Modified-release oral pharmaceutical dosage form and preparation method therefor

Abstract

Disclosed are a modified-release oral pharmaceutical dosage form and a related preparation method therefor, for example, a three-dimensional printing method is used.

Description

A controlled-release oral drug dosage form and preparation method thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] The priority claimed by this application is PCT / CN2024 / 084960 filed on March 29, 2024, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] In some aspects, the present disclosure relates to a modified release oral pharmaceutical dosage form. In other aspects, the present disclosure relates to methods of manufacturing the oral pharmaceutical dosage forms described herein, for example using three-dimensional printing methods. Background Art

[0004] After oral drug dosage forms are administered to an organism, they interact with the body to exert their therapeutic effects. The active pharmaceutical ingredient must be released before the oral drug dosage form is absorbed into the bloodstream. The drug ingredient is then dispersed or dissolved in the body through body fluids and tissues. During drug absorption, metabolism, distribution, and excretion, the structure of the drug dosage form plays a decisive role in determining the drug release profile and bioavailability. Therefore, there is a long-standing need to develop a controlled-release oral drug dosage form that can provide the desired drug levels in plasma, enhance drug efficacy, reduce side effects, and improve patient compliance with the drug.

[0005] Since poorly soluble drugs have low oral absorption and bioavailability, improving their oral absorption and bioavailability is of great significance for their drug development.

[0006] All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.

[0007] SUMMARY OF THE INVENTION

[0008] In some aspects, provided herein is a modified-release oral pharmaceutical dosage form comprising: a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles being uniformly distributed in the second erodible material, the drug particles comprising a first drug; wherein the second erodible material controls release of the drug from the oral pharmaceutical dosage form within a desired amount of time after administration of the oral pharmaceutical dosage form to a human subject.

[0009] In some embodiments, the second erodible material controls the time at which the drug particles escape from the drug component, and release of the drug particles begins immediately or within a desired amount of time after escaping the drug component.

[0010] In some embodiments, the drug particles comprise a first erodible material uniformly mixed with a first drug.

[0011] In some embodiments, the second erodible material has a melting point (Tm) of about 30-120°C.

[0012] In some embodiments, the second erodible material has a glass transition temperature (Tg) in the range of about -60°C to 80°C.

[0013] In some embodiments, the second erodible material has a viscosity of about 100-50,000 Pa·s at a temperature between Tm and (Tm+30° C.) of the second erodible material.

[0014] In some embodiments, the drug component has a viscosity of about 100-50,000 Pa·s at a temperature between Tm and (Tm+30° C.) of the second erodible material.

[0015] In some embodiments, the oral dosage form comprises a plurality of drug particles.

[0016] In some embodiments, the plurality of drug particles comprises different types of drugs.

[0017] In some embodiments, the drug size in the plurality of drug particles varies.

[0018] In some embodiments, the plurality of drug particles have different particle sizes.

[0019] In some embodiments, the plurality of drug particles comprises different types of first erodible material.

[0020] In some embodiments, the composition of the first erodible material varies among the plurality of drug particles.

[0021] In some embodiments, the oral dosage form comprises multiple pharmaceutical components.

[0022] In some embodiments, the compositions of the plurality of drug components are identical to one another.

[0023] In some embodiments, the compositions of at least two drug components of the plurality of drug components are different from each other.

[0024] In some embodiments, the plurality of medication components are the same size as one another.

[0025] In some embodiments, at least two drug components in the plurality of drug components are different in size from one another.

[0026] In some embodiments, the oral dosage form comprises a delay member comprising a third erodible material that is not mixed with the drug.

[0027] In some embodiments, the delay component surrounds the drug component, and wherein the delay component prevents release of the drug from the oral dosage form within about 0.5 hours to about 7 hours after administration of the oral dosage form to a human subject.

[0028] In some embodiments, the oral dosage form comprises a pH-based enteric component configured to erode at or above a predetermined pH value.

[0029] In some embodiments, the pH-based enteric component surrounds the drug component, and wherein the pH-based enteric component prevents release of the drug from the oral dosage form within about 1 hour to about 7 hours after administration of the oral dosage form to a human subject.

[0030] In some embodiments, the pH-based enteric component surrounds the delay component, the pH-based enteric component prevents erosion of the delay component, and wherein the delay component prevents erosion of the drug component.

[0031] In some embodiments, the drug particles comprise first drug particles and second drug particles.

[0032] In some embodiments, the first drug particles and the second drug particles have the same average particle size.

[0033] In some embodiments, the first drug particles and the second drug particles have different average particle sizes.

[0034] In some embodiments, the first drug particles comprise a first erodible material mixed with a first drug.

[0035] In some embodiments, the second drug particles comprise a fifth erodible material mixed with the second drug.

[0036] In some embodiments, the first drug and the second drug are the same.

[0037] In some embodiments, the first drug and the second drug are different.

[0038] In some embodiments, the first erodible material and the fifth erodible material are the same.

[0039] In some embodiments, the first erodible material and the fifth erodible material are different.

[0040] In some embodiments, the first drug particles and / or the second drug particles further comprise a third drug, and the third drug is uniformly mixed with the drug and the erodible material therein.

[0041] In some embodiments, the drug particles further include a second drug, and the first drug, the second drug, and the first erodible material are uniformly mixed.

[0042] In some embodiments, the pharmaceutical component comprises a first pharmaceutical component and a second pharmaceutical component.

[0043] In some embodiments, the first drug component comprises a second erodible material mixed with drug particles; and the second drug component comprises a fourth erodible material mixed with drug particles.

[0044] In some embodiments, the second erodible material and the fourth erodible material control the release of the drug in the first drug component and the second drug component, respectively.

[0045] In some embodiments, the second erodible material and the fourth erodible material each control the time when the drug particles are released from the drug component, and the drug particles begin to be released immediately or within a desired amount of time after being released from the drug component.

[0046] In some embodiments, the second erodible material and the fourth erodible material are the same.

[0047] In some embodiments, the second erodible material and the fourth erodible material are different.

[0048] In some embodiments, the drug particles are selected from one or more of first drug particles and second drug particles.

[0049] In some embodiments, the first drug component and the second drug component are in contact.

[0050] In some embodiments, the first drug component and the second drug component are not in contact.

[0051] In some embodiments, an intermediate component is included between the first drug component and the second drug component.

[0052] In some embodiments, the delay component surrounds the first drug component and the second drug component.

[0053] In some embodiments, the delay component surrounds the first drug component or the second drug component.

[0054] In some embodiments, the delay component forms a compartment that surrounds the first drug component and the second drug component.

[0055] In some embodiments, the delay component forms a compartment that surrounds the first drug component or the second drug component.

[0056] In some embodiments, the delay component forms a first compartment and a second compartment, the first compartment and the second compartment surrounding the first drug component and the second drug component, respectively.

[0057] In some embodiments, the first compartment and the second compartment are in communication.

[0058] In some embodiments, the first compartment and the second compartment are not in communication.

[0059] In some embodiments, the delay element surrounding the first drug element and the second drug element has the same thickness.

[0060] In some embodiments, the delay element surrounding the first drug element and the second drug element have different thicknesses.

[0061] In some embodiments, the drug is distributed in the drug particles in the form of an amorphous solid dispersion.

[0062] In some embodiments, the drug is distributed in the drug component as an amorphous solid dispersion.

[0063] In some embodiments, the average particle size of the drug particles is from 0.1 μm to 1000 μm.

[0064] In some aspects, provided herein are methods of preparing an oral pharmaceutical dosage form described herein, the methods comprising three-dimensionally (3D) printing the oral pharmaceutical dosage form.

[0065] In some embodiments, the method includes a method for preparing a drug component: mixing drug particles with a second erodible material, and preparing the drug component through 3D printing technology.

[0066] In some embodiments, the method includes a method for preparing drug particles: (a) premixing a first drug and a first erodible material and then filling them into a single-screw or twin-screw extruder; (b) rotating the screw to push the physical mixture for further extrusion, while the extruder interlayer is heated to a preset temperature; (c) the first drug and the first erodible material are fully mixed and continuously extruded from an end plate and / or a mold of different shapes; and (d) crushing and screening.

[0067] In some embodiments, the method includes dispensing materials according to a layer-by-layer model of an oral pharmaceutical dosage form to print the oral pharmaceutical dosage form, wherein each layer of the layer-by-layer model is printed by dispensing the following materials as needed: (a) a drug component comprising drug particles and a second erodible material; (b) a delay component comprising a third erodible material not mixed with the drug; and (c) a pH-based enteric component comprising a pH-based enteric material not mixed with the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] 1A-1L show schematic diagrams of exemplary oral pharmaceutical dosage forms provided herein.

[0069] 2A-2C illustrate various cross-sectional views of exemplary oral pharmaceutical dosage forms provided herein.

[0070] FIG3 shows an in vitro dissolution profile of an exemplary oral pharmaceutical dosage form provided herein.

[0071] FIG4 shows an in vitro dissolution profile of an exemplary oral pharmaceutical dosage form provided herein.

[0072] FIG5 shows an in vitro dissolution profile of an exemplary oral pharmaceutical dosage form provided herein.

[0073] FIG6 shows an in vitro dissolution profile of an exemplary oral pharmaceutical dosage form provided herein.

[0074] 7A and 7B show various cross-sectional views of exemplary oral pharmaceutical dosage forms provided herein.

[0075] FIG8 shows an in vitro dissolution profile of an exemplary oral pharmaceutical dosage form provided herein.

[0076] 9A-9C illustrate various cross-sectional views of exemplary oral pharmaceutical dosage forms provided herein.

[0077] FIG10 shows an in vitro dissolution profile of an exemplary oral pharmaceutical dosage form provided herein.

[0078] 11A-11C show various cross-sectional views of exemplary oral pharmaceutical dosage forms provided herein.

[0079] FIG12 shows an in vitro dissolution profile of an exemplary oral pharmaceutical dosage form provided herein. DETAILED DESCRIPTION

[0080] In some aspects, provided herein are modified-release oral pharmaceutical dosage forms. In some embodiments, the oral pharmaceutical dosage form comprises: drug particles; a drug component comprising a second erodible material admixed with the drug particles; wherein the second erodible material controls release of the drug from the oral pharmaceutical dosage form over a desired amount of time following administration of the oral pharmaceutical dosage form to a human subject. In some embodiments, the drug particles are a drug powder. In some embodiments, exposure of the drug particles to gastrointestinal fluids is based on erosion of the second erodible material.

[0081] In some aspects, provided herein are modified-release oral pharmaceutical dosage forms. In some embodiments, the oral pharmaceutical dosage form comprises: drug particles comprising a first erodible material admixed with a drug; and a drug component comprising a second erodible material admixed with the drug particles; wherein the first erodible material and the second erodible material collectively control release of the drug from the oral pharmaceutical dosage form over a desired amount of time following administration of the oral pharmaceutical dosage form to a human subject. In some embodiments, the oral pharmaceutical dosage form is configured to release the drug according to a desired release profile. In some embodiments, exposure of the drug particles to gastrointestinal fluids is based on erosion of the second erodible material.

