceptable salt thereof, and (iii) 0.2 weight percent to 20 weight percent of a cross-linker comprising residues of methylenebisacrylamide or a pharmaceutically acceptable salt thereof, wherein the weight ratio of the residues of 4-vinylbenzenesulfonic acid or a pharmaceutically acceptable salt thereof to the residues of 2-acrylamide-2-methylpropanesulfonic acid or a pharmaceutically acceptable salt thereof is in the range of 0.25:1 to 1:0.25.

[0321] Embodiment 71: The hydrogel according to embodiment 70, wherein at least 15%, at least 20%, at least 30%, at least 45% or at least 50% by weight of the cross-linked polymer material comprises residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharmaceutically acceptable salt thereof.

[0322] Embodiment 72: The hydrogel according to any one of embodiments 70-71, wherein no more than 90%, 80%, 70%, 60%, 55%, 50%, 45%, 30% or 20% by weight of the cross-linked polymer material comprises residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharmaceutically acceptable salt thereof.

[0323] Embodiment 73: The hydrogel according to any one of embodiments 70-72, wherein 0.2 wt% to 20 wt% of the cross-linked polymeric material comprises the residue of methylenebisacrylamide or a pharmaceutically acceptable salt thereof.

[0324] Embodiment 74: The hydrogel according to any one of Embodiments 70-73, wherein 1 wt% to 5 wt% of the cross-linked polymeric material comprises the residue of methylenebisacrylamide or a pharmaceutically acceptable salt thereof.

[0325] Embodiment 75: The hydrogel according to any one of embodiments 70-74, wherein at least 15%, at least 20%, at least 30%, at least 45% or at least 50% by weight of the cross-linked polymeric material comprises residues of 4-vinylbenzenesulfonic acid or a pharmaceutically acceptable salt thereof.

[0326] Embodiment 76: The hydrogel according to any one of Embodiments 70-75, wherein no more than 90%, 80%, 70%, 60%, 55%, 50%, 45%, 30% or 20% by weight of the cross-linked polymer material comprises residues of 4-vinylbenzenesulfonic acid or a pharmaceutically acceptable salt thereof.

[0327] Embodiment 77: A hydrogel according to any one of embodiments 70-76, wherein the cross-linked polymer material comprises residues of 4-vinylbenzenesulfonic acid or a pharmaceutically acceptable salt thereof and residues of 2-acrylamide-2-methylpropanesulfonic acid or a pharmaceutically acceptable salt thereof, and their weight ratio is in the range of 0.5:1 to 1:0.5 or 0.75:1 to 1:0.75.

[0328] Embodiment 78: A hydrogel according to any one of Embodiments 70-77, wherein the cross-linked polymer material has a swelling ratio 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 measured in deionized water.

[0329] Embodiment 79: A hydrogel according to any one of embodiments 70-78, wherein the cross-linked polymer material 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 and / or 100 or more measured in fasting state simulated intestinal fluid (FASSIF).

[0330] Embodiment 80: The hydrogel according to any one of embodiments 70-79, wherein the ionically chargeable hydrogel material comprises a plurality of ionically chargeable functional groups having a net anionic charge at intestinal pH.

[0331] Embodiment 81: A hydrogel according to any one of Embodiments 70-80, wherein the cross-linked polymer material swells 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 deionized water.

[0332] Embodiment 82: The hydrogel according to any one of Embodiments 70-81, wherein the cross-linked polymer material swells 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 FASSIF.

[0333] Embodiment 83: A hydrogel according to any one of Embodiments 70-82, wherein the cross-linked 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.

[0334] Embodiment 84: The hydrogel according to any one of embodiments 70-83, wherein the cross-linked polymer material has a net negative ionic charge at pH 2.

[0335] Embodiment 85: The hydrogel according to any one of embodiments 70-84, wherein the cross-linked polymer material has a net negative ionic charge at pH 5.

[0336] Embodiment 86: The hydrogel according to any one of embodiments 70-85, wherein the cross-linked polymer material has a net negative ionic charge at pH 6.

[0337] Embodiment 87: The hydrogel according to any one of embodiments 70-86, wherein the cross-linked polymer material has a net anionic charge at pH 7.

[0338] Embodiment 88: A hydrogel according to any one of embodiments 70-87, wherein the cross-linked polymer material contains negatively chargeable moieties on 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 99.9% of the monomers comprising the polymer.

[0339] Embodiment 89: A hydrogel according to any one of embodiments 70-88, wherein the cross-linked polymer material contains sulfonate or sulfate structural moieties on 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 99.9% of the monomers comprising the polymer.

