Oral drug dosage forms for colonic delivery, and their use and manufacturing methods.

Abstract

This disclosure relates, in some embodiments, to oral drug dosage forms configured to release a drug at a desired location within the colon of an individual. As provided in certain embodiments, the oral drug dosage form comprises a drug component containing an erosive material mixed with the drug, and a delay component not mixed with the drug, wherein the delay component is configured to prevent the release of the drug from the drug component until the oral drug dosage form reaches the colon of the individual after administration. In other embodiments, this disclosure relates to methods for designing the oral drug dosage forms described herein, methods for manufacturing them, such as using three-dimensional printing, and related therapeutic methods.

Description

[Technical Field]

[0001] This disclosure relates, in some embodiments, to oral drug dosage forms configured to release a drug at a desired location within the colon of an individual. In other embodiments, this disclosure relates to methods for designing oral drug dosage forms described herein, methods for manufacturing them, such as using three-dimensional printing, and related therapeutic methods. [Background technology]

[0002] Oral administration of pharmaceuticals offers convenience to many patients, including limiting doctor visits and avoiding more invasive drug delivery approaches such as injection or rectal administration. While the colon can be the site of treatment and / or drug delivery, its location near the end of the gastrointestinal tract complicates effective oral administration for colonic delivery. For example, ingested oral drug formulations must withstand the harsh pH conditions in the stomach, as well as the significantly different pH conditions downstream of the stomach, and the mechanical stresses applied throughout the digestive process before reaching the colon. The capabilities of conventional colon-targeted oral drug formulations differ in terms of specificity and obtainable release profiles. For example, some conventional colon-targeted oral drug formulations release the drug continuously throughout the gastrointestinal tract before the oral formulation reaches the colon. This results in reduced drug availability in the colon, limited applicability to the active agent that can be delivered, and an increased possibility of systemic side effects due to off-target drug release. Therefore, there remains a need in this field for oral drug formulations capable of precise colonic delivery. [Overview of the project]

[0003] In a particular embodiment, the Specified Provision provides an oral drug dosage form configured to release a drug at a desired location within the colon of an individual, the oral drug dosage form comprising a drug component comprising an erosive material mixed with the drug, and a delay component not mixed with the drug, the delay component configured to prevent the release of the drug from the drug component until the oral drug dosage form reaches the colon of the individual after administration, the delay component comprising a pH-based enteric component comprising an erosive material configured to be eroded at a predetermined pH value or higher.

[0004] In some embodiments, the retarding component further comprises an erosive retarding member, and the oral drug dosage form is configured such that the pH-based enteric coating member is eroded before the erosive retarding member. In some embodiments, the pH-based enteric coating member at least partially prevents erosion of the erosive retarding member, and the erosive retarding member at least partially prevents erosion of the drug component.

[0005] In some embodiments, the oral drug dosage form further comprises a second drug. In some embodiments, the second drug is mixed with a drug component. In some embodiments, the oral drug dosage form further comprises a second drug component comprising an erosive material mixed with the second drug, and the delay component is configured to prevent the release of the second drug from the second drug component until the oral drug dosage form reaches the colon of the individual after administration. In some embodiments, the delay component comprises a second erosive delay member, and the oral drug dosage form is configured such that a pH-based enteric coating member is eroded before the erosive delay member, the erosive delay member is eroded before the second drug component, the second drug component is eroded before the second erosive delay member, and the second erosive delay member is eroded before the drug component. In some embodiments, the pH-based enteric coating prevents at least partially the erosion of the erosion retarder, the erosion retarder prevents at least partially the erosion of the second drug component, the second drug component prevents at least partially the erosion of the second erosion retarder, and the second erosion retarder prevents at least partially the erosion of the drug component. In some embodiments, the erosive material of the erosion retarder and the erosive material of the second erosion retarder are the same. In some embodiments, the erosive material of the erosion retarder and the erosive material of the second erosion retarder are different.

[0006] In some embodiments, the oral drug dosage form further comprises a biodegradable portion. In some embodiments, the biodegradable portion is mixed with the erosive material of an erosive retarder. In some embodiments, the biodegradable portion is mixed with the drug component. In some embodiments, the retarder further comprises a biodegradable member containing the erosive material mixed with the biodegradable portion, and the oral drug dosage form is configured such that the pH-based enteric coating is eroded before the erosive retarder, the erosive retarder is eroded before the biodegradable member, and the biodegradable member is eroded before the drug component. In some embodiments, the pH-based enteric coating at least partially prevents erosion of the erosive retarder, the erosive retarder at least partially prevents erosion of the biodegradable member, and the biodegradable member at least partially prevents erosion of the drug component. In some embodiments, the biodegradable portion is digestible by one or more microorganisms present in the colon of an individual. In some embodiments, the biodegradable portion comprises one or more sugars. In some embodiments, the one or more sugars include one or more of the following: sucrose, glucose, xylose, fructose, maltose, galactose, pectin, galactomannan, dextran, inulin, chitosan, carrageenan, cellulose propionate acetate (CAP), peptidoglycan, gellan, xanthan gum, lentinan, psyllium polysaccharides, corn bran arabinoxylan, alginate, hyaluronic acid, fucoidan, shellac, agar, or maltodextrin. In some embodiments, the bacterial degradation member is a layer, and the layer has a thickness of about 0.1 mm to about 5 mm based on the direction of erosion. In some embodiments, the bacterial degradation member is about 10 mm 2 ~400mm 2 This includes the surface area exposed to gastrointestinal fluid in the individual.

[0007] In some embodiments, the retarding component does not include an erosive retarding member. In some embodiments, the erosive material of the pH-based enteric coated member comprises one or more of hypromellose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate propionate (CAP), poly(co-ethyl acrylate methacrylate), or polyvinyl acetate phthalate (PVAP). In some embodiments, the hypromellose acetate succinate is HPMCSLG / LF, HPMCSMG / MF, or HPMCSHG / LF. In some embodiments, the hydroxypropyl methylcellulose phthalate is HPMCPHP-50 or HPMCPHP-55. In some embodiments, the poly(co-ethyl acrylate methacrylate) is EudragitL100-55 or EudragitL100.

[0008] In some embodiments, the drug component includes a top surface, a bottom surface, and one or more sides, and the drug component is embedded in the delay component such that at least two of the top surface, bottom surface, or one or more sides are exposed to the gastrointestinal fluid of the solid by erosion of the delay component or in a manner thereof. In some embodiments, the oral drug dosage form does not include a shell.

[0009] In some embodiments, the oral drug dosage form further includes a shell that is not mixed with the drug, and the oral drug dosage form is configured such that the shell or a portion thereof, and a delaying member, prevent erosion of the drug component. In some embodiments, the direction of erosion of the delaying member and / or the drug component is based on the configuration of the shell.

[0010] In some embodiments, the oral drug dosage form further comprises a protease scavenger and / or a protease inhibitor. In some embodiments, the protease scavenger or protease inhibitor is mixed with a delay component or a portion thereof. In some embodiments, the protease scavenger or protease inhibitor is mixed with the erosive material of the erosive delay member.

[0011] In some embodiments, the oral drug dosage form is configured to release the drug in, near, or downstream of, one of the following: the cecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, or sigmoid colon. In some embodiments, at least 95% of the drug in the oral drug dosage form is released from the oral drug dosage form in the colon of the individual. In some embodiments, less than 2% of the drug in the oral drug dosage form is released from the oral drug dosage form outside the colon of the individual. In some embodiments, all of the drug in the oral drug dosage form is released from the oral drug dosage form in the colon of the individual.

[0012] In some embodiments, the drug component and / or delay component is in the form of one or more layers. In some embodiments, the pH-based enteric coating layer includes a top and bottom surface, the erosive delay component layer includes a top and bottom surface, the drug component layer includes a top and bottom surface, the bottom surface of the pH-based enteric coating layer is in contact with the top surface of the erosive delay component layer, and the bottom surface of the erosive delay component layer is in contact with the top surface of the drug component layer.

[0013] In some embodiments, the oral drug dosage form is configured to have two or more compartments, at least one of which contains a drug component and a delay component.

[0014] In some embodiments, the pH-based enteric coating is eroded at a pH value of approximately 5.5 or higher. In some embodiments, the pH-based enteric coating is a layer having a thickness of approximately 0.1 mm to approximately 5 mm, depending on the direction of erosion. In some embodiments, the pH-based enteric coating is approximately 10 mm 2 ~400mm 2This includes the surface area exposed to gastrointestinal fluid in the individual. In some embodiments, the outer surface of the oral drug dosage form includes a pH-based enteric coating and, optionally, a shell, before administration to the individual. In some embodiments, the pH-based enteric coating includes a thermoformable material. In some embodiments, the pH-based enteric coating is stearic acid, copolyvidone, polyvinylpyrrolidone-co-vinyl acetate, polyvinylpyrrolidone-polyvinyl acetate copolymer, crospovidone, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose or hypromellose, hydroxypropyl methylcellulose phthalate, methylcellulose, methacrylic acid copolymer, poly(methacrylate-co-ethyl acrylate), poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), poly(dimethylaminoethyl methacrylate-co-methacrylate ester), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonium ethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly(methacrylate-co-methyl methacrylate), poly(methacrylic acid- This material contains one or more of the following: co-ethyl acrylate, poly(methacrylate-co-methyl methacrylate), polyethylene oxide, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, KollicoatIR-polyvinyl alcohol, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, hydroxypropyl methylcellulose acetate succinate or hypromellose acetate succinate, methacrylate ester copolymer, ammonia alkyl methacrylate copolymer, ethylcellulose, polyvinyl acetate and polyvinylpyrrolidone, polyvinyl acetal diethylaminolactate, polyvinyl acetal diethylaminolactate, maltitol, lactose monohydrate, xylitol, isomalt, sucrose, glucose, dextran, or maltose.

[0015] In some embodiments, the pH-based enteric coating is eroded at a pH value of approximately 6.8 or higher. In some embodiments, the pH-based enteric coating is a layer having a thickness of approximately 0.1 mm to approximately 5 mm, depending on the direction of erosion. In some embodiments, the pH-based enteric coating is approximately 10 mm 2 ~400mm 2This includes the surface area exposed to gastrointestinal fluid in the individual. In some embodiments, the outer surface of the oral drug dosage form includes a pH-based enteric coating and, optionally, a shell, before administration to the individual. In some embodiments, the pH-based enteric coating includes a thermoformable material. In some embodiments, the pH-based enteric coating includes one or more of poly(methacrylic acid, methyl methacrylate), poly(methacrylic acid, methyl methacrylate), methyl acrylate, methyl methacrylate, and methacrylic acid. In some embodiments, the pH-based enteric coating includes one or more of EudragitL100, EudragitL12.5, EudragitL12.5P, EudragitL100-55, EudragitL30D, EudragitS100, EudragitS12.5, EudragitS12.5P, and EudragitFS30D.In some embodiments, the pH-based enteric coating is stearic acid, copolyvidone, polyvinylpyrrolidone-co-vinyl acetate, polyvinylpyrrolidone-polyvinyl acetate copolymer, crospovidone, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose or hypromellose, hydroxypropyl methylcellulose phthalate, methylcellulose, methacrylic acid copolymer, poly(methacrylate-co-ethyl acrylate), poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), poly(dimethylaminoethyl methacrylate-co-methacrylate ester), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonium ethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly(methacrylate-co-methyl methacrylate), poly(methacrylic acid- This material contains one or more of the following: co-ethyl acrylate, poly(methacrylate-co-methyl methacrylate), polyethylene oxide, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, KollicoatIR-polyvinyl alcohol, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, hydroxypropyl methylcellulose acetate succinate or hypromellose acetate succinate, methacrylate ester copolymer, ammonia alkyl methacrylate copolymer, ethylcellulose, polyvinyl acetate and polyvinylpyrrolidone, polyvinyl acetal diethylaminolactate, polyvinyl acetal diethylaminolactate, maltitol, lactose monohydrate, xylitol, isomalt, sucrose, glucose, dextran, or maltose.

[0016] In some embodiments, the erosion retarding member prevents the release of the drug from the drug component for at least about 10 minutes after the erosion retarding member comes into contact with the gastrointestinal fluid of the individual. In some embodiments, the erosion retarding member is a layer having a thickness of about 0.1 mm to about 5 mm, based on the direction of erosion. In some embodiments, the erosion retarding member is about 10 mm 2 ~400mm 2This includes the surface area exposed to gastrointestinal fluid in the individual. In some embodiments, the erosion retarder comprises a thermoformable material. In some embodiments, the erosion retarder comprises stearic acid, medium-chain triglyceride, glyceryl distearate, propylene glycol monolaurate, propylene glycol caprylate, oleoyl polyoxyl-6 glyceride, PEG-6 stearate, PEG-32 stearate, linoleoyl polyoxyl-6 glyceride, lauroyl polyoxyl-32 glyceride, caprylocaproyl polyoxyl-8 glyceride, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate Arete, sorbitan oleate, glyceryl monolinoleate, copolyvidone, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, crospovidone, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose or hypromellose, hydroxypropyl methylcellulose phthalate, methylcellulose, methacrylic acid copolymer, poly(methacrylate-co-ethyl acrylate), poly(butyl methacrylate-(2-dimethylamino Ethyl methacrylate-methyl methacrylate copolymer), poly(dimethylaminoethyl methacrylate-co-methacrylate ester), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonium ethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly(methacrylate-co-methyl methacrylate), poly(methacrylate-co-ethyl acrylate), poly(methacrylate-co-methyl methacrylate), polyethylene oxide, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, Colicote IR-polyvinyl alcohol, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, hydroxypropyl methylcellulose acetate succinate or hypromellose acetate succinate, methacrylate ester copolymer, ammonium alkyl methacrylate copolymer, ethylcellulose,It contains one or more of polyvinyl acetate, polyvinyl pyrrolidone, polyvinyl acetal diethylamino lactate, maltitol, lactose monohydrate, xylitol, isomalt, sucrose, glucose, dextran, maltose, lauroyl polyoxyl-32 glyceride, caprylocapryloyl polyoxyl-8 glyceride, polyoxyl(35) castor oil, vitamin E polyethylene glycol succinate, PEG-40 hydrogenated castor oil, glyceryl monolaurate, or glyceryl dibehenate.

[0017] In some embodiments, the drug component is not in direct contact with the pH-based enteric member. In some embodiments, the drug component is a controlled-release drug component. In some embodiments, the drug component is a sustained-release drug component. In some embodiments, the drug component is an immediate-release drug component. In some embodiments, the drug component is configured to release the drug from an oral dosage form for at least about 1 hour. In some embodiments, the drug component provides a drug release profile that includes a zero-order release profile, a first-order release profile, a delayed release profile, a pulsed release profile, a repeated pulsed release profile, an immediate release profile, or a sustained release profile, or a combination thereof. In some embodiments, the drug release is at least partially based on an in vitro dissolution test. In some embodiments, the drug release is at least partially based on an in vivo dissolution test. In some embodiments, the drug component has a drug mass fraction (m F ) of about 0.05 to about 0.6 of the drug. In some embodiments, the weight ratio of the drug component to the delayed component is from about 1:10 to about 10:1. In some embodiments, the drug component is a layer having a thickness of about 0.1 mm to about 5 mm based on the direction of erosion. In some embodiments, the drug component is about 10 mm 2 to about 400 mm 2This includes the surface area exposed to gastrointestinal fluid in the individual. In some embodiments, the drug component comprises a thermoformable material. In some embodiments, the drug component comprises one or more of the following: copolyvidone, polyvinylpyrrolidone-co-vinyl acetate, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose or hypromellose, polyethylene oxide, polyethylene glycol, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, KollicoatIR-polyvinyl alcohol, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, hydroxypropyl methylcellulose acetate succinate, hypromellose acetate succinate, hydroxypropyl methylcellulose phthalate, maltitol, lactose monohydrate, xylitol, isomalt, sucrose, glucose, or dextran 70. In some embodiments, the oral drug dosage form further comprises 1 to 4 additional drug components.

[0018] In some embodiments, the drug is an anti-inflammatory agent, a nonsteroidal anti-inflammatory agent, a steroid, an immunosuppressant, an antibiotic, a biological agent, an antineoplastic agent, analgesic, an anesthetic, an anticonvulsant, an antidiabetic agent, an antihistamine, an anti-infective agent, an antitumor agent, an antiparkinson's disease agent, an antirheumatic agent, an appetite stimulant, an appetite suppressant, a blood regulator, a bone metabolism regulator, a cardiovascular agent, a central nervous system depressant, a central nervous system stimulant, a decongestant, a dopamine receptor agonist, an electrolyte, a gastrointestinal agent, an immunomodulator, a muscle relaxant, a narcotic, a parasympathetic agonist, a sympathetic agonist, a sedative, a hypnotic, or a vaccine. In some embodiments, the anti-inflammatory agent is a JAK inhibitor. In some embodiments, the JAK inhibitor is tofacitinib or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-inflammatory agent is mesalazine, sulfasalazine, or valsalidide. In some embodiments, the nonsteroidal anti-inflammatory agent is ibuprofen or diclofenac. In some embodiments, the steroid is prednisolone, budesonide, or fluticasone. In some embodiments, the immunosuppressant is azathioprine, cyclosporine, or methotrexate. In some embodiments, the bioagent is a peptide, protein, antibody or fragment thereof, or nucleic acid. In some embodiments, the antibody is infliximab, adalimumab, certolizumab, pegol, golimumab, or ustekinumab. In some embodiments, the antitumor agent is fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, etoposide, larcitrexed, or oxaliplatin, or a combination thereof. In some embodiments, the oral drug dosage form contains about 0.01 mg to about 500 mg of the drug.

[0019] In some embodiments, the oral drug dosage form further comprises excipients. In some embodiments, the excipients comprise one or more of absorption enhancers, pH lowering agents, or disintegrants. In some embodiments, the excipients are mixed with the drug component.

[0020] In some embodiments, the shell comprises an insulating material that is impermeable to bodily fluids. In some embodiments, the insulating material comprises one or more of ethyl cellulose (EC), dibutyl sebacate (DBS), and titanium dioxide. In some embodiments, the insulating material is a non-erosive material. In some embodiments, the insulating material is an erosive material having a pH-based erosion and / or erosion rate that allows for the complete release of the drug from the oral drug dosage form before exposure of the drug components to bodily fluids due to erosion of the shell.

[0021] In another embodiment, this specification provides a commercially available batch of oral drug dosage forms described herein, each having a standard deviation of about 0.05 or less for each of the following: the amount of drug in the oral drug dosage form, the weight of the oral drug dosage form, the maximum cross-sectional dimension of the oral drug dosage form, and the cross-sectional dimension perpendicular to the maximum cross-sectional dimension of the oral drug dosage form. In some embodiments, the commercially available batch includes at least about 1000 different oral drug dosage forms.

[0022] In another embodiment, a method is provided for three-dimensional (3D) printing of any oral drug dosage form described herein, the method comprising printing the oral drug dosage form by distributing materials according to a layer-by-layer model of the oral drug dosage form, each layer of the layer-by-layer model being printed by distributing, as necessary, (a) shell material to form any portion of a shell in the layer, (b) drug component material to form any portion of a drug component in the layer, (c) pH-based enteric component material to form any portion of a pH-based enteric component in the layer, (d) erosion retarder component material to form any portion of an erosion retarder component in the layer, (e) biodegradable component material to form any portion of a biodegradable component in the layer, and (f) excipient component material to form any portion of an excipient component in the layer. In some embodiments, the method further comprises generating a layer-by-layer model of the oral drug dosage form. In some embodiments, the distribution is carried out via melt extrusion deposition (MED). In some embodiments, the distribution of shell material, drug component material, pH-based enteric coating material, erosion retarding component material, and shell material are each performed by different print heads. Melt extrusion deposition (MED) is a 3D printing method as described in WO2021042865A1, WO2021164660A1, WO2022089588A1, and WO2022089631A1, all of which are incorporated herein by reference.

[0023] In another embodiment, this specification provides a method for treating an individual condition, the method comprising administering to the individual any oral drug dosage form described herein. In some embodiments, the condition is a gastrointestinal disorder, a central nervous system (CNS) disorder, a cardiovascular disease, hypertension, atherosclerosis, angina pectoris, arterial occlusion, peripheral artery disease, myocardial pathology, arrhythmia, acute myocardial infarction, angina pectoris, cardiomyopathy, congestive heart failure, coronary artery disease (CAD), carotid artery disease, endocarditis, hypercholesterolemia, hyperlipidemia, peripheral artery disease (PAD), genitourinary disorders, erectile dysfunction, benign prostatic hyperplasia (BPH), renal tubular acidosis, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, urinary tract infection, fecal incontinence, or an eye disease such as glaucoma. The group consists of blepharitis, ocular hypertension, retinopathy, conjunctivitis, scleritis, retinitis, keratitis, corneal ulcer, iritis, chorioretinitis, macular edema, xerophthalmos, pulmonary diseases, asthma, pulmonary hypertension, acute respiratory distress syndrome, COPD, emphysema, pneumonia, tuberculosis, bronchitis, acute bronchitis, bronchiectasis, bronchiolitis, bronchial dysplasia, pulmonary dysplasia, Cocci (breath fungal infection), cystic fibrosis, influenza, lung cancer, mesothelioma, metabolic diseases, hypercalciuria, hyperglycemia, hyperinsulinemia, hyperinsulinemia, hyperuria, and hypoglycemia. In some embodiments, gastrointestinal disorders are selected from the group consisting of irritable bowel disease (IBD), irritable bowel syndrome (IBS), constipation, diarrhea, infection, and carcinoma. In some embodiments, IBD is associated with Crohn's disease or ulcerative colitis. In some embodiments, the carcinoma is colon cancer or colorectal cancer. In some embodiments, the CNS disorder is selected from the group consisting of neuropathic pain, stroke, dementia, Alzheimer's disease, Parkinson's disease, neurodegeneration, meningitis, spinal cord injury, cerebral vasospasm, and amyotrophic lateral sclerosis.

[0024] In another embodiment, the Specified provides a method for providing local delivery of a drug to the colon of an individual, the method comprising administering to the individual any oral drug dosage form described herein, the individual suffering from a gastrointestinal disorder.

[0025] In another embodiment, the Specified provides a method for providing systemic delivery of a drug to an individual, the method comprising administering to the individual any oral drug dosage form described herein, the individual having gastrointestinal disorders, central nervous system (CNS) disorders, cardiovascular diseases, hypertension, atherosclerosis, angina pectoris, arterial occlusion, peripheral artery disease, myocardial pathology, arrhythmias, acute myocardial infarction, angina pectoris, cardiomyopathy, congestive heart failure, coronary artery disease (CAD), carotid artery disease, endocarditis, hypercholesterolemia, hyperlipidemia, peripheral artery disease (PAD), genitourinary disorders, erectile dysfunction, benign prostatic hyperplasia (BPH), renal tubular acidosis, glucose The patient suffers from urinary tract infections, glomerulonephritis, glomerulosclerosis, fecal incontinence, eye diseases such as glaucoma, blepharitis, ocular hypertension, retinopathy, conjunctivitis, scleritis, retinitis, keratitis, corneal ulcer, iritis, chorioretinitis, macular edema, xerophthalmos, lung diseases such as asthma, pulmonary hypertension, acute respiratory distress syndrome, COPD, emphysema, pneumonia, tuberculosis, bronchitis, acute bronchitis, bronchiectasis, bronchiolitis, bronchial dysplasia, pulmonary dysplasia, Cocci (breath-bearing mycosis), cystic fibrosis, influenza, lung cancer, mesothelioma, metabolic diseases, hypercalciuria, hyperglycemia, hyperinsulinemia, hyperinsulinemia, hyperuria, or hypoglycemia.

[0026] In some embodiments, the design methods provided herein include using one or more tracking stripes so that external imaging techniques, such as X-ray imaging, can be used to evaluate the state of one or more components of the oral drug dosage form taught herein relative to the location of the oral drug dosage form in an administered individual (e.g., not yet undergoing erosion / release from the oral drug dosage form, undergoing erosion / release from the oral drug dosage form, or having completed erosion / release from the oral drug dosage form). For example, such tracking features allow a person to confirm that one or more components on the oral drug dosage form are functioning as desired, e.g., that drug release from the drug component is occurring at a desired location in the individual's gastrointestinal tract. This further enables methods including adjusting the design of the oral drug dosage form to provide the desired result. For example, if it is found that the drug component is eroding and releasing the drug at an earlier location than desired (e.g., upstream of the desired location in the gastrointestinal tract), then one or more embodiments of the delay component can be adjusted, for example, by changing the composition or thickness of its material.

[0027] In some embodiments, a method is provided for designing an oral drug dosage form configured to release a drug at a desired gastrointestinal location in an individual, wherein the oral drug dosage form comprises a drug component comprising a first erosive material mixed with the drug and a first erosive tracking stripe, a shell comprising a second tracking stripe, and a delay component not mixed with the drug, the delay component being a pH-based enteric coating configured to be eroded at a predetermined pH value or higher, the pH-based enteric coating comprising a third erosive tracking stripe, the pH-based enteric coating comprising a pH-based enteric coating comprising a second erosive delay component comprising a fourth erosive tracking stripe, and the pH-based enteric coating, alone or in combination with the shell, prevents erosion of the erosive delay component. The method comprises a delay component, including an erosive delay component, which, either alone or in combination with a shell, prevents erosion of the drug component, and includes (a) administering an oral drug dosage form to an individual; (b) imaging the individual over time to obtain the position of the oral drug dosage form and the state of a first erosive tracking stripe, a second erosive tracking stripe, a third erosive tracking stripe and a fourth tracking stripe; and (c) designing an oral drug dosage form configured to release the drug at a desired gastrointestinal location in the individual by adjusting the drug component and / or the delay component and / or the shell, or a part thereof, based on the position and state of the first erosive tracking stripe, a second erosive tracking stripe, a third erosive tracking stripe and a fourth tracking stripe.

[0028] In some embodiments, adjusting the delay component includes adjusting the pH-based enteric coating by changing one or more of the composition, the surface area exposed to body fluids after administration, or the thickness of the pH-based enteric coating. In some embodiments, adjusting the delay component includes adjusting the erosive delay coating by changing one or more of the composition, the surface area exposed to body fluids after administration, or the thickness of the erosive delay coating.

[0029] In some embodiments, this specification provides a method for designing an oral drug dosage form configured to release a drug at a desired gastrointestinal location in an individual, the oral drug dosage form comprising: a drug component, a first erosive material mixed with the drug, and a first erosive tracking stripe; a shell; a delay component not mixed with the drug, the delay component comprising a pH-based enteric coating configured to erode at a predetermined pH value or higher, and a second erosive delay component comprising a pH-based enteric coating, the pH-based enteric coating, alone or in combination with the shell, prevents erosion of the erosive delay component. The method comprises an erosive delay member, which, either alone or in combination with a shell, prevents erosion of the drug component, and includes a delay component, and the method comprises (a) administering an oral drug dosage form to an individual, (b) imaging the individual over time to obtain the position of the oral drug dosage form and the state of a first erosive tracking stripe, and (c) designing an oral drug dosage form configured to release the drug at a desired gastrointestinal location in the individual by adjusting the drug component and / or delay component and / or shell, or a part thereof, based on the position and state of the first erosive tracking stripe.

[0030] In some embodiments, the first erosive material mixed with the drug and the first erosive tracking stripe are not in direct contact with each other. In some embodiments, the shell includes a second tracking stripe, which is configured to be imaged by imaging to obtain, for example, the state of the second tracking stripe. In some embodiments, adjustment is based on the position and state of the first erosive tracking stripe and / or the second tracking stripe. In some embodiments, the pH-based enteric coating includes a third tracking stripe, which is configured to be imaged by imaging to obtain, for example, the state of the third erosive tracking stripe. In some embodiments, adjustment is based on the position and state of the first erosive tracking stripe and / or the second tracking stripe and / or the third tracking stripe. In some embodiments, the erosive delaying coating includes a fourth tracking stripe, which is configured to be imaged by imaging to obtain, for example, the state of the fourth erosive tracking stripe. In some embodiments, the adjustment is based on the position and state of the first erosive tracking stripe and / or the second tracking stripe and / or the third erosive tracking stripe and / or the fourth tracking stripe.

[0031] In some embodiments, imaging provides the location of the oral drug dosage form when the first erosive tracking stripe begins to erode. In some embodiments, imaging provides the location of the oral drug dosage form when the first erosive tracking stripe is completely eroded. In some embodiments, adjustment includes adjusting the delay component or part thereof based on the location and state of the first erosive tracking stripe indicating release earlier than desired to increase the delay of drug release from the oral drug dosage form. In some embodiments, adjustment includes adjusting the delay component or part thereof based on the location and state of the first erosive tracking stripe indicating release later than desired to reduce the delay of drug release from the oral drug dosage form.

[0032] In some embodiments, the first tracking stripe contains barium sulfate. In some embodiments, imaging includes X-ray imaging. In some embodiments, the method further includes obtaining one or more pharmacokinetic (PK) parameters related to the drug after administration of an oral drug dosage form to an individual. In some embodiments, the method further includes identifying the relationship between one or more PK parameters and the position and status information of the first tracking stripe. In some embodiments, the method further includes adjusting the drug components and / or delay components, or parts thereof, based on the relationship between one or more PK parameters and the position and status information of the first tracking stripe. In some embodiments, imaging does not include magnetic-based techniques or invasive imaging techniques.

[0033] In some embodiments, this specification provides a method for designing an oral drug dosage form configured to release a drug at a desired gastrointestinal location in an individual, the oral drug dosage form comprising a drug component comprising a first erosive material mixed with the drug, a shell, a delay component not mixed with the drug, the delay component comprising a pH-based enteric component configured to be eroded at a predetermined pH value or higher, and an erosive delay component comprising a second erosive material, wherein the pH-based enteric component prevents erosion of the erosive delay component, and the erosive delay component prevents erosion of the drug component, and An oral drug dosage form comprising a delay component and an oral drug dosage form comprising at least one tracking stripe positioned within the component, the method comprising (a) administering the oral drug dosage form to an individual; (b) imaging the individual over time to obtain the position of the oral drug dosage form and the state of at least one tracking stripe; and (c) designing an oral drug dosage form configured to release the drug at a desired gastrointestinal location in the individual by adjusting the drug component and / or delay component and / or shell, or a part thereof, based on the position and state of at least one tracking stripe.

[0034] In some embodiments, one of the tracking stripes is located within or near the drug component. In some embodiments, the tracking stripe is located within the shell. In some embodiments, one of the tracking stripes is located within a pH-based enteric coating. In some embodiments, one of the tracking stripes is located within an erosive delaying coating. In some embodiments, at least one of the at least one tracking stripe is erosive.

[0035] In some embodiments, this specification provides a method for designing an oral drug dosage form configured to release a drug at a desired gastrointestinal location in an individual, wherein the oral drug dosage form comprises a drug component comprising a first erosive material mixed with the drug, a delay component not mixed with the drug, the delay component comprising a pH-based enteric coating configured to be eroded at a predetermined pH value or higher, and an erosive delay member comprising a second erosive material, wherein the pH-based enteric coating prevents erosion of the erosive delay member, and the erosive delay member prevents erosion of the drug component, An oral drug dosage form comprising a delay component and an oral drug dosage form comprising at least one tracking stripe positioned within the component, the method comprising (a) administering the oral drug dosage form to an individual; (b) imaging the individual over time to obtain the position of the oral drug dosage form and the state of at least one tracking stripe; and (c) designing an oral drug dosage form configured to release the drug at a desired gastrointestinal location in the individual by adjusting the drug component and / or delay component, or a portion thereof, based on the position and state of at least one tracking stripe.

[0036] In some embodiments, one of the tracking stripes is located within or near the drug component. In some embodiments, one of the tracking stripes is located within a pH-based enteric coating. In some embodiments, one of the tracking stripes is located within an erosive delaying coating. In some embodiments, at least one of the at least one tracking stripes is erosive.

[0037] In some embodiments, this specification provides a method for treating ulcerative colitis, the method comprising administering to a human individual an oral drug dosage form described in any one of claims 1 to 84, the oral drug dosage form comprising a JAK inhibitor. In some embodiments, the JAK inhibitor comprises tofacitinib. In some embodiments, the oral drug dosage form comprises tofacitinib in a dose of about 11 mg or less. In some embodiments, the oral drug dosage form comprises tofacitinib in a dose of about 5.5 mg or less. In some embodiments, the oral drug dosage form is administered once daily.

[0038] Those skilled in the art will understand that modifications to the form and details of the implementations described herein may be made without departing from the scope of this disclosure. In addition, although various advantages, embodiments, and objectives have been described with reference to various implementations, the scope of this disclosure should not be limited by reference to such advantages, embodiments, and objectives.