[0082] In some aspects, provided herein are modified-release oral dosage forms. In some embodiments, the oral dosage form comprises: drug particles comprising a first erodible material mixed with a drug; a drug component comprising a second erodible material mixed with the drug particles; and a delay component comprising a third erodible material not mixed with the drug; wherein the delay component surrounds the drug component, and wherein the delay component prevents the drug from being released from the oral dosage form within about 0.5 hours to about 7 hours after administration of the oral dosage form to a human subject. In some embodiments, the oral dosage form is configured to release the drug according to a desired release profile.

[0083] In some aspects, provided herein are modified-release oral dosage forms. In some embodiments, the oral dosage form comprises: drug granules comprising a first erodible material mixed with a drug; a drug component comprising a second erodible material mixed with the drug granules; a delay component comprising a third erodible material not mixed with the drug; and a pH-based enteric component configured to erode at or above a predetermined pH value, wherein the pH-based enteric component prevents erosion of the delay component, and wherein the delay component prevents erosion of the drug component. In some embodiments, the oral dosage form is configured to release the drug according to a desired release profile.

[0084] In some aspects, provided herein are modified-release oral pharmaceutical dosage forms. In some embodiments, the oral pharmaceutical dosage form comprises: a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles are uniformly distributed within the second erodible material, the drug particles comprising a first drug; wherein the second erodible material controls the release of the drug from the oral pharmaceutical dosage form within a desired amount of time after administration of the oral pharmaceutical dosage form to a human subject. In some embodiments, the drug particles are a drug powder. In some embodiments, exposure of the drug particles to gastrointestinal fluids is based on erosion of the second erodible material. In some embodiments, the second erodible material controls the timing of release of the drug particles from the drug component, whereby release of the drug particles begins immediately or within a desired amount of time after release from the drug component.

[0085] In some aspects, provided herein are modified-release oral dosage forms. In some embodiments, the oral dosage form comprises a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles are uniformly distributed within the second erodible material, the drug particles comprising a first drug and the first erodible material; wherein the first erodible material and the second erodible material collectively control the release of the drug from the oral dosage form within a desired amount of time after administration of the oral dosage form to a human subject. In some embodiments, the oral dosage form is configured to release the drug according to a desired release profile. In some embodiments, exposure of the drug particles to gastrointestinal fluid is based on erosion of the second erodible material. In some embodiments, the second erodible material controls the timing of release of the drug particles from the drug component, such that release of the drug particles begins immediately or within a desired amount of time after release from the drug component. In some embodiments, the drug particles further comprise a second drug, and the first drug, the second drug, and the first erodible material are uniformly intermixed.

[0086] In some aspects, provided herein are modified-release oral dosage forms. In some embodiments, the oral dosage form comprises: a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles are uniformly distributed in the second erodible material, the drug particles comprising a first drug and the first erodible material; and a delay component comprising a third erodible material that is not mixed with the drug; wherein the delay component surrounds the drug component, and wherein the delay component prevents the drug from being released from the oral dosage form within about 0.5 hours to about 7 hours after administration of the oral dosage form to a human subject. In some embodiments, the oral dosage form is configured to release the drug according to a desired release profile.

[0087] In some aspects, provided herein are modified-release oral dosage forms. In some embodiments, the oral dosage form comprises: a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles being uniformly distributed in the second erodible material, the drug particles comprising a first drug and a first erodible material; a delay component comprising a third erodible material not mixed with the drug; and a pH-based enteric component configured to erode at or above a predetermined pH value, wherein the pH-based enteric component prevents erosion of the delay component, and wherein the delay component prevents erosion of the drug component. In some embodiments, the oral dosage form is configured to release the drug according to a desired release profile.

[0088] In some aspects, provided herein are modified-release oral dosage forms. In some embodiments, the oral dosage form comprises: a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles being uniformly distributed in the second erodible material, the drug particles comprising a first drug and a first erodible material; and a pH-based enteric component configured to erode at or above a predetermined pH value, wherein the pH-based enteric component prevents erosion of the drug component. In some embodiments, the oral dosage form is configured to release the drug according to a desired release profile.

[0089] In some aspects, provided herein are modified-release oral pharmaceutical dosage forms. In some embodiments, the oral pharmaceutical dosage form comprises: a first pharmaceutical component comprising a plurality of drug particles and a second erodible material, wherein the plurality of drug particles are uniformly distributed within the second erodible material; and a second pharmaceutical component comprising a plurality of drug particles and a fourth erodible material, wherein the plurality of drug particles are uniformly distributed within the fourth erodible material; wherein the second erodible material and the fourth erodible material control the release of the drug from the first pharmaceutical component and the second pharmaceutical component, respectively, and the first pharmaceutical component and the second pharmaceutical component are in contact. In some embodiments, the oral pharmaceutical dosage form is configured to release the drug according to a desired release profile.

[0090] In some aspects, provided herein are modified-release oral dosage forms. In some embodiments, the oral dosage form comprises: a first drug component comprising a plurality of drug particles and a second erodible material, the plurality of drug particles uniformly distributed within the second erodible material; and a second drug component comprising a plurality of drug particles and a fourth erodible material, the plurality of drug particles uniformly distributed within the fourth erodible material; wherein the second erodible material and the fourth erodible material control the release of the drug from the first drug component and the second drug component, respectively, and the first drug component and the second drug component are not in contact. In some embodiments, the oral dosage form is configured to release the drug according to a desired release profile. In some embodiments, an intermediate component is located between the first and second drug components. In some embodiments, the intermediate component comprises an erodible material that is not mixed with the drug. In some embodiments, the intermediate component comprises a non-erodible material that is not mixed with the drug. In some embodiments, the intermediate component has a greater erosion rate than either the first or second drug component. In some embodiments, the intermediate component has a slower erosion rate than the first drug component or the second drug component.

[0091] In some aspects, provided herein are modified-release oral dosage forms. In some embodiments, the oral dosage form comprises: a first drug component comprising a plurality of drug particles and a second erodible material, the plurality of drug particles being uniformly distributed within the second erodible material; a second drug component comprising a plurality of drug particles and a fourth erodible material, the plurality of drug particles being uniformly distributed within the fourth erodible material; and a delay component comprising a third erodible material that is not mixed with the drug; wherein the second erodible material and the fourth erodible material control the release of the drug from the first drug component and the second drug component, respectively, and wherein the delay component surrounds the first drug component and the second drug component, the delay component preventing the drug from being released from the oral dosage form within about 0.5 hours to about 7 hours after administration of the oral dosage form to a human subject. In some embodiments, the oral dosage form is configured to release the drug according to a desired release profile.

[0092] In some aspects, provided herein are modified-release oral dosage forms. In some embodiments, the oral dosage form comprises: a first drug component comprising a plurality of drug particles and a second erodible material, the plurality of drug particles uniformly distributed within the second erodible material; a second drug component comprising a plurality of drug particles and a fourth erodible material, the plurality of drug particles uniformly distributed within the fourth erodible material; and a delay component comprising a third erodible material that is not mixed with the drug; wherein the second erodible material and the fourth erodible material control the release of the drug from the first drug component and the second drug component, respectively, and wherein the delay component surrounds the first drug component, the delay component preventing the drug from being released from the oral dosage form within about 0.5 hours to about 7 hours after administration of the oral dosage form to a human subject. In some embodiments, the oral dosage form is configured to release the drug according to a desired release profile. In some embodiments, the delay component does not surround the second drug component.

[0093] In some aspects, provided herein are modified-release oral dosage forms. In some embodiments, the oral dosage form comprises: a first drug component comprising a plurality of drug particles and a second erodible material, the plurality of drug particles being uniformly distributed within the second erodible material; a second drug component comprising a plurality of drug particles and a fourth erodible material, the plurality of drug particles being uniformly distributed within the fourth erodible material; and a delay component comprising a third erodible material that is not mixed with the drug; wherein the second erodible material and the fourth erodible material control the release of the drug from the first drug component and the second drug component, respectively, and wherein the delay component surrounds the first drug component or the second drug component, the delay component preventing the drug from being released from the oral dosage form within about 0.5 hours to about 7 hours after administration of the oral dosage form to a human subject. In some embodiments, the oral dosage form is configured to release the drug according to a desired release profile.

[0094] In some aspects, provided herein are modified-release oral dosage forms. In some embodiments, the oral dosage form comprises: a drug component comprising first and second drug particles and a second erodible material, wherein the first and second drug particles are uniformly distributed in the second erodible material; the first drug particles comprise a first drug and a first erodible material, and the second drug particles comprise a second drug and a fifth erodible material; and a delay component comprising a third erodible material that is not mixed with the drug; wherein the delay component surrounds the drug component, and wherein the delay component prevents the drug from being released from the oral dosage form within about 0.5 hours to about 7 hours after administration of the oral dosage form to a human subject. In some embodiments, the oral dosage form is configured to release the drug according to a desired release profile.

[0095] In some aspects, provided herein are modified-release oral dosage forms. In some embodiments, the oral dosage form comprises: a first drug component comprising drug particles and a second erodible material; a second drug component comprising drug particles and a fourth erodible material, the drug particles comprising a first drug and the first erodible material; and a pH-based enteric component configured to erode at or above a predetermined pH; wherein the second erodible material and the fourth erodible material control the release of the drug in the first drug component and the second drug component, respectively, and wherein the pH-based enteric component surrounds the first drug component and the second drug component, the pH-based enteric component preventing the drug from being released from the oral dosage form within about 1 hour to about 7 hours after administration of the oral dosage form to a human subject. In some embodiments, the oral dosage form is configured to release the drug according to a desired release profile.

[0096] In some aspects, provided herein are modified-release oral dosage forms. In some embodiments, the oral dosage form comprises: a drug component comprising first and second drug particles and a second erodible material, wherein the first and second drug particles are uniformly distributed in the second erodible material; the first drug particles comprise a first drug and a first erodible material, and the second drug particles comprise a second drug and a fifth erodible material; and a pH-based enteric component configured to erode at or above a predetermined pH value; wherein the pH-based enteric component surrounds the drug component, and wherein the pH-based enteric component prevents the drug from being released from the oral dosage form within about 1 hour to about 7 hours after administration of the oral dosage form to a human subject. In some embodiments, the oral dosage form is configured to release the drug according to a desired release profile.