[0340] Embodiment 90: The hydrogel according to any one of embodiments 70-89, 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 cross-linked polymer material.

[0341] Embodiment 91: The hydrogel according to any one of Embodiments 70-90, wherein the ionically chargeable cross-linked polymer is in the form of hydrogel microparticles having a mesh size ranging from 0.05 mm to 2 mm and / or from 0.5 mm to 2 mm.

[0342] Embodiment 92: A hydrogel according to any one of embodiments 70-91, 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 99.9% of the monomers of the cross-linked polymer material contain negatively chargeable functional groups having a pKa of less than 5 in deionized water at a pH of about 7.

[0343] Embodiment 93: A hydrogel according to any one of embodiments 70-92, 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 99.9% of the monomers of the cross-linked polymer material contain negatively chargeable functional groups having a pKa of less than 3 in deionized water at a pH of about 7.

[0344] Embodiment 94: A hydrogel according to any one of embodiments 70-93, 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%, at least 50% over a time interval of 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 60 minutes, as determined by a protease activity assay.

[0345] Embodiment 95: The hydrogel according to any one of embodiments 70-94, wherein the ionically chargeable hydrogel material maintains or increases the active agent concentration in an active agent concentration assay in the presence of a protease over a time interval of at least 20 minutes, at least 40 minutes, or at least 60 minutes.

[0346] Embodiment 96: The hydrogel according to any one of embodiments 70-95, wherein the hydrogel is in the form of hydrogel microparticles capable of passing through a 63 micron mesh.

[0347] Embodiment 97: The dosage form according to any one of embodiments 1-69, comprising the hydrogel according to any one of embodiments 70-96.

[0348] Embodiment 98: A method of treatment according to any one of embodiments 59-69, comprising administering a dosage form according to any one of embodiments 1-69 and 97, said dosage form comprising a hydrogel according to any one of embodiments 70-96.

[0349] Incorporation by reference

[0350] All patents and patent application publications described herein are incorporated by reference in their entirety for all purposes to the same extent as if each individual patent and / or patent application publication was specifically and individually incorporated by reference. In the event of a conflict, the present application, including any definitions herein, will control.

[0351] Equivalents

[0352] Although specific embodiments have been discussed, the above description is illustrative and not restrictive. Many variations will become apparent to those skilled in the art after reading this description. The full scope of the embodiments should be determined by reference to the full scope of the claims and their equivalents and the description and such variations.

Claims

1. A pharmaceutically acceptable oral dosage form for delivering an active agent to an intestinal site, the dosage form comprising: A delivery device, the delivery device comprising: a plurality of hydrogel microparticles comprising an ionically chargeable hydrogel material comprising a cross-linked polymer material having a swelling ratio of at least 5 in deionized water; and an ionically chargeable active agent having a net ionic charge having 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; and A protective coating covers the delivery device.

2. The dosage form according to claim 1, wherein the cross-linked polymer material has a swelling ratio 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 measured in deionized water.

3. The dosage form according to any of the preceding claims, wherein the cross-linked polymer material 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 and / or 100 or more measured in fasting state simulated intestinal fluid (FASSIF).

4. A dosage form according to any one of the preceding claims, wherein the ionically chargeable hydrogel material comprises a plurality of ionically chargeable functional groups.

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

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

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

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

11. The dosage form according to any of the preceding claims, 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. A dosage form according to any one of the preceding claims, wherein when the dosage form is dispersed in water, the concentration of the ionically chargeable active agent after 10 minutes of dispersion in water is at least 20% higher than the same dosage form without the crosslinked polymer after the same period of time of dispersion in water.

13. The dosage form according to 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 30 minutes of dispersion in water is at least 50% higher than the same dosage form without the crosslinked polymer after the same period of time of dispersion in water.

14. The dosage form according to 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 60 minutes of dispersion in water is at least 100% higher than the same dosage form without the crosslinked polymer after the same period of time of dispersion in water.

15. The dosage form according to 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 90 minutes of dispersion in water is at least 200% higher than the same dosage form without the crosslinked polymer after dispersion in water for the same period of time.

16. The dosage form according to 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 the same dosage form without the crosslinked polymer after dispersion in water for the same period of time.

17. A dosage form according to any of the preceding claims, wherein the cross-linked polymer material swells 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 deionized water.

18. The dosage form according to any one of claims 1 to 16, wherein the cross-linked polymer material swells 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 FASSIF.

19. The dosage form according to any of the preceding claims, wherein the cross-linked 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.

20. A dosage form according to any one of the preceding claims, wherein the cross-linked polymeric material and the ionically chargeable active agent have a net ionic charge of the same sign at pH 2.