[0039] All references cited herein, including patent applications and publications, are incorporated in their entirety by reference. [Brief explanation of the drawing]

[0040] [Figure 1A] This specification shows a cross-sectional view of an exemplary oral drug dosage form. [Figure 1B] This specification shows a cross-sectional view of an exemplary oral drug dosage form. [Figure 1C] This specification shows a cross-sectional view of an exemplary oral drug dosage form. [Figure 1D] This specification shows a cross-sectional view of an exemplary oral drug dosage form. [Figure 1E] This specification shows a cross-sectional view of an exemplary oral drug dosage form. [Figure 1F] This specification shows a cross-sectional view of an exemplary oral drug dosage form. [Figure 1G] This specification shows a cross-sectional view of an exemplary oral drug dosage form. [Figure 1H]This specification shows a cross-sectional view of an exemplary oral drug dosage form. [Figure 1I] This specification shows a cross-sectional view of an exemplary oral drug dosage form. [Figure 1J] This specification shows a cross-sectional view of an exemplary oral drug dosage form. [Figure 1K] This specification shows a cross-sectional view of an exemplary oral drug dosage form. [Figure 2] This specification shows exemplary oral drug dosage forms, including various cross-sectional views thereof. [Figure 3] This specification shows exemplary oral drug dosage forms, including various cross-sectional views thereof. [Figure 4] This specification shows exemplary oral drug dosage forms, including various cross-sectional views thereof. [Figure 5] The in vitro dissolution profiles of exemplary oral drug dosage forms provided herein (see Tables 1A and 1B, and Figure 2) are shown, including a set of tracking stripes with the erosion of a particular component overlaid therein. For each time point in the dissolution profile, the data point is based on the mean of four measurements, and the standard deviation is provided using error bars. The in vitro delay time for oral drug dosage forms is approximately 4.5 hours. [Figure 6A] The in vitro dissolution profiles of exemplary oral drug dosage forms provided herein (see Tables 2A and 2B, and Figure 3) are shown, including a set of tracking stripes with the erosion of a particular component overlaid therein. For each time point in the dissolution profile, the data point is based on the mean of three measurements, and the standard deviation is provided using error bars. The in vitro delay time for oral drug dosage forms is approximately 4 hours. [Figure 6B] The image shows a photograph taken during the dissolution process. [Figure 7]The in vitro dissolution profiles of exemplary oral drug dosage forms provided herein (see Tables 3A and 3B, and Figure 4) are shown. For each time point in the dissolution profile, the data point is based on the mean of three measurements, and the standard deviation is provided using error bars. The in vitro delay time for oral drug dosage forms is approximately 4.5 hours. [Figure 8] The in vitro dissolution profiles of exemplary oral drug dosage forms provided herein (see Tables 4A and 4B, and Figure 4) are shown, including a set of tracking stripes with the erosion of a particular component overlaid therein. For each time point in the dissolution profile, the data point is based on the mean of three measurements, and the standard deviation is provided using error bars. The in vitro delay time for oral drug dosage forms is approximately 5 hours. [Figure 9A] The pharmacokinetic (PK) plots for the reference (XeljanzXR) and exemplary oral drug dosage forms provided herein are shown. [Figure 9B] The pharmacokinetic (PK) plots for the reference (XeljanzXR) and exemplary oral drug dosage forms provided herein are shown. [Figure 10A] This specification shows the time course of X-ray images of beagle dogs after administration of exemplary oral drug dosage forms provided herein. Annotations are provided to indicate the oral drug dosage form and to provide status information such as the onset and completion of drug release. [Figure 10B] This specification shows the time course of X-ray images of beagle dogs after administration of exemplary oral drug dosage forms provided herein. Annotations are provided to indicate the oral drug dosage form and to provide status information such as the onset and completion of drug release. [Figure 10C] This specification shows the time course of X-ray images of beagle dogs after administration of exemplary oral drug dosage forms provided herein. Annotations are provided to indicate the oral drug dosage form and to provide status information such as the onset and completion of drug release. [Figure 11] This specification shows exemplary oral drug dosage forms, including various cross-sectional views thereof. [Figure 12A]The in vitro dissolution profiles of the exemplary oral drug dosage forms provided herein (see Tables 5A - 8B and FIG. 11) are shown. For each time point of the dissolution profile, the data points are based on the average of five measurements, and the standard deviation is provided using error bars. [Figure 12B] The in vitro dissolution profiles of the exemplary oral drug dosage forms provided herein (see Tables 5A - 8B and FIG. 11) are shown. For each time point of the dissolution profile, the data points are based on the average of five measurements, and the standard deviation is provided using error bars. [Figure 12C] The in vitro dissolution profiles of the exemplary oral drug dosage forms provided herein (see Tables 5A - 8B and FIG. 11) are shown. For each time point of the dissolution profile, the data points are based on the average of five measurements, and the standard deviation is provided using error bars. [Figure 12D] The in vitro dissolution profiles of the exemplary oral drug dosage forms provided herein (see Tables 5A - 8B and FIG. 11) are shown. For each time point of the dissolution profile, the data points are based on the average of five measurements, and the standard deviation is provided using error bars. [Figure 13] Pharmacokinetic (PK) plots of the reference (Xeljanz XR) and the exemplary oral drug dosage forms provided herein are shown. <s>0000898< / s> [Figure 14A] The time - course changes of X - ray images of beagle dogs after administration of the exemplary oral drug dosage forms provided herein are shown. The oral drug dosage form is indicated, and annotations are provided to give status information such as the start and completion of drug release. [Figure 14B] The time - course changes of X - ray images of beagle dogs after administration of the exemplary oral drug dosage forms provided herein are shown. The oral drug dosage form is indicated, and annotations are provided to give status information such as the start and completion of drug release. [Figure 15] Pharmacokinetic (PK) plots measured from healthy volunteers of the reference (Xeljanz XR) and the exemplary oral drug dosage forms provided herein are shown. [Figure 16] Note: For the tags and , since they are just tags without specific text to translate within them, they are left as they are in the translation. If there was supposed to be some text associated with them in the original context, it's not clear from the provided content. The same goes for [Figure 16] . For , I'm not sure if it was meant to be just a tag or if there was text inside it in the original Japanese (or other language if it was not Japanese). If it was text, please provide more context.Shows the time-course changes of X-ray images of healthy volunteers after administration of an exemplary oral drug dosage form provided in this specification. The oral drug dosage form is pointed out, and annotations are provided to provide status information such as the start and completion of drug release.

Mode for Carrying Out the Invention

[0041] In some aspects, as described herein, an oral drug dosage form configured to release a drug at a desired location within the colon of an individual is provided, the oral drug dosage form comprising a drug component comprising an erosive material mixed with the drug, and a delay component not mixed with the drug, the delay component being configured to prevent release of the drug from the drug component until the oral drug dosage form reaches the colon of the individual after administration, the delay component comprising a pH-based enteric member comprising an erosive material configured to be eroded at a predetermined pH value or higher. In some embodiments, the oral drug dosage form is configured such that substantially all, e.g., 100%, of the drug in the oral drug dosage form is released into the colon of the individual.

[0042] The oral drug dosage forms described herein are based on the inventors' unique insights and knowledge regarding the design and manufacture of oral drug dosage forms for the precise delivery of drugs to the colon of the gastrointestinal tract. As taught and demonstrated herein, in certain embodiments, the oral drug dosage forms enable complete colonic delivery of the drug (including complete delivery within a specific region of the colon), thereby maximizing the therapeutic efficacy of a particular drug while minimizing side effects caused by the release of the drug in another region of the gastrointestinal tract. For example, such toxicity may occur when undesirable systemic absorption occurs due to the release of the drug in another region of the gastrointestinal tract. The colon is susceptible to many disease conditions, including inflammatory bowel disease, irritable bowel syndrome, constipation, diarrhea, infections, and carcinomas. In certain embodiments, the oral drug dosage forms taught herein can effectively deliver the drug to the site of the disease condition, namely the colon, to provide effective topical therapy. Furthermore, in other embodiments, the colon is a site of the gastrointestinal tract that offers the potential for effective uptake and, thereby, systemic delivery. For example, the colon has relatively low levels of several luminal and mucosal metabolic enzymes (e.g., proteases) and transporters, which provides therapeutic advantages for certain drugs that would not be absorbed into the systemic circulation if released in another part of the gastrointestinal tract. For instance, lower proteolytic activity in the colon can be beneficial for the delivery of biologics (e.g., peptides, proteins, monoclonal antibodies, nucleic acids, and vaccines). The ability of oral drug dosage forms taught herein to achieve complete colonic delivery (including delivery to specific areas of the colon) represents a significant advance in the field of drug delivery for both topical and systemic therapy.

[0043] An exemplary example of the usefulness of certain oral drug dosage forms provided herein can be found in the oral drug dosage forms described herein, which consist of drugs for the treatment of ulcerative colitis. Ulcerative colitis is a condition that affects specific areas of the gastrointestinal tract, namely, ulcerative colitis causes inflammation and ulcers in the innermost layer of the large intestine (colon) and rectum. Known drugs, such as anti-inflammatory agents including JAK inhibitors, are effective in treating individuals with ulcerative colitis by reducing inflammation and ulcer formation. However, conventional drug dosage forms, including such drugs, have been shown to have drawbacks, such as incomplete drug delivery to the required local site. This extracolonial delivery can reduce the effectiveness of such conventional oral drug dosage forms and cause systemic toxicity. The advantages of the oral drug dosage forms described herein result in a significant improvement in the treatment of such conditions, such as ulcerative colitis.

[0044] Traditionally, the oral delivery of biologics such as peptides, proteins, monoclonal antibodies, and nucleic acids (e.g., RNA) has been limited, at least in part, by the presence of digestive enzymes in the gastrointestinal tract. Vaccines may also face high levels of degradation due to the level of phagocytosis. The lower levels of functional proteolytic enzymes, functional digestive pancreatic enzymes, and phagocytosis in the colon compared to other areas of the gastrointestinal tract present an opportunity for the safe delivery of such biologics into the colon. In certain embodiments, the oral drug dosage forms taught herein can protect the biologic until release in the colon, thereby representing a significant advance in the oral delivery of such therapeutics.

[0045] Accordingly, in certain embodiments, the Specified Provision provides an oral drug dosage form configured to release a drug at a desired location within the colon of an individual, the oral drug dosage form comprising a drug component comprising an erosive material mixed with the drug, and a delay component not mixed with the drug, the delay component configured to prevent the release of the drug from the drug component until the oral drug dosage form reaches the colon of an individual after administration, the delay component comprising a pH-based enteric coating comprising an erosive material configured to be eroded above a predetermined pH value. In some embodiments, the delay component further comprises an erosive delay component, the oral drug dosage form configured such that the pH-based enteric coating component is eroded before the erosive delay component. In some embodiments, the oral drug dosage form further comprises a second drug. In some embodiments, the oral drug dosage form further comprises a bacteriolytic portion. In some embodiments, the delay component further comprises a bacteriolytic component comprising an erosive material mixed with the bacteriolytic portion. In some embodiments, the delay component does not include an erosive delay component. In some embodiments, the oral drug dosage form does not include a shell. In some embodiments, the oral drug dosage form further comprises a shell that is not mixed with the drug, and the oral drug dosage form is configured such that the shell or a portion thereof, and the delay member, prevent erosion of the drug component.

[0046] In other embodiments, this specification provides a commercially available batch of the oral drug dosage forms described herein, each having a standard deviation of about 0.05 or less for each of the following: the amount of drug in the oral drug dosage form, the weight of the oral drug dosage form, the maximum transverse dimension of the oral drug dosage form, and the transverse dimension perpendicular to the maximum transverse dimension of the oral drug dosage form. In some embodiments, the commercially available batch includes at least about 1000 different oral drug dosage forms.

[0047] In another embodiment, a method is provided for three-dimensional (3D) printing of any oral drug dosage form described herein, the method comprising printing the oral drug dosage form by distributing materials according to a layer-by-layer model of the oral drug dosage form, each layer of the layer-by-layer model being printed by distributing, as necessary, (a) shell material to form any part of a shell in the layer, (b) drug component material to form any part of a drug component in the layer, (c) pH-based enteric component material to form any part of a pH-based enteric component in the layer, (d) erosion retarder material to form any part of an erosion retarder in the layer, (e) biodegradable component material to form any part of a biodegradable component in the layer, and (f) excipient component material to form any part of an excipient component in the layer.

[0048] In other embodiments, the Specified provides a method for treating an individual condition, the method comprising administering to the individual an oral drug dosage form described herein.

[0049] In another embodiment, this specification provides a method for providing local delivery of a drug to the colon of an individual, the method comprising administering to the individual an oral drug dosage form described herein.

[0050] In other embodiments, the Specified provides a method for providing systemic delivery of a drug to an individual, the method comprising administering to the individual an oral drug dosage form described herein. I. Definition

[0051] For the purposes of interpreting this specification, the following definitions apply, and where appropriate, a singular term is also included in its plural form, and vice versa. In the event of any conflict between any definition below and any reference incorporated herein by reference, the definition given herein shall prevail.

[0052] As used herein, the terms “peptide” and “protein” may be used interchangeably to refer to polymers containing amino acid residues, and are not limited to minimum length. Such polymers may contain natural or non-natural amino acid residues, or combinations thereof, and include, but are not limited to, peptides, oligopeptides, dimers, trimers, and polymers of amino acid residues. Full-length peptides or proteins, and fragments thereof, are encompassed in this definition. The term also includes its modified species, e.g., post-translational modifications of one or more residues, e.g., methylation, phosphorylation, glycosylation, sialylation, or acetylation.

[0053] As used herein, the term "tofacitinib" includes any pharmaceutically acceptable form and its salts unless otherwise indicated. In some embodiments, tofacitinib may exist in crystalline form. In some embodiments, tofacitinib may exist in amorphous form. In some embodiments, a pharmaceutically acceptable form is any pharmaceutically acceptable form, including solvates, hydrates, isomorphs, polymorphs, cocrystals, pseudomorphs, neutral forms, acid-added salt forms, and prodrugs. In some embodiments, a pharmaceutically acceptable form is a pharmaceutically acceptable salt. Conventional concentration and recrystallization techniques may be used to produce and isolate pharmaceutically acceptable salts of JAK inhibitors, including the use of acids such as acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, mesylic acid, tosylic acid, benzoic acid, cinnamic acid, fumaric acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfamic acid, sulfonic acid, such as methanesulfonic acid, benzenesulfonic acid, and related acids. In some embodiments, tofacitinib is tofacitinib citrate.

[0054] As used herein, the terms “treat,” “treatment,” “treating,” or their equivalents refer to an approach to obtain a beneficial or desired outcome, including, for example, the alleviation of symptoms of a disease. For the purposes of this disclosure, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: alleviating one or more symptoms of a disease; reducing the severity of one or more symptoms of a disease; preventing an increase in the severity of one or more symptoms of a disease; reducing the dose of one or more other drugs required to treat and / or manage the disease; and improving quality of life.

[0055] As used herein, the term “individual” refers to mammals, including but not limited to humans, cattle, horses, cats, canids, rodents, rats, mice, dogs, or primates. In some embodiments, an individual is a human individual.

[0056] As used herein, the terms “comprising,” “having,” “containing,” and “including,” other similar forms, and their grammatical equivalents are intended to be semantically equivalent and open in that the items or items following any one of these terms do not mean an exhaustive list of such items or items, or that they are limited to only the listed items or items. For example, an article “comprising” components A, B, and C may consist of (i.e., contain only) components A, B, and C, or may contain not only components A, B, and C, but also one or more other components. Accordingly, “comprises” and similar forms, and their grammatical equivalents, are intended and should be understood to include disclosures of embodiments of “consisting essentially of” or “consisting of.”

[0057] As used herein, the term “semi-solid” and other similar forms, as well as their grammatical equivalents, refer to a viscous liquid that can flow under external forces (such as pressure, thrust, rotational force, gravity, etc.) or process conditions (such as temperature, pressure, etc.).

[0058] Where a range of values ​​is provided, unless the context explicitly indicates otherwise, each intermediate value between the upper and lower limits of that range and any other specified or intervening value within that specified range, up to one-tenth of the lower limit unit, is understood to be included in this disclosure, subject to any specifically excluded limits within the specified range. Where a specified range includes one or both limits, a range excluding either or both of those limits is also included in this disclosure.

[0059] References to "about" a value or parameter herein include (and describe) variations that are on the value or parameter itself. For example, descriptions that refer to "about X" include descriptions of "X".

[0060] As used herein, including in the appended claims, the singular forms "a", "or", and "the" include plural referents unless the context clearly dictates otherwise.

[0061] Those skilled in the art will recognize that several embodiments are possible within the scope and spirit of the present disclosure. The following description is illustrative of the present disclosure and should in no way be construed as limiting the scope of the invention described herein.

[0062] II. Oral Dosage Forms

[0063] In some aspects herein, oral dosage forms are provided that are configured to release a drug at a desired location within the colon. As described herein, in some embodiments, an oral dosage form configured to release a drug at a desired location within an individual's colon includes a drug component that includes an erosive material mixed with the drug, and a delay component that is not mixed with the drug, the delay component being configured to prevent release of the drug from the drug component until the oral dosage form reaches the individual's colon after administration, the delay component including a pH-based enteric member that includes an erosive material configured to be eroded at a predetermined pH value or higher. In some embodiments, the oral dosage form has one or more additional features, such as an erosive delay member, a second drug, and optionally, a second drug component, a bacterially degradable portion, and optionally, a bacterially degradable member, a shell, or an excipient. The oral dosage forms disclosed herein can include various combinations of the components described herein and can be arranged in a wide variety of configurations. In some examples, such as those provided in the sections below, the components and configurations are described in a modular fashion, and such descriptions are not intended to limit the scope of the oral dosage forms encompassed herein. A. Exemplary Oral Dosage Forms

[0064] For illustrative and illustrative purposes of the subject matter provided herein, certain oral drug dosage forms included herein are described in detail below.

[0065] Schematic cross-sectional diagrams of exemplary oral drug dosage forms configured to release the drug at a desired location within the colon are shown in Figures 1A–1H. As shown in Figure 1A, in some embodiments, the oral drug dosage form 100 comprises a drug component 102 containing an erosive material mixed with the drug, and a delay component not mixed with the drug, the delay component being configured to prevent the release of the drug from the drug component until the oral drug dosage form reaches the colon of the individual after administration, and the delay component comprises a pH-based enteric coating member 104 containing an erosive material configured to erode at a predetermined pH value or higher. After administration, the outer surface constituting the pH-based enteric coating member 104 is exposed to gastrointestinal fluid within the individual. For example, based on the pH of the colon or a portion thereof, when a pH threshold is met, the material on the surface of the pH-based enteric coating member 104 is eroded from the oral drug dosage form, as indicated by the directions of arrows 106, 108, 110, and 112. Based on the design of the pH-based enteric coating 104, the drug component 102 or a portion of it (e.g., the surface) can be controllably exposed to gastrointestinal fluid to control the release of the drug from the oral drug dosage form 100. For example, by having thinner thicknesses of the pH-based enteric coating 104 above and below the drug component 102 (evaluated along the direction of erosion and compared, for example, to the thickness of the sides), erosion of the pH-based enteric coating 104 first exposes the top surface 114 and bottom surface 116 of the drug component 102. Then, the drug mixed with the drug component 102 can be released from the oral drug dosage form 100, for example, by erosion. The ability to design which(s) of the drug component 102 are exposed to gastrointestinal fluid enables, at least in part, control over the release of the drug from the oral drug dosage form 100.

[0066] As shown in Figure 1B, in some embodiments, the delay component further includes an erosive delay member 204 that is not mixed with the drug. After administration, the outer surface of the oral drug dosage form 200 constituting the pH-based enteric coating member 202 is exposed to gastrointestinal fluid within the body. For example, based on the pH of the colon or a portion thereof, or its vicinity, once a pH threshold is met, the material on the surface of the pH-based enteric coating member 202 is eroded from the oral drug dosage form 200, as indicated by the directions of arrows 208 and 210. Based on the design of the pH-based enteric coating member 202, the erosive delay member 204, or a portion thereof (e.g., the surface), can be controlledly exposed to gastrointestinal fluid. Based on exposure to gastrointestinal fluid, the erosive delay member 204 is eroded accordingly, and then an embodiment of the drug component 206 is exposed to gastrointestinal fluid, thereby providing the release of the drug from the oral drug dosage form 100. The design of the delay component allows for the exposure of certain aspects of the drug component 206, at least partially, to enable the acquisition of a controlled release profile for the drug from the oral drug dosage form 200.

[0067] As shown in Figures 1C and 1D, in certain embodiments, the oral drug dosage forms provided herein, e.g., 300 and 400, comprise two or more components, e.g., drug components. Such dosage forms can be designed for sequential erosion (or at least partially sequential erosion), as shown for the drug component in Figure 1C, or for compartment-based erosion, as shown for the drug component in Figure 1D. Specifically, as shown in Figure 1C, after administration, the outer surface of the oral drug dosage form 300 constituting the pH-based enteric coating member 302 is exposed to gastrointestinal fluid within the body. For example, based on the pH of the colon or a portion thereof, or its vicinity, once a pH threshold is met, the material on the surface of the pH-based enteric coating member 302 is eroded from the oral drug dosage form, as indicated by the directions of arrows 310 and 312. Based on the design of the pH-based enteric coating member 302, an erosion-delaying member 304, or a portion thereof (e.g., the surface), can be controlledly exposed to gastrointestinal fluid. Based on exposure to gastrointestinal fluid, the erosive delay member 304 is eroded accordingly, and then an aspect of the second drug component 306 is exposed to the gastrointestinal fluid, thereby providing the release of the second drug from the oral drug dosage form 300. Based on exposure to gastrointestinal fluid, the second drug component 306 is eroded accordingly, and then an aspect of the drug component 308 is exposed to the gastrointestinal fluid, thereby providing the release of the drug from the oral drug dosage form 300. The design of the delay component allows certain aspects of the second drug component 306 to be exposed so as to obtain a release control profile for the second drug from the oral drug dosage form 300. The design of the delay component and / or the second drug component 306 allows certain aspects of the drug component 308 to be exposed so as to obtain a release control profile for the drug from the oral drug dosage form 300. The drug and the second drug may be the same or different. In some embodiments, an intermediate material, such as a second erosive retarder, is positioned between at least a portion of the second drug component 306 and the drug component 308.

[0068] As shown in Figure 1D, a compartment-based approach can be employed to design the oral drug dosage form 400 taught herein. After administration, the outer surface of the oral drug dosage form 400 constituting the pH-based enteric coating member 402 is exposed to gastrointestinal fluid within the body. For example, based on the pH of the colon or a portion thereof, or its vicinity, once a pH threshold is met, the material on the surface of the pH-based enteric coating member 402 is eroded from the oral drug dosage form 400, as indicated by the directions of arrows 410 and 412. Based on the design of the pH-based enteric coating member 402, an erosion retarder member 404, or a portion thereof (e.g., the surface), can be controlledly exposed to gastrointestinal fluid. Based on exposure to gastrointestinal fluid, the erosion retarder member 404 is eroded accordingly, and then embodiments of the drug component 406 and the second drug component 408 are exposed to gastrointestinal fluid, thereby providing the release of the drug from the oral drug dosage form 400 and the second drug, respectively. The design of the delaying component allows for control over drug release, such as achieving separate drug release, simultaneous drug release, or partially overlapping drug release. In some embodiments, the second erosive delaying member is associated with the second drug component 408 such that the second drug component 408 does not depend on the erosive delaying member 404 for drug release. As described herein, the oral drug dosage form may contain many compartments containing the drug and / or other embodiments of the oral drug dosage form, such as the bacteriolytic moiety and / or excipients.

[0069] As described herein, certain other components, such as a bacteriolytic portion (e.g., mixed with the bacteriolytic member) and excipients, can be formulated into the oral drug dosage forms provided herein. For example, as shown in Figure 1E, after administration, the outer surface of the oral drug dosage form 500 constituting the pH-based enteric member 502 is exposed to gastrointestinal fluid within the body. For example, based on the pH of the colon or a portion thereof, or its vicinity, once a pH threshold is met, the material on the surface of the pH-based enteric member 502 is eroded from the oral drug dosage form 500, as indicated by the directions of arrows 510 and 512. Based on the design of the pH-based enteric member 502, an erosion retarder 504, or a portion thereof (e.g., the surface), can be controlledly exposed to gastrointestinal fluid. Based on exposure to gastrointestinal fluid, the erosion retarder 504 is eroded accordingly, and then the portion of the bacteriolytic member mixed with the bacteriolytic portion 506 is exposed to gastrointestinal fluid. Next, the bacterial degradation member 506 is degraded to expose an aspect of the drug component 508, thereby providing drug release from the oral drug dosage form 500. The design of the delaying component (in Figure 1E, the delaying component includes a pH-based enteric-coated component 502, an erosive delaying component 504, and a bacterial degradation member 506) allows for the exposure of a specific aspect of the drug component 508 so as to provide a controlled release profile for the drug from the oral drug dosage form 500.

[0070] In a particular embodiment, the oral drug dosage forms provided herein include a shell. As shown in Figures 1F-1H, the oral drug dosage form 600 is configured to release the drug at a desired location in the colon, and the oral drug dosage form includes a drug component comprising a first erosive material mixed with the drug; a shell not mixed with the drug, wherein the shell is associated with at least a portion of the drug component, for example, through one or more sides of the drug component; and a delay component not mixed with the drug, wherein the delay component comprises a pH-based enteric coating configured to be eroded at a predetermined pH value or higher, and an erosive delay component comprising an erosive material. As will be described in detail below, as shown in Figure 1F, the delay component comprises a pair of layers of pH-based enteric coating and a pair of layers of erosive delay components sandwiching the drug component, wherein the pH-based enteric coating and the shell prevent erosion of the erosive delay component, and the erosive delay component and the shell prevent erosion of the drug component.

[0071] A cross-sectional view of oral drug dosage form 600 is shown in Figure 1F. Oral drug dosage form 600 comprises a shell 602 containing an insulating material impermeable to body fluids, and a drug component 604 containing a first corrosive material mixed with the drug. As shown in Figure 1F, the drug component 604 forms a layer including a top surface 606, a bottom surface 608, and one or more sides, e.g., 610, and one or more sides of the layer of the drug component are related to the shell, e.g., in direct contact with it. The use of directional terms such as top, bottom, and sides is intended to facilitate the explanation of the present disclosure provided herein and should not be construed as limiting the scope of the invention provided herein. The delay component of oral drug dosage form 600 is not mixed with the drug and comprises a pH-based enteric coating configured to be eroded at a predetermined pH value or higher, and an erosive delay component containing an erosive material. The pH-based enteric coating and shell prevent erosion of the erosive delay component, and the erosive delay component and shell prevent erosion of the drug component. Specifically, in oral drug dosage form 600 shown in Figure 1F, the delay component comprises a pair of layers: an erosive delay component 612 in the first layer, a pH-based enteric coating 618 in the first layer, an erosive delay component 622 in the second layer, and a pH-based enteric coating 624 in the second layer. The oral drug dosage form 600 is configured such that the top surface 606 of the layer of drug component 604 is in direct contact with the bottom surface 614 of the erosive retarder member 612 of the first layer, and the top surface 616 of the erosive retarder member 612 of the first layer is in direct contact with the bottom surface 620 of the pH-based enteric coating member 618 of the first layer. The layers of the second set of retarder components are arranged similarly, specifically, the bottom surface 608 of the layer of drug component 604 is in direct contact with the erosive retarder member 622 of the second layer, and the erosive retarder member 622 of the second layer is in direct contact with the pH-based enteric coating member 624 of the second layer. As shown in Figure 1F, the pH-based enteric coating members 618, 624 and the shell 602 completely surround the erosive retarder members 612, 622 and the drug component 604.

[0072] The oral drug dosage form 600 in Figure 1F is configured such that, when administered to a human individual, as the oral drug dosage form begins to pass through the human individual's gastrointestinal system and is exposed to gastrointestinal fluid having an appropriate pH value, such as a pH value of 5.5 or higher, the top surface 622 of the first layer of the pH-based enteric coating 618 and the bottom surface 626 of the second layer of the pH-based enteric coating 624 are eroded away from the oral drug dosage form 600 in the directions of the individual arrows 628 and 630. As shown in Figure 1G, at a certain time after administration to a human individual, the pH-based enteric coating members of the first and second layers (618 and 624 as shown in Figure 1F) are eroded away from the oral drug dosage form 600, exposing the top surface 616 of the erosion retarder member 612 of the first layer and the bottom surface 632 of the erosion retarder member 622 of the second layer to the gastrointestinal fluid. The erosive delay members of the first and second layers are eroded away from the oral drug dosage form 600 in the directions of the individual arrows 634 and 636. As shown in Figure 1H, at a certain time after administration to a human subject, the erosive delay members of the first and second layers (shown in Figures 1H and 1G) The 612 and 622) are eroded away from the oral drug dosage form 600, exposing the top 606 and bottom 608 of the drug component 604, and the drug is released from the oral drug dosage form through the erosion of the drug component 604, for example in the direction of arrows 638 and 640. In some embodiments, the drug component is dispersed, and at least a portion of the drug component is released from the oral drug dosage form and further eroded to release the drug in a human organism.

[0073] As described herein, certain other components, such as biodegradable portions (e.g., mixed with biodegradable members) and excipients, can be formulated into oral drug dosage forms provided herein, for example, as shown in Figure 1I. Oral drug dosage form 700 comprises a shell 702 comprising an insulating material impermeable to body fluids, and a drug component 704 comprising a first corrosive material mixed with a drug. As shown in Figure 1I, the drug component 704 forms a layer comprising a top surface 706, a bottom surface 708, and one or more sides, for example 710, and one or more sides of the layer of the drug component are associated with the shell and, for example, in direct contact with it. The use of directional terms such as top, bottom, and sides is intended to facilitate the description of the present disclosure provided herein and should not be construed as limiting the scope of the invention provided herein. The biodegradable members 732 and 734 then decompose to expose embodiments of the drug components 706 and 708, thereby providing the release of the drug from oral drug dosage form 700. The delay component of oral drug dosage form 700 is not mixed with the drug and comprises a pH-based enteric coating configured to be eroded at a predetermined pH value or higher, and an erosive delay component containing an erosive material, wherein the pH-based enteric coating and shell prevent erosion of the erosive delay component, and the erosive delay component and shell prevent erosion of the drug component. Specifically, in oral drug dosage form 700 shown in Figure 1I, the delay component comprises a pair of layers: an erosive delay component 712 in the first layer, a pH-based enteric coating component 718 in the first layer, an erosive delay component 722 in the second layer, and a pH-based enteric coating component 724 in the second layer. The oral drug dosage form 700 is configured such that the top surface 706 of the layer of drug component 704 is in direct contact with the bottom surface 714 of the erosive retarder member 712 of the first layer, and the top surface 716 of the erosive retarder member 712 of the first layer is in direct contact with the bottom surface 720 of the pH-based enteric coating member 718 of the first layer. The layers of the second set of retarder components are arranged similarly, specifically, the bottom surface 708 of the layer of drug component 704 is in direct contact with the erosive retarder member 722 of the second layer, and the erosive retarder member 722 of the second layer is in direct contact with the pH-based enteric coating member 724 of the second layer.As shown in Figure 1I, the pH-based enteric coating members 718, 724 and the shell 702 completely surround the erosion retarder members 712, 722, the bacterial degradation members 732, 734, and the drug component 704.

[0074] This specification provides further forms of oral drug dosage forms, for example, as shown in Figure 1J. An oral drug dosage form 800 comprises a shell 802 containing an insulating material impermeable to body fluids, and a drug component 804 containing a first corrosive material mixed with a drug. As shown in Figure 1J, the drug component 804 forms a layer including a top surface 806, a bottom surface 808, and one or more sides, for example 810, where one or more sides of the layer of the drug component are associated with the shell and, for example, in direct contact with it. The use of directional terms such as top, bottom, and sides is intended to facilitate the explanation of the present disclosure provided herein and should not be construed as limiting the scope of the invention provided herein. Next, a bacterial degradation member 832 degrades to expose embodiments of the drug components 806 and 808, thereby providing the release of the drug from the oral drug dosage form 800. The delay component of oral drug dosage form 800 is not mixed with the drug and comprises a pH-based enteric coating member configured to be eroded at a predetermined pH value or higher, and an erosive delay component containing an erosive material. The pH-based enteric coating member and shell prevent erosion of the erosive delay component, and the erosive delay component and shell prevent erosion of the drug component. Specifically, in oral drug dosage form 800 of Figure 1J, the delay component comprises a pair of layers: an erosive delay component 812 in the first layer, a pH-based enteric coating member 818 in the first layer, an erosive delay component 822 in the second layer, and a pH-based enteric coating member 824 in the second layer. The oral drug dosage form 800 is configured such that the top surface 806 of the layer of drug component 804 is in direct contact with the bottom surface 814 of the erosive retarder member 812 of the first layer, and the top surface 816 of the erosive retarder member 812 of the first layer is in direct contact with the bottom surface 820 of the pH-based enteric coating member 818 of the first layer. The layers of the second set of retarder components are arranged similarly, specifically, the bottom surface 808 of the layer of drug component 804 is in direct contact with the erosive retarder member 822 of the second layer, and the erosive retarder member 822 of the second layer is in direct contact with the pH-based enteric coating member 824 of the second layer. As shown in Figure 1J, the pH-based enteric coating members 818, 824 and the shell 802 completely surround the erosive retarder members 812, 822, the bacterial degradation member 832 and the drug component 804.In some embodiments, the oral drug dosage form is configured such that the drug component is released from the oral drug dosage form at several points after administration, for example, after erosion by another component of the drug dosage form, such as a bacterial degrading agent. In such embodiments, the release of the drug from the drug component takes into account, for example, the surface area of ​​the drug component exposed to gastrointestinal fluid.

[0075] In a particular embodiment, the oral drug dosage form provided herein includes a first pH-based enteric coating and a second pH-based enteric coating. As shown in Figure 1K, after administration, the outer surface of the oral drug dosage form 900 constituting the first pH-based enteric coating 902 is exposed to gastrointestinal fluid within the body. When the first pH threshold is met, for example, based on a pH value of about 5.5 or higher, or a portion thereof, the material of the first pH-based enteric coating 902 is eroded from its surface, for example, as indicated by the directions of arrows 910 and 912. Based on the design of the first pH-based enteric coating 902, it is possible to prevent gastric fluid from penetrating the oral drug dosage form 900. Then, when the second pH threshold is met, for example, based on the pH in or near the colon or a portion thereof, the material on the surface of the second pH-based enteric coating 906 is eroded from the oral drug dosage form 900. Based on the design of the second pH-based enteric coating member 906, the drug can be prevented from being released in the small intestine. Based on the designs of the first pH-based enteric coating member 902 and the second pH-based enteric coating member 906, the erosive delay member 904, or a portion thereof (e.g., the surface), can be controllably exposed to gastrointestinal fluid. Based on exposure to gastrointestinal fluid, the erosive delay member 904 is eroded accordingly, thereby providing the release of the drug from the oral drug dosage form 900. The design of the delay component (in Figure 1K, the delay component includes the first pH-based enteric coating member 902, the second pH-based enteric coating member 906, and the erosive delay member 904) allows certain aspects of the drug component 908 to be exposed so as to provide a controlled release profile for the drug from the oral drug dosage form 900.

[0076] In some embodiments, the description of oral drug dosage forms and related methods provided herein is facilitated by describing the thickness of components such as a single layer of erosion retarder. In some embodiments, the thickness of components such as a single layer of erosion retarder is measured from a surface, such as the top face, in a direction substantially parallel to the direction of erosion. For example, as shown in Figure 1G, the thickness of a single layer of erosion retarder not mixed with drug 612 is provided.