[0097] In some embodiments, the second erodible material has a melting point of about 30-120°C. In some embodiments, the second erodible material has a melting point of about 30-110°C. In some embodiments, the second erodible material has a melting point of about 30-100°C. In some embodiments, the second erodible material has a melting point of about 35-120°C. In some embodiments, the second erodible material has a melting point of about 35-110°C. In some embodiments, the second erodible material has a melting point of about 35-100°C.

[0098] In some embodiments, the second erodible material has a glass transition temperature (Tg) of about -60°C to 80°C. In some embodiments, the second erodible material has a glass transition temperature (Tg) of about -60°C to 70°C. In some embodiments, the second erodible material has a glass transition temperature (Tg) of about -60°C to 60°C. In some embodiments, the second erodible material has a glass transition temperature (Tg) of about -50°C to 80°C. In some embodiments, the second erodible material has a glass transition temperature (Tg) of about -50°C to 70°C. In some embodiments, the second erodible material has a glass transition temperature (Tg) of about -50°C to 60°C.

[0099] In some embodiments, the second erodible material has a viscosity of 100-50,000 Pa·s at a temperature between Tm of the second erodible material and (Tm+30°C). In some embodiments, the second erodible material has a viscosity of 1,000-50,000 Pa·s at a temperature between Tm of the second erodible material and (Tm+30°C). In some embodiments, the second erodible material has a viscosity of 1,000-40,000 Pa·s at a temperature between Tm of the second erodible material and (Tm+30°C). In some embodiments, the second erodible material has a viscosity of 2,000-40,000 Pa·s at a temperature between Tm of the second erodible material and (Tm+30°C). In some embodiments, the second erodible material has a viscosity of 100-50,000 Pa·s at a temperature between Tm of the second erodible material and (Tm+20°C). In some embodiments, the second erodible material has a viscosity of 1000-50,000 Pa·s at a temperature between Tm of the second erodible material and (Tm+20°C). In some embodiments, the second erodible material has a viscosity of 1000-40,000 Pa·s at a temperature between Tm of the second erodible material and (Tm+20°C). In some embodiments, the second erodible material has a viscosity of 2000-40,000 Pa·s at a temperature between Tm of the second erodible material and (Tm+20°C). In some embodiments, the second erodible material has a viscosity of 1000-50,000 Pa·s at a temperature between Tm of the second erodible material and (Tm+10°C). In some embodiments, the second erodible material has a viscosity of 1000-50,000 Pa·s at a temperature between Tm of the second erodible material and (Tm+10°C). In some embodiments, the second erodible material has a viscosity of 1000-40000 Pa·s at a temperature between Tm and (Tm+10°C) of the second erodible material. In some embodiments, the second erodible material has a viscosity of 2000-40000 Pa·s at a temperature between Tm and (Tm+10°C) of the second erodible material.

[0100] In some embodiments, the viscosity of the drug assembly at a temperature between the Tm of the second erodible material and (Tm + 30° C.) is between 100 and 50,000 Pa·s. In some embodiments, the viscosity of the drug assembly at a temperature between the Tm of the second erodible material and (Tm + 30° C.) is between 1,000 and 50,000 Pa·s. In some embodiments, the viscosity of the drug assembly at a temperature between the Tm of the second erodible material and (Tm + 30° C.) is between 1,000 and 40,000 Pa·s. In some embodiments, the viscosity of the drug assembly at a temperature between the Tm of the second erodible material and (Tm + 30° C.) is between 2,000 and 40,000 Pa·s. In some embodiments, the viscosity of the drug assembly at a temperature between the Tm of the second erodible material and (Tm + 20° C.) is between 100 and 50,000 Pa·s. In some embodiments, the viscosity of the drug assembly at a temperature between the Tm of the second erodible material and (Tm + 20° C.) is between 1,000 and 50,000 Pa·s. In some embodiments, the viscosity of the drug assembly at a temperature between the Tm of the second erodible material and (Tm + 20° C.) is between 1,000 and 40,000 Pa·s. In some embodiments, the viscosity of the drug assembly at a temperature between the Tm of the second erodible material and (Tm + 20° C.) is between 2,000 and 40,000 Pa·s. In some embodiments, the viscosity of the drug assembly at a temperature between the Tm of the second erodible material and (Tm + 10° C.) is between 100 and 50,000 Pa·s. In some embodiments, the viscosity of the drug assembly at a temperature between the Tm of the second erodible material and (Tm + 10° C.) is between 1,000 and 50,000 Pa·s. In some embodiments, the drug component has a viscosity of 1000-40000 Pa·s at a temperature between Tm and (Tm+10°C) of the second erodible material. In some embodiments, the drug component has a viscosity of 2000-40000 Pa·s at a temperature between Tm and (Tm+10°C) of the second erodible material.

[0101] In some embodiments, the second erodible material is selected from one or more of poloxamer, polyethylene glycol, polyethylene oxide, carnauba wax, cetyl alcohol polyether / cetoacetate, polyoxyethylene stearyl ether, mono- and distearic acid glyceryl, distearic acid glyceryl, shellac, palmitic acid, polyethylene glycol stearate, span, lauroyl polyoxyethylene glyceride, vitamin E polyethylene glycol succinate, and stearic acid.

[0102] In some embodiments, the average particle size of the pharmaceutical particles is from 0.1 μm to 1000 μm. In some embodiments, the average particle size of the pharmaceutical particles is from 1 μm to 800 μm. In some embodiments, the average particle size of the pharmaceutical particles is from 10 μm to 500 μm. In some embodiments, the average particle size of the pharmaceutical particles is from 100 μm to 500 μm, for example, 150 μm, 200 μm, 350 μm, 400 μm, 450 μm. In some embodiments, the average particle size of the pharmaceutical particles is from 10 μm to 100 μm, for example, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm. In some embodiments, the pharmaceutical particles have an average particle size of 500 μm to 900 μm, for example, 550 μm, 600 μm, 650 μm, 700 μm, 750 μm, 800 μm, 850 μm. In some embodiments, the pharmaceutical particles have a particle size distribution of about 0.35 or less. In some embodiments, the pharmaceutical particles have a particle size distribution of about 0.1 to about 0.3, such as about any one of 0.15, 0.2, or 0.25.

[0103] In other aspects, provided herein are commercial batches of oral dosage forms of any of the oral dosage forms described herein. In some embodiments, the commercial batch has a standard deviation of about 0.05 or less for any one or more of the following: the average particle size of the drug particles; the amount of drug in the oral dosage form; the weight of the oral dosage form; the maximum span dimension of the oral dosage form and the span dimension of the oral dosage form perpendicular to the maximum span dimension, or the diameter of the oral dosage form.

[0104] In other aspects, provided herein is a method of preparing any of the oral dosage forms described herein, the method comprising three-dimensionally (3D) printing the oral dosage form. In some embodiments, the oral dosage form comprises: a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles uniformly distributed in the second erodible material, the drug particles comprising a first drug and a first erodible material; and a delay component comprising a third erodible material not mixed with the drug, wherein the method comprises: (a) dispensing the drug component; and (b) dispensing the delay component to form the oral dosage form.

[0105] In other aspects, provided herein is a method of preparing any of the oral dosage forms described herein, the method comprising three-dimensionally (3D) printing the oral dosage form. In some embodiments, the oral dosage form comprises: a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles are uniformly distributed in the second erodible material, the drug particles comprising a first drug and a first erodible material; and a pH-based enteric component configured to dissolve at or above a predetermined pH value, wherein the method comprises: (a) dispensing the drug component; and (b) dispensing the pH-based enteric component to form the oral dosage form.

[0106] In other aspects, provided herein is a method of preparing any of the oral dosage forms described herein, the method comprising three-dimensionally (3D) printing the oral dosage form. In some embodiments, the oral dosage form comprises: a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles uniformly distributed in the second erodible material, the drug particles comprising a first drug and a first erodible material; a delay component comprising a third erodible material not mixed with the drug; and a pH-based enteric component configured to dissolve at or above a predetermined pH value, wherein the method comprises: (a) dispensing the drug component; (b) dispensing the delay component; and (c) dispensing the pH-based enteric component to form the oral dosage form.

[0107] The oral dosage forms described herein are based, at least in part, on the inventors' unique insights and discoveries regarding the design of oral dosage forms that improve the release of poorly soluble drugs. In this invention, an amorphous solid dispersion (ASD) of a poorly soluble drug is mixed with a first erodible material to form drug particles. These particles are then mixed with a second erodible material and fabricated into a drug assembly using 3D printing technology. The drug is uniformly dispersed in the first erodible material in the ASD form, significantly increasing the dissolution of the poorly soluble drug, promoting drug absorption, and improving bioavailability. The first and second erodible materials work together to control drug release according to a desired release profile. Using 3D printing technology, the drug particles are uniformly mixed with the second erodible material, resulting in uniform distribution of the drug particles throughout the drug assembly. This ensures high consistency in drug loading across multiple oral dosage forms, and also ensures good particle mixing uniformity across different locations within the same oral dosage form. The drug particles of the oral drug dosage form described herein are convenient for extrusion molding after being mixed with the second soluble material. The second soluble material has excellent rheological properties, can increase the fluidity of each component in the drug component, facilitates extrusion molding, and can reduce the temperature required for the drug component in the 3D printing process, greatly avoiding the generation of impurities due to high temperature, and is suitable for the development of oral drug dosage forms for heat-sensitive drugs. The soluble material of the drug component or delayed component of the oral drug dosage form described herein can prevent water from penetrating into the tablet core in advance while being dissolved, thereby avoiding drug crystallization. When the drug particles in the oral drug dosage form described herein are quick-release particles, the drug particles can be quickly dispersed in the body fluids while the second soluble material in the drug component is dissolved, greatly increasing the surface area of ​​the drug in contact with the body fluids and increasing the drug release rate. The oral drug dosage form described herein is also suitable for 3D printing of heat-sensitive drugs, avoiding the situation where heat-sensitive drugs are prone to generate impurities during the preparation process, greatly expanding the application scenarios of the drug.

[0108] I. Definition of Terms

[0109] For the purposes of interpreting this specification, the following definitions will apply. In the event that any definition set forth below conflicts with any document incorporated herein by reference, the set forth definition shall control.

[0110] As used herein, the use of the term "treatment" or its equivalents refers to a method for obtaining a beneficial or desired result (including, for example, alleviating the symptoms of a disease). For the purposes of this disclosure, a beneficial or desired clinical result includes, but is not limited to, one or more of the following: alleviating one or more symptoms caused by the disease, reducing the severity of one or more symptoms caused by the disease, preventing an increase in the severity of one or more symptoms caused by the disease, reducing the dosage of one or more other drugs required to treat and / or control the disease, and improving the quality of life.

[0111] As used herein, the term "subject" refers to a mammal, and includes, but is not limited to, a human, cow, horse, cat, canine, rodent, rat, mouse, dog, or primate. In some embodiments, the subject is a human subject.