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

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

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

24. A dosage form according to any one of the preceding claims, wherein when the cross-linked polymer material is exposed to an aqueous liquid containing an ionically chargeable active agent, the ratio of the fraction of ionically chargeable active agent absorbed in the cross-linked polymer material to the fraction of water absorbed in the cross-linked polymer is from 0.1:1 to 0.7:

1.

25. A dosage form according to any one of the preceding claims, further comprising a penetration enhancer.

26. The dosage form according to claim 25, wherein the permeation enhancer has one or more ionically chargeable groups, and wherein the cross-linked 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. A dosage form according to any one of claims 25-26, wherein the cross-linked polymer 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. A dosage form according to any one of claims 25-26, wherein the cross-linked 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. The dosage form according to any one of claims 25-26, wherein the cross-linked 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. The dosage form according to any one of the preceding claims, comprising at least 50 mg, at least 100 mg, at least 200 mg, at least 300 mg, or at least 450 mg of the cross-linked polymeric material and less than 1 g of the cross-linked polymeric material.

31. A dosage form according to any of the preceding claims, wherein the cross-linked polymer material comprises 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. A dosage form according to any of the preceding claims, wherein the ratio of the mass of cross-linked polymer 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. A dosage form according to any of the preceding claims, wherein the cross-linked polymer material contains ionically chargeable moieties on 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 99.9% of the monomers comprising the polymer.

34. A dosage form according to any of the preceding claims, wherein the cross-linked polymer material contains negatively chargeable moieties on 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 99.9% of the monomers comprising the polymer.

35. A dosage form according to any one of claims 1-33, wherein the cross-linked polymer material contains positively chargeable moieties on 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 99.9% of the monomers comprising the polymer.

36. A dosage form according to claim 34, wherein the cross-linked polymer material contains carboxylate moieties on 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 99.9% of the monomers comprising the polymer.

37. A dosage form according to claim 34, wherein the cross-linked polymer material contains phosphate structural moieties on 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 99.9% of the monomers comprising the polymer.

38. A dosage form according to claim 34, wherein the cross-linked polymer material contains sulfonate moieties or sulfate moieties on 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 99.9% of the monomers comprising the polymer.

39. The dosage form according to claim 38, wherein the 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 cross-linked polymer material.

40. The dosage form according to any one of the preceding claims, wherein the cross-linked polymer material comprises the residue of 2-acrylamido-2-methylpropanesulfonic acid or a pharmaceutically acceptable salt thereof.

41. A dosage form according to 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 cross-linked polymeric material comprises residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharmaceutically acceptable salt thereof.

42. The dosage form according to any one of the preceding claims, wherein the cross-linked polymer comprises a cross-linking agent comprising a residue of methylenebisacrylamide or a pharmaceutically acceptable salt thereof.

43. The dosage form according to claim 42, wherein 0.2% to 20% by weight of the cross-linked polymeric material comprises the residue of methylenebisacrylamide or a pharmaceutically acceptable salt thereof.

44. The dosage form according to claim 43, wherein from 1% to 5% by weight of the cross-linked polymeric material comprises the residue of methylenebisacrylamide or a pharmaceutically acceptable salt thereof.

45. A dosage form according to any one of the preceding claims, wherein the cross-linked polymer material comprises the residue of 4-vinylbenzenesulfonic acid or a pharmaceutically acceptable salt thereof.

46. ​​A dosage form according to 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 cross-linked polymeric material comprises residues of 4-vinylbenzenesulfonic acid or a pharmaceutically acceptable salt thereof.

47. A dosage form according to any one of the preceding claims, wherein the cross-linked polymer material comprises residues of 4-vinylbenzenesulfonic acid or a pharmaceutically acceptable salt thereof and residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharmaceutically acceptable salt thereof in a weight ratio ranging from 0.25:1 to 1:0.25, 0.5:1 to 1:0.5 or 0.75:1 to 1:0.

75.

48. The dosage form according to any one of the preceding claims, wherein the ionically chargeable cross-linked polymer material comprises carboxylate and / or carboxylic acid groups.

49. A dosage form according to any preceding claim, wherein prior to administration to a patient, the hydrogel microparticles contain less than 10% by weight of ionically chargeable active agent in the internal dosage form volume occupied by the hydrogel microparticles.

50. The dosage form according to claim 40, wherein the hydrogel microparticles have a mesh size ranging from 0.05 mm to 2 mm, and / or from 0.5 mm to 2 mm.