[0077] Figure 2 shows an exemplary oral drug dosage form containing a drug. As shown in Figure 2, the oral drug dosage form includes a shell not mixed with the drug, an internal drug component containing a first erosive material mixed with the drug, and a delay component not mixed with the drug, the delay component comprising two layers of pH-based enteric coating configured to erode above a predetermined pH value, and three layers of erosive delay components containing the erosive material, each layer of pH-based enteric coating and the shell preventing erosion of the individual layers of erosive delay components, and the erosive delay components and the shell preventing erosion of the drug component. After administration, the two layers of erosive delay components are exposed to gastrointestinal fluid so that erosion of the layers of pH-based enteric coating begins to erode the two layers of erosive delay components. Erosion of one of the layers of erosive delay components exposes one surface of the drug component. Erosion of one layer of the erosive retarder exposes another layer of the erosive retarder (described as the VA64 layer, but not limited to such a material) on one side of the drug component. After erosion of the VA64 layer of the erosive retarder, another surface of the drug component is exposed. The exposed surface of the drug component is eroded, releasing the drug from the oral drug dosage form. As shown in Figure 2, the oral drug dosage form may contain tracking features such as tracking stripes and / or loops. Such tracking stripes are useful in the development and optimization of the oral drug dosage form, for example, by using imaging of the individual after administration, for example, using X-rays, to determine the location of erosion in the embodiment of the drug dosage form. Oral drug dosage forms without one or more tracking stripes are also included in the disclosures provided herein. For example, as the oral drug dosage form is developed and optimized, tracking stripes may no longer be necessary. In such embodiments, a portion of the tracking stripe may be replaced by the embedded material, and / or additional adjustments may be made, such as adjustments to one or more drug component characteristics (e.g., surface area, thickness, drug mass fraction), in consideration of the absence of the tracking stripe. The dimensions shown in Figure 2 are shown in Table 1A.

[0078] [Table 1A]

[0079] In some embodiments, the shell comprises ethylcellulose (EC, e.g., EC-N10), dibutyl sebacate (DBS), and titanium dioxide (TiO2). In some embodiments, the pH-based enteric coating comprises vinyl acetate copolymer (VA64), Eudragit® L100-55 (poly(methacrylate-co-ethyl acrylate, L100-55)), and triethyl citrate (TEC). In some embodiments, the erosion retarder comprises hydroxypropylcellulose (e.g., HPCJF), anhydrous dibasic calcium phosphate (CaHPO4), and TEC. In some embodiments, the erosion retarder, such as the VA64 layer, is VA It contains 64 and polyethylene glycol (PEG, e.g., PEG4000). In some embodiments, the drug component includes a drug such as tofacitinib, e.g., tofacitinib citrate. In some embodiments, the drug component includes a drug such as tofacitinib, e.g., tofacitinib citrate, barium sulfate (BaSO4), and PEG such as PEG20000. In some embodiments, the tracking strip includes barium sulfate (BaSO4) and PEG such as PEG20000.

[0080] In some embodiments, the oral drug dosage forms in Table 1A include the weight of each component listed in Table 1B in w / w% and the total weight.

[0081] [Table 1B]

[0082] An exemplary oral drug dosage form containing a drug is shown in Figure 3. As shown in Figure 3, the oral drug dosage form comprises a shell not mixed with the drug, an internal drug component containing a first erosive material mixed with the drug, and a delay component not mixed with the drug, the delay component comprising two layers of pH-based enteric coating configured to erode above a predetermined pH value, and two layers of erosive delay components containing the erosive material, where each layer of pH-based enteric coating and the shell prevents erosion of the individual layers of erosive delay components, and the erosive delay components and the shell prevent erosion of the drug component. After administration, erosion of the layers of pH-based enteric coating exposes the erosive delay components to gastrointestinal fluid so that they then begin to erode. Next, erosion of the layers of erosive delay components exposes the surface of the drug component so that erosion releases the drug from the oral drug dosage form. As shown in Figure 3, the oral drug dosage form may contain tracking stripes. Such tracking stripes are useful in the development and optimization of oral drug dosage forms, for example, by using imaging of the individual after administration, for example, using X-rays, to determine the location of erosion of the drug dosage form. Oral drug dosage forms that do not have one or more tracking stripes are also included in the disclosures provided herein. For example, as oral drug dosage forms are developed and optimized, tracking stripes may no longer be necessary. The dimensions shown in Figure 3 are shown in Table 2A.

[0083] [Table 2A]

[0084] In some embodiments, the shell comprises ethylcellulose (EC, e.g., EC-N10), dibutyl sebacate (DBS), and titanium dioxide (TiO2). In some embodiments, the pH-based enteric coating comprises vinyl acetate copolymer (VA64), Eudragit® L100-55 (poly(methacrylate-co-ethyl acrylate), L100-55), and triethyl citrate (TEC). In some embodiments, the erosion retardant comprises hydroxypropylcellulose (e.g., HPCJF), calcium hydrophosphate (CaHPO4), and TEC. In some embodiments, the drug component comprises a drug such as tofacitinib, e.g., tofacitinib citrate. In some embodiments, the drug component comprises a drug such as tofacitinib, e.g., tofacitinib citrate, VA64, and TEC. In some embodiments, the tracking strip comprises barium sulfate (BaSO4), VA64, and TEC.

[0085] In some embodiments, the oral drug dosage forms in Table 2A include the weight of each component listed in Table 2B in w / w% and the total weight.

[0086] [Table 2B]

[0087] An exemplary oral drug dosage form containing a drug is shown in Figure 4. As shown in Figure 4, the oral drug dosage form comprises a shell not mixed with the drug, an internal drug component containing a first erosive material mixed with the drug, and a delay component not mixed with the drug, the delay component comprising two layers of pH-based enteric coating configured to erode above a predetermined pH value, and two layers of erosive delay components containing the erosive material, each layer of pH-based enteric coating and the shell preventing erosion of the individual layers of erosive delay components, and the erosive delay components and the shell preventing erosion of the drug component. After administration, the erosive delay components are exposed to gastrointestinal fluid so that erosion of the layers of pH-based enteric coating begins to erode the erosive delay components. Next, erosion of the layers of erosive delay components exposes the surface of the drug component so that erosion releases the drug from the oral drug dosage form. As shown in Figure 4, the oral drug dosage form may contain tracking stripes. Such tracking stripes are useful in the development and optimization of oral drug dosage forms, for example, by using imaging of the individual after administration, for example, using X-rays, to determine the location of erosion of the drug dosage form. Oral drug dosage forms that do not have one or more tracking stripes are also included in the disclosures provided herein. For example, as oral drug dosage forms are developed and optimized, tracking stripes may no longer be necessary. The dimensions shown in Figure 4 are shown in Table 3A.

[0088] [Table 3A]

[0089] In some embodiments, the shell comprises ethylcellulose (EC, e.g., EC-N10), dibutyl sebacate (DBS), and titanium dioxide (TiO2). In some embodiments, the pH-based enteric coating comprises vinyl acetate copolymer (VA64), Eudragit® L100-55 (poly(methacrylate-co-ethyl acrylate, L100-55)), triethyl citrate (TEC), and titanium dioxide (TiO2). In some embodiments, the erosion retardant comprises hydroxypropyl cellulose (e.g., HPCJF), TEC, vitamin E polyethylene glycol 1000 succinate (TPGS), and TiO2. In some embodiments, the drug component comprises a drug such as tofacitinib, e.g., tofacitinib citrate. In some embodiments, the drug component comprises a drug such as tofacitinib, e.g., tofacitinib citrate, VA64, and TEC. In some embodiments, the tracking strip or tracking loop comprises barium sulfate (BaSO4), VA64, and TEC.

[0090] In some embodiments, the oral drug dosage forms in Table 3A include the weight of each component listed in Table 3B in w / w% and the total weight.

[0091] [Table 3B]

[0092] An exemplary oral drug dosage form containing a drug is shown in Figure 4. As shown in Figure 4, the oral drug dosage form comprises a shell not mixed with the drug, an internal drug component containing a first erosive material mixed with the drug, and a delay component not mixed with the drug, the delay component comprising two layers of pH-based enteric coating configured to erode above a predetermined pH value, and two layers of erosive delay components containing the erosive material, where each layer of pH-based enteric coating and the shell prevents erosion of the individual layers of erosive delay components, and the erosive delay components and the shell prevent erosion of the drug component. After administration, erosion of the layers of pH-based enteric coating exposes the erosive delay components to gastrointestinal fluid so that they then begin to erode. Next, erosion of the layers of erosive delay components exposes the surface of the drug component so that erosion releases the drug from the oral drug dosage form. As shown in Figure 4, the oral drug dosage form may contain tracking stripes. Such tracking stripes are useful in the development and optimization of oral drug dosage forms, for example, by using imaging of the individual after administration, for example, using X-rays, to determine the location of erosion of the drug dosage form. Oral drug dosage forms that do not have one or more tracking stripes are also included in the disclosures provided herein. For example, as oral drug dosage forms are developed and optimized, tracking stripes may no longer be necessary. The dimensions shown in Figure 4 are shown in Table 4A.

[0093] [Table 4A]

[0094] In some embodiments, the shell comprises ethylcellulose (EC, e.g., EC-N10), dibutyl sebacate (DBS), and titanium dioxide (TiO2). In some embodiments, the pH-based enteric coating comprises vinyl acetate copolymer (VA64), Eudragit® L100-55 (poly(methacrylate-co-ethyl acrylate, L100-55)), triethyl citrate (TEC), and titanium dioxide (TiO2). In some embodiments, the erosion retardant comprises hydroxypropyl cellulose (e.g., HPCJF), TEC, vitamin E polyethylene glycol 1000 succinate (TPGS), and TiO2. In some embodiments, the drug component comprises a drug such as tofacitinib, e.g., tofacitinib citrate, VA64, and TEC. In some embodiments, the drug component comprises a drug such as tofacitinib, e.g., tofacitinib citrate. In some embodiments, the tracking strip or tracking loop comprises barium sulfate (BaSO4), VA64, and TEC.

[0095] In some embodiments, the oral drug dosage forms in Table 4A include the weight of each component listed in Table 4B in w / w% and the total weight.

[0096] [Table 4B]

[0097] Exemplary oral drug dosage forms containing a drug are described below based on the dimensional descriptors provided in Figure 11. The oral drug dosage forms in Figure 11 do not include a shell. As shown in Figure 11, the oral drug dosage form includes an internal drug component containing a first erosive material mixed with the drug, and a delay component not mixed with the drug, the delay component comprising a pH-based enteric coating configured to erode above a predetermined pH value, and an erosive delay component containing the erosive material. After administration, erosion of the pH-based enteric coating exposes at least a portion of the erosive delay component to gastrointestinal fluid so that the erosive delay component (or a portion thereof) begins to erode. Subsequently, erosion of the erosive delay component exposes one or more surfaces of the drug component so that the erosion releases the drug from the oral drug dosage form. As shown in Figure 11, the oral drug dosage form may contain tracking features such as tracking stripes or loops (such terms may be used interchangeably). Such tracking stripes are useful in the development and optimization of oral drug dosage forms, for example, by using imaging of the individual after administration, for example, using X-rays, to determine the location of erosion of the drug dosage form. Oral drug dosage forms that do not have one or more tracking stripes are also included in the disclosures provided herein. For example, as oral drug dosage forms are developed and optimized, tracking stripes may no longer be necessary. The dimensions shown in Figure 11 are shown in Table 5A. H1 is 2.38 mm and H2 is 1.92 mm.

[0098] [Table 5A]

[0099] In some embodiments, the pH-based enteric coating comprises hypromellose acetate succinate AS-LG (HPMCASLG), triethyl citrate (TEC), and titanium dioxide (TiO2). In some embodiments, the erosion retardant comprises hydroxypropyl cellulose (e.g., HPCJF), TEC, vitamin E polyethylene glycol 1000 succinate (TPGS), and TiO2. In some embodiments, the drug component comprises a drug such as tofacitinib, e.g., tofacitinib citrate. In some embodiments, the drug component comprises a drug such as tofacitinib, e.g., tofacitinib citrate, VA64, and TEC. In some embodiments, the drug component comprises a drug such as tofacitinib, e.g., tofacitinib citrate. In some embodiments, the tracking strip or tracking loop comprises barium sulfate (BaSO4), VA64, and TEC.

[0100] In some embodiments, the oral drug dosage forms in Table 5A include the weight of each component listed in Table 5B in w / w% and the total weight.

[0101] [Table 5B]

[0102] Exemplary oral drug dosage forms, including drugs, are described below based on the dimensional descriptors provided in Figure 11. The oral drug dosage forms in Figure 11 do not include a shell. As shown in Figure 11, oral drug dosage forms may include tracking features such as tracking stripes or loops (such terms may be used interchangeably). Such tracking stripes are useful in the development and optimization of oral drug dosage forms, for example, by using imaging of the individual after administration, for example, using X-rays, to determine the location of erosion of the drug dosage form. Oral drug dosage forms that do not have one or more tracking stripes are also included in the disclosures provided herein. For example, as oral drug dosage forms are developed and optimized, tracking stripes may become unnecessary. The dimensions shown in Figure 11 are shown in Table 6A. H1 is 1.59 mm and H2 is 1.13 mm.

[0103] [Table 6A]

[0104] In some embodiments, the pH-based enteric coating comprises hypromellose acetate succinate AS-LG (HPMCASLG), triethyl citrate (TEC), and titanium dioxide (TiO2). In some embodiments, the erosion retardant comprises hydroxypropyl cellulose (e.g., HPCJF), TEC, vitamin E polyethylene glycol 1000 succinate (TPGS), and TiO2. In some embodiments, the drug component comprises a drug such as tofacitinib, e.g., tofacitinib citrate. In some embodiments, the drug component comprises a drug such as tofacitinib, e.g., tofacitinib citrate, VA64, and TEC. In some embodiments, the drug component comprises a drug such as tofacitinib, e.g., tofacitinib citrate. In some embodiments, the tracking strip or tracking loop comprises barium sulfate (BaSO4), VA64, and TEC.

[0105] In some embodiments, the oral drug dosage forms in Table 6A include the weight of each component listed in Table 6B in w / w% and the total weight.

[0106] [Table 6B]

[0107] Exemplary oral drug dosage forms, including drugs, are described below based on the dimensional descriptors provided in Figure 11. The oral drug dosage forms in Figure 11 do not include a shell. As shown in Figure 11, oral drug dosage forms may include tracking features such as tracking stripes or loops (such terms may be used interchangeably). Such tracking stripes are useful in the development and optimization of oral drug dosage forms, for example, by using imaging of the individual after administration, for example, using X-rays, to determine the location of erosion of the drug dosage form. Oral drug dosage forms that do not have one or more tracking stripes are also included in the disclosures provided herein. For example, as oral drug dosage forms are developed and optimized, tracking stripes may no longer be necessary. The dimensions shown in Figure 11 are shown in Table 7A.

[0108] [Table 7A]

[0109] In some embodiments, the pH-based enteric coating comprises hypromellose acetate succinate AS-LG (HPMCASLG), triethyl citrate (TEC), and titanium dioxide (TiO2). In some embodiments, the erosion retardant comprises hydroxypropyl cellulose (e.g., HPCJF), TEC, vitamin E polyethylene glycol 1000 succinate (TPGS), and TiO2. In some embodiments, the drug component comprises a drug such as tofacitinib, e.g., tofacitinib citrate. In some embodiments, the drug component comprises a drug such as tofacitinib, e.g., tofacitinib citrate, VA64, and TEC. In some embodiments, the drug component comprises a drug such as tofacitinib, e.g., tofacitinib citrate. In some embodiments, the tracking strip or tracking loop comprises barium sulfate (BaSO4), VA64, and TEC.

[0110] In some embodiments, the oral drug dosage forms in Table 7A include the weight of each component listed in Table 7B in w / w% and the total weight.

[0111] [Table 7B]

[0112] Exemplary oral drug dosage forms containing the drug are described below based on the dimensional descriptors provided in Figure 11. The oral drug dosage forms in Figure 11 do not include a shell or tracking stripe. The dimensions shown in Figure 11 are shown in Table 8A.

[0113] [Table 8A]

[0114] In some embodiments, the pH-based enteric coating comprises hypromellose acetate succinate AS-LG (HPMCASLG), acetyl tributyl citrate (ATBC), and titanium dioxide (TiO2). In some embodiments, the erosion retardant comprises hydroxypropyl cellulose (e.g., HPCJF), TEC, vitamin E polyethylene glycol 1000 succinate (TPGS), and TiO2. In some embodiments, the drug component comprises a drug such as tofacitinib, e.g., tofacitinib citrate. In some embodiments, the drug component comprises a drug such as tofacitinib, e.g., tofacitinib citrate, VA64, hydroxypropyl cellulose (HPCSSL), and triacetin.

[0115] In some embodiments, the oral drug dosage forms in Table 8A include the weight of each component listed in Table 8B in w / w% and the total weight.

[0116] [Table 8B] B. Components and composition of oral drug formulations described herein

[0117] In certain embodiments, this specification provides an oral drug dosage form comprising (1) a drug component comprising an erosive material mixed with a drug, and (2) a delay component not mixed with the drug, wherein the delay component comprises a pH-based enteric member configured to erode at a predetermined pH value or higher, and optionally one or more additional features described herein, such as (i) an erosive delay component comprising an erosive material, (ii) a bacterial degradation component comprising a bacterial degradation portion, or (iii) an excipient component comprising an excipient. In any of the above embodiments, the oral drug dosage form may contain a shell not mixed with the drug. The components described herein may be in the form of one or more layers. In some embodiments, the delay component of the oral drug dosage form comprises two or more sets of layers of pH-based enteric member and optionally, an erosive delay component (e.g., a first set of pH-based enteric member and erosive delay component of the first layer, and a second set of pH-based enteric member and erosive delay component of the second layer). Furthermore, the components of the oral drug dosage forms described herein may be arranged such that the oral drug dosage form includes one or more compartments, for example, a first compartment containing the drug component and a second compartment containing a bacterial degrading agent and / or excipient.

[0118] In some embodiments, an oral drug dosage form is provided which is configured to release the drug at a desired location in the colon of an individual, the oral drug dosage form comprising a drug component comprising an erosive material mixed with the drug, and a delay component not mixed with the drug, the delay component being configured to prevent the release of the drug from the drug component until the oral drug dosage form reaches the colon of the individual after administration, the delay component comprising a pH-based enteric component comprising an erosive material configured to be eroded at a predetermined pH value or higher.

[0119] In some embodiments, the oral drug dosage form does not include an erosive retarder, and for example, the oral drug dosage form essentially consists of a drug component and a pH-based enteric coating. In some embodiments, the erosive material of the pH-based enteric coating includes one or more of the following: hypromellose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate propionate (CAP), poly(co-ethyl acrylate methacrylate), or polyvinyl acetate phthalate (PVAP). In some embodiments, the hypromellose acetate succinate is HPMCSLG / LF, HPMCSMG / MF, or HPMCSHG / LF. In some embodiments, the hydroxypropyl methylcellulose phthalate is HPMCPHP-50 or HPMCPHP-55. In some embodiments, the poly(co-ethyl acrylate methacrylate) is EudragitL100-55 or EudragitL100.

[0120] In some embodiments, an oral drug dosage form is provided configured to release the drug at a desired location in the colon of an individual, the oral drug dosage form comprising a drug component containing an erosive material mixed with the drug, and a delay component not mixed with the drug, the delay component configured to prevent the release of the drug from the drug component until the oral drug dosage form reaches the colon of the individual after administration, the delay component comprising a pH-based enteric component containing an erosive material configured to be eroded above a predetermined pH value, and an erosive delay component, the oral drug dosage form configured such that the pH-based enteric component is eroded before the erosive delay component. In some embodiments, the oral drug dosage form is configured such that the pH-based enteric component is eroded before the erosive delay component. In such embodiments, the pH-based enteric component does not need to be completely eroded before the erosive delay component begins to erode (although in some embodiments this does). In some embodiments, the pH-based enteric coating prevents at least partially the erosion of the erosion retarding member (e.g., the pH-based enteric coating is in direct contact with the erosion retarding member), and the erosion retarding member prevents at least partially the erosion of the drug component (e.g., the erosion retarding member is in direct contact with the drug component). In some embodiments, the oral drug dosage form includes one or more intermediate materials positioned between the other components of the oral drug dosage form, such as intermediate materials not mixed with the drug.

[0121] In embodiments provided herein, an oral drug dosage form comprises a second drug. The second drug can be positioned within and / or mixed with any aspect of the oral drug dosage form. In some embodiments, the second drug is mixed with a drug component. In some embodiments, the oral drug dosage form further comprises a second drug component mixed with the second drug (which may be the same as or different from the drug of the drug component). The second drug component mixed with the second drug component can be positioned in a wide variety of configurations based on the desired release of the second drug (in some embodiments, the drug). For example, in some embodiments, the drug component is embedded in the second drug component, and the oral drug dosage form is configured such that a pH-based enteric coating is eroded before an erosive retarder, the erosive retarder is eroded before the second drug component, the second drug component is eroded before the second erosive retarder, and the second erosive retarder is eroded before the drug component. In some embodiments, the second drug component is located in a separate compartment from the drug component, for example, to allow independent release of the second drug and the drug. In some embodiments, the oral drug dosage form includes a second drug component and a second erosion retarder component. In such embodiments, the oral drug dosage form is configured such that a pH-based enteric coating is eroded before the erosion retarder component, the erosion retarder component is eroded before the second drug component, the second drug component is eroded before the second erosion retarder component, and the second erosion retarder component is eroded before the drug component. The above embodiments can be extrapolated to the inclusion of additional drugs and drug components, such as two or more drugs, three or more drugs, four or more drugs, five or more drugs, etc.

[0122] In embodiments provided herein, the oral drug dosage form includes a biodegradable portion. The biodegradable portion may be positioned within and / or mixed with the embodiment of the oral drug dosage form, but generally, the biodegradable portion is not mixed with the pH-based enteric coating. In some embodiments, the biodegradable portion is mixed with the erosive material of the erosive retarder member. In some embodiments, the biodegradable portion is mixed with the drug component. For example, in some embodiments, the drug component provides control over drug release in the colon, and the drug component further includes the biodegradable portion. In some embodiments, the oral drug dosage form includes a biodegradable member comprising an erosive material mixed with the biodegradable portion. The biodegradable member can be positioned in a wide variety of configurations. For example, in some embodiments, the retarder component further includes a biodegradable member comprising an erosive material mixed with the biodegradable portion, and the oral drug dosage form is configured such that the pH-based enteric coating is eroded before the erosive retarder member, the erosive retarder member is eroded before the biodegradable member, and the biodegradable member is eroded before the drug component. In some embodiments, the pH-based enteric coating prevents at least partially the erosion retarding member, the erosion retarding member prevents at least partially the erosion of the bacterial degradation member, and the bacterial degradation member prevents at least partially the erosion of the drug component. In some embodiments, the bacterial degradation portion and / or bacterial degradation member are located in a separate compartment from the drug component.

[0123] In the embodiments provided herein, the oral drug dosage form includes an excipient. The excipient can be positioned within and / or mixed with any aspect of the oral drug dosage form. In some embodiments, the excipient is mixed with the erosive material of an erosive retarder member. In some embodiments, the excipient is mixed with the drug component. In some embodiments, the oral drug dosage form includes an excipient component comprising an erosive material mixed with the excipient. The excipient component can be positioned in a wide variety of configurations. For example, in some embodiments, the excipient component further comprises an erosive material mixed with the excipient, and the oral drug dosage form is configured such that the pH-based enteric coating member is eroded before the erosive retarder member, the erosive retarder member is eroded before the excipient component, and the excipient component is eroded before the drug component. In some embodiments, the excipient and / or excipient component are located in a separate compartment from the drug component.

[0124] In some embodiments, the excipient is an absorption enhancer. In some embodiments, the oral drug dosage form is configured for topical delivery and does not include an excipient that is an absorption enhancer. In some embodiments, the oral drug dosage form is configured for systemic delivery and includes an excipient that is an absorption enhancer.

[0125] In embodiments provided herein, the oral drug dosage form includes an adjuvant. The adjuvant is administered via The adjuvant can be positioned within and / or mixed with any aspect of the oral drug dosage form. In some embodiments, the adjuvant is mixed with the erosive material of the erosive retarder member. In some embodiments, the adjuvant is mixed with the drug component. In some embodiments, the oral drug dosage form includes an adjuvant component comprising the erosive material mixed with the adjuvant. The adjuvant component can be positioned in a wide variety of configurations. For example, in some embodiments, the excipient component further comprises the erosive material mixed with the adjuvant, and the oral drug dosage form is configured such that the pH-based enteric coating member is eroded before the erosive retarder member, the erosive retarder member is eroded before the adjuvant component, and the adjuvant component is eroded before the drug component. In some embodiments, the adjuvant and / or the adjuvant component are located in a separate compartment from the drug component. In some embodiments, the adjuvant is selected based on the fact that the drug is a bioagent. For example, in some embodiments, when the drug is a peptide bioagent, the adjuvant is a protease scavenger and / or protease inhibitor. In some embodiments, when the drug is a nucleic acid bioagent, the adjuvant is lipid nanoparticles (LNPs). In some embodiments, the lipid nanoparticles are selected from the group consisting of ionizable lipids, helper lipids, cholesterol, and pegylated lipids (PEG-lipids).

[0126] In some embodiments, the oral drug dosage form does not include a shell. In some embodiments, the oral drug dosage form includes a shell that is not mixed with the drug component. In such embodiments, the oral drug dosage form is configured such that the shell or a portion thereof and a delaying member prevent erosion of the drug component. In some embodiments, the direction of erosion of the delaying member and / or the drug component is based on the configuration of the shell.

[0127] For any of the oral drug dosage forms described herein, one or more embodiments of the oral drug dosage form may be configured in the form of layers, such as layers having a top surface, a bottom surface, and thickness. Furthermore, geometric configurations of embodiments of oral drug dosage forms, such as drug components including a spherical shape or a part thereof, are assumed herein. In some embodiments, one or more embodiments of the oral drug dosage form may be configured in the form of compartments. In some embodiments, the oral drug dosage form includes one or more compartments containing one or more drug components. In some embodiments, the oral drug dosage form includes one or more compartments containing one or more drug components, such as excipients and / or adjuvant components, and one or more additional embodiments.

[0128] The oral drug dosage forms described herein may be, for example, any size, shape, or weight suitable for oral administration. In some embodiments, the oral drug dosage form is suitable for oral administration to an individual, and the size, shape, and / or weight of the oral drug dosage form are based on the attributes of the individual. In some embodiments, the individual's attributes are one or more of height, weight, or age. In some embodiments, the individual is an infant. In some embodiments, the individual is a child. In some embodiments, the individual is a young adult. In some embodiments, the individual is an adult.

[0129] In some embodiments, the maximum transverse dimension of the oral drug dosage form, for example, the maximum diameter, is about 1 mm to about 25 mm, for example, about 2 mm to about 10 mm, about 5 mm to about 12 mm, about 8 mm to about 15 mm, about 5 mm to about 10 mm, or about 7 mm to about 9 mm. In some embodiments, the maximum transverse dimension of the oral drug dosage form, for example, the maximum diameter, is less than about 25 mm, for example, less than about 24 mm, 23 mm, 22 mm, 21 mm, 20 mm, 19 mm, 18 mm, 17 mm, 16 mm, 15 mm, 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm, 2 mm, or 1 mm. In some embodiments, the maximum transverse dimension of the oral drug dosage form, for example, the maximum diameter, is greater than about 1 mm and is greater than any of the following: about 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, or 25 mm. In some embodiments, the maximum transverse dimension of the oral drug dosage form, for example, the maximum diameter, is about 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, or 25 mm.

[0130] In some embodiments, the oral drug dosage form has a thickness of about 1 mm to about 25 mm, for example, about 2 mm to about 10 mm, about 5 mm to about 12 mm, about 8 mm to about 15 mm, about 5 mm to about 10 mm, or about 7 mm to about 9 mm. In some embodiments, the oral drug dosage form has a thickness of less than about 25 mm, for example, less than about 24 mm, 23 mm, 22 mm, 21 mm, 20 mm, 19 mm, 18 mm, 17 mm, 16 mm, 15 mm, 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm, 2 mm, or 1 mm. In some embodiments, the oral drug dosage form has a thickness greater than about 1 mm, for example, about 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, or 25 mm. In some embodiments, the oral drug dosage form has a thickness of about 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, or 25 mm.

[0131] In some embodiments, the shape of the oral drug dosage form includes cylindrical, elliptical, bullet-shaped, arrowhead-shaped, triangular, arc-triangular, square, arc-square, rectangular, arc-rectangular, rhombus, pentagon, hexagon, octagon, crescent, almond-shaped, or combinations thereof.

[0132] In some embodiments, the shape of the oral drug dosage form includes cylindrical, elliptical, bullet-shaped, arrowhead-shaped, triangular, arc-triangular, square, arc-square, rectangular, arc-rectangular, rhombus, pentagon, hexagon, octagon, crescent, almond-shaped, or a combination thereof, and the maximum transverse dimension of the oral drug dosage form, for example, the maximum diameter, is any of approximately 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, or 25 mm.

[0133] In some embodiments, the total weight of the oral drug dosage form is approximately 20 mg to approximately 1500 mg, for example, approximately 50 mg to approximately 150 mg, approximately 150 mg to approximately 250 mg, approximately 160 mg to approximately 170 mg, approximately 250 mg to approximately 350 mg, approximately 350 mg to approximately 450 mg, approximately 450 mg to approximately 550 mg, approximately 550 mg to approximately 650 mg, approximately 650 mg to approximately 750 mg, approximately 750 mg to approximately 850 mg, approximately 850 mg to approximately 950 mg, approximately 950 mg to approximately 1050 mg, approximately 1050 mg to approximately 1150 mg, approximately 1150 mg to approximately 1250 mg, approximately 1250 mg to approximately 1350 mg, or approximately 1350 mg to approximately 1450 mg. In some embodiments, the total weight of the oral drug dosage form is less than approximately 1500 mg, for example, approximately 1450 mg, 1400 mg, 1350 mg, 1300 mg, 1250 mg, 1200 mg, 1150 mg, 1100 mg, 1050 mg, 1000 mg, 950 mg, 900 mg, 850 mg, 800 mg, 750 mg, 700 mg, 650 mg, 600 mg, 550 mg, 500 mg, 475 mg, 4 Less than any of the following: 50mg, 425mg, 400mg, 375mg, 350mg, 325mg, 300mg, 275mg, 250mg, 225mg, 200mg, 175mg, 150mg, 125mg, 100mg, 95mg, 90mg, 85mg, 80mg, 75mg, 70mg, 65mg, 60mg, 55mg, 50mg, 45mg, 40mg, 35mg, 30mg, or 25mg. In some embodiments, the total weight of the oral drug dosage form is greater than about 20 mg, for example, about 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg g, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, or 1450 mg, whichever is greater.In some embodiments, the total weight of the oral drug dosage form is approximately 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 160 mg, 165 mg, 170 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 32 mg The dosage is one of the following: 5mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, or 1450mg.

[0134] As disclosed herein, the components of an oral drug dosage form may consist of a number of shapes and sizes. Unless otherwise specified, references to a particular shape, size, and measurement reflect the oral drug dosage form before administration to a human organism, for example, before erosion of any of its components. Further discussion of the components of the oral drug dosage forms provided herein is included in the following sections. Such a modular discussion of components does not limit the scope of the invention, and those skilled in the art will readily understand how certain features from the following sections can be combined with the oral drug dosage forms taught herein. 1. Drug components

[0135] The oral drug dosage forms disclosed herein include a drug component comprising an erosive material mixed with a drug. The drug components incorporated herein may be formed using a number of materials having various shapes, sizes and erosion rates (including materials having a range of drug mass fractions). In some embodiments, the oral drug dosage form includes a second drug component comprising a drug, and the drug and / or the erosive material of the drug component and the second drug component may be the same or different. In some embodiments, the oral drug dosage form comprises two or more compartments, and various configurations of the drug component are assumed herein such that a compartment may contain one drug component, two or more drug components, or no drug components at all. Further descriptions of drug components are applicable to additional drug components, such as a second drug component.

[0136] In some embodiments, the drug component is a layer. In some embodiments, the drug component includes a layer comprising a plurality of beads, for example, a plurality of nanoparticles.

[0137] In some embodiments, the drug component is surrounded, for example, completely surrounded, by a delay component (e.g., a pH-based enteric coating, and optionally, an erosive delay component and / or shell). In some embodiments, the drug component is configured to have a surface, including one or more surfaces designed to be exposed to body fluids (e.g., gastrointestinal fluid) after administration of the oral drug dosage form to a human individual and after erosion / dissolution of the delay component. In some embodiments, the drug component is a layer including a top and bottom surface. In some embodiments, the drug component includes one or more sides, such as sides substantially perpendicular to the top or bottom surface of the drug component. In some embodiments, at least one of the one or more sides of the drug component is associated with (e.g., in direct contact with) an embodiment of the delay component and / or shell of the oral drug dosage form. For example, in some embodiments, the oral drug dosage form is configured such that, after erosion of the delay component, which includes a pH-based enteric coating and optionally an erosive delay component, the drug component maintains its position relative to the shell for a period of time during which at least a portion of the drug component is eroded in the presence of body fluids.

[0138] In some embodiments, the drug component has a predetermined shape and / or surface area and is configured to provide, for example, a desired release profile of the drug from an oral drug dosage form. For example, in some embodiments, the drug component releases the drug from the oral drug dosage form based on erosion of the drug component at any interface (e.g., apex and / or basal) exposed to body fluids. In some embodiments, the drug component has a apex and basal, whose extent is determined by exposure to body fluids during administration to an individual, for example. In some embodiments, the apex and basal of the drug component are exposed to body fluids simultaneously. In some embodiments, the apex and / or basal of the drug component, or at least a portion thereof, is flat (e.g., within a surface tolerance threshold measured between two parallel planes). In some embodiments, the apex and / or basal of the drug component is not flat and includes, for example, certain features that extend beyond the apex plane or surface tolerance threshold. The surface(s) of the drug component exposed to body fluids, e.g., the apex and / or basal, can have any shape based on the surface exposed to body fluids. In some embodiments, the surface(s) of the drug component exposed to bodily fluids may be capsule, circular, elliptical, bullet-shaped, arrowhead-shaped, triangular, arc-triangular, square, arc-square, rectangular, arc-rectangular, rhombus, pentagon, hexagon, octagon, crescent-shaped, almond-shaped, or a combination thereof.