[0112] As used herein, the terms "comprising," "having," "containing," and "including," and other similar forms and their grammatical equivalents are intended to be equivalent in meaning and to be open-ended, i.e., one or more items following any of these words is not intended to be an exhaustive listing of the one or more items, nor is it intended to be limited to the listed one or more items. For example, an article that "comprising" components A, B, and C can consist of components A, B, and C (i.e., contain only components A, B, and C), or can contain not only components A, B, and C, but also one or more other components. Thus, it is intended to be understood that "comprising" and its similar forms and its grammatical equivalents include disclosure of embodiments that "consist essentially of" or "consist of."

[0113] It should be understood that when a range of values ​​is provided, every intervening value (to the tenth of the unit of the lower limit) between the upper and lower limit of that range and any other stated or intervening value in that stated range is also encompassed within the disclosure, subject to any specifically excluded limit in the stated range, unless the context clearly dictates otherwise. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also encompassed within the disclosure.

[0114] Reference herein to "about" a value or parameter includes (and describes) variations with respect to that value or parameter itself. For example, a description referring to "about X" includes a description of "X."

[0115] As used herein, the term "particles" or equivalents thereof refers to particles having an average particle size of 0.1 μm to 1000 μm, and includes but is not limited to solid, liquid, and semi-solid forms. Solid particles include but are not limited to granular and powdered forms, and liquid forms include but are not limited to droplets and oil droplets. In some embodiments, the particles are granular. In some embodiments, the particles are powdered. In some embodiments, the particles are approximately spherical in shape. In some embodiments, the particles are irregular in shape.

[0116] As used herein, the term "plurality of drug particles," "multiple drug particles," or their equivalents refers to a composition comprising at least about two or more drug particles. For example, an oral dosage form may contain at least about 25, 50, 75, 100, 250, 500, 750, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000 drug particles; or at least about two, three, four, five, six, seven, eight, nine, or ten drug particles.

[0117] As used herein, the term "particle mixing uniformity" or its equivalent refers to the measurement method described in the "Technical Guidelines for the Study of Mixing Uniformity and Unit Uniformity of Controlled Dosages for Chemical Oral Solid Preparations" (Trial Version) issued by the China Food and Drug Administration. Specifically, at least 10 sampling points are selected throughout the batch, with at least three samples taken from each sampling point; one sample is tested at each sampling point, and the relative standard deviation (RSD) of all samples is calculated (n ≥ 10). Particle mixing is considered uniform if all individual values ​​are within ±10.0% (absolute) of the mean and the RSD is ≤ 5.0%.

[0118] As used herein, the term "uniformly distributed" or equivalent terms refers to a macroscopically homogeneous mixture of the components in the mixture.

[0119] As used herein, the term "capsule-shaped" or equivalent terms thereof refers to an elongated strip shape comprising two parallel lines and two arcs, wherein the two parallel lines are connected by the two arcs.

[0120] As used herein, including the appended claims, the singular forms "a," "an," "or," and "the" include plural referents unless the context clearly dictates otherwise.

[0121] II. Oral Dosage Forms

[0122] In some aspects, provided herein are modified-release oral dosage forms. In some embodiments, the oral dosage form comprises: a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles are uniformly distributed within the second erodible material, the drug particles comprising a first drug and the first erodible material; wherein the first and second erodible materials collectively control the release of the drug from the oral dosage form within a desired amount of time following administration of the oral dosage form to a human subject. In some embodiments, the oral dosage form further comprises a delay component comprising a third erodible material not mixed with the drug. In some embodiments, the oral dosage form further comprises a pH-based enteric component configured to erode at or above a predetermined pH. In some embodiments, the drug component comprises a first drug component comprising the second erodible material mixed with the drug particles, and a second drug component comprising a fourth erodible material mixed with the drug particles. In some embodiments, the drug particles include first drug particles and second drug particles, wherein the first drug particles include a first erodible material mixed with a drug, and the second drug particles include a fifth erodible material mixed with the drug. In some embodiments, the drug particles further include a second drug, and the first drug, the second drug, and the first erodible material are uniformly mixed.

[0123] The oral dosage forms disclosed herein may include various combinations of the components described herein and may be arranged in various array configurations. Such components and configurations used to form the oral dosage forms are configured to achieve a desired release profile of the drug. In some cases, such components and configurations are described in a modular manner, and such descriptions are not intended to limit the scope of the oral dosage forms encompassed herein.

[0124] In some embodiments, the second erodible material has a melting point of about 30-120°C. In some embodiments, the second erodible material has a melting point of about 30-110°C. In some embodiments, the second erodible material has a melting point of about 30-100°C. In some embodiments, the second erodible material has a melting point of about 35-120°C. In some embodiments, the second erodible material has a melting point of about 35-110°C. In some embodiments, the second erodible material has a melting point of about 35-100°C. In some embodiments, the second erodible material has a melting point (Tm) of about 30-120°C. In some embodiments, the viscosity of the second erodible material at a temperature between the Tm of the second erodible material and (Tm + 30°C) is 1000-50,000 Pa·s. In some embodiments, the viscosity of the drug component at a temperature between the Tm of the second erodible material and (Tm + 30°C) is 1000-50,000 Pa·s. When the printing temperature of the drug component is within this temperature range, the second erodible material is in a liquid or semi-solid state, exhibiting excellent rheological properties and facilitating extrusion after mixing with the drug particles. The second erodible material provides support while ensuring stable filament production, effectively reducing the printing temperature of the drug component and preventing impurities generated by high temperatures. In some embodiments, the "viscosity" described herein is measured under the following conditions: Test instrument: Anton Paar MCR102; Test procedure: Temperature sweep (oscillation); Initial normal force: 0; Temperature ramp range: 30°C to 80°C; Temperature ramp rate: 2°C / min; DMA test section parameters: Shear strain: 0.1%, Angular frequency: 10 rad / s.

[0125] In some embodiments, the oral dosage forms described herein have substantially flat top and bottom surfaces. In some embodiments, the thickness measured between the top and bottom surfaces of the oral dosage form is substantially uniform. In some embodiments, the top surface is capsule-shaped. In some embodiments, the top surface is circular. In some embodiments, the bottom surface is capsule-shaped. In some embodiments, the bottom surface is circular.

[0126] In some embodiments, the top surface and / or bottom surface of the oral dosage form is uneven. In some embodiments, the top surface and / or bottom surface of the oral dosage form is printed with a logo (such as a text logo, a graphic logo).

[0127] For purposes of illustration and to facilitate understanding of certain components and their configurations, Figures 1A-1I provide cross-sectional views of exemplary oral pharmaceutical dosage forms described herein.

[0128] In some aspects of the present disclosure, as shown in FIG1A , an exemplary oral dosage form includes a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles are uniformly distributed within the second erodible material, and the drug particles comprise a first drug and the first erodible material. As shown in FIG1A , the drug component has a top surface, a side surface, and a bottom surface. In some embodiments, the second erodible material is uniformly intermixed with the drug particles. The oral dosage form of FIG1A is configured such that, when administered to a human subject and subjected to bodily fluids, the top, side, and bottom surfaces of the drug component are simultaneously exposed to bodily fluids and erode simultaneously, initiating release of the drug particles. The first erodible material of the drug particles begins to erode, releasing the drug. In some embodiments, the onset and duration of drug release can be adjusted by adjusting the composition of the first or second erodible material, respectively. In some embodiments, the rate of drug release at a specific release site can be adjusted by adjusting the average particle size of the drug particles. In some embodiments, the oral dosage form includes a plurality of drug particles. In some embodiments, the oral dosage form comprises a plurality of drug particles. In some embodiments, the drug species within the plurality of drug particles are different. In some embodiments, the drug sizes within the plurality of drug particles are different. In some embodiments, the particle sizes of the plurality of drug particles are different. In some embodiments, the first erodible material species within the plurality of drug particles are different. In some embodiments, the first erodible material compositions within the plurality of drug particles are different. In some embodiments, the oral dosage form comprises a plurality of drug components. In some embodiments, the composition or size of the plurality of drug components are the same as or different from one another.

[0129] In some aspects of the present disclosure, as shown in FIG. 1B , an exemplary oral dosage form includes: a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles uniformly distributed within the second erodible material, the drug particles comprising a first drug and the first erodible material; and a delay component comprising a third erodible material unmixed with the drug. As shown in FIG. 1B , the drug component has a top surface, a side surface, and a bottom surface, and the delay component has a top surface, a side surface, and a bottom surface. In some embodiments, the delay component surrounds the drug component. The oral dosage form of FIG. 1B is configured such that, when administered to a human subject and subjected to bodily fluids, the top, side, and bottom surfaces of the delay component are simultaneously exposed to bodily fluids and erode simultaneously. In some embodiments, the onset of drug release can be adjusted by adjusting the composition or thickness of the delay component. For example, increasing the thickness of the delay component can further delay the onset of drug release; decreasing the thickness of the delay component can reduce the delayed release of the drug. In some embodiments, the onset of drug release can be adjusted by adjusting the density of the delay component. For example, by increasing the density of the delay component, the initial release time of the drug can be further delayed; by decreasing the density of the delay component, the delayed release time of the drug can be reduced.

[0130] In some aspects of the present disclosure, as shown in FIG1C , an exemplary oral drug dosage form includes: a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles are uniformly distributed in the second erodible material, the drug particles comprising a first drug and a first erodible material; a delay component comprising a third erodible material not mixed with the drug; and a pH-based enteric component configured to erode at or above a predetermined pH value. As shown in FIG1C , the drug component has a top surface, a side surface, and a bottom surface, the delay component has a top surface, a side surface, and a bottom surface, and the pH-based enteric component has a top surface, a side surface, and a bottom surface. In some embodiments, the pH-based enteric component surrounds the delay component, and the delay component surrounds the drug component. The oral pharmaceutical dosage form of Figure 1C is configured such that when administered to a human subject and subjected to body fluids, the top, side, and bottom surfaces of the pH-based enteric component are simultaneously exposed to the body fluids and erode at or above a predetermined pH value, and then the top, side, and bottom surfaces of the delayed component are exposed to the body fluids and begin to erode.

[0131] In some aspects of the present disclosure, as shown in FIG. 1D , an exemplary oral drug dosage form includes: a first drug component comprising a plurality of drug particles and a second erodible material, the plurality of drug particles being uniformly distributed within the second erodible material; a second drug component comprising a plurality of drug particles and a fourth erodible material, the plurality of drug particles being uniformly distributed within the fourth erodible material; and a delay component comprising a third erodible material that is not mixed with the drug. As shown in FIG. 1D , the first and second drug components each have a top surface, a side surface, and a bottom surface, and the delay component has a top surface, a side surface, and a bottom surface. In some embodiments, the delay component surrounds the first and second drug components. In some embodiments, the thickness of the delay component surrounding the first and second drug components is the same. In some embodiments, the thickness of the delay component surrounding the first and second drug components is different. In some embodiments, the timing of drug release from the first and second drug components can be adjusted by adjusting the thickness of the delay component surrounding the first and second drug components, respectively. In some embodiments, the timing of drug release from the first and second drug components is adjusted by adjusting the density of the delay component surrounding the first and second drug components, respectively. The oral dosage form of FIG1D is configured such that, when administered to a human subject and subjected to bodily fluids, the top, side, and bottom surfaces of the delay component are simultaneously exposed to the bodily fluids and erode simultaneously.