51. A dosage form according to any one of the preceding claims, comprising a capsule form.

52. A dosage form according to any one of the preceding claims, comprising a tablet form.

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

54. A dosage form according to any one of the preceding claims, wherein the protective coating comprises a sustained release coating.

55. A dosage form according to any one of the preceding claims, comprising a capsule coated with an enteric coating.

56. The dosage form according to any one of the preceding claims, wherein the cross-linked polymer material comprises negatively chargeable functional groups having a pKa of less than 5 in deionized water at a pH of about 7.

57. The dosage form according to any one of the preceding claims, wherein the cross-linked polymer material comprises negatively chargeable functional groups having a pKa of less than 3 in deionized water at a pH of about 7.

58. A dosage form according to 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 99.9% of the monomers of the cross-linked polymeric material contain negatively chargeable functional groups having a pKa of less than 5 in deionized water at a pH of about 7.

59. A dosage form according to 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 99.9% of the monomers of the cross-linked polymeric material contain negatively chargeable functional groups having a pKa of less than 3 in deionized water at a pH of about 7.

60. 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 claim 1.

61. A dosage form or method according to any preceding claim, wherein the ionically chargeable hydrogel material reduces the activity of one or more proteases in a region of the intestinal tract.

62. A dosage form or method according to any of the preceding claims, wherein the one or more proteases have a net ionic charge having a sign opposite 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.

63. The dosage form or method according to any of the preceding claims, 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%, at least 50% over a time interval of 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 60 minutes, as determined by a protease activity assay.

64. A dosage form or method according to any one of the preceding claims, wherein the delivery device comprising the ionically chargeable hydrogel material maintains or increases the concentration of the active agent at the intestinal site in the presence of a protease relative to a delivery device not containing the ionically chargeable hydrogel material.

65. The dosage form or method according to claim 65, wherein the delivery device comprising an 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 over a time interval of at least 20 minutes, at least 40 minutes, or at least 60 minutes.

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

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

68. A dosage form or method according to any preceding claim, wherein the hydrogel microparticles have a mesh size ranging from 0.05 mm to 2 mm, and / or from 0.5 mm to 2 mm.

69. A dosage form or method according to any preceding claim, wherein the hydrogel microparticles are capable of passing through a 63 micron mesh.

70. A dosage form or method according to any preceding claim, wherein the dosage form comprises an active agent that is susceptible to degradation by proteases in the intestinal tract.

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

72. A hydrogel comprising an ionically chargeable cross-linked polymer material comprising (i) at least 10 weight percent residues of 4-vinylbenzenesulfonic acid or a pharmaceutically acceptable salt thereof, (ii) at least 10 weight percent residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharmaceutically acceptable salt thereof, and (iii) 0.2 weight percent to 20 weight percent of a cross-linker comprising residues of methylenebisacrylamide or a pharmaceutically acceptable salt thereof, wherein the weight ratio of residues of 4-vinylbenzenesulfonic acid or a pharmaceutically acceptable salt thereof to residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharmaceutically acceptable salt thereof is in the range of 0.25:1 to 1:0.

25.

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

74. The hydrogel according to any one of claims 72-73, wherein no more than 90%, 80%, 70%, 60%, 55%, 50%, 45%, 30% or 20% by weight of the cross-linked polymeric material comprises residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharmaceutically acceptable salt thereof.

75. The hydrogel according to any one of claims 72 to 74, wherein 0.2% to 20% by weight of the cross-linked polymeric material comprises the residue of methylenebisacrylamide or a pharmaceutically acceptable salt thereof.

76. The hydrogel according to any one of claims 72 to 75, wherein from 1% to 5% by weight of the cross-linked polymeric material comprises the residue of methylenebisacrylamide or a pharmaceutically acceptable salt thereof.

77. The hydrogel according to 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 cross-linked polymeric material comprises residues of 4-vinylbenzenesulfonic acid or a pharmaceutically acceptable salt thereof.

78. The hydrogel according to any one of claims 72-77, wherein no more than 90%, 80%, 70%, 60%, 55%, 50%, 45%, 30% or 20% by weight of the cross-linked polymeric material comprises residues of 4-vinylbenzenesulfonic acid or a pharmaceutically acceptable salt thereof.

79. The hydrogel according to any one of claims 72 to 78, wherein the cross-linked polymer material comprises residues of 4-vinylbenzenesulfonic acid or a pharmaceutically acceptable salt thereof and residues of 2-acrylamido-2-methylpropanesulfonic acid or a pharmaceutically 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.

80. The dosage form according to any one of claims 1-71, comprising the hydrogel according to any one of claims 72-79.

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

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