[0139] In some embodiments, the surface(s) of the drug component first exposed to body fluids, e.g., the top and bottom surfaces, are approximately 10 mm in diameter. 2 ~400mm 2 For example, about 20mm 2 ~about 200mm 2 , about 20mm 2 ~approximately 100mm 2 , about 20mm 2 ~about 60mm 2 , about 30mm 2 ~approximately 50mm 2 It has one of the following surface areas. In some embodiments, the surface(s) of the drug component that are first exposed to the body fluid, e.g., the top and bottom surfaces, are at least about 20 mm 2 For example, at least about 22 mm2 , 24mm 2 , 26mm 2 , 28mm 2 , 30mm 2 , 32mm 2 ,33mm 2 , 34mm 2 , 36mm 2 , 38mm 2 , 40mm 2 , 42mm 2 , 44mm 2 , 46mm 2 , 48mm 2 , 50mm 2 , 52mm 2 , 54mm 2 , 56mm 2 , 58mm 2 , 60mm 2 , 65mm 2 , 70mm 2 , 80mm 2 , 85mm 2 , 90mm 2 , 95mm 2 , 100mm 2 , 110mm 2 , 120mm 2 , 130mm 2 , 140mm 2 , 150mm 2 , 160mm 2 , 170mm 2 , 180mm 2 , 190mm 2 , 200mm 2 , 225mm 2 , 250mm 2 , 275mm 2 , 300mm 2 , 325mm 2 , 350mm 2 , 375mm 2 , or 400mm 2 It has one of the following surface areas. In some embodiments, the surface(s) of the drug component first exposed to the body fluid, e.g., the top and bottom surfaces, is approximately 400 mm². 2 Less than, for example, 400mm 2 , 375mm 2 , 350mm 2 , 325mm2 、300 mm 2 、275 mm 2 、250 mm 2 、225 mm 2 、200 mm 2 、190 mm 2 、180 mm 2 、170 mm 2 、160 mm 2 、150 mm 2 、140 mm 2 、130 mm 2 、120 mm 2 、110 mm 2 、100 mm 2 、95 mm 2 、90 mm 2 、85 mm 2 、80 mm 2 、75 mm 2 、70 mm 2 、65 mm 2 、60 mm 2 、58 mm 2 、56 mm 2 、54 mm 2 、52 mm 2 、50 mm 2 、48 mm 2 、46 mm 2 、44 mm 2 、42 mm 2 、40 mm 2 、38 mm 2 、36 mm 2 、34 mm 2 、32 mm 2 、30 mm 2 、28 mm 2 、26 mm 2 、24 mm 2 、22 mm 2 、or less than 20 mm 2 and has a surface area of less than any of the above. In some embodiments, the surface of the drug component first exposed to body fluid, such as the top and bottom surfaces, is about 20 mm 2 、21 mm 2 、22 mm 2 、23 mm 2 、24 mm 2 、25 mm 2 、26 mm 2 、27 mm2 、28mm 2 、29mm 2 、30mm 2 、31mm 2 、32mm 2 、33mm 2 、34mm 2 、35mm 2 、36mm 2 、37mm 2 、38mm 2 、39mm 2 、40mm 2 、41mm 2 、42mm 2 、43mm 2 、44mm 2 、45mm 2 、46mm 2 、47mm 2 、48mm 2 、49mm 2 、50mm 2 、51mm 2 、52mm 2 、53mm 2 、54mm 2 、55mm 2 、56mm 2 、57mm 2 、58mm 2 、59mm 2 、60mm 2 、65mm 2 、70mm 2 、80mm 2 、85mm 2 、90mm 2 、95mm 2 、100mm 2 、110mm 2 、120mm 2 、130mm 2 、140mm 2 、150mm 2 、160mm 2 、170mm 2 、180mm 2 、190mm 2 、200mm 2 、225mm 2 、250mm 2 、275mm 2 、300mm 2, 325mm 2 , 350mm 2 , 375mm 2 , or 400mm 2 It has one of the following surface areas.

[0140] In some embodiments, the surface(s) of the drug component exposed to body fluids are substantially uniform over the entire thickness of the drug component (for example, determined by the distance of the drug component substantially perpendicular to the top and / or bottom surfaces), and, for example, as the drug component is eroded, the surface(s) exposed to body fluids have the same surface area. In some embodiments, the surface(s) of the drug component exposed to body fluids differ in two or more respects, and, for example, as the drug component is eroded, the surface(s) exposed to body fluids change during the erosion of the drug component, for example, increasing and / or decreasing. In some embodiments, the shape of the surface(s) of the drug component exposed to body fluids is uniform over the entire thickness of the drug component, and, for example, as the drug component is eroded, the surface(s) exposed to body fluids have the same shape. In some embodiments, the shape of the surface(s) of the drug component exposed to body fluids differs in two or more respects. In some embodiments, the drug component includes a bottom surface having substantially the same surface area as the surface area of ​​the top surface of the drug component. In some embodiments, the drug component includes a bottom surface having a surface area different from the surface area of ​​the top surface of the drug component.

[0141] In some embodiments, the surface of the drug component first exposed to body fluids, e.g., the top or bottom surface, has a maximum cross-sectional dimension of about 5 mm to about 20 mm, e.g., about 5 mm to about 15 mm, about 6 mm to about 13 mm, or about 7 mm to about 11 mm. In some embodiments, the surface of the drug component first exposed to body fluids, e.g., the top or bottom surface, has a maximum cross-sectional dimension of at least about 5 mm, e.g., at least about 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, or 20 mm. In some embodiments, the surface of the drug component first exposed to body fluids, e.g., the top or bottom surface, has a maximum transverse dimension of less than about 20 mm, e.g., less than any of the following: about 19 mm, 18 mm, 17 mm, 16 mm, 15 mm, 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, or 5 mm. In some embodiments, the surface of the drug component first exposed to body fluids, e.g., the top or bottom surface, has a maximum transverse dimension of any of the following: about 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, or 20 mm.

[0142] In some embodiments, the surface of the drug component first exposed to the body fluid, for example, the top or bottom surface, has a transverse dimension perpendicular to the maximum transverse dimension, which is about 1 mm to about 15 mm, for example, about 2 mm to about 15 mm, about 2 mm to about 6 mm, or about 1 to about 5 mm. In some embodiments, the surface of the drug component first exposed to the body fluid, for example, the top or bottom surface, has a transverse dimension perpendicular to the maximum transverse dimension, which is at least about 1 mm, for example, at least about 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, or 15 mm. In some embodiments, the surface of the drug component first exposed to body fluids, for example, the top or bottom surface, has a transverse dimension perpendicular to the maximum transverse dimension of less than about 15 mm, for example, less than any of about 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm, 2 mm, or 1 mm. In some embodiments, the surface of the drug component first exposed to body fluids, for example, the top or bottom surface, has a transverse dimension perpendicular to the maximum transverse dimension of any of about 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, or 15 mm.

[0143] In some embodiments, the drug component, for example, the drug component layer, has a thickness of about 0.1 mm to about 5 mm, for example, about 0.2 mm to about 2 mm, about 0.5 mm to about 1.5 mm, or about 0.8 mm to about 1.4 mm. In some embodiments, the drug component, for example, the drug component layer, has a thickness of at least about 0.1 mm, for example, at least about 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.2 mm, 2.4 mm, 2.6 mm, 2.8 mm, 3.0 mm, 3.2 mm, 3.4 mm, 3.6 mm, 3.8 mm, 4.0 mm, 4.2 mm, 4.4 mm, 4.6 mm, 4.8 mm, or 5 mm. In some embodiments, the drug component, for example, the drug component layer, has a thickness of less than about 5 mm, for example, less than any of the following: about 4.8 mm, 4.6 mm, 4.4 mm, 4.2 mm, 4.0 mm, 3.8 mm, 3.6 mm, 3.4 mm, 3.2 mm, 3.0 mm, 2.8 mm, 2.6 mm, 2.4 mm, 2.2 mm, 2.0 mm, 1.9 mm, 1.8 mm, 1.7 mm, 1.6 mm, 1.5 mm, 1.4 mm, 1.3 mm, 1.2 mm, 1.1 mm, 1.0 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, or 0.1 mm. In some embodiments, the drug component, for example, the drug component layer, has a thickness of approximately 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.2 mm, 2.4 mm, 2.6 mm, 2.8 mm, 3.0 mm, 3.2 mm, 3.4 mm, 3.6 mm, 3.8 mm, 4.0 mm, 4.2 mm, 4.4 mm, 4.6 mm, 4.8 mm, or 5 mm.

[0144] In some embodiments, the drug component, for example, the drug component layer, includes a top surface and a bottom surface, and the thickness measured between the top surface and the bottom surface is substantially uniform, such as within 20% of the average thickness.

[0145] In some embodiments, the drug component is present in a drug mass fraction (m) of approximately 0.05 to approximately 0.6, for example, approximately 0.05 to approximately 0.1, approximately 0.2 to approximately 0.5, approximately 0.3 to approximately 0.4, or approximately 0.3 to approximately 0.35. F ) has. In some embodiments, the drug component has a drug mass fraction (m) of at least about 0.05, for example, at least about 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, or 0.6. F ) has. In some embodiments, the drug component has a drug mass fraction (m) of less than about 0.6, for example, less than about 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1 or 0.05. F ) has. In some embodiments, the drug component has a drug mass fraction (m) of any of the following: about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55 or 0.6 of the drug component. F ) has.

[0146] In some embodiments, the drug component is configured for an immediate drug release profile, for example, an erosive material mixed with the drug is eroded (dissolved) upon contact with body fluids (e.g., gastrointestinal fluid), releasing the drug from the oral drug dosage form according to the immediate drug release profile. In some embodiments, the drug component is completely eroded within a period of about 1 minute to about 1 hour from the time of contact with gastrointestinal fluid, for example, about 5 minutes to about 30 minutes, about 5 minutes to about 20 minutes, or about 10 minutes to about 20 minutes. In some embodiments, the drug component is completely eroded within a period of less than about 1 hour from the time of contact with gastrointestinal fluid, for example, about 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute.

[0147] In some embodiments, the drug component is configured for a sustained drug release profile, for example, an erosive material mixed with the drug is eroded (dissolved) upon contact with body fluids (e.g., gastrointestinal fluid), releasing the drug from the oral drug dosage form according to the sustained drug release profile. In some embodiments, the drug component is completely eroded over a period of about 1 to 7 hours, for example, about 2 to 4 hours, or for example, about 2 to 3 hours, from the time of contact with gastrointestinal fluid. In some embodiments, the drug component is completely eroded over a period of at least about 1 hour, for example, at least about 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, or 7 hours, from the time of contact with gastrointestinal fluid.

[0148] In some embodiments, the amount of drug in the drug component is approximately 0.5 mg to approximately 500 mg. In some embodiments, the amount of drug in the drug component is approximately 1 mg or more, for example, approximately 5 mg or more, 10 mg or more, 15 mg or more, 20 mg or more, 25 mg or more, 30 mg or more, 35 mg or more, 40 mg or more, 45 mg or more, 50 mg or more, 55 mg or more, 60 mg or more, 65 mg or more, 70 mg or more, 75 mg or more, 80 mg or more, 85 mg or more, 90 mg or more, 95 mg or more, 100 mg or more, 110 mg or more, 120 mg or more, 130 mg or more, 140 mg or more, 150 mg or more, 160 mg or more, 170 mg or more, 180 mg or more, 190 mg or more, 200 mg The above amounts are 210 mg or more, 220 mg or more, 230 mg or more, 240 mg or more, 250 mg or more, 260 mg or more, 270 mg or more, 280 mg or more, 290 mg or more, 300 mg or more, 310 mg or more, 320 mg or more, 330 mg or more, 340 mg or more, 350 mg or more, 360 mg or more, 370 mg or more, 380 mg or more, 390 mg or more, 400 mg or more, 410 mg or more, 420 mg or more, 430 mg or more, 440 mg or more, 450 mg or more, 460 mg or more, 470 mg or more, 480 mg or more, 490 mg or more, or 500 mg or more.

[0149] In some embodiments, the weight ratio of the drug component to the delaying component is approximately 1:10 to approximately 10:1, for example, approximately 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, or 9:1.

[0150] In some embodiments, the oral drug dosage form contains one or more drug components. For example, in some embodiments, the oral drug dosage form contains drug components. In some embodiments, the oral drug dosage form contains two drug components. In some embodiments, the oral drug dosage form contains three drug components. In some embodiments, the oral drug dosage form contains four drug components. In some embodiments, the oral drug dosage form contains five drug components. In embodiments containing two or more drug components, the drug components may be the same or different from each other, for example, having the same or different shapes, sizes and / or configurations.

[0151] In some embodiments, the drug component, for example, the drug component layer, comprises a thermoplastic material, for example, a thermoplastic polymer. In some embodiments, the drug component, for example, the drug component layer, comprises a matrix material, a plasticizer, or a material comprising one or more of other additives, such as fillers, binders, lubricants, flow enhancers, and disintegrants.

[0152] In some embodiments, the drug component comprises one or more of the following: copolyvidone, polyvinylpyrrolidone-co-vinyl acetate, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose or hypromellose, polyethylene oxide, polyethylene glycol, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, KollicoatIR-polyvinyl alcohol, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, hydroxypropyl methylcellulose acetate succinate, hypromellose acetate succinate, hydroxypropyl methylcellulose phthalate, maltitol, lactose monohydrate, xylitol, isomalt, sucrose, glucose, or dextran 70.

[0153] In some embodiments, the plasticizer is one or more of the following: triethyl citrate, vitamin E polyethylene glycol succinate, acetylated triethyl citrate, tributyl citrate, O-acetyl tributyl citrate, polyoxyl 15 hydroxystearate, PEG-40 hydrogenated castor oil, polyoxyl 35 castor oil, dibutyl sebacate, diethyl phthalate, glycerin, methyl 4-hydroxybenzoate, castor oil, oleic acid, triacetin, polyalkylene glycol, stearic acid, palmitic acid, malic acid, polyethylene glycol, lauroyl PEG-32 glyceride, poloxamer 188, poloxamer 407, acetyl tributyl citrate, D-sorbitol, propylene glycol, diethyl phthalate, citric acid, glyceryl behenate, D-mannitol, polysorbate, sorbitan monostearate, sorbitan monooleate, or polyoxyl 40 stearate.

[0154] In some embodiments, other additives include acacia, alginate, alginic acid, aluminum acetate, butylparaben, butylated hydroxytoluene, citric acid, calcium carbonate, candelilla wax, croscarmellose sodium, powdered sugar, colloidal silicone dioxide, cellulose, plain or anhydrous calcium phosphate, carnuba wax, corn starch, carboxymethylcellulose calcium, disodium ethylenediaminetetraacetate, dehydrated calcium hydrogen phosphate, cetylpyridine chloride, dicalcium phosphate, tricalcium phosphate, dicalcium phosphate, disodium hydrogen phosphate, dimethicone, sodium erythrosine, ethylenediaminetetraacetate, gelatin, glyceryl monooleate, iron oxides, iron oxide yellow, iron oxide red, lacto One or more of the following: cellulose (hydrated, anhydrous, monohydrate, or spray-dried), microcrystalline cellulose, magnesium carbonate, magnesium oxide, methylparaben, polysorbate 80, propyleneparaben, potassium bicarbonate, potassium sorbate, potato starch, phosphoric acid, polyoxyethylene (40) stearate, sodium glycolate starch, pregelatinized starch, cross-linked sodium, sodium lauryl sulfate, starch, silicon dioxide, sodium benzoate, sucrose, sorbic acid, sodium carbonate, sodium saccharin, sodium alginate, silica gel, sorbitan monooleate, sodium chloride, dehydrated sodium citrate, sodium starch, carboxymethylcellulose, succinic acid, sodium propionate, titanium dioxide, or talc. 2. Drugs in oral dosage form

[0155] In some embodiments, the drug in the drug component of the oral drug dosage forms described herein can be any drug. In some embodiments, the drug is an anti-inflammatory agent, a nonsteroidal anti-inflammatory agent, a steroid, an immunosuppressant, an antibiotic, a biological agent, an antineoplastic agent, analgesic, an anesthetic, an anticonvulsant, an antidiabetic agent, an antihistamine, an anti-infective agent, an antitumor agent, an antiparkinson's disease agent, an antirheumatic agent, an appetite stimulant, an appetite suppressant, a blood regulator, a bone metabolism regulator, a cardiovascular agent, a central nervous system depressant, a central nervous system stimulant, a decongestant, a dopamine receptor agonist, an electrolyte, a gastrointestinal agent, an immunomodulator, a muscle relaxant, a narcotic, a parasympathetic agonist, a sympathetic agonist, a sedative, a hypnotic, or a vaccine. In some embodiments, the vaccine is a peptide-based vaccine or a nucleic acid-based vaccine such as an mRNA-based vaccine. In some embodiments, nucleic acid-based vaccines include RNA such as transfer RNA (tRNA), ribosomal RNA (rRNA), or messenger RNA (mRNA).

[0156] In some embodiments, the anti-inflammatory agent is a JAK inhibitor. In some embodiments, the drug is a JAK inhibitor. A JAK inhibitor is a drug that interferes with the JAK-STAT signaling pathway, such as an inhibitor of one or more components involved in the JAK-STAT signaling pathway (e.g., JAKinib). Components involved in the JAK-STAT signaling pathway and their inhibitors are known in the art. See, for example, Rawlingsetal, JCellSci, 117, 2004; and Schwartzetal, NatRevDrugDiscov, 17, 2017. In some embodiments, the JAK inhibitor is an inhibitor of one or more of Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), or tyrosine kinase 2 (TYK2). In some embodiments, the JAK inhibitor is an inhibitor of JAK1 and JAK3. In some embodiments, the JAK inhibitor is an inhibitor of JAK1, JAK3, and JAK2. In some embodiments, the JAK inhibitor is an inhibitor of JAK1, JAK3, JAK2, and TYK2. In some embodiments, the JAK inhibitor is an inhibitor of JAK1 and JAK2. In some embodiments, the JAK inhibitor is an inhibitor of JAK1, JAK2, and TYK2. In some embodiments, the JAK inhibitor is a pan-JAK inhibitor that inhibits all JAKs. In some embodiments, the drug is a JAK inhibitor (including a JAK1 inhibitor and / or a JAK2 inhibitor and / or a JAK3 inhibitor), a sphingosine 1-phosphate (S1P) receptor antagonist, an S1P receptor 1 modulator, an S1P receptor 5 modulator, a glucocorticoid receptor (GCR) antagonist, a tyrosine kinase (TYK) 2 inhibitor, a cyclooxygenase (COX) inhibitor, a dihydrofolate reductase (DHFR) inhibitor, or an epithelial-mesenchymal metastasis (EMT) inhibitor, or a drug that acts in any one or more of the manner described above.

[0157] In some embodiments, the drug is an S1P receptor antagonist, such as amicelimod or a pharmacological salt thereof. In some embodiments, the drug is amicelimod hydrochloride.

[0158] In some embodiments, the drug is a JAK1 inhibitor and a TYK2 inhibitor, such as brepocitinib or a pharmacological salt thereof. In some embodiments, the drug is brepocitinib tosylate.

[0159] In some embodiments, the drug is a GCR antagonist, such as budesonide or a pharmacological salt thereof. In some embodiments, the drug is budesonide.

[0160] In some embodiments, the drug is a TYK2 inhibitor, such as duclavacitinib or a pharmacological salt thereof. In some embodiments, the drug is duclavacitinib hydrochloride.

[0161] In some embodiments, the drug is an S1P receptor 1 modulator, such as etrasimodo or a pharmacological salt thereof. In some embodiments, the drug is etrasimodoarginine.

[0162] In some embodiments, the drug is a JAK1 inhibitor, such as filgotinib or a pharmacological salt thereof. In some embodiments, the drug is filgotinib maleate.

[0163] In some embodiments, the drug is a JAK inhibitor, such as ivarmasitinib or a pharmacological salt thereof. In some embodiments, the drug is ivarmasitinib sulfate.

[0164] In some embodiments, the drug is a JAK1 inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, and a TYK2 inhibitor (e.g., a pan-Janus kinase inhibitor), such as izencitinib or a pharmacological salt thereof. In some embodiments, the drug is izencitinib.

[0165] In some embodiments, the drug is a COX inhibitor and a DHFR inhibitor, such as mesalamine or a pharmacological salt thereof. In some embodiments, the drug is mesalamine.

[0166] In some embodiments, the drug is an S1P receptor 1 modulator and an S1P receptor 5 modulator, such as ozanimod or a pharmacological salt thereof. In some embodiments, the drug is ozanimod hydrochloride.

[0167] In some embodiments, the drug is an EMT inhibitor and a JAK3 inhibitor, such as litrucitinib or a pharmacological salt thereof. In some embodiments, the drug is litrucitinib.

[0168] In some embodiments, the drug is a JAK1 inhibitor, a JAK2 inhibitor, or a JAK3 inhibitor, such as tofacitinib or a pharmacological salt thereof. In some embodiments, the drug is tofacitinib citrate.

[0169] In some embodiments, the drug is a JAK1 inhibitor, such as upadacitinib or a pharmacological salt thereof. In some embodiments, the drug is upadacitinib tartrate.

[0170] In some embodiments, the JAK inhibitor is selected from the group consisting of tofacitinib, inhibitors, baricitinib, celduratinib, curbitacin I, desernotinib, fedratinib, filgotinib, gandotinib, itacitinib, restaurtinib, momerotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, sorucitinib, upadacitinib, BMS-986165, CHZ868, and SHR0302, or pharmaceutically acceptable salts thereof. In some embodiments, the oral drug dosage form comprises a plurality of JAK inhibitors, each JAK inhibitor selected from the group consisting of tofacitinib, inhibitors, baricitinib, celduratinib, curbitacin I, desernotinib, fedratinib, filgotinib, gandotinib, itacitinib, restaurtinib, momerotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, sorucitinib, upadacitinib, BMS-986165, CHZ868, and SHR0302, or pharmaceutically acceptable salts thereof.

[0171] In some embodiments, the JAK inhibitor is tofacitinib or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is tofacitinib citrate, e.g., tofacitinib monocitrate. In some embodiments, the JAK inhibitor is tofacitinib tartrate, e.g., tofacitinib monotartrate. In some embodiments, the JAK inhibitor is tofacitinib malate, e.g., tofacitinib monomalate. In some embodiments, the JAK inhibitor is tofacitinib oxalate, e.g., tofacitinib monooxalate.

[0172] In some embodiments, the JAK inhibitor is a pharmaceutically acceptable salt in amorphous form. In some embodiments, the JAK inhibitor is a pharmaceutically acceptable salt in crystalline form.

[0173] In some embodiments, the anti-inflammatory agent is mesalazine, sulfasalazine, or valsalazid.

[0174] In some embodiments, the nonsteroidal anti-inflammatory agent is ibuprofen or diclofenac.

[0175] In some embodiments, the steroid is prednisolone, budesonide, or fluticasone.

[0176] In some embodiments, the immunosuppressant is azathioprine, cyclosporine, or methotrexate.

[0177] In some embodiments, the bioagent is a peptide. In some embodiments, the peptide is a linear peptide, such as insulin. In some embodiments, the peptide is a cyclic peptide, such as octreotide. In some embodiments, the bioagent is an antibody or a fragment thereof, such as a monoclonal antibody. In some embodiments, the bioagent is a nucleic acid, such as DNA, RNA, their analogues, or a combination thereof. In some embodiments, the peptide is octreotide. In some embodiments, the antibody is infliximab, adalimumab, certolizumab, pegol, golimumab, or ustekinumab.

[0178] In some embodiments, the antitumor agent is fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, etoposide, larcitrexed, or oxaliplatin, or a combination thereof.

[0179] In some embodiments, the amount of drug in the oral drug dosage form is approximately 0.5 mg to approximately 500 mg. In some embodiments, the amount of drug in the drug component is approximately 1 mg or more, for example, approximately 5 mg or more, 10 mg or more, 15 mg or more, 20 mg or more, 25 mg or more, 30 mg or more, 35 mg or more, 40 mg or more, 45 mg or more, 50 mg or more, 55 mg or more, 60 mg or more, 65 mg or more, 70 mg or more, 75 mg or more, 80 mg or more, 85 mg or more, 90 mg or more, 95 mg or more, 100 mg or more, 110 mg or more, 120 mg or more, 130 mg or more, 140 mg or more, 150 mg or more, 160 mg or more, 170 mg or more, 180 mg or more, 190 mg or more, 200 mg The above amounts are 210 mg or more, 220 mg or more, 230 mg or more, 240 mg or more, 250 mg or more, 260 mg or more, 270 mg or more, 280 mg or more, 290 mg or more, 300 mg or more, 310 mg or more, 320 mg or more, 330 mg or more, 340 mg or more, 350 mg or more, 360 mg or more, 370 mg or more, 380 mg or more, 390 mg or more, 400 mg or more, 410 mg or more, 420 mg or more, 430 mg or more, 440 mg or more, 450 mg or more, 460 mg or more, 470 mg or more, 480 mg or more, 490 mg or more, or 500 mg or more. In some embodiments, the amount of drug in the drug component is about 500 mg or less, for example, about 490 mg or less, 480 mg or less, 470 mg or less, 460 mg or less, 450 mg or less, 440 mg or less, 430 mg or less, 420 mg or less, 410 mg or less, 400 mg or less, 390 mg or less, 380 mg or less, 370 mg or less, 360 mg or less, 350 mg or less, 340 mg or less, 330 mg or less, 320 mg or less, 310 mg or less, 300 mg or less, 290 mg or less, 280 mg or less, 270 mg or less. The amount is 260 mg or less, 250 mg or less, 240 mg or less, 230 mg or less, 220 mg or less, 210 mg or less, 200 mg or less, 190 mg or less, 180 mg or less, 170 mg or less, 160 mg or less, 150 mg or less, 140 mg or less, 130 mg or less, 120 mg or less, 110 mg or less, 100 mg or less, 90 mg or less, 80 mg or less, 70 mg or less, 60 mg or less, 50 mg or less, 40 mg or less, 30 mg or less, 20 mg or less, 10 mg or less, 5 mg or less, or 1 mg or less.In some embodiments, the amount of drug in the drug component is approximately 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 2 The dosage is one of the following: 10mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, or 500mg. 3. Delayed component

[0180] The oral drug dosage forms described herein include a delay component configured to control, for example, prevent and / or inhibit the release of the drug from the oral drug dosage form to deliver the drug to a desired location in the colon. As described herein, the delay component is not mixed with the drug component. In some embodiments, the delay component does not contain the drug, e.g., the active pharmaceutical component. In some embodiments, the delay component contains another drug. Furthermore, embodiments of the delay component may be mixed with another drug, e.g., a bacteriogenic moiety or an excipient.

[0181] In some embodiments, the delay component surrounds the drug component. In some embodiments, the delay component completely surrounds the drug component.

[0182] In some embodiments, the delay component at least partially surrounds, for example, the drug component (e.g., through its embodiment). For example, in some embodiments, the drug component is sandwiched between two erosive delay layers, and the two erosive delay layers are sandwiched between two pH-based enteric layers. In some embodiments, the delay component is formed from any number of layers of pH-based enteric layers and erosive delay layers. In some embodiments, when the drug component is at least partially surrounded, for example, sandwiched by the layers of the delay component, the layers may form a symmetrical or asymmetrical structure. For example, in some embodiments, the drug component is sandwiched between two erosive delay layers, and the two erosive delay layers are sandwiched between two pH-based enteric layers. In some embodiments, the drug component is sandwiched between two erosive delay layers, and an additional erosive delay layer is added to the distal surface of one of the two erosive delay layers of the drug component, and the drug component and the erosive delay layer are sandwiched between two pH-based enteric layers. i. pH-based enteric coating

[0183] The delaying components described herein include pH-based enteric coatings, for example, pH-based enteric coating layers. In some embodiments, the pH-based enteric coating includes two or more layers of pH-based enteric material, for example, two layers of pH-based enteric material.

[0184] In some embodiments, an oral drug dosage form comprises one or more pH-based enteric-coated components, which may be the same or different from one another, for example, having the same or different shapes, sizes, and / or configurations. For example, in some embodiments, an oral drug dosage form comprises a first pH-based enteric-coated component and a second pH-based enteric-coated component. In some embodiments, the first pH-based enteric-coated component and the second pH-based enteric-coated component have different pH levels at which the individual materials begin to erode. In some embodiments, the oral drug dosage form is configured such that the first pH-based enteric-coated component is eroded before the second pH-based enteric-coated component is exposed to body fluids after administration to an individual.

[0185] pH-based enteric coatings are configured to erode at a pH value above a desired level. As is understood in the art, different regions of the human gastrointestinal tract have different pH environments. The use of such pH-based enteric coatings helps to control the erosion of this component of the oral drug dosage forms described herein until it reaches a desired location in the gastrointestinal tract. In some embodiments, pH-based enteric coatings are eroded at a pH value of about 5.5 to about 8, for example, about 5.5 to about 7.5 and about 6 to about 7. In some embodiments, the pH-based enteric coating is eroded at a pH of approximately 5.5 or higher, for example, approximately 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.

[0186] pH-based enteric coatings may be formed using a number of materials having various shapes and sizes. In some embodiments, the pH-based enteric coating is a single layer of pH-based enteric material. In some embodiments, the pH-based enteric coating is configured to have a surface having a predetermined shape and surface area, such as a surface exposed to body fluids during administration of an oral drug dosage form to a human organism. For example, in some embodiments, the pH-based enteric coating has a top surface and a bottom surface, with the top surface being exposed to body fluids before the bottom surface. In some embodiments, the pH-based enteric coating is a layer having a top surface and a bottom surface. In some embodiments, the top surface of the pH-based enteric coating is not flat and includes certain features that extend beyond the top surface plane or a surface tolerance threshold (measured between two parallel planes), for example, to reduce adhesion of the pH-based enteric coating or a portion thereof to parts of the body of a human organism. In some embodiments, the top surface of the pH-based enteric coating or at least a portion thereof is flat or within the surface tolerance threshold.

[0187] In some embodiments, a pH-based enteric coating surrounds the drug component. In such embodiments, there is either no additional material, such as an erosion retarder, between the pH-based enteric coating and the drug component, or it is possible for such additional material to be present.

[0188] The surface of a pH-based enteric-coated component, for example, a pH-based enteric-coated component layer, can have any shape based on the surface exposed to body fluids at the time of administration. In some embodiments, the surface may be a capsule, circular, elliptical, bullet-shaped, arrowhead-shaped, triangular, arc-triangular, square, arc-square, rectangular, arc-rectangular, rhombus, pentagon, hexagon, octagon, crescent, almond-shaped, or a combination thereof.

[0189] In some embodiments, the surface of the pH-based enteric coating, for example, the pH-based enteric coating layer, is approximately 10 mm thick. 2 ~400mm 2 For example, about 20mm 2 ~about 200mm 2 , about 20mm 2 ~approximately 100mm 2 , about 20mm 2 ~about 60mm 2 , about 30mm 2 ~approximately 50mm 2 It has one of the following surface areas. In some embodiments, the surface of the pH-based enteric coating is at least about 20 mm 2 For example, at least about 22 mm 2 , 24mm 2 , 26mm 2 , 28mm 2 , 30mm 2 , 32mm 2 ,33mm 2 , 34mm 2 , 36mm 2 , 38mm 2 , 40mm 2 , 42mm 2 , 44mm 2 , 46mm 2 , 48mm 2 , 50mm 2 , 52mm 2 , 54mm 2, 56mm 2 , 58mm 2 , 60mm 2 , 65mm 2 , 70mm 2 , 80mm 2 , 85mm 2 , 90mm 2 , 95mm 2 , 100mm 2 , 110mm 2 , 120mm 2 , 130mm 2 , 140mm 2 , 150mm 2 , 160mm 2 , 170mm 2 , 180mm 2 , 190mm 2 , 200mm 2 , 225mm 2 , 250mm 2 , 275mm 2 , 300mm 2 , 325mm 2 , 350mm 2 , 375mm 2 , or 400mm 2 It has one of the following surface areas. In some embodiments, the surface of the pH-based enteric coating is approximately 400 mm². 2 Less than, for example, 400mm 2 , 375mm 2 , 350mm 2 , 325mm 2 , 300mm 2 , 275mm 2 , 250mm 2 , 225mm 2 , 200mm 2 , 190mm 2 , 180mm 2 , 170mm 2 , 160mm 2 , 150mm 2 , 140mm 2 , 130mm 2 , 120mm 2 , 110mm 2 , 100mm 2 , 95mm 2 , 90mm 2 , 85mm2 , 80mm 2 , 75mm 2 , 70mm 2 , 65mm 2 , 60mm 2 , 58mm 2 , 56mm 2 , 54mm 2 , 52mm 2 , 50mm 2 , 48mm 2 , 46mm 2 , 44mm 2 , 42mm 2 , 40mm 2 , 38mm 2 , 36mm 2 , 34mm 2 , 32mm 2 , 30mm 2 , 28mm 2 , 26mm 2 , 24mm 2 , 22mm 2 , or 20mm 2 It has a surface area less than either of the following. In some embodiments, the surface of the pH-based enteric coated member is about 20 mm 2 , 21mm 2 , 22mm 2 , 23mm 2 , 24mm 2 , 25mm 2 , 26mm 2 , 27mm 2 , 28mm 2 , 29mm 2 , 30mm 2 , 31mm 2 , 32mm 2 ,33mm 2 , 34mm 2 , 35mm 2 , 36mm 2 , 37mm 2 , 38mm 2 , 39mm 2 , 40mm 2 , 41mm 2 , 42mm 2 , 43mm 2 , 44mm 2 , 45mm 2 , 46mm 2 , 47mm2 , 48mm 2 , 49mm 2 , 50mm 2 , 51mm 2 , 52mm 2 , 53mm 2 , 54mm 2 , 55mm 2 , 56mm 2 , 57mm 2 , 58mm 2 , 59mm 2 , 60mm 2 , 65mm 2 , 70mm 2 , 80mm 2 , 85mm 2 , 90mm 2 , 95mm 2 , 100mm 2 , 110mm 2 , 120mm 2 , 130mm 2 , 140mm 2 , 150mm 2 , 160mm 2 , 170mm 2 , 180mm 2 , 190mm 2 , 200mm 2 , 225mm 2 , 250mm 2 , 275mm 2 , 300mm 2 , 325mm 2 , 350mm 2 , 375mm 2 , or 400mm 2 It has one of the following surface areas.

[0190] In some embodiments, the surface area of ​​the pH-based enteric coating exposed to bodily fluids is uniform across the entire thickness of the pH-based enteric coating, for example, the surface exposed to bodily fluids has the same surface area as the pH-based enteric coating is eroded. In some embodiments, the surface area of ​​the pH-based enteric coating exposed to bodily fluids differs in two or more respects, for example, the surface area of ​​the surface exposed to bodily fluids changes during the erosion of the pH-based enteric coating, for example, increasing and / or decreasing. In some embodiments, the surface shape of the pH-based enteric coating exposed to bodily fluids is uniform across the entire thickness of the pH-based enteric coating. In some embodiments, the surface shape of the pH-based enteric coating exposed to bodily fluids differs in two or more respects.

[0191] In some embodiments, the surface of a pH-based enteric coating member, for example, a pH-based enteric coating member layer, has a maximum cross-sectional dimension of about 5 mm to about 20 mm, for example, about 5 mm to about 15 mm, about 6 mm to about 13 mm, or about 7 mm to about 11 mm. In some embodiments, the surface of a pH-based enteric coating member has a maximum cross-sectional dimension of at least about 5 mm, for example, at least about 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, or 20 mm. In some embodiments, the surface of a pH-based enteric coating member has a maximum cross-sectional dimension of less than about 20 mm, for example, less than any of about 19 mm, 18 mm, 17 mm, 16 mm, 15 mm, 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, or 5 mm. In some embodiments, the surface of the pH-based enteric coating member has a maximum transverse dimension of approximately 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, or 20 mm.