[0132] In some aspects of the present disclosure, as shown in FIG1E , an exemplary oral drug dosage form includes: a drug component comprising first and second drug particles and a second erodible material, wherein the first and second drug particles are uniformly distributed within the second erodible material; the first drug particles comprising a first drug and a first erodible material, and the second drug particles comprising a second drug and a fifth erodible material; and a delay component comprising a third erodible material that is not mixed with the drug. As shown in FIG1E , the first and second drug particles are uniformly mixed with the second erodible material. In some embodiments, the average particle size of the first and second drug particles is the same or different. In some embodiments, the onset release time or sustained release time of the first and second drug particles, respectively, can be adjusted by adjusting the average particle size of the first and second drug particles. In some embodiments, the onset release time or sustained release time of the first and second drug particles, respectively, can be adjusted by adjusting the type of erodible material in the first and second drug particles, respectively. In some embodiments, the delay component surrounds the drug component. The oral dosage form of FIG1E is configured such that, when administered to a human subject and subjected to bodily fluids, the top, side, and bottom surfaces of the delay component are simultaneously exposed to the bodily fluids and erode simultaneously. In some embodiments, the first and second drug particles are each selected from one or more of immediate-release particles, sustained-release particles, and delayed-release particles.

[0133] In some aspects of the present disclosure, as shown in FIG1F , an exemplary oral drug dosage form includes: a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles are uniformly distributed in the second erodible material, the drug particles comprising a first drug; and a delay component comprising a third erodible material that is not mixed with the drug. As shown in FIG1F , the drug component has a top surface, a side surface, and a bottom surface, and the delay component has a top surface, a side surface, and a bottom surface. In some embodiments, the delay component surrounds the drug component. The oral drug dosage form of FIG1F is configured such that, when administered to a human subject and subjected to bodily fluids, the top, side, and bottom surfaces of the delay component are simultaneously exposed to bodily fluids and the top, side, and bottom surfaces are simultaneously eroded. In some embodiments, the drug particles contain only the drug, and the drug is in the form of a powder. In some embodiments, the drug particles contain only the drug, and the drug is in the form of particles.

[0134] In some aspects of the present disclosure, as shown in FIG. 1G , an exemplary oral dosage form includes: a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles uniformly distributed within the second erodible material, the drug particles comprising a first drug and a first erodible material; and a pH-based enteric component configured to erode at or above a predetermined pH value. As shown in FIG. 1G , the drug component has a top surface, a side surface, and a bottom surface, and the pH-based enteric component has a top surface, a side surface, and a bottom surface. In some embodiments, the pH-based enteric component surrounds the drug component. The oral dosage form of FIG. 1G is configured such that, when administered to a human subject and subjected to bodily fluids, the top, side, and bottom surfaces of the pH-based enteric component are simultaneously exposed to bodily fluids, erode at or above the predetermined pH value, and subsequently the top, side, and bottom surfaces of the drug component are exposed to bodily fluids and begin to erode.

[0135] In some aspects of the present disclosure, as shown in FIG1H , an exemplary oral dosage form includes a first drug component comprising a plurality of drug particles and a second erodible material, wherein the plurality of drug particles are uniformly distributed in the second erodible material; a second drug component comprising a plurality of drug particles and a fourth erodible material, wherein the plurality of drug particles are uniformly distributed in the fourth erodible material; and a pH-based enteric component configured to erode at or above a predetermined pH value. As shown in FIG1H , the drug component has a top surface, a side surface, and a bottom surface, and the pH-based enteric component has a top surface, a side surface, and a bottom surface. In some embodiments, the pH-based enteric component surrounds the drug component. The oral dosage form of FIG1H is configured such that, when administered to a human subject and subjected to body fluids, the top, side, and bottom surfaces of the pH-based enteric component are simultaneously exposed to the body fluids and erode at or above a predetermined pH value, followed by exposure of the top, side, and bottom surfaces of the drug component to the body fluids and initiation of erosion. In some embodiments, the fourth erodible material is the same as the second erodible material. In some embodiments, the fourth erodible material is different from the second erodible material.

[0136] In some aspects of the present disclosure, as shown in FIG. 1I , an exemplary oral dosage form includes: a drug component comprising first and second drug particles and a second erodible material, wherein the first and second drug particles are uniformly distributed in the second erodible material; the first drug particles comprising a first drug and a first erodible material, and the second drug particles comprising a second drug and a fifth erodible material; and a pH-based enteric component configured to erode at or above a predetermined pH value. As shown in FIG. 1I , the drug component has a top surface, a side surface, and a bottom surface, and the pH-based enteric component has a top surface, a side surface, and a bottom surface. In some embodiments, the pH-based enteric component surrounds the drug component. The oral dosage form of FIG. 1I is configured such that, when administered to a human subject and subjected to body fluids, the top, side, and bottom surfaces of the pH-dependent enteric component are simultaneously exposed to body fluids and erode at or above a predetermined pH value, followed by exposure of the top, side, and bottom surfaces of the drug component to body fluids and initiation of erosion. In some embodiments, the first erodible material is the same as the fifth erodible material. In some embodiments, the first erodible material is different from the fifth erodible material.

[0137] In some aspects of the present disclosure, as shown in Figure 1J, an exemplary oral drug dosage form includes: a first drug component, the first drug component comprising a plurality of drug particles and a second erodible material, the plurality of drug particles being uniformly distributed in the second erodible material; a second drug component, the second drug component comprising a plurality of drug particles and a fourth erodible material, the plurality of drug particles being uniformly distributed in the fourth erodible material; and a delay component, the delay component comprising a third erodible material that is not mixed with the drug; wherein the second erodible material and the fourth erodible material control the release of the drug in the first drug component and the second drug component, respectively, and wherein the delay component surrounds the first drug component, the delay component does not surround the second drug component, and the delay component prevents the drug in the first drug component from being released from the oral drug dosage form within about 0.5 hours to about 7 hours after the oral drug dosage form is administered to a human subject.

[0138] In some aspects of the present disclosure, as shown in FIG1K , an exemplary oral drug dosage form includes: a first drug component comprising a plurality of drug particles and a second erodible material, wherein the plurality of drug particles are uniformly distributed within the second erodible material; and a second drug component comprising a plurality of drug particles and a fourth erodible material, wherein the plurality of drug particles are uniformly distributed within the fourth erodible material; wherein the second erodible material and the fourth erodible material control the release of the drug from the first drug component and the second drug component, respectively, and the first drug component and the second drug component are in contact. In some aspects of the present disclosure, the first drug component and the second drug component are stacked one above the other. In some aspects of the present disclosure, the first drug component and the second drug component are stacked back to back.

[0139] In some aspects of the present disclosure, as shown in FIG. 1L , an exemplary oral drug dosage form includes: a first drug component comprising a plurality of drug particles and a second erodible material, the plurality of drug particles uniformly distributed within the second erodible material; and a second drug component comprising a plurality of drug particles and a fourth erodible material, the plurality of drug particles uniformly distributed within the fourth erodible material. The second erodible material and the fourth erodible material control the release of the drug from the first and second drug components, respectively. The first and second drug components are not in contact, and an intermediate component is disposed between the first and second drug components. In some embodiments, the intermediate component comprises an erodible material that does not mix with the drug. In some embodiments, the intermediate component comprises an insoluble material that does not mix with the drug. In some embodiments, the intermediate component has a greater erosion rate than the first or second drug component. In some embodiments, the intermediate component has a lesser erosion rate than the first or second drug component. In some embodiments, the intermediate component isolates the first or second drug component.

[0140] As disclosed herein, components of the oral dosage form can be configured into a variety of shapes and sizes. Unless otherwise specified, references to certain shapes, sizes, and measurements reflect the oral dosage form prior to administration to a human subject (e.g., prior to erosion of any component of the oral dosage form).

[0141] i.Drug particles

[0142] Oral pharmaceutical dosage forms disclosed herein include particles comprising a drug. In some embodiments, the drug particles comprise an erodible material comprising the drug. The drug particles can be formed using a variety of materials having different shapes and sizes, including materials having a range of drug mass fractions. In some embodiments, the drug particles do not comprise an erodible material. In some embodiments, the drug particles comprise a first drug. In some embodiments, the drug particles comprise a first drug and a second drug.

[0143] In some embodiments, the pharmaceutical particles are selected from one or more of a solid form, a liquid form, or a semi-solid form. In some embodiments, the pharmaceutical particles are in a solid form. In some embodiments, the pharmaceutical particles are selected from one or more of a granular form or a powdered form.

[0144] In some embodiments, the average particle size of the pharmaceutical particles is from 0.1 μm to 1000 μm. In some embodiments, the average particle size of the pharmaceutical particles is from 1 μm to 800 μm. In some embodiments, the average particle size of the pharmaceutical particles is from 10 μm to 500 μm. In some embodiments, the average particle size of the pharmaceutical particles is from 100 μm to 500 μm, for example, 150 μm, 200 μm, 350 μm, 400 μm, 450 μm. In some embodiments, the average particle size of the pharmaceutical particles is from 10 μm to 100 μm, for example, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm. In some embodiments, the pharmaceutical particles have an average particle size of 500 μm to 900 μm, for example, 550 μm, 600 μm, 650 μm, 700 μm, 750 μm, 800 μm, 850 μm. In some embodiments, the pharmaceutical particles have a particle size distribution of about 0.35 or less. In some embodiments, the pharmaceutical particles have a particle size distribution of about 0.1 to about 0.3, such as about any one of 0.15, 0.2, or 0.25.

[0145] In some embodiments, the erodible material in the drug particles is selected from one or more of a drug diffusion material, a filler, a binder, a lubricant, a disintegrant, or a plasticizer. In some embodiments, the drug diffusion material comprises a swellable polymer impregnated with a drug, for example, such that the drug is released from the drug diffusion material upon swelling. In some embodiments, the drug diffusion material comprises any one or more of cellulose acetate phthalate (CAP), quaternary amino methacrylate copolymer, poly(lactide-co-glycolide) (PLGA), ethylene-vinyl acetate copolymer, polyethylene (PE), polycaprolactone (PCL), polylactic acid (PLA), cellulose acetate butyrate (CAB), cellulose acetate (CA), polyvinyl acetate (PVAc), polyvinyl acetal aminoacetate (AEA), poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), ethyl cellulose (EC), polyvinyl acetate (PVAc), polyvinyl pyrrolidone (PVP), and crospovidone.

[0146] In some embodiments, the filler is selected from one or more of copolyvidone (PVP / VA), polyvinyl alcohol (PVA), polyethylene glycol (PEG), polyvinyl pyrrolidone (VA), hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), lactose, mannitol, sorbitol, xylitol, erythritol, sucrose, starch, microcrystalline cellulose, calcium hydrogen phosphate or dextrin. In some embodiments, the binder is selected from one or more of gum arabic, starch, pullulan, gelatin, ethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrin. In some embodiments, the lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, sodium stearyl fumarate, polyethylene glycol or silicon dioxide. In some embodiments, the disintegrant is selected from one or more of cross-linked polyvinyl ketone, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, partially pregelatinized starch or sodium starch glycolate. In some embodiments, the plasticizer is selected from one or more of triethyl citrate (TEC), vitamin E polyethylene glycol succinate (TPGS), acetin, acetylated triethyl citrate, tributyl citrate, o-acetyl tributyl citrate, polyethylene glycol 15-hydroxystearate, PEG-40-hydrogenated castor oil, polyethylene glycol 35-castor oil, dibutyl sebacate, diethyl phthalate, glycerol, methyl 4-hydroxybenzoate, castor oil, oleic acid, triacetin and polyalkylene glycol.

[0147] In some embodiments, the pharmaceutical particles comprise first pharmaceutical particles and second pharmaceutical particles. In some embodiments, the first pharmaceutical particles are immediate-release particles. In some embodiments, the first pharmaceutical particles are sustained-release particles. In some embodiments, the first pharmaceutical particles are delayed-release particles. In some embodiments, the second pharmaceutical particles are immediate-release particles. In some embodiments, the second pharmaceutical particles are sustained-release particles. In some embodiments, the second pharmaceutical particles are delayed-release particles.

[0148] In some embodiments, the first drug particles comprise a first erodible material mixed with a first drug. In some embodiments, the second drug particles comprise a fifth erodible material mixed with a second drug. In some embodiments, the first erodible material and the fifth erodible material are the same. In some embodiments, the first erodible material and the fifth erodible material are different.

[0149] In some embodiments, the drug particles have a mass fraction of about 0.01% to about 60%, such as about 0.02% to about 50% or about 0.03% to about 40%, based on the weight of the oral dosage form. In some embodiments, the drug particles have a drug mass fraction of at least about 0.1%, such as at least about 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, or 0.6%. In some embodiments, the drug particles have a drug mass fraction of less than about 60%, such as less than about 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10%. In some embodiments, the drug particles have a drug mass fraction of about any of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%.

[0150] In some embodiments, the amount of the drug in the drug particles is about 1 mg to about 50 mg, such as any one of about 1 mg to about 25 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 9 mg to about 12 mg, about 10 mg to about 12 mg, about 19 mg to about 23 mg, or about 21 mg to about 23 mg. In some embodiments, the amount of the drug in the drug particles is about 1 mg or more, such as any one of about 3 mg or more, 4 mg or more, 5 mg or more, 6 mg or more, 7 mg or more, 8 mg or more, 9 mg or more, 10 mg or more, 11 mg or more, 12 mg or more, 13 mg or more, 14 mg or more, 15 mg or more, 16 mg or more, 17 mg or more, 18 mg or more, 19 mg or more, 20 mg or more, 21 mg or more, 22 mg or more, 23 mg or more, 24 mg or more, or 25 mg or more. In some embodiments, the amount of the drug in the drug particles is about 25 mg or less, such as about any of 24 mg or less, 23 mg or less, 22 mg or less, 21 mg or less, 20 mg or less, 19 mg or less, 18 mg or less, 17 mg or less, 16 mg or less, 15 mg or less, 14 mg or less, 13 mg or less, 12 mg or less, 11 mg or less, 10 mg or less, 9 mg or less, 8 mg or less, 7 mg or less, 6 mg or less, 5 mg or less, 4 mg or less, or 3 mg or less. In some embodiments, the amount of the drug in the drug particles is about any of 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, or 25 mg.

[0151] In some embodiments, the drug in the drug particles of the oral dosage form described herein can be any drug. In some embodiments, the drug is selected from one or more of a small molecule compound, a polypeptide, a protein, a nucleic acid, an antibody, or a microorganism. In some embodiments, the pharmaceutically active material is selected from one or more of a small molecule compound, a polypeptide, and a protein.

[0152] In some embodiments, the drug is uniformly dispersed in the first erodible material in the form of an amorphous solid dispersion (ASD).