[0192] In some embodiments, the surface of a pH-based enteric coating member, for example, a pH-based enteric coating member layer, has a transverse dimension perpendicular to the maximum transverse dimension, such as about 1 mm to about 15 mm, for example, about 2 mm to about 10 mm, about 2 mm to about 6 mm, or about 1 to about 5 mm. In some embodiments, the surface of a pH-based enteric coating member has a transverse dimension perpendicular to the maximum transverse dimension, such as at least about 1 mm, for example, at least about 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, or 15 mm. In some embodiments, the surface of a pH-based enteric coating member has a transverse dimension perpendicular to the maximum transverse dimension, such as less than about 15 mm, for example, less than about 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm, 2 mm, or 1 mm. In some embodiments, the surface of the pH-based enteric coating has a transverse dimension perpendicular to the maximum transverse dimension, which is approximately 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, or 15 mm.

[0193] In some embodiments, the pH-based enteric coating layer has a thickness of about 0.1 mm to about 5 mm, for example, about 0.2 mm to about 2 mm, about 0.5 mm to about 1.5 mm, or about 0.8 mm to about 1.4 mm. In some embodiments, the pH-based enteric-coated component layer has a thickness of at least about 0.1 mm, for example, at least about 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.2 mm, 2.4 mm, 2.6 mm, 2.8 mm, 3.0 mm, 3.2 mm, 3.4 mm, 3.6 mm, 3.8 mm, 4.0 mm, 4.2 mm, 4.4 mm, 4.6 mm, 4.8 mm, or 5 mm. In some embodiments, the pH-based enteric-coated component layer has a thickness of less than about 5 mm, for example, less than any of the following: about 4.8 mm, 4.6 mm, 4.4 mm, 4.2 mm, 4.0 mm, 3.8 mm, 3.6 mm, 3.4 mm, 3.2 mm, 3.0 mm, 2.8 mm, 2.6 mm, 2.4 mm, 2.2 mm, 2.0 mm, 1.9 mm, 1.8 mm, 1.7 mm, 1.6 mm, 1.5 mm, 1.4 mm, 1.3 mm, 1.2 mm, 1.1 mm, 1.0 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, or 0.1 mm. In some embodiments, the pH-based enteric-coated component layer has a thickness of approximately 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.2 mm, 2.4 mm, 2.6 mm, 2.8 mm, 3.0 mm, 3.2 mm, 3.4 mm, 3.6 mm, 3.8 mm, 4.0 mm, 4.2 mm, 4.4 mm, 4.6 mm, 4.8 mm, or 5 mm.

[0194] In some embodiments, the pH-based enteric-coated component layer includes a top and a bottom surface, and the thickness measured between the top and bottom surfaces is substantially uniform, such as within 20% of the average thickness.

[0195] In some embodiments, the pH-based enteric coating, for example, the pH-based enteric coating layer, comprises a thermoplastic material, for example, a thermoplastic polymer. In some embodiments, the pH-based enteric coating, for example, the pH-based enteric coating layer, comprises a matrix material, a plasticizer, or a material comprising one or more other additives, for example, fillers, binders, lubricants, flow enhancers, and disintegrants.

[0196] In some embodiments, the pH-based enteric coating is stearic acid, copolyvidone, polyvinylpyrrolidone-co-vinyl acetate, polyvinylpyrrolidone-polyvinyl acetate copolymer, crospovidone, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose or hypromellose, hydroxypropyl methylcellulose phthalate, methylcellulose, methacrylic acid copolymer, poly(methacrylate-co-ethyl acrylate), poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), poly(dimethylaminoethyl methacrylate-co-methacrylate ester), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonium ethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly(methacrylate-co-methyl methacrylate), poly(methacrylate-co This comprises one or more of the following: -ethyl acrylate, poly(methacrylate-comethyl methacrylate), polyethylene oxide, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, Kollicoat IR-polyvinyl alcohol, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, hydroxypropyl methylcellulose acetate succinate or hypromellose acetate succinate, methacrylate ester copolymer, ammonia alkyl methacrylate copolymer, ethylcellulose, polyvinyl acetate and polyvinylpyrrolidone, polyvinyl acetal diethylaminolactate, polyvinyl acetal diethylaminolactate, maltitol, lactose monohydrate, xylitol, isomalt, sucrose, glucose, dextran 70, or maltose.

[0197] In some embodiments, the plasticizer is one or more of the following: triethyl citrate, vitamin E polyethylene glycol succinate, acetylated triethyl citrate, tributyl citrate, O-acetyl tributyl citrate, polyoxyl 15 hydroxystearate, PEG-40 hydrogenated castor oil, polyoxyl 35 castor oil, dibutyl sebacate, diethyl phthalate, glycerin, methyl 4-hydroxybenzoate, castor oil, oleic acid, triacetin, polyalkylene glycol, stearic acid, palmitic acid, malic acid, polyethylene glycol, lauroyl PEG-32 glyceride, poloxamer 188, poloxamer 407, acetyl tributyl citrate, D-sorbitol, propylene glycol, diethyl phthalate, citric acid, glyceryl behenate, D-mannitol, polysorbate, sorbitan monostearate, sorbitan monooleate, or polyoxyl 40 stearate.

[0198] In some embodiments, other additives include acacia, alginate, alginic acid, aluminum acetate, butylparaben, butylated hydroxytoluene, citric acid, calcium carbonate, candelilla wax, croscarmellose sodium, powdered sugar, colloidal silicone dioxide, cellulose, plain or anhydrous calcium phosphate, carnuba wax, corn starch, carboxymethylcellulose calcium, disodium ethylenediaminetetraacetate, dehydrated calcium hydrogen phosphate, cetylpyridine chloride, dicalcium phosphate, tricalcium phosphate, dicalcium phosphate, disodium hydrogen phosphate, dimethicone, sodium erythrosine, ethylenediaminetetraacetate, gelatin, glyceryl monooleate, iron oxides, iron oxide yellow, iron oxide red, lacto One or more of the following: cellulose (hydrated, anhydrous, monohydrate, or spray-dried), microcrystalline cellulose, magnesium carbonate, magnesium oxide, methylparaben, polysorbate 80, propyleneparaben, potassium bicarbonate, potassium sorbate, potato starch, phosphoric acid, polyoxyethylene (40) stearate, sodium glycolate starch, pregelatinized starch, cross-linked sodium, sodium lauryl sulfate, starch, silicon dioxide, sodium benzoate, sucrose, sorbic acid, sodium carbonate, sodium saccharin, sodium alginate, silica gel, sorbitan monooleate, sodium chloride, dehydrated sodium citrate, sodium starch, carboxymethylcellulose, succinic acid, sodium propionate, titanium dioxide, or talc.

[0199] In some embodiments where the retarding component does not contain an erosive retarding member (for example, the retarding component essentially consists of a pH-based enteric-coated member), the erosive material of the pH-based enteric-coated member includes one or more of hypromellose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate propionate (CAP), poly(co-ethyl acrylate methacrylate), or polyvinyl acetate phthalate (PVAP). In some embodiments, the hypromellose acetate succinate is HPMCSLG / LF, HPMCSMG / MF, or HPMCSHG / LF. In some embodiments, the hydroxypropyl methylcellulose phthalate is HPMCPHP-50 or HPMCPHP-55. In some embodiments, the poly(co-ethyl acrylate methacrylate) is EudragitL100-55 or EudragitL100. ii. Erosion-delaying member

[0200] In certain embodiments, the oral drug dosage forms provided herein include an erosion retarder comprising an erosion material that is different from or the same as the erosion material of the drug component. Generally, the erosion retarder is arranged in the oral drug dosage form so that, after administration to an individual, it is not exposed to body fluids until the pH-based enteric-coated component is eroded (e.g., substantially completely eroded). In some embodiments, the retarder component described herein includes an erosion retarder, e.g., an erosion retarder layer. In some embodiments, the erosion retarder comprises two or more layers of erosion retarder material, e.g., two layers of erosion retarder material. In some embodiments, the oral drug dosage form includes one or more erosion retarders, and one or more erosion retarders may be the same or different from one another, e.g., have the same or different shapes, sizes, and / or configurations.

[0201] In some embodiments, the erosion retarder surrounds the drug component. In such embodiments, there is either no additional material between the erosion retarder and the drug component, or it is possible for additional material to be present.

[0202] The erosion retarder is configured to erode over a predetermined period of time after exposure to bodily fluids, such as after erosion (e.g., substantially complete erosion) of a pH-based enteric coating or its layer. In some embodiments, the erosion retarder is eroded over a period of about 1 minute to about 7 hours, for example, substantially eroded, to expose another component of the oral drug dosage form. In some embodiments, the erosion retarder is eroded over a period of at least about 5 minutes, for example, at least about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, or 7 hours, for example, substantially eroded, to expose another component of the oral drug dosage form. The timing of erosion of the erosion retarder or its layer can be based on many factors, including composition and thickness.

[0203] The erosion retarder may be formed using a number of materials having various shapes and sizes. In some embodiments, the erosion retarder is a single layer of erosion retarder material. In some embodiments, the erosion retarder is configured to have a surface having a predetermined shape and surface area, such as a surface exposed to body fluids during administration of an oral drug dosage form to a human individual. For example, in some embodiments, the erosion retarder has a top surface and a bottom surface, with the top surface being exposed to body fluids before the bottom surface. In some embodiments, the erosion retarder is a layer having a top surface and a bottom surface. In some embodiments, the top surface of the erosion retarder is not flat and includes certain features that extend beyond, for example, the top surface plane or a surface tolerance threshold (measured between two parallel planes). In some embodiments, the top surface of the erosion retarder, or at least a portion thereof, is flat or within the surface tolerance threshold.

[0204] The surface of the erosion retarder, for example, the erosion retarder layer, can have any shape based on the surface exposed to body fluids at the time of administration. In some embodiments, the surface includes capsule, circular, elliptical, bullet-shaped, arrowhead-shaped, triangular, arc-triangular, square, arc-square, rectangular, arc-rectangular, rhombus, pentagon, hexagon, octagon, crescent, almond-shaped, or a combination thereof.

[0205] In some embodiments, the surface of the erosion retarding member, for example, the erosion retarding member layer, is approximately 10 mm thick. 2 ~400mm 2 For example, about 20mm 2 ~about 200mm 2 , about 20mm 2 ~approximately 100mm 2 , about 20mm 2 ~about 60mm 2 , about 30mm 2 ~approximately 50mm 2 It has one of the following surface areas. In some embodiments, the surface of the erosion retarder is at least about 20 mm 2 For example, at least about 22 mm 2 , 24mm 2 , 26mm 2 , 28mm 2 , 30mm 2 , 32mm 2 ,3·BR>Rmm 2 , 34mm 2 , 36mm 2 , 38mm 2 , 40mm 2 , 42mm 2 , 44mm 2 , 46mm 2 , 48mm 2 , 50mm 2 , 52mm 2 , 54mm 2 , 56mm 2 , 58mm 2 , 60mm 2 , 65mm 2 , 70mm 2 , 80mm 2 , 85mm 2 , 90mm 2 , 95mm 2, 100mm 2 , 110mm 2 , 120mm 2 , 130mm 2 , 140mm 2 , 150mm 2 , 160mm 2 , 170mm 2 , 180mm 2 , 190mm 2 , 200mm 2 , 225mm 2 , 250mm 2 , 275mm 2 , 300mm 2 , 325mm 2 , 350mm 2 , 375mm 2 , or 400mm 2 It has one of the following surface areas. In some embodiments, the surface of the erosive retarding member is approximately 400 mm 2 Less than, for example, 400mm 2 , 375mm 2 , 350mm 2 , 325mm 2 , 300mm 2 , 275mm 2 , 250mm 2 , 225mm 2 , 200mm 2 , 190mm 2 , 180mm 2 , 170mm 2 , 160mm 2 , 150mm 2 , 140mm 2 , 130mm 2 , 120mm 2 , 110mm 2 , 100mm 2 , 95mm 2 , 90mm 2 , 85mm 2 , 80mm 2 , 75mm 2 , 70mm 2 , 65mm 2 , 60mm 2 , 58mm 2 , 56mm 2 , 54mm 2 , 52mm2 , 50mm 2 , 48mm 2 , 46mm 2 , 44mm 2 , 42mm 2 , 40mm 2 , 38mm 2 , 36mm 2 , 34mm 2 , 32mm 2 , 30mm 2 , 28mm 2 , 26mm 2 , 24mm 2 , 22mm 2 , or 20mm 2 It has a surface area less than either of the following. In some embodiments, the surface of the erosion retarder is about 20 mm 2 , 21mm 2 , 22mm 2 , 23mm 2 , 24mm 2 , 25mm 2 , 26mm 2 , 27mm 2 , 28mm 2 , 29mm 2 , 30mm 2 , 31mm 2 , 32mm 2 ,33mm 2 , 34mm 2 , 35mm 2 , 36mm 2 , 37mm 2 , 38mm 2 , 39mm 2 , 40mm 2 , 41mm 2 , 42mm 2 , 43mm 2 , 44mm 2 , 45mm 2 , 46mm 2 , 47mm 2 , 48mm 2 , 49mm 2 , 50mm 2 , 51mm 2 , 52mm 2 , 53mm 2 , 54mm 2 , 55mm 2 , 56mm2 , 57mm 2 , 58mm 2 , 59mm 2 , 60mm 2 , 65mm 2 , 70mm 2 , 80mm 2 , 85mm 2 , 90mm 2 , 95mm 2 , 100mm 2 , 110mm 2 , 120mm 2 , 130mm 2 , 140mm 2 , 150mm 2 , 160mm 2 , 170mm 2 , 180mm 2 , 190mm 2 , 200mm 2 , 225mm 2 , 250mm 2 , 275mm 2 , 300mm 2 , 325mm 2 , 350mm 2 , 375mm 2 , or 400mm 2 It has one of the following surface areas.

[0206] In some embodiments, the surface area of ​​the erosive retarder exposed to bodily fluids is uniform across the entire thickness of the erosive retarder, for example, the surface exposed to bodily fluids has the same surface area as the erosive retarder is eroded. In some embodiments, the surface area of ​​the erosive retarder exposed to bodily fluids differs in two or more respects, for example, the surface area of ​​the surface exposed to bodily fluids changes during the erosion of the erosive retarder, for example, increasing and / or decreasing. In some embodiments, the shape of the surface of the erosive retarder exposed to bodily fluids is uniform across the entire thickness of the erosive retarder. In some embodiments, the shape of the surface of the erosive retarder exposed to bodily fluids differs in two or more respects.

[0207] In some embodiments, the surface of the erosion retarder member, for example, the erosion retarder member layer, has a maximum cross-sectional dimension of about 5 mm to about 20 mm, for example, about 5 mm to about 15 mm, about 6 mm to about 13 mm, or about 7 mm to about 11 mm. In some embodiments, the surface of the erosion retarder member has a maximum cross-sectional dimension of at least about 5 mm, for example, at least about 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, or 20 mm. In some embodiments, the surface of the erosion retarder member has a maximum cross-sectional dimension of less than about 20 mm, for example, less than any of about 19 mm, 18 mm, 17 mm, 16 mm, 15 mm, 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, or 5 mm. In some embodiments, the surface of the erosion retarding member has a maximum transverse dimension of approximately 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, or 20 mm.

[0208] In some embodiments, the surface of the erosion retarder member, for example, the erosion retarder member layer, has a transverse dimension perpendicular to the maximum transverse dimension, such as about 1 mm to about 15 mm, for example, about 2 mm to about 10 mm, about 2 mm to about 6 mm, or about 1 to about 5 mm. In some embodiments, the surface of the erosion retarder member has a transverse dimension perpendicular to the maximum transverse dimension, such as at least about 1 mm, for example, at least about 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, or 15 mm. In some embodiments, the surface of the erosion retarder member has a transverse dimension perpendicular to the maximum transverse dimension, such as less than about 15 mm, for example, less than about 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm, 2 mm, or 1 mm. In some embodiments, the surface of the erosion retarding member has a transverse dimension perpendicular to the maximum transverse dimension, which is approximately 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, or 15 mm.

[0209] In some embodiments, the erosive retarding member layer has a thickness of about 0.1 mm to about 5 mm, for example, about 0.2 mm to about 2 mm, about 0.5 mm to about 1.5 mm, about 0.6 mm to about 1.6 mm, or about 0.8 mm to about 1.4 mm. In some embodiments, the erosion retarding member layer has a thickness of at least about 0.1 mm, for example, at least about 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.2 mm, 2.4 mm, 2.6 mm, 2.8 mm, 3.0 mm, 3.2 mm, 3.4 mm, 3.6 mm, 3.8 mm, 4.0 mm, 4.2 mm, 4.4 mm, 4.6 mm, 4.8 mm, or 5 mm. In some embodiments, the erosive retardation layer has a thickness of less than about 5 mm, for example, less than any of the following: about 4.8 mm, 4.6 mm, 4.4 mm, 4.2 mm, 4.0 mm, 3.8 mm, 3.6 mm, 3.4 mm, 3.2 mm, 3.0 mm, 2.8 mm, 2.6 mm, 2.4 mm, 2.2 mm, 2.0 mm, 1.9 mm, 1.8 mm, 1.7 mm, 1.6 mm, 1.5 mm, 1.4 mm, 1.3 mm, 1.2 mm, 1.1 mm, 1.0 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, or 0.1 mm. In some embodiments, the erosive retardation layer has a thickness of approximately 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.2 mm, 2.4 mm, 2.6 mm, 2.8 mm, 3.0 mm, 3.2 mm, 3.4 mm, 3.6 mm, 3.8 mm, 4.0 mm, 4.2 mm, 4.4 mm, 4.6 mm, 4.8 mm, or 5 mm. In some embodiments, the erosive retardation layer has a thickness of approximately 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, or 1.6 mm.The inventors of this disclosure have found that when the delay layer is thick, the surface of the delay layer is more likely to gel, allowing the drug to pass through the gastrointestinal tract without being released in the colon, while when the delay layer is thin, some surfaces of the delay layer are pre-damaged due to uneven fluid flow, making the drug more likely to be released. Therefore, it is necessary to produce a delay layer of the correct thickness to ensure that the drug is released in the colon without the delay layer gelling, and that the drug is pre-released without being affected by bodily fluids.

[0210] In some embodiments, the erosive retarding member layer includes a top surface and a bottom surface, and the thickness measured between the top surface and the bottom surface is substantially uniform, such as within 20% of the average thickness.

[0211] In some embodiments, the erosive retarder, for example, the erosive retarder layer, comprises a thermoplastic material, for example, a thermoplastic polymer. In some embodiments, the erosive retarder, for example, the erosive retarder layer, comprises a matrix material, a plasticizer, or a material comprising one or more of other additives, such as fillers, binders, lubricants, flow promoters, inorganic salts, and disintegrants. The inventors of the present disclosure have found that the erosive retarder layer of the present disclosure continues to be eroded without gelation resulting in delayed drug release, and is, for example, erodible layer by layer.

[0212] In some embodiments, the thermoplastic polymer is stearic acid, medium-chain triglyceride, glyceryl distearate, propylene glycol monolaurate, propylene glycol caprylate, oleoyl polyoxyl-6 glyceride, PEG-6 stearate, PEG-32 stearate, linoleoyl polyoxyl-6 glyceride, lauroyl polyoxyl-32 glyceride, caprylocaproyl polyoxyl-8 glyceride, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan oleate, glyceryl Lyceryl monolinoleate, copolyvidone, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, crospovidone, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose or hypromellose, hydroxypropyl methylcellulose phthalate, methylcellulose, methacrylic acid copolymer, poly(methacrylate-co-ethyl acrylate), poly(butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate copolymer), poly(dimethyl (aminoethyl methacrylate-co-methacrylate), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonium ethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly(methacrylate-co-methyl methacrylate), poly(methacrylate-co-ethyl acrylate), poly(methacrylate-co-methyl methacrylate), polyethylene oxide, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft Polymers, polyethylene glycol-polyvinyl alcohol graft copolymer, Colicote IR-polyvinyl alcohol, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, hydroxypropyl methylcellulose acetate succinate or hypromellose acetate succinate, methacrylate ester copolymer, ammonium alkyl methacrylate copolymer, ethylcellulose, polyvinyl acetate and polyvinylpyrrolidone, polyvinyl acetal diethylaminolactic acid, polyvinyl acetal diethylaminolactic acid, maltitol,The material comprises one or more of the following: lactose monohydrate, xylitol, isomalt, sucrose, glucose, dextran 70, maltose, lauroyl polyoxyl-32 glyceride, caprylocaproyl polyoxyl-8 glyceride, polyoxyl(35) castor oil, vitamin E polyethylene glycol succinate, PEG-40 hydrogenated castor oil, glyceryl monolinoleate, or glyceryl dibehenate. In some embodiments, the thermoplastic polymer comprises one or more of hydroxypropyl cellulose and vitamin E polyethylene glycol succinate. In some embodiments, the weight of the thermoplastic polymer is 60-85% of the weight of the erosion retardant member.

[0213] In some embodiments, the plasticizer is one or more of the following: triethyl citrate, vitamin E polyethylene glycol succinate, acetylated triethyl citrate, tributyl citrate, O-acetyl tributyl citrate, polyoxyl 15 hydroxystearate, PEG-40 hydrogenated castor oil, polyoxyl 35 castor oil, dibutyl sebacate, diethyl phthalate, glycerin, methyl 4-hydroxybenzoate, castor oil, oleic acid, triacetin, polyalkylene glycol, stearic acid, palmitic acid, malic acid, polyethylene glycol, lauroyl PEG-32 glyceride, poloxamer 188, poloxamer 407, acetyl tributyl citrate, D-sorbitol, propylene glycol, diethyl phthalate, citric acid, glyceryl behenate, D-mannitol, polysorbate, sorbitan monostearate, sorbitan monooleate, or polyoxyl 40 stearate. In some embodiments, the plasticizer is triethyl citrate. In some embodiments, the weight of the plasticizer is 5-20% of the weight of the erosion retarder. In some embodiments, the weight of the plasticizer is 10-15% of the weight of the erosion retarder.

[0214] In some embodiments, the inorganic salt is one or more of the following: calcium phosphate, calcium hydrogen phosphate, disodium hydrogen phosphate, sodium carbonate, sodium chloride, sodium phosphate, calcium hydrogen phosphate, calcium carbonate, calcium chloride, potassium phosphate, dipotassium hydrogen phosphate, potassium carbonate, and potassium chloride. In some embodiments, the inorganic salt is calcium hydrogen phosphate. In some embodiments, the weight of the inorganic salt is 5-20% of the weight of the erosion retarder. In some embodiments, the weight of the inorganic salt is 10% of the weight of the erosion retarder.

[0215] In some embodiments, other additives include acacia, alginic acid, aluminum acetate, butylparaben, butylated hydroxytoluene, citric acid, calcium carbonate, candelilla wax, croscarmellose sodium, powdered sugar, colloidal silicone dioxide, cellulose, plain or anhydrous calcium phosphate, carnuba wax, corn starch, carboxymethylcellulose calcium, disodium ethylenediaminetetraacetate, dehydrated calcium hydrogen phosphate, cetylpyridine chloride, calcium hydrogen phosphate, dicalcium phosphate, tricalcium phosphate, dicalcium phosphate, disodium hydrogen phosphate, dimethicone, sodium erythrosine, ethylenediaminetetraacetate, gelatin, glyceryl monooleate, iron oxides, iron oxides, yellow iron oxide, red iron oxide, lactose ( One or more of the following (hydrated, anhydrous, monohydrate, or spray-dried), microcrystalline cellulose, magnesium carbonate, magnesium oxide, methylparaben, polysorbate 80, propyleneparaben, potassium bicarbonate, potassium sorbate, potato starch, phosphoric acid, polyoxyethylene (40) stearic acid, sodium starch glycolate, gelatinized starch, sodium crosslinking, sodium lauryl sulfate, starch, silicon dioxide, sodium benzoate, sucrose, sorbic acid, sodium carbonate, sodium saccharin, sodium alginate, silica gel, sodium monooleate, sodium chloride, sodium metabisulfite, dehydrated sodium citrate, sodium starch, carboxymethylcellulose, succinic acid, sodium propionate, titanium dioxide, or talc. iii. Bacterial decomposition portion and bacterial decomposition component

[0216] In certain embodiments, the oral drug dosage forms provided herein include a bacterogradable portion. As described herein, the bacterogradable portion is a portion that can be digested by one or more bacteria present in or likely to be present in the colon of an individual. Such a portion can assist in colon-specific digestion of one or more embodiments of the oral drug dosage form. In some embodiments, the bacterogradable portion is mixed with an embodiment of the oral drug dosage form, such as an erosive retarder or a drug component. In some embodiments, the retarder further includes a bacterogradable portion comprising an erosive material mixed with the bacterogradable portion. In some embodiments in which the oral drug dosage form includes a bacterogradable portion, the oral drug dosage form is configured such that a pH-based enteric-coated portion is eroded before the erosive retarder, the erosive retarder is eroded before the bacterogradable portion, and the bacterogradable portion is eroded before the drug component. In some embodiments, the oral drug dosage form includes a bacteriolytic member, the pH-based enteric coating at least partially prevents erosion of the erosion retarding member, the erosion retarding member at least partially prevents erosion of the bacteriolytic member, and the bacteriolytic member at least partially prevents erosion of the drug component. In some embodiments, the oral drug dosage form includes one or more bacteriolytic members, which may be the same or different from one another, for example, having the same or different shapes, sizes, and / or configurations.

[0217] In some embodiments, the bacterially degradable portion is digestible by one or more microorganisms present in the colon of an individual. In some embodiments, the bacterially degradable portion contains one or more sugars. In some embodiments, the one or more sugars include one or more of the following: sucrose, glucose, xylose, fructose, maltose, galactose, pectin, galactomannan, dextran, inulin, chitosan, carrageenan, cellulose propionate acetate (CAP), peptidoglycan, gellan, xanthan gum, lentinan, psyllium polysaccharide, corn bran arabinoxylan, alginate, hyaluronic acid, fucoidan, shellac, agar, or maltodextrin.

[0218] In some embodiments, the oral drug dosage form contains an amount of bacterial degradation portion ranging from about 0.5 mg to about 500 mg. In some embodiments, the amount of bacterial degradation portion in the oral drug dosage form is about 1 mg or more, for example, about 5 mg or more, 10 mg or more, 15 mg or more, 20 mg or more, 25 mg or more, 30 mg or more, 35 mg or more, 40 mg or more, 45 mg or more, 50 mg or more, 55 mg or more, 60 mg or more, 65 mg or more, 70 mg or more, 75 mg or more, 80 mg or more, 85 mg or more, 90 mg or more, 95 mg or more, 100 mg or more, 110 mg or more, 120 mg or more, 130 mg or more, 140 mg or more, 150 mg or more, 160 mg or more, 170 mg or more, 180 mg or more, 190 mg or more, 20 The dosage is any of the following: 0 mg or more, 210 mg or more, 220 mg or more, 230 mg or more, 240 mg or more, 250 mg or more, 260 mg or more, 270 mg or more, 280 mg or more, 290 mg or more, 300 mg or more, 310 mg or more, 320 mg or more, 330 mg or more, 340 mg or more, 350 mg or more, 360 mg or more, 370 mg or more, 380 mg or more, 390 mg or more, 400 mg or more, 410 mg or more, 420 mg or more, 430 mg or more, 440 mg or more, 450 mg or more, 460 mg or more, 470 mg or more, 480 mg or more, 490 mg or more, or 500 mg or more.In some embodiments, the amount of bacterially degradable portion in the oral drug dosage form is approximately 500 mg or less, for example, approximately 490 mg or less, 480 mg or less, 470 mg or less, 460 mg or less, 450 mg or less, 440 mg or less, 430 mg or less, 420 mg or less, 410 mg or less, 400 mg or less, 390 mg or less, 380 mg or less, 370 mg or less, 360 mg or less, 350 mg or less, 340 mg or less, 330 mg or less, 320 mg or less, 310 mg or less, 300 mg or less, 290 mg or less, 280 mg or less, 270 mg The following are limits: 260mg or less, 250mg or less, 240mg or less, 230mg or less, 220mg or less, 210mg or less, 200mg or less, 190mg or less, 180mg or less, 170mg or less, 160mg or less, 150mg or less, 140mg or less, 130mg or less, 120mg or less, 110mg or less, 100mg or less, 90mg or less, 80mg or less, 70mg or less, 60mg or less, 50mg or less, 40mg or less, 30mg or less, 20mg or less, 10mg or less, 5mg or less, or 1mg or less. In some embodiments, the amount of bacterially degraded portion in the oral drug dosage form is approximately 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg. The dosage is one of the following: g, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, or 500mg.

[0219] In some embodiments, the biodegradable component is configured to be eroded over a predetermined period of time (including within a predetermined period of time) after exposure to bodily fluids, such as after erosion (e.g., substantially complete erosion) of a pH-based enteric-coated component or its layer and / or an erosion-delaying component or its layer. In some embodiments, the biodegradable component is eroded over a period of about 1 minute to about 7 hours, for example, substantially eroded, to expose another component of the oral drug dosage form. In some embodiments, the biodegradable component is eroded over a period of at least about 5 minutes, for example, at least about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, or 7 hours, for example, substantially eroded, to expose another component of the oral drug dosage form. The timing of erosion of the biodegradable component or its layer may be based on many factors, including the composition (e.g., the type and / or amount of the biodegradable portion) and thickness.

[0220] The biodegradable member may be formed using a number of materials having various shapes and sizes. In some embodiments, the biodegradable member is a single layer of biodegradable material. In some embodiments, the biodegradable member is configured to have a surface having a predetermined shape and surface area, such as a surface exposed to body fluids during administration of an oral drug dosage form to a human individual. For example, in some embodiments, the biodegradable member has a top surface and a bottom surface, with the top surface being exposed to body fluids before the bottom surface. In some embodiments, the biodegradable member is a layer having a top surface and a bottom surface. In some embodiments, the top surface of the biodegradable member is not flat and includes certain features that extend beyond, for example, the top surface plane or a surface tolerance threshold (measured between two parallel planes). In some embodiments, the top surface of the biodegradable member, or at least a portion thereof, is flat or within the surface tolerance threshold.

[0221] In some embodiments, the bacterial degradation member surrounds the drug component. In such embodiments, there is either no additional material, such as an erosion retarding member, between the bacterial degradation member and the drug component, or it is possible for such additional material to be present.

[0222] The surface of the bacterial degrading member, for example, the bacterial degrading member layer, can have any shape based on the surface exposed to body fluids at the time of administration. In some embodiments, the surface includes capsule, circular, elliptical, bullet-shaped, arrowhead-shaped, triangular, arc-triangular, square, arc-square, rectangular, arc-rectangular, rhombus, pentagon, hexagon, octagon, crescent, almond-shaped, or a combination thereof.

[0223] In some embodiments, the surface of the bacterial decomposition member, for example, the bacterial decomposition member layer, is approximately 10 mm thick. 2 ~400mm 2 For example, about 20mm 2 ~about 200mm 2 , about 20mm 2 ~approximately 100mm 2 , about 20mm 2 ~about 60mm 2 , about 30mm 2 ~approximately 50mm 2 It has one of the following surface areas. In some embodiments, the surface of the bacterial decomposition member is at least about 20 mm 2 For example, at least about 22 mm 2 , 24mm 2 , 26mm 2 , 28mm 2 , 30mm 2 , 32mm 2 ,33mm 2 , 34mm 2 , 36mm 2 , 38mm 2 , 40mm 2 , 42mm 2 , 44mm 2 , 46mm 2 , 48mm 2 , 50mm 2 , 52mm 2 , 54mm 2 , 56mm 2 , 58mm 2, 60mm 2 , 65mm 2 , 70mm 2 , 80mm 2 , 85mm 2 , 90mm 2 , 95mm 2 , 100mm 2 , 110mm 2 , 120mm 2 , 130mm 2 , 140mm 2 , 150mm 2 , 160mm 2 , 170mm 2 , 180mm 2 , 190mm 2 , 200mm 2 , 225mm 2 , 250mm 2 , 275mm 2 , 300mm 2 , 325mm 2 , 350mm 2 , 375mm 2 , or 400mm 2 It has one of the following surface areas. In some embodiments, the surface of the bacterial decomposition member is approximately 400 mm 2 Less than, for example, 400mm 2 , 375mm 2 , 350mm 2 , 325mm 2 , 300mm 2 , 275mm 2 , 250mm 2 , 225mm 2 , 200mm 2 , 190mm 2 , 180mm 2 , 170mm 2 , 160mm 2 , 150mm 2 , 140mm 2 , 130mm 2 , 120mm 2 , 110mm 2 , 100mm 2 , 95mm 2 , 90mm 2 , 85mm 2 , 80mm 2 , 75mm 2, 70mm 2 , 65mm 2 , 60mm 2 , 58mm 2 , 56mm 2 , 54mm 2 , 52mm 2 , 50mm 2 , 48mm 2 , 46mm 2 , 44mm 2 , 42mm 2 , 40mm 2 , 38mm 2 , 36mm 2 , 34mm 2 , 32mm 2 , 30mm 2 , 28mm 2 , 26mm 2 , 24mm 2 , 22mm 2 , or 20mm 2 It has a surface area less than either of the following. In some embodiments, the surface of the bacterial decomposition member is about 20 mm 2 , 21mm 2 , 22mm 2 , 23mm 2 , 24mm 2 , 25mm 2 , 26mm 2 , 27mm 2 , 28mm 2 , 29mm 2 , 30mm 2 , 31mm 2 , 32mm 2 ,33mm 2 , 34mm 2 , 35mm 2 , 36mm 2 , 37mm 2 , 38mm 2 , 39mm 2 , 40mm 2 , 41mm 2 , 42mm 2 , 43mm 2 , 44mm 2 , 45mm 2 , 46mm 2 , 47mm 2 , 48mm 2 , 49mm 2 , 50mm2 , 51mm 2 , 52mm 2 , 53mm 2 , 54mm 2 , 55mm 2 , 56mm 2 , 57mm 2 , 58mm 2 , 59mm 2 , 60mm 2 , 65mm 2 , 70mm 2 , 80mm 2 , 85mm 2 , 90mm 2 , 95mm 2 , 100mm 2 , 110mm 2 , 120mm 2 , 130mm 2 , 140mm 2 , 150mm 2 , 160mm 2 , 170mm 2 , 180mm 2 , 190mm 2 , 200mm 2 , 225mm 2 , 250mm 2 , 275mm 2 , 300mm 2 , 325mm 2 , 350mm 2 , 375mm 2 , or 400mm 2 It has one of the following surface areas.