[0153] In some embodiments, the small molecule compound is selected from tofacitinib, lidocaine, 11-di-deuteriolinoleic acid ethyl ester, 16-dehydropregnenolone, 3,5-diiodothyronine, 5-fluoro-2-deoxycytidine, 6-mercaptopurine, abacavir, abiraterone, acamprosate, acarbose, aceclidine, aceclofenac, acetylenic acid, acetaminophen, acetylcysteine, acetyl-L-carnitine, acetylsalicylic acid, acyclovir, acipimox, azalast, aclidinium bromide, acolbifene, acotiamide, acrivastine, actarik, adapalene, adefovir dipivoxil, afatinib, agomelatine, edenafil, alerelin acetate, alatrofloxacin, albendazole, salbutamol sulfate, alcaftadine, alendronic acid, alfacalcidol, alfa Salon, alfentanil, alfuzosin, aliskiren, alitretinoin, allisartan medoxomil, allopregnanolone, allopurinol, almotriptan, alogliptin, alosetron, alphaketoglutarate, lipoic acid, alprazolam, alprostadil, altretinoin, aluminum sulfate, alvimopan, amantadine, ambrisentan, ambroxol, amphetamine, amphetamine sulfonated divinylbenzene, amipridine, amifostine, amikacin, amiloride, aminoacetyl, levulinic acid, aminopterin, amiodarone, amisulpride, amitriptyline, amlexanol, amlodipine, ammonium lactate, amodiaquine, amorolfine, ansuloprine, amoxicillin amphetamine, amphetamine, ampicillin, ampiroxicam, amrinone, amrubicin, guaiacine, alogliptin, anagrelide, anamorelin ... Nastrazole, Ancrol, Andrographolide, Anecortave, Anidulafungin, Aniracetam, Anistreplase, Anlotinib, Antazoline, Antroquinol, Apatinib, Apixaban, Apomorphine, Apremilast, Aprepitant, Aritabine, Arandipine, Arbekacin, Arformoterol, Argatroban, Aripiprazole, Armodafinil, Arsenite, Artemether, Artemisinin, Artesunate, asenapine, asimadolin, astragaloside, anaprevir, atazanavir, atenolol, atomoxetine, atorvastatin, atovaquone, atrasentan, atropine, auranofin, avanafil, avibactam, axitinib, azacitidine, cytidine, azasetron, azelaic acid, azelastine, azelnidipine, azilsartan, azimilide, aztreonam, azivudine, Baclofen, bafatinib, baicalin, balofloxacin, balsalazide, bambuterol, baricitinib, barnidipine, bazedoxifene, beclomethasone dipropionate, beclomethasone dipropionate, bedoraclonidone, belotecan, benazepril, phenylcyclidine bromide, bendamustine, benidipine, benserazide, benzalkonium chloride, benznidazole, benzocaine, benzoyl peroxide, benzyldamine, bepotastine, benzyl alcohol Lacontan, beraprost, besifloxacin, besifovir, besipiridine, β-olephene, betahistine, betaine, betamethasone, betamipron, betaxolol, bethanechol, uracil, betrixaban, bevacizumab, bexarotene, bezafibrate, biapenem, bicalutamide, bicyclol, bificon, bilastine, bimatoprost, bismuth gallate, ecabet,Bisoprolol, bitaspiramycin, bleomycin, blonanserin, boceprevir, bortezomib, bosentan, bosutinib, bolfaxantane, brepirazole, brimonidine, pyrimidine, brivaracetam, brivudine, bromazepam, bromfenac, bromocriptine, brotizolam, bucinolol, buladesine, budesonide, buflomedil, bunazosin, bupivacaine, buprenorphine, bupropion, brixafor, buserelin, buspirone, busulfan, butenafine, butorphanol, butylphthalide, cabazitaxel, cabergoline, cabozantinib, cadrofloxacin, caffeine, calcipotriol, calcitriol, carfatan, calmangafodipir, camostat, camptothecin, canagliflozin, candesartan, cangrelor, capecitabine, captopril, carbamazepine, Carbetocin, carbitoxin, carbidopa, carbinoxamine, carbocysteine, carboplatin, carbidopa, carfilzomib, carglutamic acid, carilara, carmustine, carteolol, carumonam, carvedilol, caspofungin, catechin, cediranib, cefaclor, cefadroxil, cefathiamidine, cefcaprine, cefdinir, cefditoren pivoxil, cefepime, ceftazidime Metformin, ceftriaxone, cefoperazone, ceftriaxone, cefotaxime, cefotiam, cefazolin, cefpirome, cefpodoxime, cefprozil, ceftaroline, ceftazidime, ceftibuten, ceftoroxil, ceftriaxone, cefuroxime, celecoxib, celigosivir, celiprolol, ceritinib, cetirizine, cetirizine, cetraxate, cevimeline, chenodeoxycholic acid , chlormadinone, chlorogenic acid, chlorpheniramine, chlorthalidone, cholecalciferol, bile acid, choline alfoscerate, choline fenofibrate, ciclesonide, ciclopirox olamine, cyclosporine, cidofovir, cidoxepin, cilastatin, cilazapril, cilnidipine, cilostazol, cimetidine, cinacalcet, cinepazide, cinipride, ciprofibrate, ciprofloxacin, atracurium, cisplatin, citalopram, citicoline, citrulline, cladribine, clarithromycin, clavulanic acid, clazotin, clevidipine, clavudine, clioquinol, clobazam, clobetasol, clofibrate, clofazimine, clomipramine, clonazepam, clonidine, clopidogrel, clotrimazole, clozapine, adenosylcobalamin, cobitetra, codeine, colchicine, cholecalciferol, colesevelam, colestipol Lan, caufocel, conivaptan, 11-deoxycortisol 17α-vinylpropionic acid, clerimod, crizotinib, cromoglycine, cyanocobalamin, cyclosporin, cyclobenzaprine, cyclophosphamide, cyclosporine, cyproterone acetate, cytarabine, dabigatran etexilate, dabrafenib, daclatasvir, dacomitinib, dalbavancin, dalcetrapib, aminopyridine, dalfopristin, danazol, dantrolene, darusetide, dapiprazole, dapivirine, dapoxetine, dapsone, darifenacin, darunavir, dasabuvir, dasatinib, daunorubicin, decitabine, laroxacin, deflazacort, delafloxacin, delafloxacin, delazolam, delapril, delavirdine, denibulin, desoxyandrographolide, desflurane, desipramine, loratadine, desmopressin, desogestrel, desonide,Desvenlafaxine, dextromethorphan, verteporfin, levodopa, venlafaxine, dexamethasone, dexamethasone penate, dexamphetamine, dexanabinol, iron dextran, dexketoprofen tromethamine, dexlansoprazole, dexmedetomidine, methylphenidate, dexrazoxane, sotalol, dextrosucrose, dextroamphetamine, dextromethorphan, dextropropoxyphene, diacerein, diacetylmorphine , epoxylactol, diazepam, diazoxide choline, diclofenac, diclofenac, dicycloplatin, didanol, norgestrel, difluprednate, digoxin, linolenic acid, dihydroergotamine, diltiazem, dimethoate, dimethyl fumarate, dileracetam, dinoprostone, diphenylcyclopropene, dipyridamole, tobramycin, desufenton, disulfiram, anthracene, methadone Ketone, docarbamine, docetaxel, glycolic acid, dofetilide, dolasetron, dolutegravir, domperidone, sorafenib, donepezil, dopamine, doripenem, dorzolamide, dositaxel, docuronium chloride, doxazosin, doxepin hydrochloride, doxepin hydrochloride, doxefiridine, doxofylridine, doxofylline, adriamycin, doxycycline, doxylamine succinate, dronabinol, dronedarone, dronabinol Spironone, droxidopa, D-tagatose, duloxetine, dutasteride, ebastine, eberconazole, ebselen, ecabet, isoconazole, edaravone, edoxaban, efavirenz, efinaconazole, ilonicer, efonidpine, ethguanam, icosapent glyceride, elagolix, eldecalciferol, ilisimol, eletriptan, eltrombopag, efavirenz Tegvir, emedastine, empagliflozin, enlicasin, emtricitabine, enalapril, enclomiphene, tamoxifen, enoxacin, enprostil, entacapone, entecavir, entinostat, enzalutamide, epalrestat, eperisone, ephedrine, epirubicin, epirubicin, epitinib, eplerenone, epoprostenol, aprepitant, iloxifen Dexamethasone, eprosartan, eprosartan, epsartan, erdosteine, eribulin, erlotinib, ertapenem, erythromycin, escitalopram, esketamine, ketamine, eslicarbazepine, esmolol, esomeprazole, estratetraol, estradiol, aspirin, eszopiclone, ethambutol, ethaselen, ethinyl estradiol, ethyl fumarate, ethinyl estradiol, etidronic acid, etimicin, etizolam, etodolac, etonogestrel, etoposide, etoricoxib, etravirine, isoelastin, everolimus, exemestane, ezetimibe, fadrozole, fluocinolone, famciclovir, famotidine, fampridine, faropenem, fasoracetam, fasudil, favipiravir, febabamate, febuxostat, tromethamine, felodipine, fenfluramine, fenofibrate, fenold Pan, fenoterol, fenretinide, fentanyl, fenticonazole, ferric citrate, maltol iron, fesorotrol, fexinidazole, fexofenadine, fidaxomicin, fimasartan, finaflon, finasteride, fingolimod, flecainide, fleroxacin, flibanserin, fluoxetine, floxuridine, fluconazole, fludarabine, flumazenil, flunisolide, fluocinolone acetonide, fluorouracil, fluoxetine,Flupirtine, flurbiprofen, fluerythromycin, fluticasone, flutrimazole, fluvastatin, fluvoxamine, folic acid, folinic acid, fomepizole, formestane, formoterol, forodesine, fusampretan, fosaprepitant, fluconazole, fosfomycin, fosinopril, fosamicin, fosphenytoin, fospropofol, fotemustine, frovatriptan, fruquintinib, fudosteine, fulvestrant, furosemide , fusidic acid, gabapentin, gabapentin enacarbil, gabexate, gadobutrol, gadoversetamide, galantamine, gallium nitrate, gambogic acid, ganaxolone, ganirelix, garexolactone, gatifloxacin, gefitinib, gemcitabine, gemfibrozil, gemifloxacin, gentamicin, gentiopicroside, gepirone, gestodene, gestrinone, timolol, glatiramer, glibenclamide, Gliclazide, glimepiride, glipizide, glufosfamide, glutamine, glycerylbenzene, glycopyrrolate, glycopyrrolate, glycyrrhizic acid, glolomod, gogliptin, granisetron, guaifenesin, guaimesal, guanfacine, gusperimox, halobetasol, halofantrine, halometasone, hyaluronic acid, hydrochlorothiazide, hydrocodone, hydrocortisone, hydromorphone, hydroxocobalamin, hydroxyurea, hydroxychloroquine, hydroxyprogesterone caproate, hypericin, apodutan, ibrutinib, ibudilast, ibuprofen, ibutilide, epimedium, elapridine, eicosapentaenoic acid, ethyl eicosapentaenoic acid, icotinib, idebenone, idoxuridine, ifetroban, iguratimod, ilaprazole, iloperidone, iloprost, imatinib, imidapril, imipenem, imiquimod , ericoxib, incadronic acid, indacaterol, indapamide, indolozine, indinavir, indesitron, indomethacin, indolaamine, enacalciferol, ipratropium, ipratropium bromide, ipratropium bromide, irbesartan, irinotecan, irinotecan sulfosaccharide, ilofofen, esoflavone, isoflurane, isoniazid, unoprostone isopropyl ester, isosorbide, isosweet Chrysanthemum, isotretinoin, isradipine, istradefylline, itopride, itraconazole, ivabradine, ixabepilone, ketamine, ketoconazole, ketoprofen, ketorolac, ketotifen, scopolamine B, lacidipine, lacosamide, lactitol, laflunomide, lafutidine, lamivudine, lamotrigine, landiolol, nanamivir, lanoconazole, lansoprazole, lanthanum carbonate, lapatinib, laquinimod, lasofoxifene, latanoprost, ledipasvir, leflunomide, lenalidomide, lentinan, lercanidipine, letrozole, leucine, leuprorelin, levalbuterol, levamisole, levamlodipine, levetiracetam, levobupivacaine, levocabastine, levocarnitine, levocetirizine, levodopa, levofloxacin, levo 18-Methylnorgestrel, levonorgestrel, 18-methylnorgestrel butyrate, 18-methylnorgestrel hydrochloride ...Lorazepam, lornoxicam, losartan, losartan potassium, loteprednol, lovastatin, loxoprofen, levapraziquantel, clometamicin, mafenide, magnesium isoglycyrrhizinate, mangafodipir, manidipine, mannitol, maraviroc, maribavir, masitinib, mebendazole, nitrogen mustard, methylcobalamin, megestrol acetate, meloxicam, memantine, menatetrenol, mepacrine, adipexole, paramethoxazole, thiothiazide, mercaptopurine, meropenem, mesalamine, metacavir, metadoxine, analgin, metaxalone, ergobenyl ester, metformin, methadone, methazolamide, methotrexate, methoxyflurane, methylvaleric acid, methylnaltrexone, methylphenidate, 6-methylprednisolone, methylprednisolone acetonide, methylene blue, methyltyrosine, metoclopramide, metoprolol, Metronidazole, metyrapone, mibefradil, miconazole, midazolam, midodrine, midostaurin, mifepristone, miglitol, milnacipran, milrinone, miltefosine, milnacipran, minocycline, minodronic acid, minoxidil, mirabegron, mironafil, mirtazapine, misoprostol, mitiglinide, mitoxantrone, mivotifen, mizolastine, mizoribine, moclobemide , modafinil, doxycycline, modipadil, moexipril, mofenzolac, morpholinone, mometasone furoate, glycyrrhizic acid, monobenzone, luminol, monoterpene perillyl alcohol, montelukast, moricizine, tigecycline, morpholinidazole, morphine, morphine glucuronide, mosapride, moxidectin, moxifloxacin, moxonidine, mozavaptan, mupirocin, mycophenolate mofetil, myristyl nicotinate, nabumetone, N-acetylcysteine, nadifloxacin, nadolol, naftifine, natopidil, nalbuphine, nalfurapine, nalmefene, naloxone ether, naloxone, naltrexone, nandrolone decanoate, naphazoline, naphthoquine, naproxen, naratriptan, nalaxapase, nateglinide, nebivolol, nedaplatin, nedocromil, nelarabine, nelfinavir, nemopril , nemofloxacin, neostigmine, nepatant, nepafenac, nepicastat, neratinib, neridronic acid, netilmicin, netupitant, nevirapine, niacin, nicotinic acid, nicardipine, nicergoline, nicorandil, nicotinoid, nicotine, nitrosamide, nifedipine, nifekalant, nifaviroc, nifurtimox, nifurox, nikkomycin, nilotinib, nilutamide, nilvadipine , nimesulide, nimodipine, morpholinidazole, nisoldipine, nitazoxanide, nitisinone, nitrendipine, nitroglycerin, nizatidine, nolatrexate, nomegestrol, norepinephrine, norethindrone, norfloxacin, norgestimate, obeticholic acid, octenidine, succinylcholine, ofloxacin, olanzapine, olaparib, olesoxime, olmesartan, indacate Luo, Olodaterol, Olopatadine, Olprinone, Olsalazine, Oltipraz, Ogliptine, Omeprazole, Omoconazole, Onapristone, Ondansetron, Opipa, Methylphenidate, Oxanolide, Oritavancin, Orlistat, Ornithine Phenylacetic Acid, Ornoprostil, Oseltamivir, Ospemifene, Oxaliplatin, Oxaliplatin, Oxaloacetic Acid, Oxazepam, Oxcarbazepine,Oxfendazole, oxiracetam, oxybutynin, oxycodone, oxymetazoline, oxymorphone, oxytocin, ozagrel, ozegrel, azepam, paclitaxel, paliperidone, pamidol, palonosetron, parovatine, panipenem, panobinostat, pantoprazole, acetaminophen, parecoxib, paricalcitol, paritaprevir, parogliptin, paromomycin, paroxetine, and patupirone , pazopanib, pazufloxacin, pebiprofen, pemetrexed, pemirolast, pemirolast potassium, pemirolast, penciclovir, longtonine, pentamidine, pentetic acid, pentostatin, pentoxifylline, peramivir, perampanel, thiophenylthiocarbamide, perfluoropentane, perfluorooctylammonium bromide, pergolide, perifosine, perindopril, perospirone, phenclorone, phenoxybenzamine hydrochloride, phenoxybenzamine hydrochloride Termin, topiramate, phentermine, phentolamine, phenytoin, sapelloin, pidotimod, pilsicainide, pimazolin, pimecrolimus, pimobendan, pioglitazone, piperidone, pipecuronium, piperacillin, piperaquine, piracetam, pirarubicin, pirfenidone, pirmenol, pirotinib, piroxicam, pitavastatin, pixantron, pleconil, plerixafor, pudafilox, pomalidomide, ponatinib, porfimer, posaconazole, clavulanic acid, paradefovir, pudefovir, aminopterin, pramipexole, pramiracetam, prusatrone, prasterone, prasugrel, pravastatin, prazosin, phenylephrine, prednisolone, prednisolone, prednisone, pregabalin, benzimidazole, prilocaine, procaterol, prochlorperazine, the progestogen dinosulfiram Progestins, proguanil, promethazine, propafenone, propagermanium, propofol, propranolol, proxolol, pruca, prulifloxacin, Prussian blue, pseudoephedrine, puerarin, praquintinib, pyrazinamide, pyridoxamine, pyridoxine, pyrimethamine, bisquinazide, pyronaridine, quazepam, quetiapine, quinapril, quinidine, quinine, quinazolidinone, rabeprazole, cardotriol, radotitol Amine, raloxifene, raloxifene, naloxifene, raltegravir, raltitrexed, ramatroban, ramelton, ramipril, ramosetron, ranitidine, ranolazine, rasagiline, rebamipide, reboxetine, ibuprofen, naproxen, glycopyrrolate, diclofenac, mebendazole, progesterone, zoledronic acid, regorafenib, remifentanil, repaglinide, repirinast, amiloride Xanox, chlorcycline, bucillamine, guanabenz, clomiphene, mazindol, naltrexone, nitisinone, retigabine, rosiglitazone, resiquimod, repagliptin, retapaline, retapamulin, retigabine, tretinoin, revaprazan, rhein, ribavirin, rifabutin, rifampicin, rifamycin, rifapentine, rifaximin, rilapladib, rilpivirine, rilpivirine hydrochloride, riluzole, rimexolone, risquat, riociguat, risedronate, risperidone, ritonavir, rivaroxaban, rivastigmine, rizatriptan, roflumilast, rotamycin, rolapitant, ropinirole, ropivacaine, rosiglitazone, rosuvastatin, rotigotine, roxithromycin, rubitecan, rufinamide, rufloxacin, rupatadine, ruxolitinib,Levotronidazole, sacubitril, safinamide, salbutamol, salicylic acid, salmeterol, salvicin, 3-carboxamide-4-hydroxycyclopentyl methylphenidate, amlodipine, sapropterin, saquinavir, sacatinib, sargrelate, saxagliptin, scopolamine, secnidazole, selegiline, selumetinib, seroquel, cilardastat, celiprolol, sertaconazole, ser Nitrate, sertraline, sesquiterpenes, sevelamer, sevoflurane, sibutramine, sildenafil, silodosin, simiprevir, cimotinib, simvastatin, cinotecan, siponimod, sirolimus, sitafloxacin, sitagliptin, sivelaxate, sizolan, sizofil, modafinil, sobuzosine, aescin, benzoic acid, cromoglycine, glycidazole, guarene Acid, hyaluronic acid, ibandronic acid, hydroxybutyric acid, phenylacetic acid, phenylbutyric acid, pyruvic acid, sofosbuvir, solifenacin, sorafenib, sorbitol, sparfloxacin, spirapril, stavudine, stironin, stiripentol, strontium ranelate, sultalan zinc, sugammadex, sulbactam, suxindrine, methoxypyrazine, sulfasalazine, surufatinib, sumatriptan, sunitinib, sulfasalazine Tadalafil, suramin sodium, verapamil, rilpivirine, tacalcitol, tacrine, tacrolimus, tadalafil, clofentac, tafenoquine, talaporfin, talipexol, tatirellin, tamibarotene, tamoxifen, tamsulosin, tapentadol, talinacin, tasimelteon, taquinimod, tazarotene, tazobactam, tipopenem moxibustion, tecovir, tedisa Rice, tedizolid, fluazifop, tegaserod, teicoplanin, telaprevir, telaprevir, telaprevir, telbivudine, telmisartan, temocapril, temoporphin, temoporfin, temozolomide, sirolimus, teneligliptin, tenofovir, tenoxicam, teprenone, terazosin, terbinafine, terguride, teriflunomide, tesofensine, tetracycline, tetrathiomolybdate, tetracycline Hydrozoline, tetrahydronaphthazoline, thalidomide, thiophenenorphine, thiotepa, ticagrelor, ticlopidine, tigecycline, tiludronic acid, timolol, timolol maleate, tinidazole, metronidazole, tioconazole, tiopronin, tiotropium bromide, tipedin, tipepidine, tipifarnib, tipranavir, tirapazamine, tirazad, tirofiban, oxcarbazepine, tirofiban, tirofiban Zanidine, tobramycin, tocosolan, tofacitinib, togliflozin, tolcapone, tolimide, tolperisone, tolterodine, tolvaptan, tonabersat, topiramate, topinostat, topotecan, torasemide, toremifene, torsedot, tosufloxacin, trabectedin, tramadol, trametinib, trandolapril, tranexamic acid, tranilast, tantolol, trazodone, tra Gliptin, Susulfan, Retinoic acid, Triamcinolone acetonide, Triazolam, Trichlorothiazide, Triciribine, Triclabendazole, Triclocarban, Trientine, Trilostane, Trimebutine, Trimegestone, Trimethoprim, Tropisetron, Trospium chloride, Trovafloxacin, Troxipidate, Tubuterol, Tylerdipine, Ubenimex, Ubidecarenone, Udenafil, Ulinafil, Ulipristal,Ubetasol, urapidil, valacyclovir, valdecoxib, valganciclovir, valrubicin, valsartan, vandetanib, vanoxetine, vardenafil, varenicline, vestregl, vemurafenib, venlafaxine, verapamil, phenazine, vernakalant, verteporfin, vesirinone, vesnalidone, vesnarinone, vicagrelor, vigabatrin, vilanterol, vilazodone, vildagliptin, voriconazole, vorinostat, vortioxetine, One or more of zemilofiban, milofiban, imipenem, ukenafil, zafirlukast, zalcitabine, zaleplon, zaltoprofen, zanamivir, zidovudine, ziprasidone, levofenpril, zoledronic acid, zolmitriptan, zolpidem, zonisamide, zopiclone, zotepine, zukasethin, zuclopenthixol, tofaptan, ramelteonide, or pharmaceutically acceptable salts, esters, prodrugs, hydrates, deuterated compounds, or stereoisomers thereof.