[0224] In some embodiments, the surface area of ​​the biodegrading member exposed to bodily fluids is uniform throughout the entire thickness of the biodegrading member, for example, the surface exposed to bodily fluids has the same surface area as the biodegrading member is eroded. In some embodiments, the surface area of ​​the biodegrading member exposed to bodily fluids differs in two or more respects, for example, the surface area of ​​the surface exposed to bodily fluids changes between erosions of the biodegrading member, for example, increasing and / or decreasing. In some embodiments, the shape of the surface of the biodegrading member exposed to bodily fluids is uniform throughout the entire thickness of the biodegrading member. In some embodiments, the shape of the surface of the biodegrading member exposed to bodily fluids differs in two or more respects.

[0225] In some embodiments, the surface of the bacterial decomposition member, for example, the bacterial decomposition member layer, has a maximum cross-sectional dimension of about 5 mm to about 20 mm, for example, about 5 mm to about 15 mm, about 6 mm to about 13 mm, or about 7 mm to about 11 mm. In some embodiments, the surface of the bacterial decomposition member has a maximum cross-sectional dimension of at least about 5 mm, for example, at least about 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, or 20 mm. In some embodiments, the surface of the bacterial decomposition member has a maximum cross-sectional dimension of less than about 20 mm, for example, less than any of about 19 mm, 18 mm, 17 mm, 16 mm, 15 mm, 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, or 5 mm. In some embodiments, the surface of the bacterial decomposition member has a maximum transverse dimension of approximately 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, or 20 mm.

[0226] In some embodiments, the surface of the bacterial decomposition member, for example, the bacterial decomposition member layer, has a transverse dimension perpendicular to the maximum transverse dimension, such as about 1 mm to about 15 mm, for example, about 2 mm to about 10 mm, about 2 mm to about 6 mm, or about 1 to about 5 mm. In some embodiments, the surface of the bacterial decomposition member has a transverse dimension perpendicular to the maximum transverse dimension, such as at least about 1 mm, for example, at least about 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, or 15 mm. In some embodiments, the surface of the bacterial decomposition member has a transverse dimension perpendicular to the maximum transverse dimension, such as less than about 15 mm, for example, less than about 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm, 2 mm, or 1 mm. In some embodiments, the surface of the bacterial decomposition member has a transverse dimension perpendicular to the maximum transverse dimension, which is approximately 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, or 15 mm.

[0227] In some embodiments, the bacterial decomposition layer has a thickness of about 0.1 mm to about 5 mm, for example, about 0.2 mm to about 2 mm, about 0.5 mm to about 1.5 mm, or about 0.8 mm to about 1.4 mm. In some embodiments, the bacterial decomposition layer has a thickness of at least about 0.1 mm, for example, at least about 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.2 mm, 2.4 mm, 2.6 mm, 2.8 mm, 3.0 mm, 3.2 mm, 3.4 mm, 3.6 mm, 3.8 mm, 4.0 mm, 4.2 mm, 4.4 mm, 4.6 mm, 4.8 mm, or 5 mm. In some embodiments, the bacterial decomposition member layer has a thickness of less than about 5 mm, for example, less than any of the following: about 4.8 mm, 4.6 mm, 4.4 mm, 4.2 mm, 4.0 mm, 3.8 mm, 3.6 mm, 3.4 mm, 3.2 mm, 3.0 mm, 2.8 mm, 2.6 mm, 2.4 mm, 2.2 mm, 2.0 mm, 1.9 mm, 1.8 mm, 1.7 mm, 1.6 mm, 1.5 mm, 1.4 mm, 1.3 mm, 1.2 mm, 1.1 mm, 1.0 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, or 0.1 mm. In some embodiments, the bacterial decomposition member layer has a thickness of approximately 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.2 mm, 2.4 mm, 2.6 mm, 2.8 mm, 3.0 mm, 3.2 mm, 3.4 mm, 3.6 mm, 3.8 mm, 4.0 mm, 4.2 mm, 4.4 mm, 4.6 mm, 4.8 mm, or 5 mm.

[0228] In some embodiments, the bacterial degradation layer includes a top surface and a bottom surface, and the thickness measured between the top and bottom surfaces is substantially uniform, such as within 20% of the average thickness.

[0229] In some embodiments, the biodegradable member, for example, the biodegradable member layer, comprises a thermoplastic material, for example, a thermoplastic polymer. In some embodiments, the biodegradable member, for example, the biodegradable member layer, comprises a matrix material, a plasticizer, or a material comprising one or more of other additives, such as fillers, binders, lubricants, flow promoters, and disintegrants.

[0230] In some embodiments, the bacterial degradation material is stearic acid, medium-chain triglyceride, glyceryl distearate, propylene glycol monolaurate, propylene glycol caprylate, oleoyl polyoxyl-6 glyceride, PEG-6 stearate, PEG-32 stearate, linoleoyl polyoxyl-6 glyceride, lauroyl polyoxyl-32 glyceride, caprylocaproyl polyoxyl-8 glyceride, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan oleate, glyceryl monolinoleate, copolividone, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, crospovidone, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropyl Methylcellulose or hypromellose, hydroxypropyl methylcellulose phthalate, methylcellulose, methacrylic acid copolymer, poly(methacrylate-co-ethyl acrylate), poly(butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate copolymer), poly(dimethylaminoethyl methacrylate-co-methacrylate ester), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonium ethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly(methacrylate-co-methyl methacrylate), poly(methacrylate-co-ethyl acrylate), poly(methacrylate-co-methyl methacrylate), polyethylene oxide, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-poly This product contains one or more of the following: vinyl alcohol graft copolymer, Colicote IR-polyvinyl alcohol, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, hydroxypropyl methylcellulose acetate succinate or hypromellose acetate succinate, methacrylate ester copolymer, ammonium alkyl methacrylate copolymer, ethylcellulose, polyvinyl acetate and polyvinylpyrrolidone, polyvinyl acetal diethylaminolactic acid, polyvinyl acetal diethylaminolactic acid, maltitol, lactose monohydrate, xylitol, isomalt, sucrose, glucose, dextran 70, maltose, lauroyl polyoxyl-32 glyceride, caprylocaproyl polyoxyl-8 glyceride, polyoxyl(35) castor oil, vitamin E polyethylene glycol succinate, PEG-40 hydrogenated castor oil, glyceryl monolinoleate, or glyceryl dibehenate. 4. Shell

[0231] In a particular embodiment, the Specified Provisions provide an oral drug dosage form comprising a shell.

[0232] In some embodiments, the shell comprises an insulating material that is impermeable to bodily fluids such as gastrointestinal fluid. In some embodiments, the shell comprises an insulating material that is impermeable to specific bodily fluids such as gastric fluid. In some embodiments, the shell comprises an insulating material that is impermeable to bodily fluids at a specific pH, e.g., impermeable to bodily fluids with a pH less than about 7, such as less than about 7.5, 8, or 8.5 (for example, the shell is not eroded until exposed to a pH greater than about 7, such as greater than about 7.5, 8, or 8.5). In some embodiments, the shell comprises a non-erosive material, e.g., an insulating material that is substantially not eroded during administration to a human organism. In some embodiments, the shell comprises an insulating material that is non-erosive to specific bodily fluids such as gastric fluid.

[0233] In some embodiments, the shell comprises an insulating material which is an erosive material having pH-sensitive erosion and / or erosion rate that allows for the complete release of the drug from the drug component of the oral drug dosage form before exposure of the drug component to bodily fluids due to erosion of the shell.

[0234] In some embodiments, the shell comprises a selectively permeable insulating material. For example, in some embodiments, the shell is permeable to body fluids but impermeable to drugs.

[0235] The shells provided herein are configured to have surfaces such as outward-facing surfaces exposed to body fluids during administration of an oral drug dosage form to a human organism. In some embodiments, the shell is configured to control the exposure of other components of the oral drug dosage form to body fluids (e.g., pH-based enteric coatings and erosion retarding components) to guide their erosion. In some embodiments, the outer surface of the shell is not flat and includes certain features that extend beyond a top plane or a surface tolerance threshold (measured between two parallel planes), for example, to reduce adhesion of the shell or any part thereof to parts of the human organism's body. In some embodiments, the outer surface of the shell or at least a portion thereof is flat or within the surface tolerance threshold.

[0236] The surface of the shell can have any shape based on the surface exposed to bodily fluids. In some embodiments, the surface of the shell may have the shape of a capsule, cylinder, elliptical cylinder, circle, ellipse, bullet, arrowhead, triangle, arc-triangle, square, arc-square, rectangle, arc-rectangle, rhombus, pentagon, hexagon, octagon, crescent, almond, or a combination thereof, based on the surface exposed to bodily fluids. In some embodiments, the shell forms an annular shape, and other components of the oral drug dosage form are contained within the annular shape (e.g., drug components, pH-based enteric coatings, and erosion retarding components).

[0237] In some embodiments, the shell has a maximum transverse dimension of about 5 mm to about 20 mm, for example, about 5 mm to about 15 mm, about 6 mm to about 13 mm, or about 7 mm to about 11 mm. In some embodiments, the shell has a maximum transverse dimension of at least about 5 mm, for example, at least about 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, or 20 mm. In some embodiments, the shell has a maximum transverse dimension of less than about 20 mm, for example, less than about 19 mm, 18 mm, 17 mm, 16 mm, 15 mm, 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, or 5 mm. In some embodiments, the shell has a maximum transverse dimension of approximately 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, or 20 mm. In some embodiments, the maximum transverse dimension is measured across the surface of the oral drug dosage form.

[0238] In some embodiments, the shell has a transverse dimension perpendicular to the maximum transverse dimension, ranging from about 5 mm to about 20 mm, for example, about 5 mm to about 15 mm, about 6 mm to about 13 mm, or about 7 mm to about 11 mm. In some embodiments, the shell has a transverse dimension perpendicular to the maximum transverse dimension, ranging from at least about 5 mm, for example, at least about 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, or 20 mm. In some embodiments, the shell has a transverse dimension perpendicular to the maximum transverse dimension, ranging from less than about 20 mm, for example, less than about 19 mm, 18 mm, 17 mm, 16 mm, 15 mm, 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, or 5 mm. In some embodiments, the shell has a transverse dimension perpendicular to the maximum transverse dimension, which is approximately 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, or 20 mm. In some embodiments, the transverse dimension perpendicular to the maximum transverse dimension is measured across the surface of the oral drug dosage form.

[0239] In some embodiments, the shell is configured to have a thickness that prevents and / or inhibits the exposure of the components or parts of the oral drug dosage form to body fluids. In some embodiments, the shell has a thickness of about 0.3 mm to about 3 mm, measured from the outer surface of the oral drug dosage form to its other components, for example, about 0.3 to about 1 mm, about 0.4 mm to about 2 mm, or about 0.5 mm to about 1.5 mm. In some embodiments, the shell has a thickness of at least about 0.3 mm, for example, at least about 0.4, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.2 mm, 2.4 mm, 2.6 mm, 2.8 mm, or 3.0 mm. In some embodiments, the shell has a thickness of less than about 3 mm, for example, less than any of the following: about 2.8 mm, 2.6 mm, 2.4 mm, 2.2 mm, 2.0 mm, 1.9 mm, 1.8 mm, 1.7 mm, 1.6 mm, 1.5 mm, 1.4 mm, 1.3 mm, 1.2 mm, 1.1 mm, 1.0 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, or 0.3 mm. In some embodiments, the shell has a thickness of approximately 0.3, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.2 mm, 2.4 mm, 2.6 mm, 2.8 mm, or 3.0 mm.

[0240] In some embodiments, the shell comprises a thermoplastic material, such as a thermoplastic polymer. In some embodiments, the shell comprises a matrix material, a plasticizer, or a material comprising one or more other additives, such as fillers, binders, lubricants, flow enhancers, and disintegrants.

[0241] In some embodiments, the matrix material is copolyvidone, polyvinylpyrrolidone-co-vinyl acetate, polyvinylpyrrolidone-polyvinyl acetate copolymer, crospovidone, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose or hypromellose, hydroxypropyl methylcellulose phthalate, methylcellulose, methacrylic acid copolymer, poly(methacrylate-co-ethyl acrylate), poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), poly(dimethylaminoethyl methacrylate-co-methacrylate ester), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonium ethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly(methacrylate-co-methyl methacrylate), poly(methacrylate-co- It contains one or more of the following: ethyl acrylate, poly(methacrylate-comethyl methacrylate), polyethylene oxide, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, Kollicoat IR-polyvinyl alcohol, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, hydroxypropyl methylcellulose acetate succinate or hypromellose acetate succinate, methacrylate ester copolymer, ammonia alkyl methacrylate copolymer, ethylcellulose, polyvinyl acetate and polyvinylpyrrolidone, polyvinyl acetal diethylaminolactate, polyvinyl acetal diethylaminolactate, maltitol, lactose monohydrate, xylitol, isomalt, sucrose, glucose, dextran 70, or maltose.

[0242] In some embodiments, the plasticizer is one or more of the following: triethyl citrate, vitamin E polyethylene glycol succinate, acetylated triethyl citrate, tributyl citrate, O-acetyl tributyl citrate, polyoxyl 15 hydroxystearate, PEG-40 hydrogenated castor oil, polyoxyl 35 castor oil, dibutyl sebacate, diethyl phthalate, glycerin, methyl 4-hydroxybenzoate, castor oil, oleic acid, triacetin, polyalkylene glycol, stearic acid, palmitic acid, malic acid, polyethylene glycol, lauroyl PEG-32 glyceride, poloxamer 188, poloxamer 407, acetyl tributyl citrate, D-sorbitol, propylene glycol, diethyl phthalate, citric acid, glyceryl behenate, D-mannitol, polysorbate, sorbitan monostearate, sorbitan monooleate, or polyoxyl 40 stearate.

[0243] In some embodiments, other additives include acacia, alginate, alginic acid, aluminum acetate, butylparaben, butylated hydroxytoluene, citric acid, calcium carbonate, candelilla wax, croscarmellose sodium, powdered sugar, colloidal silicone dioxide, cellulose, plain or anhydrous calcium phosphate, carnuba wax, corn starch, carboxymethylcellulose calcium, disodium ethylenediaminetetraacetate, dehydrated calcium hydrogen phosphate, cetylpyridine chloride, dicalcium phosphate, tricalcium phosphate, dicalcium phosphate, disodium hydrogen phosphate, dimethicone, sodium erythrosine, ethylenediaminetetraacetate, gelatin, glyceryl monooleate, iron oxides, iron oxide yellow, iron oxide red, lacto One or more of the following: cellulose (hydrated, anhydrous, monohydrate, or spray-dried), microcrystalline cellulose, magnesium carbonate, magnesium oxide, methylparaben, polysorbate 80, propyleneparaben, potassium bicarbonate, potassium sorbate, potato starch, phosphoric acid, polyoxyethylene (40) stearate, sodium glycolate starch, pregelatinized starch, cross-linked sodium, sodium lauryl sulfate, starch, silicon dioxide, sodium benzoate, sucrose, sorbic acid, sodium carbonate, sodium saccharin, sodium alginate, silica gel, sorbitan monooleate, sodium chloride, dehydrated sodium citrate, sodium starch, carboxymethylcellulose, succinic acid, sodium propionate, titanium dioxide, or talc. 5. Additional ingredients

[0244] In some embodiments, the oral drug dosage form includes one or more additional components.

[0245] In some embodiments, the oral drug dosage form includes excipients.

[0246] In some embodiments, the excipient is mixed with the drug component. In some embodiments, the excipient is mixed with an erosive retarder. In some embodiments, the excipient is mixed with a bacteriogenic degrader. In some embodiments, the excipient is mixed with an excipient component, which includes an erosive material. In some embodiments, the excipient includes one or more of an absorption enhancer, a pH lowering agent, or a disintegrant. In some embodiments, the excipient is selected based on whether the oral drug dosage form or the drug in it is intended for local or systemic delivery. For example, an absorption enhancer may be found to be particularly useful in an oral drug dosage form formulated for systemic delivery. In some embodiments, the oral drug dosage form includes a drug intended for systemic delivery and a drug intended for local delivery (e.g., placed in different compartments of the oral drug dosage form), and the oral drug dosage form is configured such that an absorption-enhancing excipient is released to aid in the systemic uptake of the drug intended for systemic delivery.

[0247] In some embodiments, the oral drug dosage form includes an adjuvant. For example, certain drugs, such as bioagents, such as peptides and / or nucleic acids, may benefit from an adjuvant that helps protect the drug once released into the gastrointestinal tract, thereby improving its uptake. In some embodiments, the adjuvant is a protease scavenger and / or protease inhibitor. In some embodiments, the protease scavenger or protease inhibitor is mixed with a delay component or a part thereof (e.g., an erosive delay component). In some embodiments, the protease scavenger or protease inhibitor is mixed with the erosive material of the erosive delay component.

[0248] In some embodiments, additional components include, for example, an outer coating. In some embodiments, the outer coating is a flavor coating. In some embodiments, the outer coating is a sugar coating. In some embodiments, the outer coating is a cosmetic coating. In some embodiments, the outer coating is a color coating. In some embodiments, the outer coating is a film coating. In some embodiments, the outer coating is a polymer coating. In some embodiments, additional components include labels such as a company name, abbreviation or logo; drug labels or drug names such as a drug brand name and / or drug chemical name or abbreviation; drug quantity or strength; identification barcode; or any combination thereof. C. Oral drug dosage forms and their release profiles

[0249] The oral drug dosage forms described herein are configured to release the drug at a desired location within the colon of an individual. In some embodiments, the oral drug dosage form is configured to release the drug in or near one of the following: the cecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, or sigmoid colon, or downstream thereof. In some embodiments, at least about 95% (e.g., at least about 96%, 97%, 98%, 99%, or 100%) of the drug in the oral drug dosage form is released from the oral drug dosage form in the colon of the individual. In some embodiments, less than about 2% of the drug in the oral drug dosage form (e.g., less than about 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%) is released from the oral drug dosage form outside the colon of the individual. In some embodiments, substantially all (including all) of the drug in the oral drug dosage form is released from the oral drug dosage form in the colon of the individual.

[0250] In some embodiments, the oral drug dosage form is configured to release the drug in, near, or downstream of the individual's ileum. In some embodiments, the oral drug dosage form is configured to release the drug in, near, or downstream of the individual's large intestine (colon) or a portion thereof. In some embodiments, the oral drug dosage form is configured to release the drug in, near, or downstream of the cecum, ascending colon, transverse colon, descending colon, and / or sigmoid colon. In some embodiments, the oral drug dosage form is configured to release the drug in, near, or upstream of the rectum.

[0251] Within a desired location in the colon for drug release, the oral drug dosage forms described herein may be configured to release the drug according to any release profile. In some embodiments, the oral drug dosage form is configured to release the drug according to a controlled release profile. In some embodiments, the controlled release profile is an immediate release profile. For example, as described herein, the drug component releases the drug contained therein in any of the following: about 1 hour or less, for example, about 50 minutes or less, 40 minutes or less, 30 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, 9 minutes or less, 8 minutes or less, 7 minutes or less, 6 minutes or less, 5 minutes or less, 4 minutes or less, 3 minutes or less, 2 minutes or less, or 1 minute or less. In some embodiments, the controlled release profile is a sustained release profile. For example, as described herein, a drug component releases the drug over a period of at least about 1 hour, for example, at least about 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, or 7 hours. In some embodiments, the drug component of an oral drug dosage form is configured to release the drug from the oral drug dosage form over a period of at least about 1 hour, for example, at least about 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, or 8 hours.

[0252] In some embodiments, the oral drug dosage form is configured to provide a drug release profile including a zero-order release profile, a primary release profile, a delayed-release profile, a pulsed-release profile, a repeated-pulsed-release profile, an immediate-release profile, or a sustained-release profile, or a combination thereof.

[0253] As described herein, in some embodiments, the oral drug dosage form may include other drugs (including two or more, three or more, four or more, or five or more). In such embodiments, the other drugs may be released according to any desired drug release profile. In some embodiments, the desired drug release profile of the other drugs includes a zero-order release profile, a primary-order release profile, a delayed-release profile, a pulsed-release profile, a repeated-pulsed-release profile, an immediate-release profile, a sustained-release profile, or a combination thereof.

[0254] In some embodiments, the drug release is based at least in part on an in vitro lysis study, such as the one described in U.S. Patent No. 10,350,822, which is incorporated herein by reference in whole. In some embodiments, the drug release is based at least in part on an in vivo lysis study, such as the one described in U.S. Patent No. 2021 / 0196638A, which is incorporated herein by reference in whole. III. Commercial batches

[0255] In some embodiments, this specification provides a commercially available batch of at least about 100 oral drug dosage forms described herein. In some embodiments, the commercially available batch includes at least one of at least about 250, 500, 750, 1,000, 2,500, 5,000, 7,500, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000, or 100,000 oral drug dosage forms described herein.

[0256] In some embodiments, a commercially available batch has a standard deviation of about 0.1 or less, for example, 0.05 or less, for one or more of the following: the amount of drug and / or pharmaceuticals such as the bacterial degradation portion in the oral drug dosage form, the weight of the oral drug dosage form, the maximum transverse dimension of the oral drug dosage form, the transverse dimension perpendicular to the maximum transverse dimension of the oral drug dosage form, and the layer thickness. IV. Methods for producing and designing oral drug dosage forms described herein.

[0257] In some embodiments, methods for producing the oral drug dosage forms described herein are provided. In some embodiments, the production method includes a three-dimensional (3D) printing technique for forming at least one or a portion of the components of the oral drug dosage forms described herein. In some embodiments, the 3D printing technique, which enables precise control of drug release, can be achieved by fine-tuning different parameters such as shape, fill density, or composition.

[0258] In some embodiments, a method for three-dimensional (3D) printing of an oral drug dosage form is provided, the method comprising printing the oral drug dosage form by distributing material according to a layer-by-layer model of the oral drug dosage form (for example, based on the thickness of the material deposited by the pass of the printer head), each layer of the layer-by-layer model being printed by distributing, as necessary, (a) shell material to form any part of the shell in the layer, (b) drug component material to form any part of the drug component in the layer, (c) pH-based enteric component material to form any part of the pH-based enteric component in the layer, (d) erosion retarder material to form any part of the erosion retarder in the layer, (e) biodegradable component material to form any part of the biodegradable component in the layer, and (f) excipient component material to form any part of the excipient component in the layer.

[0259] In some embodiments, an oral drug dosage form comprises (a) a drug component comprising an erosive material mixed with a drug, and (b) a pH-based enteric component (not mixed with the drug) comprising an erosive material configured to be eroded at a predetermined pH value or higher, and the 3D printing method comprises printing the oral drug dosage form by distributing materials according to a layer-by-layer model of the oral drug dosage form (for example, based on the thickness of the material deposited by the pass of the printer head), and each layer of the layer-by-layer model is printed by distributing, as necessary, (a) a drug component material to form any portion of the drug component in the layer, and (b) a pH-based enteric component material to form any portion of the pH-based enteric component in the layer. In some embodiments, the method further comprises generating a layer-by-layer model of the oral drug dosage form.

[0260] In some embodiments, an oral drug dosage form includes (a) a drug component comprising an erosive material mixed with a drug; (b) a pH-based enteric component (not mixed with the drug) comprising an erosive material configured to erode at a predetermined pH value or higher; and (c) an erosive retarder component comprising an erosive material not mixed with the drug. The 3D printing method includes printing the oral drug dosage form by distributing materials according to a layer-by-layer model of the oral drug dosage form (for example, based on the thickness of the material deposited by the pass of the printer head), and each layer of the layer-by-layer model is printed by distributing, as necessary, (a) a drug component material to form any portion of the drug component in the layer; (b) a pH-based enteric component material to form any portion of the pH-based enteric component in the layer; and (c) an erosive retarder material to form any portion of the erosive retarder component in the layer. In some embodiments, the method further includes generating a layer-by-layer model of the oral drug dosage form.

[0261] In some embodiments, an oral drug dosage form comprises (a) a drug component comprising an erosive material mixed with a drug; (b) a pH-based enteric component (not mixed with the drug) comprising an erosive material configured to be eroded at a predetermined pH value or higher; and (c) a biodegradable component comprising a biodegradable portion. The 3D printing method comprises printing the oral drug dosage form by distributing materials according to a layer-by-layer model of the oral drug dosage form (for example, based on the thickness of the material deposited by the pass of the printer head), and each layer of the layer-by-layer model is printed by distributing, as necessary, (a) a drug component material to form any portion of the drug component in the layer; (b) a pH-based enteric component material to form any portion of the pH-based enteric component in the layer; and (c) a biodegradable component material to form any portion of the biodegradable component in the layer. In some embodiments, the method further comprises generating a layer-by-layer model of the oral drug dosage form.

[0262] In some embodiments, an oral drug dosage form includes (a) a drug component comprising an erosive material mixed with a drug; (b) a pH-based enteric component (not mixed with the drug) comprising an erosive material configured to erode at a predetermined pH value or higher; (c) an erosive retarder component comprising an erosive material not mixed with the drug; and (d) a biodegradable component comprising a biodegradable portion. The 3D printing method includes printing the oral drug dosage form by distributing materials according to a layer-by-layer model of the oral drug dosage form (for example, based on the thickness of the material deposited by the pass of the printer head), wherein each layer of the layer-by-layer model is printed by distributing, as necessary, (a) a drug component material to form any portion of the drug component in the layer; (b) a pH-based enteric component material to form any portion of the pH-based enteric component in the layer; and (c) an erosive retarder material to form any portion of the erosive retarder in the layer and a biodegradable component material to form any portion of the biodegradable component in the layer. In some embodiments, the method further includes generating a layer-by-layer model of oral drug dosage forms.

[0263] In some embodiments, an oral drug dosage form comprises (a) a drug component comprising an erosive material mixed with a drug; (b) a pH-based enteric component (not mixed with the drug) comprising an erosive material configured to be eroded at a predetermined pH value or higher; and (c) an excipient component comprising an excipient. The 3D printing method comprises printing the oral drug dosage form by distributing materials according to a layer-by-layer model of the oral drug dosage form (for example, based on the thickness of the material deposited by the pass of the printer head), and each layer of the layer-by-layer model is printed by distributing, as necessary, (a) a drug component material to form any portion of the drug component in the layer; (b) a pH-based enteric component material to form any portion of the pH-based enteric component in the layer; and (c) an excipient component material to form any portion of the excipient component in the layer. In some embodiments, the method further comprises generating a layer-by-layer model of the oral drug dosage form.

[0264] In some embodiments, an oral drug dosage form comprises (a) a drug component comprising an erosive material mixed with a drug; (b) a pH-based enteric component (not mixed with a drug) comprising an erosive material configured to erode at a predetermined pH value or higher; (c) an erosive retarder component comprising an erosive material not mixed with a drug; and (d) an excipient component comprising an excipient. The 3D printing method comprises printing the oral drug dosage form by distributing materials according to a layer-by-layer model of the oral drug dosage form (for example, based on the thickness of the material deposited by the pass of the printer head), wherein each layer of the layer-by-layer model is printed by distributing, as necessary, (a) a drug component material to form any portion of the drug component in the layer; (b) a pH-based enteric component material to form any portion of the pH-based enteric component in the layer; (c) an erosive retarder material to form any portion of the erosive retarder component in the layer; and (d) an excipient component material to form any portion of the excipient component in the layer. In some embodiments, the method further includes generating a layer-by-layer model of oral drug dosage forms.

[0265] In some embodiments, the oral drug dosage form includes (a) a drug component comprising an erosive material mixed with the drug, (b) a pH-based enteric coating (not mixed with the drug) comprising an erosive material configured to be eroded at a predetermined pH value or higher, (c) an erosive retarder comprising an erosive material not mixed with the drug, (d) a biodegradable component comprising a biodegradable portion, and (e) an excipient component comprising an excipient, wherein the 3D printing method distributes the material according to a layer-by-layer model of the oral drug dosage form (for example, based on the thickness of the material deposited by the printer head passes). The method includes printing an oral drug dosage form, wherein each layer of the layer-by-layer model is printed by distributing, as necessary, (a) a drug component material to form any portion of the drug component in the layer, (b) a pH-based enteric component material to form any portion of the pH-based enteric component in the layer, (c) an erosion retarder component material to form any portion of the erosion retarder component in the layer, (d) a biodegradable component material to form any portion of the biodegradable component in the layer, and (e) an excipient component material to form any portion of the excipient component in the layer. In some embodiments, the method further includes generating a layer-by-layer model of the oral drug dosage form.

[0266] In any of the embodiments described above, the oral drug dosage form may further include a shell that is not mixed with the drug. In embodiments in which the oral drug dosage form includes a shell, the method further includes printing the oral drug dosage form by distributing the material according to a layer-by-layer model of the oral drug dosage form (for example, based on the thickness of the material deposited by the pass of the printer head), and each layer of the layer-by-layer model is printed by distributing, if necessary, the shell material to form any portion of the shell within the layer.

[0267] As used herein, “printing,” “three-dimensional printing,” “3D printing,” “additive manufacturing,” or their equivalents refer to the process of generating three-dimensional objects, such as oral drug dosage forms, layer by layer using digital design. The basic processes of three-dimensional printing are described in U.S. Patents 5,204,055, 5,260,009, 5,340,656, 5,387,380, 5,503,785, and 5,633,021. Additional U.S. patents and patent applications relating to three-dimensional printing include U.S. Patent Nos. 5,490,962, 5,518,690, 5,869,170, 6,530,958, 6,280,771, 6,514,518, 6,471,992, 8,828,411, and U.S. Patent Publication Nos. 2002 / 0015728, 2002 / 0106412, 2003 / 0143268, 2003 / 0198677, and 2004 / 0005360. The contents of the above U.S. patents and patent applications are incorporated herein by reference in their entirety. In some embodiments, additive manufacturing techniques are used to produce the oral drug dosage forms described herein. In some embodiments, layer-by-layer technology is used to produce the oral drug dosage forms described herein. 3D printing is well suited to the production of oral drug dosage forms having complex geometric shapes and compositions according to the present invention, as it can handle a variety of pharmaceutical materials and allow for localized control of both composition and structure.

[0268] In some embodiments, when used with respect to, for example, a drug component layer or a retarder component layer (e.g., a pH-based enteric coating layer and / or an erosive retarder component layer), the layer refers to the composition of the components of an oral drug dosage form and may include multiple printed layers of the same material. In some embodiments, the layer has a predetermined packing density, such as a three-dimensional print packing density. In some embodiments, the layer, for example, the drug component layer, includes multiple printed layers between about 5 to about 2500 printed layers, for example, about 10 to about 2500 printed layers, about 25 to about 100 printed layers, about 50 to about 200 printed layers, about 100 to about 200 printed layers, about 150 to about 250 printed layers, about 200 to about 250 printed layers, about 500 to about 1000 printed layers, or about 2000 to about 2400 printed layers. In some embodiments, the thickness of the printed layer is approximately 5 mm or less, for example, approximately 4 mm, 3 mm, 2 mm, 1 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, 0.1 mm, 0.09 mm, 0.08 mm, 0.07 mm, 0.06 mm, 0.05 mm, 0.04 mm, 0.03 mm, 0.02 mm, or 0.01 mm or less. In some embodiments, the thickness of the printed layer is approximately 5 mm, 4 mm, 3 mm, 2 mm, 1 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, 0.1 mm, 0.09 mm, 0.08 mm, 0.07 mm, 0.06 mm, 0.05 mm, 0.04 mm, 0.03 mm, 0.02 mm, or 0.01 mm.

[0269] Different 3D printing methods are being developed for manufacturing raw materials, equipment, and solidification. These 3D printing methods include binder deposition (Gibsonetal., Additive Manufacturing Technologies: 3D Printing, Rapid Prototyping, and Direct Digital Manufacturing., 2nd ed. Springer, New York, 2015; Katstraetal., Oraldosageforms fabricated by three-dimensional printing, JControlRelease, 66, 2000; Katstraetal., Fabrication of complex oral delivery forms by three-dimensional printing, Dissertation in Materials Science and Engineering, Massachusetts). See etts Institute of Technology, 2001; Lipsonetal, Fabricated: The New World of 3D Printing, John Wiley & Sons, Inc., 2013; Jonathan, Karim 3D Printing Inpharmaceutics: A New Tool for Designing Customized Drug Delivery Systems, IntJPharm, 499, 2016; Material spraying (see Jonathan, Karim 3D Printing Inpharmaceutics: A New Tool for Designing Customized Drug Delivery Systems, IntJPharm, 499, 2016); Extrusion (see Gibsonetal, Additive Manufacturing T This includes technologies (see: 3D Printing, Rapid Prototyping, and Direct Digital Manufacturing. 2nd ed. Springer, New York, 2015) and photopolymerization (see: Melchelsetal., Areview on stereolithography and its application in biomedical engineering. Biomaterials, 31, 2010).

[0270] In some embodiments, the oral drug dosage forms described herein are 3D printed using extrusion. In some embodiments, the 3D printing method includes using twin-screw extrusion. In the extrusion process, the material is extruded from a robot-controlled print head through a print nozzle. Unlike binder deposition, which requires a powder bed, extrusion can be printed on any substrate. A variety of materials, including thermoplastic materials, pastes and colloidal suspensions, silicones, and other semi-solids disclosed herein, can be extruded for three-dimensional printing. One extrusion printing method is fused extrusion deposition (MED), in which layers of material are printed using the extruded material from the print head to form the components of the oral drug dosage form. Another common type of extrusion printing is fused deposition modeling (FDM), which uses a solid polymer filament for printing. In FDM, a gear system drives the filament to extrude into a heated nozzle assembly (see Gibsonetal., Additive Manufacturing Technologies: 3D Printing, Rapid Prototyping, and Direct Digital Manufacturing, 2nd ed. Springer, New York, 2015).

[0271] In some embodiments, 3D printing is carried out by semi-solid extrusion, such as semi-solid extrusion of a material containing a bioagent, e.g., polypeptide or nucleic acid. In some embodiments, 3D printing is carried out by MED and semi-solid extrusion, e.g., semi-solid extrusion, to produce a drug component mixed with a bioagent, and by MED to produce other components. In some embodiments, 3D printing is carried out by MED to produce a retarder component or shell, and then 3D printing is carried out by semi-solid extrusion to produce a drug component mixed with a bioagent at a lower temperature than MED. In some embodiments, the drug in the drug component can maintain stability by semi-solid extrusion.

[0272] In some embodiments, 3D printing is performed by melt extrusion deposition (MED). In some embodiments, the melt extrusion deposition technique includes preparing the material to be distributed, such as by preparing a powder in a hot melt extruder, and then supplying the material to a MED printhead. The MED printhead then distributes the material to form an oral drug dosage form in an additional manner (layer-by-layer deposition). In some embodiments, each material of the oral drug dosage form, such as a sustained-release drug component, a delay member, and a shell, is distributed from a different MED printhead. In some embodiments, the MED printhead distributes the material according to instructions compiled in one or more G-code files. Exemplary MED techniques are disclosed, for example, in WO2018 / 210183, WO2019 / 137333, WO2018137686, and U.S. 10,201,503, all of which are incorporated herein by reference in their entirety.

[0273] In some embodiments, the melt extrusion deposition 3D printing technique includes (a) preparing each component material by melting and extruding the component materials, and (b) printing the oral drug dosage form using a layer-by-layer technique. In some embodiments, the melt extrusion deposition 3D printing technique further includes preparing a printer head for printing. In some embodiments, preparing a drug component material includes melting and extruding the drug component material. In some embodiments, preparing a drug component material includes mixing the components of the drug component material, such as any thermoformable components and drugs. In some embodiments, preparing a drug component material includes weighing its components, mixing the components, and melting and extruding the drug component material. In some embodiments, preparing a shell material includes melting and extruding the shell material. In some embodiments, preparing a shell material includes mixing the components of the shell material, such as its any thermoformable components. In some embodiments, preparing a shell material includes weighing its components, mixing the components, and melting and extruding the shell material. In some embodiments, preparing a pH-based enteric material involves melting and extruding the pH-based enteric material. In some embodiments, preparing a pH-based enteric material involves mixing the components of the pH-based enteric material, such as any thermoformable components. In some embodiments, preparing a pH-based enteric material involves weighing each component, mixing the components, and melting and extruding the pH-based enteric material. In some embodiments, preparing an erosion retarder material involves melting and extruding the erosion retarder material. In some embodiments, preparing an erosion retarder material involves mixing the components of the erosion retarder material, such as any thermoformable components. In some embodiments, preparing an erosion retarder material involves weighing each component, mixing the components, and melting and extruding the erosion retarder material. In some embodiments, preparing a bacteriolytic material involves melting and extruding the bacteriolytic material.In some embodiments, preparing a biodegradable component material involves mixing components of the biodegradable component material, such as any thermoformable components and biodegradable portions. In some embodiments, preparing a biodegradable component material involves weighing each component, mixing the components, and melting and extruding the biodegradable component material. In some embodiments, preparing an excipient component material involves melting and extruding the excipient component material. In some embodiments, preparing an excipient component material involves mixing components of the excipient component material, such as any thermoformable components and excipient portions. In some embodiments, preparing an excipient component material involves weighing each component, mixing the components, and melting and extruding the excipient component material.

[0274] In some embodiments, preparing the printer head for printing includes loading formed component materials, such as drug component materials, into the printer head. In some embodiments, preparing the printer head for printing includes setting the printer head temperature. In some embodiments, preparing the printer head for printing includes setting and applying the supply pressure to the printer head. In some embodiments, applying the supply pressure is completed after the printer head temperature has reached a predetermined level. In some embodiments, printing of oral drug dosage forms is performed layer by layer (e.g., additive manufacturing). In some embodiments, the method includes using separate printer heads for each component material (e.g., a first printer head for distributing drug component materials, a second printer head for distributing shell materials, a third printer head for distributing pH-based enteric coating material, and a fourth printer head for distributing erosive retarding component material). In some embodiments, the manufacturing method is designed and implemented based on a desired total number of oral drug dosage forms to be manufactured in a production run. For example, in some embodiments, smaller production runs (e.g., fewer than 1,000 oral drug dosage forms for product development or clinical trials) are desired, and the manufacturing method includes preparing each component material (e.g., weighing the components of the component material, mixing the components, and hot-melt extruding to form the component material), and then printing each oral drug dosage form layer by layer (e.g., additive manufacturing). In some embodiments, larger production runs (e.g., commercial mass production runs of more than 1,000 oral drug dosage forms) are desired, and the manufacturing method includes preparing each component material (e.g., weighing the components of the component material, mixing the components, and hot-melt extruding to form the component material, with the hot-melt extrusion performed using a twin-screw extruder), and then printing each oral drug dosage form layer by layer (e.g., additive manufacturing). In some embodiments, the component material is formed at least partially using a twin-screw extruder. In some embodiments, larger production runs include distributing the component material from the twin-screw extruder to each printer head via a flow distribution module.In some embodiments, larger production operations are performed through the cooperation of multiple modules. For example, in some embodiments, the manufacturing method includes using a system comprising: a material supply module for receiving a set of component materials for printing; a flow distribution module including a flow distribution plate, wherein the material supply module is configured to transport a single flow corresponding to the set of component materials for printing to the flow distribution plate, and the flow distribution plate includes multiple channels for dividing a single flow into multiple flows; multiple nozzles; and one or more controllers for controlling the multiple nozzles to distribute the multiple flows based on multiple nozzle-specific parameters. In some embodiments, the system further includes a printing platform configured to receive the distributed multiple flows, and the printing platform is configured to move to form a batch of pharmaceuticals. In some embodiments, the system includes multiple printing platforms.

[0275] In some embodiments, 3D printing is carried out by fused deposition modeling (FDM). In some embodiments, 3D printing is carried out by melt extrusion deposition or hot melt extrusion combined with 3D printing techniques such as FDM. In some embodiments, 3D printing is carried out by non-filament FDM. In some embodiments, 3D printing is carried out by inkjet printing. In some embodiments, 3D printing is carried out by powder sintering additive manufacturing (SLS). In some embodiments, 3D printing is carried out by stereolithography (SLA or SL). In some embodiments, 3D printing is performed by PolyJet, Multi-JetPrintingSystem (MJP), Perfactory, SolidObjectUltraviolet-LaserPrinter, Biologetter, 3DBiorinting, RapidFreezePrototyping, BenchtopSystem, SelectiveDepositionLamination (SDL), LaminatedObjetManufacturing (LOM), UltrasonicConsolidation, ColorJetPrinting (CJP), EOSINTSystems, LaserEngineeredNetShaping (LENS), and AerosolJetSystem, ElectronBeamMelting (EBM), LaserCUSING®, SelectiveLaserMelting (SLM), PhenixPX™Series, Microsintering, DigitalPartMaterialization (DPM), or VXSystem.

[0276] In some embodiments, the 3D printing method described herein includes a continuous feeding method. In some embodiments, the 3D printing method described herein includes a batch feeding method.

[0277] The method instructions for 3D printing drug dosage forms disclosed herein may be generated in a variety of ways, including direct coding, derivation from solid CAD models, or other means specific to the computer interface and application software of the 3D printer. These instructions may include information regarding the number and spatial arrangement of droplets, as well as general 3D printing parameters such as droplet spacing and the volume or mass of fluid per droplet in each linear dimension (X, Y, Z). For a given set of materials, these parameters may be adjusted to improve the quality of the structure created. The overall resolution of the structure created is a function of powder particle size, droplet size, printing parameters, and material properties.

[0278] In some embodiments, one or more components of an oral drug dosage form are created separately, for example, printed separately, and then assembled to form the oral drug dosage form. In some embodiments, all components of an oral drug dosage form are created in a single method, for example, printed in a single method, without requiring subsequent assembly. For example, in some embodiments, the oral drug dosage form is produced using layer-by-layer 3D printing technology.

[0279] The oral drug dosage forms and their components described in this application can be printed on a commercial scale. For example, in some embodiments, the methods disclosed herein may be used to 3D print oral drug dosage forms at a rate of 10,000 to 100,000 units per hour. In some embodiments, the methods disclosed herein may be used to 3D print oral drug dosage forms at a rate of 10,000 to 100,000 units per hour. In some embodiments, the methods disclosed herein may be used to 3D print dose units at a rate of 10,000 to 100,000 units per hour. In some embodiments, the methods disclosed herein may be used to 3D print dose units at a rate of 10,000 to 100,000 units per hour.

[0280] The 3D printing methods described herein encompass printing materials in any order that enables the production of oral drug dosage forms or components thereof.

[0281] In some embodiments, the 3D printing method includes designing an oral drug dosage form or its components, either entirely or partially, on a computer system. In some embodiments, the method includes inputting a desired local drug release profile and / or parameters of the oral drug dosage form into a computer system. In some embodiments, the method includes providing one or more parameters to be printed, e.g., layer surface area, thickness, drug mass fraction, erosion rate. In some embodiments, the method includes providing a desired drug release profile. In some embodiments, the method includes creating a virtual image of the item to be printed. In some embodiments, the method includes creating a computer model containing predetermined parameters. In some embodiments, the method includes supplying predetermined parameters to a 3D printer and printing the item according to such predetermined parameters. In some embodiments, the method includes creating a 3D drawing of the item to be printed based on predetermined parameters, the 3D drawing being created on a computer system. In some embodiments, the method includes converting the 3D drawing into 3D printing code, e.g., G-code, e.g., slicing. In some embodiments, the method includes executing the 3D printing code using a computer system and thereby printing according to the method described herein.

[0282] In some embodiments, the methods provided herein include one or more packaging steps. In some embodiments, the packaging step includes packaging each individual dosage form into a separate container, such as a laminated film and a pouch for pharmaceutical packaging. In some embodiments, the packaging step includes packaging a plurality of packaged dosage forms into a carton.

[0283] In some embodiments, the method further includes one or more in-process quality control steps. For example, in some embodiments, after manufacturing a dosage form, the in-process quality control step includes one or more of the following: evaluating the appearance or characteristics of the dosage form, evaluating the weight of the dosage form, and evaluating the dimensions of the dosage form. In some embodiments, to pass the in-process quality control step, the evaluated characteristics must be within a predetermined threshold. In some embodiments, after each dosage form has been packaged, the in-process quality control step includes evaluating the seal of each dosage form, for example, for tightness and / or fill volume. In some embodiments, after packaging in a carton, the in-process quality control step includes verifying the fill volume of the carton.

[0284] In some embodiments, the design methods provided herein include using one or more tracking stripes so that external imaging techniques, such as X-ray imaging, can be used to evaluate the state of one or more components of the oral drug dosage form taught herein relative to the location of the oral drug dosage form in an administered individual (e.g., not yet undergoing erosion / release from the oral drug dosage form, undergoing erosion / release from the oral drug dosage form, or having completed erosion / release from the oral drug dosage form). For example, such tracking features allow a person to confirm that one or more components on the oral drug dosage form are functioning as desired, e.g., that drug release from the drug component is occurring at a desired location in the individual's gastrointestinal tract. This further enables methods including adjusting the design of the oral drug dosage form to provide the desired result. For example, if it is found that the drug component is eroding and releasing the drug at an earlier location than desired (e.g., upstream of the desired location in the gastrointestinal tract), then one or more embodiments of the delay component can be adjusted, for example, by changing the composition or thickness of its material.

[0285] In some embodiments, a method is provided for designing an oral drug dosage form configured to release the drug at a desired gastrointestinal location in an individual, comprising: a drug component comprising a first erosive material mixed with the drug and a first erosive tracking stripe; a shell comprising a second tracking stripe; and a delay component not mixed with the drug, wherein the delay component is a pH-based enteric coating configured to be eroded at a predetermined pH value or higher, wherein the pH-based enteric coating comprises a third erosive tracking stripe; and an erosive delay component comprising a second erosive material, wherein the erosive delay component comprises a fourth erosive tracking stripe, and the pH-based enteric coating, alone or in combination with the shell, prevents erosion of the erosive delay component and the erosive delay portion The material comprises a delay component, which includes an erosive delay member, which prevents erosion of the drug component, either alone or in combination with a shell, and the method comprises (a) administering an oral drug dosage form to an individual; (b) imaging the individual over time to obtain the position of the oral drug dosage form and the state of a first erosive tracking stripe, a second erosive tracking stripe, a third erosive tracking stripe and a fourth tracking stripe; and (c) designing an oral drug dosage form configured to release the drug at a desired gastrointestinal location in the individual by adjusting the drug component and / or delay component and / or shell, or a part thereof, based on the position and state of the first erosive tracking stripe, a second erosive tracking stripe, a third erosive tracking stripe and a fourth tracking stripe.

[0286] In some embodiments, adjusting the delay component includes adjusting the pH-based enteric coating by changing one or more of the composition, the surface area exposed to body fluids after administration, or the thickness of the pH-based enteric coating. In some embodiments, adjusting the delay component includes adjusting the erosive delay coating by changing one or more of the composition, the surface area exposed to body fluids after administration, or the thickness of the erosive delay coating.

[0287] In some embodiments, this specification provides a method for designing an oral drug dosage form configured to release a drug at a desired gastrointestinal location in an individual, the oral drug dosage form comprising: a drug component, a first erosive material mixed with the drug, and a first erosive tracking stripe; a shell; a delay component not mixed with the drug, the delay component comprising a pH-based enteric coating configured to erode at a predetermined pH value or higher, and a second erosive delay component comprising a pH-based enteric coating, the pH-based enteric coating, alone or in combination with the shell, prevents erosion of the erosive delay component. The method comprises an erosive delay member, which, either alone or in combination with a shell, prevents erosion of the drug component, and includes a delay component, and the method comprises (a) administering an oral drug dosage form to an individual, (b) imaging the individual over time to obtain the position of the oral drug dosage form and the state of a first erosive tracking stripe, and (c) designing an oral drug dosage form configured to release the drug at a desired gastrointestinal location in the individual by adjusting the drug component and / or delay component and / or shell, or a part thereof, based on the position and state of the first erosive tracking stripe.

[0288] In some embodiments, the first erosive material mixed with the drug and the first erosive tracking stripe are not in direct contact with each other. In some embodiments, the shell includes a second tracking stripe, which is configured to be imaged by imaging to obtain, for example, the state of the second tracking stripe. In some embodiments, adjustment is based on the position and state of the first erosive tracking stripe and / or the second tracking stripe. In some embodiments, the pH-based enteric coating includes a third tracking stripe, which is configured to be imaged by imaging to obtain, for example, the state of the third erosive tracking stripe. In some embodiments, adjustment is based on the position and state of the first erosive tracking stripe and / or the second tracking stripe and / or the third tracking stripe. In some embodiments, the erosive delaying coating includes a fourth tracking stripe, which is configured to be imaged by imaging to obtain, for example, the state of the fourth erosive tracking stripe. In some embodiments, the adjustment is based on the position and state of the first erosive tracking stripe and / or the second tracking stripe and / or the third erosive tracking stripe and / or the fourth tracking stripe.

[0289] In some embodiments, imaging provides the location of the oral drug dosage form when the first erosive tracking stripe begins to erode. In some embodiments, imaging provides the location of the oral drug dosage form when the first erosive tracking stripe is completely eroded. In some embodiments, adjustment includes adjusting the delay component or part thereof based on the location and state of the first erosive tracking stripe indicating release earlier than desired to increase the delay of drug release from the oral drug dosage form. In some embodiments, adjustment includes adjusting the delay component or part thereof based on the location and state of the first erosive tracking stripe indicating release later than desired to reduce the delay of drug release from the oral drug dosage form.

[0290] In some embodiments, the first tracking stripe contains barium sulfate. In some embodiments, imaging includes X-ray imaging. In some embodiments, the method further includes obtaining one or more pharmacokinetic (PK) parameters related to the drug after administration of an oral drug dosage form to an individual. In some embodiments, the method further includes identifying the relationship between one or more PK parameters and the position and status information of the first tracking stripe. In some embodiments, the method further includes adjusting the drug components and / or delay components or parts thereof based on the relationship between one or more PK parameters and the position and status information of the first tracking stripe. In some embodiments, imaging does not include magnetic-based techniques or invasive imaging techniques.

[0291] In some embodiments, this specification provides a method for designing an oral drug dosage form configured to release a drug at a desired gastrointestinal location in an individual, the oral drug dosage form comprising: a drug component comprising a first erosive material mixed with the drug; a shell; a delay component not mixed with the drug, the delay component comprising a pH-based enteric coating configured to be eroded at a predetermined pH value or higher; and an erosive delay member comprising a second erosive material, wherein the pH-based enteric coating prevents erosion of the erosive delay member, and the erosive delay member prevents erosion of the drug component. The method comprises (a) administering the oral drug dosage form to an individual; (b) imaging the individual over time to obtain the position of the oral drug dosage form and the state of the at least one tracking stripe; and (c) designing an oral drug dosage form configured to release the drug at a desired gastrointestinal location in the individual by adjusting the drug component and / or the delay component and / or the shell, or a part thereof, based on the position and state of the at least one tracking stripe.

[0292] In some embodiments, one of the tracking stripes is located within or near the drug component. In some embodiments, the tracking stripe is located within the shell. In some embodiments, one of the tracking stripes is located within a pH-based enteric coating. In some embodiments, one of the tracking stripes is located within an erosive delaying coating. In some embodiments, at least one of the at least one tracking stripe is erosive.

[0293] In some embodiments, this specification provides a method for designing an oral drug dosage form configured to release a drug at a desired gastrointestinal location in an individual, wherein the oral drug dosage form comprises a drug component comprising a first erosive material mixed with the drug, a delay component not mixed with the drug, the delay component comprising a pH-based enteric coating configured to be eroded at a predetermined pH value or higher, and an erosive delay member comprising a second erosive material, wherein the pH-based enteric coating prevents erosion of the erosive delay member, and the erosive delay member prevents erosion of the drug component, An oral drug dosage form comprising a delay component and an oral drug dosage form comprising at least one tracking stripe positioned within the component, the method comprising (a) administering the oral drug dosage form to an individual; (b) imaging the individual over time to obtain the position of the oral drug dosage form and the state of at least one tracking stripe; and (c) designing an oral drug dosage form configured to release the drug at a desired gastrointestinal location in the individual by adjusting the drug component and / or delay component, or a portion thereof, based on the position and state of at least one tracking stripe.

[0294] In some embodiments, one of the tracking stripes is located within or near the drug component. In some embodiments, one of the tracking stripes is located within a pH-based enteric coating. In some embodiments, one of the tracking stripes is located within an erosive delaying coating. In some embodiments, at least one of the at least one tracking stripes is erosive.

[0295] In some embodiments, methods are provided for designing and / or modifying oral drug dosage forms described herein, configured to release the drug at a desired location within the colon of an individual. In some embodiments, the modification includes modifying the delaying component or part thereof to increase the delay of drug release from the oral drug dosage form. As described herein, “modification” can mean changing a parameter that affects, for example, the rate at which a component is eroded from the oral drug dosage form. For example, in some embodiments, “modification” can mean changing one or more of the following: thickness, drug mass fraction, density, composition, surface area exposed to body fluids, or erosion rate of the material. In some embodiments, the modification is based on data obtained from studies of the oral drug dosage forms described herein, such as in vitro and / or in vivo studies, e.g., cumulative dissolution profiles or PK studies. Techniques for modifying the characteristics of oral drug dosage forms to increase or decrease the delay of drug release therefrom are known in the art and include, for example, modifications of thickness, surface area, and material properties. Modification techniques are described in U.S. Patent No. 10,350,822, which is incorporated herein by reference in its entirety.

[0296] In some embodiments, the design method further includes obtaining, for example, measuring, one or more drug-related pharmacokinetic (PK) parameters after administration of an oral drug dosage form to an individual. PK parameters are well known in the art, for example, T det , T max , C max and AUC. A design method including PK parameters is described in U.S. Patent No. 2021 / 0196638A, which is incorporated herein by reference in its entirety. V. Methods of treatment and / or delivery

[0297] In some embodiments, methods for treating a condition are provided herein, comprising administering an oral drug dosage form described herein to an individual (by mouth). In some embodiments, methods for providing local delivery of a drug to the colon of an individual are provided herein, comprising administering an oral drug dosage form described herein to an individual (by mouth) to treat, for example, an individual suffering from a gastrointestinal disorder. In some embodiments, methods for providing systemic delivery of a drug to an individual are provided herein, comprising administering an oral drug dosage form described herein to an individual (by mouth) to deliver, for example, a bioagent such as a peptide or nucleic acid.

[0298] The oral drug dosage forms described herein may encompass a wide variety of drugs, and therefore, their use may be useful for treating a wide variety of conditions. In some embodiments, the conditions include gastrointestinal disorders, central nervous system (CNS) disorders, cardiovascular diseases, hypertension, atherosclerosis, angina pectoris, arterial occlusion, peripheral artery disease, myocardial pathology, arrhythmias, acute myocardial infarction, angina pectoris, cardiomyopathy, congestive heart failure, coronary artery disease (CAD), carotid artery disease, endocarditis, hypercholesterolemia, hyperlipidemia, peripheral artery disease (PAD), genitourinary disorders; erectile dysfunction, benign prostatic hyperplasia (BPH), renal tubular acidosis, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, urinary tract infections, fecal incontinence, and eye diseases such as glaucoma. The group consists of blepharitis, ocular hypertension, retinopathy, conjunctivitis, scleritis, retinitis, keratitis, corneal ulcer, iritis, chorioretinitis, macular edema, xerophthalmos, pulmonary diseases, asthma, pulmonary hypertension, acute respiratory distress syndrome, COPD, emphysema, pneumonia, tuberculosis, bronchitis, acute bronchitis, bronchiectasis, bronchiolitis, bronchial dysplasia, pulmonary dysplasia, Cocci (breath fungal infection), cystic fibrosis, influenza, lung cancer, mesothelioma, metabolic diseases, hypercalciuria, hyperglycemia, hyperinsulinemia, hyperinsulinemia, hyperuria, and hypoglycemia. In some embodiments, gastrointestinal disorders are selected from the group consisting of irritable bowel disease (IBD), irritable bowel syndrome (IBS), constipation, diarrhea, infection, and carcinoma. In some embodiments, IBD is associated with Crohn's disease or ulcerative colitis. In some embodiments, the carcinoma is colon cancer or colorectal cancer. In some embodiments, the CNS disorder is selected from the group consisting of neuropathic pain, stroke, dementia, Alzheimer's disease, Parkinson's disease, neurodegeneration, meningitis, spinal cord injury, cerebral vasospasm, and amyotrophic lateral sclerosis.

[0299] In some embodiments, a method is provided for local delivery of a drug to the colon of an individual, the method comprising administering an oral drug dosage form described herein to the individual, the individual suffering from a gastrointestinal disorder. In some embodiments, the gastrointestinal disorder is selected from the group consisting of irritable bowel disease (IBD), irritable bowel syndrome (IBS), constipation, diarrhea, infection, and carcinoma. In some embodiments, IBD is associated with Crohn's disease or ulcerative colitis. In some embodiments, carcinoma is colon cancer or colorectal cancer. In some embodiments, the oral drug dosage form comprises an anti-inflammatory agent, a nonsteroidal anti-inflammatory agent, or a steroid. In some embodiments, the drug component comprises tofacitinib, for example, tofacitinib citrate.

[0300] In some embodiments, a method for treating ulcerative colitis is provided, the method comprising administering an oral drug dosage form described herein to a human individual, the oral drug dosage form comprising a JAK inhibitor. In some embodiments, the JAK inhibitor comprises tofacitinib. In some embodiments, the oral drug dosage form comprises tofacitinib in a dose of about 11 mg or less. In some embodiments, the oral drug dosage form comprises tofacitinib in a dose of about 5.5 mg or less. In some embodiments, the method comprises administering the oral drug dosage form once daily.

[0301] In some embodiments, a method for treating ulcerative colitis is provided, the method comprising administering an oral drug dosage form described herein to a human individual, the drug component comprising a JAK inhibitor. In some embodiments, the JAK inhibitor comprises tofacitinib. In some embodiments, the oral drug dosage form comprises tofacitinib in a dose of about 5.5 mg or less. In some embodiments, the method comprises administering the oral drug dosage form once daily.

[0302] In some embodiments, a method for treating ulcerative colitis is provided, the method comprising administering an oral drug dosage form described herein to a human individual, the drug component comprising tofacitinib 5.5 mg, and the method comprising administering the oral drug dosage form once daily.

[0303] In some embodiments, methods are provided for systemic delivery of a drug to an individual, the method comprising administering (orally) an oral drug dosage form described herein to the individual, the individual having gastrointestinal disorders, central nervous system (CNS) disorders, cardiovascular diseases, hypertension, atherosclerosis, angina pectoris, arterial occlusion, peripheral artery disease, myocardial pathology, arrhythmias, acute myocardial infarction, angina pectoris, cardiomyopathy, congestive heart failure, coronary artery disease (CAD), carotid artery disease, endocarditis, hypercholesterolemia, hyperlipidemia, peripheral artery disease (PAD), genitourinary disorders; erectile dysfunction, benign prostatic hyperplasia (BPH), renal tubular acidosis, diabetes. The patient suffers from diseased nephropathy, glomerulonephritis, glomerulosclerosis, urinary tract infections, fecal incontinence, eye diseases such as glaucoma, blepharitis, ocular hypertension, retinopathy, conjunctivitis, scleritis, retinitis, keratitis, corneal ulcer, iritis, chorioretinitis, macular edema, xerophthalmos, lung diseases such as asthma, pulmonary hypertension, acute respiratory distress syndrome, COPD, emphysema, pneumonia, tuberculosis, bronchitis, acute bronchitis, bronchiectasis, bronchiolitis, bronchial dysplasia, pulmonary dysplasia, Cocci (breath-bearing mycosis), cystic fibrosis, influenza, lung cancer, mesothelioma, metabolic diseases, hypercalciuria, hyperglycemia, hyperinsulinemia, hyperinsulinemia, hyperuria, or hypoglycemia. In some embodiments, the oral drug dosage form includes a bioagent such as a peptide, antibody, or nucleic acid (e.g., RNA). In some embodiments, the RNA is selected from the group consisting of transfer RNA (tRNA), ribosomal RNA (rRNA), or messenger RNA (mRNA).

[0304] Those skilled in the art will recognize that several embodiments are possible within the scope and spirit of the disclosure of this application. The disclosure is further illustrated by the following embodiments, which should not be construed as limiting the disclosure to the scope or spirit of the specific procedures described herein. [Examples]

[0305] Example 1 This example illustrates the design, manufacture, and testing of an oral drug dosage form described herein, comprising tofacitinib citrate.

[0306] The release characteristics of the four oral drug dosage forms provided in Tables 1A-4B were first evaluated in vitro. Because the oral drug dosage forms are designed to release the drug from both sides, during the dissolution test, the oral drug dosage forms adhered to the bottom of the steel rod in the test container. The rod was fixed 1.5 cm from the center of the container, while the lower edge of the oral drug dosage form was adjusted approximately 1 cm above the top of the paddle blade. The longest axis of the oral drug dosage form was oriented tangentially to the flow stream.

[0307] To mimic in vivo gastric and intestinal environmental conditions, two-step lysis was performed sequentially in biologically relevant media for FaSSGF and FaSSIF. For the first 0.5 hours, 250 mL of FASSGF was used to mimic gastric conditions, and then the lysis medium was switched to 250 mL of FASSIF to mimic intestinal conditions. The procedure was performed at a speed of 100 RPM using a USP instrument II (paddle) maintained at a temperature of 37 ± 0.5°C in the vessel. The cumulative lysis profiles of tofacitinib from each oral drug dosage form tested are shown in Figure 5 (oral drug dosage forms in Tables 1A and 1B), Figure 6 (oral drug dosage forms in Tables 2A and 2B), Figure 7 (oral drug dosage forms in Tables 3A and 3B), and Figure 8 (oral drug dosage forms in Tables 4A and 4B). The data in Figure 5 represent the quadruple study, and the results are the mean plus or minus standard deviation between replicates. As shown in Figure 5, the delay in drug release from the oral drug dosage form was approximately 4.5 hours. The data in Figure 6A represent a triple test, and the results are the mean plus or minus standard deviation between replicates. As shown in Figure 6A, the delay in drug release from the oral drug dosage form was approximately 4 hours. The phenomenon during the dissolution process was observed and photographed, as shown in Figure 6B, showing that the surface of the drug dosage form of this application did not gelatinize during the dissolution process. The data in Figure 7 represent a triple test, and the results are the mean plus or minus standard deviation between replicates. As shown in Figure 7, the delay in drug release from the oral drug dosage form was approximately 4.5 hours. The data in Figure 8 represent a triple test, and the results are the mean plus or minus standard deviation between replicates. As shown in Figure 8, the delay in drug release from the oral drug dosage form was approximately 5 hours. The corresponding X-ray analysis results of the structural components within each oral drug dosage form are shown in Figures 5, 6, and 8. These in vitro results demonstrate that drug release from oral drug formulations can be effectively delayed when evaluated in a biologically relevant medium with an appropriate volume of 250 mL in each of the simulated liquids, and indicate the potential for colon-targeted delivery of this prototype tablet with a layer thickness-delay time relationship for optimization.

[0308] PK and X-ray tests were performed using Beagle dogs. Beagle dogs (non-naive, age: 15-16 months, sex: male, weight: 7.9-8.8 kg) were purchased from BeijingMarshallBiotechnologyCo.,Ltd. (Beijing, China). The dogs were housed in the animal facilities of 3DBioOptimaCo.,Ltd. in accordance with FDA regulations for animal maintenance and experimentation. Each animal was housed individually in a stainless steel cage in a controlled environment (temperature 16-26°C, humidity 40-70%, 12h light / 12h dark cycle). Each dog was marked with an ear tattoo. Prior to administration, the dogs were transferred to the facilities of SuzhouChuxinPetHospitalCo.,Ltd. for two days of acclimatization, where animal experiments and livestock farming were conducted.

[0309] Dogs were fasted and injected with pentagastrin before oral administration to adjust the stomach pH to mimic the pH conditions in a fasted human stomach. For animals orally administered one oral drug dosage form, X-ray scans were scheduled to be recorded, and X-ray image acquisition was extended until the barium sulfate in the oral drug dosage form disappeared, demonstrating the completion of drug release. In parallel, blood samples were collected from the jugular veins of beagle dogs. Reference drug: Xeljanz (登録商標) For animals orally administered XR, only blood samples were collected from the jugular vein of beagle dogs. PK parameters were calculated using the WinNonlin version 8.0 (Pharsight, St. Louis, USA) non-compartment model. X-ray images were used to evaluate the location, transit time, and release characteristics within the GI tube at different time points. PK results are shown in Table 9.

[0310] [Table 9] Note: # T det and T max For this, the median is shown instead of the mean, and the range is shown instead of the standard deviation (SD). NA: Not applicable. *Since the number of dogs for each dosage form in Tables 1A and 1B, and Tables 3A and 3B was 2, the PK parameters were the mean values, not the standard deviation (SD).

[0311] The PK curves for the tested oral drug dosage forms are shown in Figures 9A and 9B. X-ray images are shown in Figures 10A (Tables 1A and 1B), 10B (Tables 3A and 3B), and 10C (Tables 4A and 4B). Each X-ray image shows the time of capture, drug release onset, and drug release completion. Example 2

[0312] This example illustrates the design, manufacture, and testing of an oral drug dosage form described herein, comprising tofacitinib citrate.

[0313] The release characteristics of the four oral drug dosage forms provided in Tables 5A-8B were first evaluated in vitro. The cumulative dissolution test was performed in two stages: an acid stage to simulate the stomach and a buffer stage to simulate the conditions downstream of the stomach. In the acid stage, 750 mL of 0.1 N hydrochloric acid was placed in the test container, and the rest of the apparatus was assembled. The medium was equilibrated to 37 ± 0.5 °C. One test oral drug dosage form was placed in the basket, the container was covered, and the apparatus was operated at 100 rpm. After 2 hours, 4.5 mL of the solution was removed and filtered through a 0.22 μm hydrophilic syringe filter. To proceed to the buffer stage, the apparatus was stopped and 250 mL of 0.2 mol / L sodium phosphate solution was immediately added to the acidic medium at 37 °C. The solutions were then mixed, and the pH was adjusted to 6.8 ± 0.05 with 2 mol / L hydrochloric acid solution or 2 mol / L sodium hydroxide. The apparatus was restarted and operated as described above. 4.5 mL of the solution was removed at different time points and filtered through a 0.22 μm hydrophilic syringe filter. The removed solutions were then tested to generate cumulative dissolution profiles.

[0314] The cumulative dissolution profiles of tofacitinib from each oral drug dosage form tested are shown in Figures 12A (oral drug dosage forms from Tables 5A and 5B), 12B (oral drug dosage forms from Tables 6A and 6B), 12C (oral drug dosage forms from Tables 7A and 7B), and 12D (oral drug dosage forms from Tables 8A and 8B). The data in Figures 12A-12D represent the quintuple trials, and the results are the mean plus or minus standard deviation between replicates. As shown in Figure 12A, the drug release delay from the oral drug dosage form was approximately 7.5 hours. As shown in Figure 12B, the drug release delay from the oral drug dosage form was approximately 5 hours. As shown in Figure 12C, the drug release delay from the oral drug dosage form was approximately 5.5 hours. As shown in Figure 12D, the drug release delay from the oral drug dosage form was approximately 8.5 hours.

[0315] These in vitro results demonstrate that drug release from oral drug formulations can be effectively delayed when evaluated in a biologically relevant medium with an appropriate volume of 250 mL in each of the simulated liquids, and indicate the potential for colon-targeted delivery of this prototype tablet with a layer thickness-delay time relationship for optimization.

[0316] PK and X-ray tests were performed using Beagle dogs. Beagle dogs (non-naive, age: 15-16 months, sex: male, weight: 7.9-8.8 kg) were purchased from BeijingMarshallBiotechnologyCo.,Ltd. (Beijing, China). The dogs were housed in the animal facilities of 3DBioOptimaCo.,Ltd. in accordance with FDA regulations for animal maintenance and experimentation. Each animal was housed individually in a stainless steel cage in a controlled environment (temperature 16-26°C, humidity 40-70%, 12h light / 12h dark cycle). Each dog was marked with an ear tattoo. Prior to administration, the dogs were transferred to the facilities of SuzhouChuxinPetHospitalCo.,Ltd. for two days of acclimatization, where animal experiments and livestock farming were conducted.

[0317] Dogs were fasted and injected with pentagastrin before oral administration to adjust the stomach pH to mimic the pH conditions in a fasted human stomach. For animals orally administered one oral drug dosage form, X-ray scans were scheduled to be recorded, and X-ray image acquisition was extended until the barium sulfate in the oral drug dosage form disappeared, demonstrating the completion of drug release. In parallel, blood samples were collected from the jugular veins of beagle dogs. Reference drug: Xeljanz (登録商標) For animals orally administered XR, only blood samples were collected from the jugular vein of beagle dogs. PK parameters were calculated using the WinNonlin version 8.0 (Pharsight, St. Louis, USA) non-compartment model. X-ray images were used to evaluate the location, transit time, and release characteristics within the GI tube at different time points. PK results are shown in Table 10.

[0318] [Table 10] Note: # T det and T max For this, the median is shown instead of the mean, and the range is shown instead of the standard deviation (SD). NA: Not applicable.

[0319] The PK curves for the tested oral drug dosage forms are shown in Figure 13. X-ray images are shown in Figures 14A (Tables 5A and 5B, Figure 511) and 14B (Tables 6A and 6B, Figure 11). Each X-ray image shows the time of capture, drug release onset, and drug release completion.

[0320] Two candidate tablets were administered to healthy subjects to validate in vivo targeted colon drug delivery. This study was an open-label, randomized, single-dose, 3-period, 3-sequence, 3-directional crossover radiographic imaging and pharmacokinetic study in healthy subjects. Twelve healthy volunteers were enrolled in the study. Candidate tablets 1 and 2, as well as a reference model drug, were administered in the morning under fasting conditions according to the randomized design. There was a flushing period of at least 4 days between each treatment. Radiographic images and PK samples were collected at predetermined time points. Tablet intestinal transit and drug release characteristics were evaluated based on radiographic images. Drug plasma concentrations were determined by LC-MS / MS analysis. PK results in healthy volunteers are shown in Table 11.

[0321] [Table 11] Note: *For tablets 5A and 5B, the plasma concentration for 3 subjects fell below the lower limit of quantification, so n=9 was used.

[0322] The PK curves for the tested oral drug dosage forms are shown in Figure 15. X-ray images are shown in Figure 16 (Tables 6A and 6B, Figure 11). Each X-ray image shows the time of capture, drug release onset, and drug release completion.

[0323] X-ray imaging results showed that the candidate tablets could be tracked in the gastrointestinal tract. Results from the majority of subjects (8 out of 12 in both study treatments) suggested that both candidate tablets released the drug into the colonic region. Tablets 5A and 5B were tracked in the ascending colon (3 subjects), the transverse colon (2 subjects), the transverse colon to descending colon (1 subject), the descending colon (1 subject), and the descending colon to sigmoid colon (1 subject), compared to tablets 6A and 6B (7 subjects in the ascending colon and 1 subject in the transverse colon).

[0324] The pharmacokinetic results for tablets 5A and 5B, 6A and 6B, and the reference tablet showed median (range) absorption T at 8.0h (7.0-11.0h), 7.0h (5.0-8.0h), and 0.0h (0.0-0.0h), respectively. lagReflecting the delayed-release characteristics of candidate tablets, the colon-release characteristics of the 3D-printed test formulation were confirmed.

[0325] Drug release and tracking images demonstrated that the release location / time for the 3D-printed tablets occurred as predicted. The MED® 3D-printed tablets, with their sequential two-stage control mechanism, were able to accurately deliver drugs to the human colon, suggesting their potential application in IBD therapy.

Claims

1. An oral drug dosage form configured to release the drug at a desired location within the colon of an individual, wherein the oral drug dosage form is A drug component comprising an erosive material mixed with the aforementioned drug, The drug comprises a delaying component that is not mixed with the aforementioned drug, The delaying component is configured to prevent the release of the drug from the drug component until the oral drug dosage form reaches the colon of the individual after administration. The aforementioned delayed component is, An oral drug dosage form comprising a pH-based enteric-coated component containing an erosive material configured to be eroded at a predetermined pH value or higher.

2. The oral drug dosage form according to claim 1, wherein the delaying component further comprises an erosive delaying member, and the oral drug dosage form is configured such that the pH-based enteric coating member is eroded before the erosive delaying member.

3. The oral drug dosage form according to claim 2, wherein the pH-based enteric coating prevents at least partially the erosion of the erosion retarding member, and the erosion retarding member prevents at least partially the erosion of the drug component.

4. An oral drug dosage form according to any one of claims 1 to 3, further comprising a second drug.

5. The oral drug dosage form according to claim 4, wherein the second drug is mixed with the drug component.

6. The oral drug dosage form according to claim 4, further comprising a second drug component comprising an erosive material mixed with the second drug, wherein the delaying component is configured to prevent the release of the second drug from the second drug component until the oral drug dosage form reaches the colon of the individual after administration.

7. The oral drug dosage form according to claim 6, wherein the delaying component includes a second erosive delaying member, and the oral drug dosage form is configured such that the pH-based enteric-coated member is eroded before the erosive delaying member, the erosive delaying member is eroded before the second drug component, the second drug component is eroded before the second erosive delaying member, and the second erosive delaying member is eroded before the drug component.

8. The oral drug dosage form according to claim 7, wherein the pH-based enteric coating prevents at least partially the erosion of the erosion retarding member, the erosion retarding member prevents at least partially the erosion of the second drug component, the second drug component prevents at least partially the erosion of the second erosion retarding member, and the second erosion retarding member prevents at least partially the erosion of the drug component.

9. The oral drug dosage form according to claim 7 or 8, wherein the erosive material of the erosive delay member and the erosive material of the second erosive delay member are the same.

10. The oral drug dosage form according to claim 7 or 8, wherein the erosive material of the erosive delay member and the erosive material of the second erosive delay member are different.

11. An oral drug dosage form according to any one of claims 2 to 10, further comprising a bacterial degradation portion.

12. The oral drug dosage form according to claim 11, wherein the bacterial decomposition portion is mixed with the erosive material of the erosive retarding member.

13. The oral drug dosage form according to claim 11, wherein the bacterial decomposition portion is mixed with the drug component.

14. The oral drug dosage form according to any one of claims 11 to 13, wherein the delaying component further comprises a bacterial degrading member containing an erosive material mixed with the bacterial degrading portion, and the oral drug dosage form is configured such that the pH-based enteric-coated member is eroded before the erosive delaying member, the erosive delaying member is eroded before the bacterial degrading member, and the bacterial degrading member is eroded before the drug component.

15. The oral drug dosage form according to claim 14, wherein the pH-based enteric coating prevents at least partially the erosion of the erosion retarding member, the erosion retarding member prevents at least partially the erosion of the bacterial degradation member, and the bacterial degradation member prevents at least partially the erosion of the drug component.

16. The oral drug formulation according to any one of claims 11 to 15, wherein the bacterially decomposable portion is digestible by one or more microorganisms present in the colon of the individual.

17. The oral drug dosage form according to any one of claims 11 to 16, wherein the bacterial decomposition portion contains one or more types of sugars.

18. The oral drug dosage form according to claim 17, wherein the one or more sugars include one or more of the following: sucrose, glucose, xylose, fructose, maltose, galactose, pectin, galactomannan, dextran, inulin, chitosan, carrageenan, cellulose propionate acetate (CAP), peptidoglycan, gellan, xanthan gum, lentinan, psyllium polysaccharide, corn bran arabinoxylan, alginate, hyaluronic acid, fucoidan, shellac, agar, or maltodextrin.

19. The oral drug dosage form according to any one of claims 14 to 18, wherein the bacterial decomposition member is a layer, and the layer has a thickness of about 0.1 mm to about 5 mm based on the direction of erosion.

20. The aforementioned bacterial decomposition member is approximately 10 mm ２ ~400mm ２ The oral drug dosage form according to any one of claims 14 to 19, comprising the surface area exposed to gastrointestinal fluid in the individual.

21. The oral drug dosage form according to any one of claims 1 to 20, wherein the delaying component does not include an erosive delaying member.

22. The oral drug dosage form according to claim 21, wherein the erosive material of the pH-based enteric-coated member comprises one or more of hypromellose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate propionate (CAP), poly(methacrylate-co-ethyl acrylate), or polyvinyl acetate phthalate (PVAP).

23. The oral drug dosage form according to claim 22, wherein the hypromellose acetate succinate is HPMCSLG / LF, HPMCSMG / MF, or HPMCSHG / LF.

24. The oral drug dosage form according to claim 22, wherein the hydroxypropyl methylcellulose phthalate is HPMCPHP-50 or HPMCPHP-55.

25. The oral drug dosage form according to claim 22, wherein the poly(methacrylate-coethyl acrylate) is Eudragit L100-55 or Eudragit L100.

26. The oral drug dosage form according to any one of claims 1 to 25, wherein the drug component comprises a top surface, a bottom surface, and one or more side surfaces, and the drug component is embedded in the delaying component such that, by erosion of the delaying component or by any manner thereof, at least two surfaces of the top surface, the bottom surface, or at least one of the one or more side surfaces are exposed to the gastrointestinal fluid of the organism.

27. The oral drug dosage form is the oral drug dosage form according to any one of claims 1 to 26, wherein the oral drug dosage form does not include a shell.

28. The oral drug dosage form according to any one of claims 1 to 25, further comprising a shell that is not mixed with the drug, wherein the oral drug dosage form is configured such that the shell or a portion thereof and the delay member prevent erosion of the drug component.

29. The oral drug dosage form according to claim 28, wherein the direction of erosion of the delaying component and / or the drug component is based on the configuration of the shell.

30. An oral drug dosage form according to any one of claims 1 to 29, further comprising a protease scavenger and / or a protease inhibitor.

31. The oral drug dosage form according to claim 30, wherein the protease scavenger or the protease inhibitor is mixed with the delaying component or a portion thereof.

32. The oral drug dosage form according to claim 30 or 31, wherein the protease scavenger or the protease inhibitor is mixed with the erosive material of the erosive delay member.

33. The oral drug dosage form according to any one of claims 1 to 32, wherein the oral drug dosage form is configured to release the drug in the vicinity of or downstream of any one of the cecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, or sigmoid colon.

34. The oral drug dosage form according to any one of claims 1 to 33, wherein at least about 95% of the drug in the oral drug dosage form is released from the oral drug dosage form in the colon of the individual.

35. The oral drug dosage form according to any one of claims 1 to 34, wherein less than 2% of the drug in the oral drug dosage form is released from the oral drug dosage form outside the colon of the individual.

36. The oral drug dosage form according to any one of claims 1 to 35, wherein the entirety of the drug in the oral drug dosage form is released from the oral drug dosage form in the colon of the individual.

37. The oral drug dosage form according to any one of claims 2 to 36, wherein the drug component and / or the delaying component are in the form of one or more layers.

38. The layer of the pH-based enteric-coated member includes a top surface and a bottom surface. The layer of the erosive delay member includes a top surface and a bottom surface, The layer of the drug component includes a top surface and a bottom surface. The bottom surface of the layer of the pH-based enteric coating member is in contact with the top surface of the layer of the erosive delay member. The oral drug dosage form according to claim 37, wherein the bottom surface of the layer of the erosive delay member is in contact with the top surface of the layer of the drug component.

39. The oral drug dosage form according to any one of claims 1 to 38, wherein the oral drug dosage form is configured to have two or more compartments, and at least one compartment contains the drug component and the delaying component.

40. The oral drug dosage form according to any one of claims 1 to 39, wherein the pH-based enteric coating is eroded at a pH value of approximately 5.5 or higher.

41. The oral drug dosage form according to any one of claims 1 to 40, wherein the pH-based enteric coating is a layer having a thickness of about 0.1 mm to about 5 mm based on the direction of erosion.

42. The pH-based enteric coating is approximately 10 mm ２ ~400mm ２ The oral drug dosage form according to any one of claims 1 to 41, comprising the surface area exposed to gastrointestinal fluid in the individual.

43. The oral drug dosage form according to any one of claims 1 to 42, wherein the outer surface of the oral drug dosage form includes the pH-based enteric coating and, optionally, the shell, before administration to the individual.

44. The oral drug dosage form according to any one of claims 1 to 43, wherein the pH-based enteric-coated member comprises a thermoformable material.

45. The pH-based enteric-coated component is stearic acid, copolyvidone, polyvinylpyrrolidone-co-vinyl acetate, polyvinylpyrrolidone-polyvinyl acetate copolymer, crospovidone, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose or hypromellose, hydroxypropyl methylcellulose phthalate, methylcellulose, methacrylic acid copolymer, poly(methacrylate-co-ethyl acrylate), poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), poly(dimethylaminoethyl methacrylate-co-methacrylate ester), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonium ethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly(methacrylate-co-methyl methacrylate), poly(methacrylate-co-ethyl acrylate), poly(meth An oral drug dosage form according to any one of claims 1 to 44, comprising one or more of the following: acrylic acid-comethyl methacrylate), polyethylene oxide, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, Kollicoat IR-polyvinyl alcohol, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, hydroxypropyl methylcellulose acetate succinate or hypromellose acetate succinate, methacrylate ester copolymer, ammoniaalkyl methacrylate copolymer, ethylcellulose, polyvinyl acetate and polyvinylpyrrolidone, polyvinyl acetal diethylaminolactate, polyvinyl acetal diethylaminolactate, maltitol, lactose monohydrate, xylitol, isomalt, sucrose, glucose, dextran, or maltose.

46. The oral drug dosage form according to any one of claims 2 to 45, wherein the erosive delaying member prevents the release of the drug from the drug component for at least about 10 minutes after the erosive delaying member has come into contact with the gastrointestinal fluid of the individual.

47. The oral drug dosage form according to any one of claims 2 to 46, wherein the erosive delaying member is a layer having a thickness of about 0.1 mm to about 5 mm based on the direction of erosion.

48. The erosive delay member is approximately 10 mm ２ ~400mm ２ The oral drug dosage form according to any one of claims 2 to 47, comprising the surface area exposed to gastrointestinal fluid in the individual.

49. The oral drug dosage form according to any one of claims 2 to 48, wherein the erosive delaying member comprises a thermoformable material.

50. The aforementioned erosion-delaying member is stearic acid, medium-chain triglyceride, glyceryl distearate, propylene glycol monolaurate, propylene glycol caprylate, oleoyl polyoxyl-6 glyceride, PEG-6 stearate, PEG-32 stearate, linoleoyl polyoxyl-6 glyceride, lauroyl polyoxyl-32 glyceride, caprylocaproyl polyoxyl-8 glyceride, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan oleate, glyceryl monolinoleate Copolyvidone, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, crospovidone, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose or hypromellose, hydroxypropyl methylcellulose phthalate, methylcellulose, methacrylic acid copolymer, poly(methacrylate-co-ethyl acrylate), poly(butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate copolymer), poly(dimethylaminoethyl methacrylate) Poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonium ethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly(methacrylate-co-methyl methacrylate), poly(methacrylate-co-ethyl acrylate), poly(methacrylate-co-methyl methacrylate), polyethylene oxide, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol Polyvinyl alcohol graft copolymer, Colicote IR-polyvinyl alcohol, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, hydroxypropyl methylcellulose acetate succinate or hypromellose acetate succinate, methacrylate ester copolymer, ammonium alkyl methacrylate copolymer, ethylcellulose, polyvinyl acetate and polyvinylpyrrolidone, polyvinyl acetal diethylaminolactic acid, polyvinyl acetal diethylaminolactic acid, maltitol, lactose monohydrate, xylitol,An oral drug dosage form according to any one of claims 2 to 49, comprising one or more of isomalt, sucrose, glucose, dextran, maltose, lauroyl polyoxyl-32 glyceride, caprylocaproyl polyoxyl-8 glyceride, polyoxyl (35) castor oil, vitamin E polyethylene glycol succinate, PEG-40 hydrogenated castor oil, glyceryl monolinoleic acid, or glyceryl dibehenate.

51. The oral drug dosage form according to any one of claims 1 to 50, wherein the drug component is not in direct contact with the pH-based enteric coating member.

52. The oral drug dosage form according to any one of claims 1 to 51, wherein the drug component is a controlled-release drug component.

53. The oral drug dosage form according to any one of claims 1 to 51, wherein the drug component is a sustained-release drug component.

54. The oral drug dosage form according to any one of claims 1 to 51, wherein the drug component is an immediate-release drug component.

55. The oral drug dosage form according to any one of claims 1 to 51, wherein the drug component is configured to release the drug from the oral drug dosage form for at least about one hour.

56. The oral drug dosage form according to any one of claims 1 to 55, wherein the drug component is configured to provide a drug release profile including a zero-order release profile, a primary release profile, a delayed release profile, a pulsed release profile, a repeated pulsed release profile, an immediate release profile, or a sustained release profile, or a combination thereof.

57. The oral drug dosage form according to any one of claims 1 to 56, wherein the release of the drug is at least partially based on an in vitro dissolution test.

58. The oral drug dosage form according to any one of claims 1 to 57, wherein the release of the drug is at least partially based on an in vivo dissolution test.

59. The drug component is approximately 0.05 to approximately 0.6 in drug mass fraction (m Ｆ An oral drug dosage form according to any one of claims 1 to 58, having the following characteristics:

60. The oral drug dosage form according to any one of claims 1 to 59, wherein the weight ratio of the drug component to the delaying component is about 1:10 to about 10:

1.

61. The oral drug dosage form according to any one of claims 1 to 60, wherein the drug component is a layer having a thickness of about 0.1 mm to about 5 mm based on the direction of erosion.

62. The drug component is about 10 mm ２ to about 400 mm ２ The oral pharmaceutical dosage form according to any one of claims 1 to 61, including the surface area exposed to gastrointestinal fluid in the individual.

63. The oral drug dosage form according to any one of claims 1 to 62, wherein the drug component comprises a thermoformable material.

64. The oral drug dosage form according to any one of claims 1 to 63, wherein the drug component comprises one or more of the following: copolyvidone, polyvinylpyrrolidone-co-vinyl acetate, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose or hypromellose, polyethylene oxide, polyethylene glycol, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, KollicoatIR-polyvinyl alcohol, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, hydroxypropyl methylcellulose acetate succinate, hypromellose acetate succinate, hydroxypropyl methylcellulose phthalate, maltitol, lactose monohydrate, xylitol, isomalt, sucrose, glucose, or dextran.

65. An oral drug dosage form according to any one of claims 1 to 64, further comprising 1 to 4 additional drug components.

66. The oral drug dosage form according to any one of claims 1 to 65, wherein the drug is an anti-inflammatory agent, a non-steroidal anti-inflammatory agent, a steroid, an immunosuppressant, an antibiotic, an antineoplastic agent, an analgesic, an anesthetic, an anticonvulsant, an antidiabetic agent, an antihistamine, an anti-infective agent, an antitumor agent, an antiparkinson's disease agent, an antirheumatic agent, an appetite stimulant, an appetite suppressant, a blood regulator, a bone metabolism regulator, a cardiovascular agent, a central nervous system depressant, a central nervous system stimulant, a decongestant, a dopamine receptor agonist, an electrolyte, a gastrointestinal drug, an immunomodulator, a muscle relaxant, a narcotic, a parasympathetic agonist, a sympathetic agonist, a sedative, a hypnotic, or a vaccine.

67. The oral drug dosage form according to claim 66, wherein the anti-inflammatory agent is a JAK inhibitor.

68. The oral drug dosage form according to claim 67, wherein the JAK inhibitor is tofacitinib or a pharmaceutically acceptable salt thereof.

69. The oral drug dosage form according to claim 66, wherein the anti-inflammatory agent is mesalazine, sulfasalazine, or valsalazid.

70. The oral drug formulation according to claim 66, wherein the nonsteroidal anti-inflammatory agent is ibuprofen or diclofenac.

71. The oral drug dosage form according to claim 66, wherein the steroid is prednisolone, budesonide, or fluticasone.

72. The oral drug dosage form according to claim 57, wherein the immunosuppressant is azathioprine, cyclosporine, or methotrexate.

73. The oral drug dosage form according to claim 66, wherein the antitumor agent is fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, etoposide, larcitrexed, or oxaliplatin, or a combination thereof.

74. An oral drug dosage form according to any one of claims 1 to 73, comprising approximately 0.01 mg to approximately 500 mg of the drug.

75. An oral drug dosage form according to any one of claims 1 to 74, further comprising an excipient.

76. The oral drug dosage form according to claim 75, wherein the excipient comprises one or more of an absorption enhancer, a pH lowering agent, or a disintegrant.

77. The oral drug dosage form according to claim 75 or 76, wherein the excipient is mixed with the drug component.

78. The oral drug dosage form according to any one of claims 28 to 77, wherein the shell comprises an insulating material that is impermeable to body fluids.

79. The oral drug dosage form according to claim 78, wherein the insulating material comprises one or more of ethylcellulose (EC), dibutyl sebacate (DBS), and titanium dioxide.

80. The oral drug dosage form according to claim 78 or 79, wherein the insulating material is a non-corrosive material.

81. The oral drug dosage form according to any one of claims 78 to 80, wherein the insulating material is an erosive material having a pH-based erosion and / or erosion rate that allows for the complete release of the drug from the oral drug dosage form before exposure of the drug component to bodily fluids due to erosion of the shell.

82. The oral drug dosage form according to any one of claims 1 to 81, further comprising a second pH-based enteric coating.

83. The oral drug dosage form according to claim 82, wherein the pH-based enteric coating is eroded from the oral drug dosage form or a portion thereof at a pH value of approximately 5.5 or higher.

84. The oral drug dosage form according to claim 82 or 83, wherein the second pH-based enteric coating is eroded from the oral drug dosage form or a portion thereof at a pH value of approximately 6.8 or higher.

85. A commercially available batch of an oral drug dosage form according to any one of claims 1 to 84, wherein the commercially available batch is The amount of drug in the oral drug dosage form, The weight of the aforementioned oral drug dosage form, The maximum transverse dimensions of the oral drug dosage form, and A commercially available batch having a standard deviation of approximately 0.05 or less for each of the transverse dimensions perpendicular to the maximum transverse dimension of the oral drug dosage form.

86. The commercial batch according to claim 85, wherein the commercial batch comprises at least about 1,000 oral drug dosage forms.

87. A method for three-dimensional (3D) printing of an oral drug dosage form according to any one of claims 1 to 84, wherein the method is: The process includes distributing materials according to a layer-by-layer model of the oral drug dosage form to print the oral drug dosage form, wherein each layer of the layer-by-layer model is, if necessary, for each layer, (a) Shell material for forming any part of the shell in the layer, (b) A drug component material for forming any portion of the drug component in the layer, (c) pH-based enteric coating material for forming any portion of the pH-based enteric coating in the layer, (d) Erosion retarding member material for forming any portion of the erosion retarding member in the layer, (e) a bacterial decomposition member material for forming any portion of the bacterial decomposition member in the layer, and (f) A method of printing by distributing excipient material to form any portion of the excipient component in the layer.

88. The method according to claim 87, further comprising generating the layer-by-layer model of the oral drug dosage form.

89. The method according to claim 87 or 88, wherein the distribution is carried out via melt extrusion deposition (MED).

90. The method according to any one of claims 87 to 89, wherein the distribution of the shell material, the distribution of the drug component material, the distribution of the pH-based enteric coating material, the distribution of the erosive retarding material, and the distribution of the shell material are each performed by different print heads.

91. A method for treating a condition in an individual, wherein the method is A method comprising administering to the individual an oral drug dosage form according to any one of claims 1 to 84.

92. The aforementioned conditions include gastrointestinal disorders, central nervous system (CNS) disorders, cardiovascular diseases, hypertension, atherosclerosis, angina pectoris, arterial occlusion, peripheral artery disease, myocardial pathology, arrhythmias, acute myocardial infarction, angina pectoris, cardiomyopathy, congestive heart failure, coronary artery disease (CAD), carotid artery disease, endocarditis, hypercholesterolemia, hyperlipidemia, peripheral artery disease (PAD), urogenital disorders, erectile dysfunction, benign prostatic hyperplasia (BPH), renal tubular acidosis, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, urinary tract infections, fecal incontinence, eye diseases such as glaucoma, blepharitis, and ocular hypertension. The method according to claim 91, selected from the group consisting of retinopathy, conjunctivitis, scleritis, retinitis, keratitis, corneal ulcer, iritis, chorioretinitis, macular edema, xerophthalmos, pulmonary disease asthma, pulmonary hypertension, acute respiratory distress syndrome, COPD, emphysema, pneumonia, tuberculosis, bronchitis, acute bronchitis, bronchiectasis, bronchiolitis, bronchial dysplasia, pulmonary dysplasia, Coccygeus, cystic fibrosis, influenza, lung cancer, mesothelioma, metabolic diseases, hypercalciuria, hyperglycemia, hyperinsulinemia, hyperinsulinemia, hyperuria, and hypoglycemia.

93. The method according to claim 92, wherein the gastrointestinal disorder is selected from the group consisting of irritable bowel disease (IBD), irritable bowel syndrome (IBS), constipation, diarrhea, infection, and carcinoma.

94. The method according to claim 93, wherein the IBD is related to Crohn's disease or ulcerative colitis.

95. The method according to claim 93, wherein the carcinoma is colon cancer or colorectal cancer.

96. The method according to claim 93, wherein the CNS disorder is selected from the group consisting of neuropathic pain, stroke, dementia, Alzheimer's disease, Parkinson's disease, neurodegeneration, meningitis, spinal cord injury, cerebral vasospasm, and amyotrophic lateral sclerosis.

97. A method for providing local delivery of a drug to the colon of an individual, wherein the method is A method comprising administering to the individual an oral drug dosage form according to any one of claims 1 to 84, wherein the individual is suffering from a gastrointestinal disorder.

98. A method for providing systemic delivery of a drug to an individual, wherein the method is The method comprises administering to the individual an oral drug dosage form described in any one of claims 1 to 84, wherein the individual has gastrointestinal disorders, central nervous system (CNS) disorders, cardiovascular diseases, hypertension, atherosclerosis, angina pectoris, arterial occlusion, peripheral artery disease, myocardial pathology, arrhythmias, acute myocardial infarction, angina pectoris, cardiomyopathy, congestive heart failure, coronary artery disease (CAD), carotid artery disease, endocarditis, hypercholesterolemia, hyperlipidemia, peripheral artery disease (PAD), genitourinary disorders, erectile dysfunction, benign prostatic hyperplasia (BPH), renal tubular acidosis, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, Methods for treating urinary tract infections, fecal incontinence, eye diseases such as glaucoma, blepharitis, ocular hypertension, retinopathy, conjunctivitis, scleritis, retinitis, keratitis, corneal ulcer, iritis, chorioretinitis, macular edema, xerophthalmos, lung diseases such as asthma, pulmonary hypertension, acute respiratory distress syndrome, COPD, emphysema, pneumonia, tuberculosis, bronchitis, acute bronchitis, bronchiectasis, bronchiolitis, bronchial dysplasia, pulmonary dysplasia, Coccygeus, cystic fibrosis, influenza, lung cancer, mesothelioma, metabolic diseases, hypercalciuria, hyperglycemia, hyperinsulinemia, hyperinsulinemia, hyperuria, or hypoglycemia.

99. A method for designing an oral drug dosage form configured to release the drug at a desired gastrointestinal location in the individual, The aforementioned oral drug dosage form is A drug component, A first corrosive material mixed with a drug, A drug component comprising a first erosive tracking stripe, A shell containing a second tracking stripe, A delay component that is not mixed with the drug, wherein the delay component is A pH-based enteric coating component configured to be eroded at a predetermined pH value or higher, The pH-based enteric coating includes a third erosive tracking stripe, An erosion-delaying member comprising a second erosive material, The erosive delay member includes a fourth erosive tracking stripe, The pH-based enteric coating, used alone or in combination with the shell, prevents erosion of the erosive retarding member. The erosive retarding member comprises a retarding component, which, either alone or in combination with the shell, prevents the erosion of the drug component. The aforementioned method, (a) Administering the oral drug dosage form to an individual, (b) Image the individual over time to obtain the position of the oral drug dosage form and the state of the first erosion tracking stripe, the second erosion tracking stripe, the third erosion tracking stripe and the fourth tracking stripe, (c) A method comprising designing the oral drug dosage form configured to release the drug at a desired gastrointestinal location in the individual by adjusting the drug component and / or delay component and / or shell, or a part thereof, based on the position and state of the first erosive tracking stripe, the second erosive tracking stripe, the third erosive tracking stripe, and the fourth track stripe.

100. The method according to claim 99, wherein adjusting the delaying component includes adjusting the pH-based enteric-coated member by changing one or more of the composition, the surface area exposed to body fluids after administration, or the thickness of the pH-based enteric-coated member.

101. The method according to claim 99 or 100, wherein adjusting the delaying component includes adjusting the erosive delaying member by changing one or more of the composition, the surface area exposed to body fluids after administration, or the thickness of the erosive delaying member.

102. A method for treating ulcerative colitis, wherein the method is A method comprising administering to a human individual an oral drug dosage form according to any one of claims 1 to 84, wherein the oral drug dosage form comprises a JAK inhibitor.

103. The method according to claim 102, wherein the JAK inhibitor comprises tofacitinib.

104. The method according to claim 103, wherein the oral drug dosage form comprises tofacitinib in an amount of about 11 mg or less.

105. The method according to claim 103 or 104, wherein the oral drug dosage form comprises tofacitinib in an amount of about 5.5 mg or less.

106. The oral drug dosage form is administered once daily, according to any one of claims 99 to 105.

107. A method for designing an oral drug dosage form configured to release the drug at a desired gastrointestinal location in the individual, The aforementioned oral drug dosage form is A drug component, A first corrosive material mixed with a drug, A drug component comprising a first erosive tracking stripe, Shell and, A delay component that is not mixed with the drug, wherein the delay component is A pH-based enteric-coated component configured to be eroded at a predetermined pH value or higher, An erosion-delaying member comprising a second erosive material, The pH-based enteric coating, used alone or in combination with the shell, prevents erosion of the erosive retarding member. The erosive retarding member comprises a retarding component, which, either alone or in combination with the shell, prevents the erosion of the drug component. The aforementioned method, (a) Administering the oral drug dosage form to an individual, (b) Image the individual over time to obtain the position of the oral drug dosage form and the state of the first erosive tracking stripe, (c) A method comprising designing the oral drug dosage form configured to release the drug at a desired gastrointestinal location in the individual, by adjusting the drug component and / or delay component and / or shell, or a part thereof, based on the position and state of the first erosive tracking stripe.

108. The method according to claim 107, wherein the first erosive material mixed with the drug and the first erosive tracking stripe are not in direct contact with each other.

109. The method according to claim 107 or 108, wherein the shell includes a second tracking stripe, the second tracking stripe is configured to be imaged by the imaging to obtain, for example, the state of the second tracking stripe.

110. The method according to claim 109, wherein the adjustment is based on the position and state of the first erosive tracking stripe and / or the second tracking stripe.

111. The method according to any one of claims 107 to 110, wherein the pH-based enteric coated member includes a third tracking stripe, the third tracking stripe is configured to be imaged by the imaging to obtain, for example, the state of the third erosive tracking stripe.

112. The method according to claim 111, wherein the adjustment is based on the position and state of the first erosive tracking stripe and / or the second tracking stripe and / or the third tracking stripe.

113. The method according to any one of claims 107 to 112, wherein the erosive delay member includes a fourth tracking stripe, and the fourth tracking stripe is configured to be imaged by the imaging to obtain, for example, the state of the fourth erosive tracking stripe.

114. The method according to claim 113, wherein the adjustment is based on the position and state of the first erosive tracking stripe and / or the second tracking stripe and / or the third erosive tracking stripe and / or the fourth tracking stripe.

115. The method according to any one of claims 107 to 114, wherein when the first erosive tracking stripe begins to be eroded, the imaging provides the location of the oral drug dosage form.

116. The method according to any one of claims 107 to 115, wherein when the first erosive tracking stripe is completely eroded, the imaging provides the position of the oral drug dosage form.

117. The method according to any one of claims 107 to 116, wherein the adjustment includes adjusting the delaying component or a portion thereof based on the position and state of the first erosive tracking stripe which indicates release earlier than desired, thereby increasing the delay of release of the drug from the oral drug dosage form.

118. The method according to any one of claims 107 to 113, wherein the adjustment includes adjusting the delaying component or a portion thereof based on the position and state of the first erosive tracking stripe which indicates a slower release than desired, thereby reducing the delay in the release of the drug from the oral drug dosage form.

119. A method for designing an oral drug dosage form configured to release the drug at a desired gastrointestinal location in the individual, The aforementioned oral drug dosage form is A drug component comprising a first corrosive material mixed with the aforementioned drug, Shell and, A delay component that is not mixed with the drug, wherein the delay component is A pH-based enteric-coated component configured to be eroded at a predetermined pH value or higher, An erosion-delaying member comprising a second erosive material, The pH-based enteric coating prevents erosion of the erosive retarding member. The erosive retarding member includes a retarding component that includes an erosive retarding member that prevents the erosion of the drug component, The oral drug dosage form includes at least one tracking stripe positioned within its components, The aforementioned method, (a) Administering the oral drug dosage form to an individual, (b) Image the individual over time to obtain the position of the oral drug dosage form and the state of the at least one tracking stripe, (c) A method comprising designing the oral drug dosage form configured to release the drug at a desired gastrointestinal location in the individual by adjusting the drug component and / or delay component and / or shell, or a part thereof, based on the position and state of the at least one tracking stripe.

120. The method according to claim 119, wherein the tracking stripe is located within or near the drug component.

121. The method according to claim 119 or 120, wherein the tracking stripe is located within the shell.

122. The method according to any one of claims 119 to 121, wherein the tracking stripe is located within the pH-based enteric-coated member.

123. The method according to any one of claims 119 to 122, wherein the tracking stripe is located within the erosive delay member.

124. The method according to any one of claims 119 to 123, wherein at least one of the at least one tracking stripes is erosive.

125. A method for designing an oral drug dosage form configured to release the drug at a desired gastrointestinal location in the individual, The aforementioned oral drug dosage form is A drug component comprising a first corrosive material mixed with the aforementioned drug, A delay component that is not mixed with the drug, wherein the delay component is A pH-based enteric-coated component configured to be eroded at a predetermined pH value or higher, An erosion-delaying member comprising a second erosive material, The pH-based enteric coating prevents erosion of the erosive retarding member. The erosive retarding member includes a retarding component that includes an erosive retarding member that prevents the erosion of the drug component, The oral drug dosage form includes at least one tracking stripe positioned within its components, The aforementioned method, (a) Administering the oral drug dosage form to an individual, (b) Image the individual over time to obtain the position of the oral drug dosage form and the state of the at least one tracking stripe, (c) A method comprising designing the oral drug dosage form configured to release the drug at a desired gastrointestinal location in the individual by adjusting the drug component and / or delay component, or a portion thereof, based on the position and state of the at least one tracking stripe.

126. The method according to claim 125, wherein the tracking stripe is located within or near the drug component.

127. The method according to claim 125 or 126, wherein the tracking stripe is located within the pH-based enteric-coated member.

128. The method according to any one of claims 125 to 127, wherein the tracking stripe is located within the erosive delay member.

129. The method according to any one of claims 125 to 128, wherein at least one of the at least one tracking stripes is erosive.

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