[0154] In some embodiments, the polypeptide is selected from one or more of insulin, antidiuretic hormone, calcitonin, calcitonin gene-related peptide, parathyroid hormone, luteinizing hormone, erythropoietin, tissue plasminogen activator, growth hormone, adrenocorticotropic hormone, interleukin, enkephalin, epinephrine, GLP-1 receptor agonist, semaglutide, liraglutide, dulaglutide, exenatide, octreotide, teriparatide, vancomycin, linaclotide, plecanatide, cyclosporine, talatorelin, acetaminopressin, maximorelin, and glucagon-like peptide-2 (GLP-2) analogs (e.g., teduglutide).

[0155] In some embodiments, the protein is selected from proteins related to medicine, agriculture, scientific research and other industrial fields. In some embodiments, the protein is selected from one or more of blood factors, colony stimulating factors, interleukins, growth factors, tumor necrosis factors (TNF) and enzymes. In some embodiments, the protein is selected from asparaginase, glutaminase, arginase, arginine deaminase, adenosine deaminase ribonuclease, cytosine deaminase, trypsin, chymotrypsin, papain, epidermal growth factor (EGF), insulin-like growth factor (IGF), transforming growth factor (TGF), nerve growth factor (NGF), platelet-derived growth factor (PDGF), bone morphogenetic protein (BMP), fibroblast growth factor, somatostatin, somatostatin, colony stimulating factor (CSF), coagulation factors, tumor necrosis factor, interferon, gastrointestinal peptide, vasoactive intestinal peptide (VIP) , cholecystokinin (CCK), gastrin, secretin, hormone, pancreatic enzyme, superoxide dismutase, thyrotropin-releasing hormone (TRH), thyroid-stimulating hormone, luteinizing hormone, luteinizing hormone-releasing hormone (LHRH), tissue-type plasminogen activator, receptor antagonist (IL-1RA), leptin, growth hormone, granulocyte-monocyte colony-stimulating factor (GM-CSF), adenosine deaminase, uricase, asparaginase, asparaginase, chorionic gonadotropin, heparin, atrial natriuretic peptide, hemoglobin, retroviral vector, relaxin, cyclosporine, oxytocin, ankyrin repeat protein, affinity body one or more.

[0156] In some embodiments, nucleic acid refers to an oligomer or polymer comprising at least two linked nucleotides or nucleotide derivatives, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) linked together by a phosphodiester bond or other phosphate ester. In some embodiments, nucleic acid includes DNA molecules and RNA molecules. In some embodiments, nucleic acid can be single-stranded or double-stranded, and can be cDNA.

[0157] In some embodiments, the antibody is selected from Abagovomab, Abciximab, Actoxumab, Adalimumab, Adecatumumab, Aducanumab, Afelimomab, Afutuzumab, Alacizumab, pegol), ALD518, Alemtuzumab, Alirocumab, Altumomab pentetate, Amatuximab, Anatumomab mafenatox, Anifrolumab, Anrukinzumab, Apolizumab, Arcitumomab, Aselizumab, Atinumab, Atlizumab, Atorolimumab, Bapineuzumab, Basiliximab, Bavituximab, Bectumomab, Belimumab, Benralizumab, Bertilimumab, Besilesomab, Bevacizumab, Bezlotoxumab, Biciromab, Bimagrumab, Bivatuzumab mertansine), Blinatumomab, Blosozumab, Brentuximab vedotin, Briakinumab, Brodalumab, Canakinumab, Cantuzumab mertansine, Cantuzumabravtansine, Caplacizumab, Capromab pendetide, Carlumab, Catumaxomab,cBR96-doxorubicin immunoconjugate, Cedelizumab, Certolizumab begol, Cetuximab, Citatuzumabbogatox, Cixutumumab, Clazakizumab, Clenoliximab, Clivatuzumab tetraxetan, Conatumumab, Concizumab, Crenezumab, Dacetuzumab, Daclizumab, Dalotuzumab, Daratumumab mab), Demcizumab, Denosumab, Detumomab, Dorlimomabaritox, Drozitumab, Duligotumab, Dupilumab, Dusigitumab, Ecromeximab, Eculizumab, Edobacomab, Edrecolomab, Efalizumab, Efungumab, Eldelumab, Elotuzumab, Elsilimomab, Enavatuzumab, Enlimomab pegol), Enokizumab, Enoticumab, Ensituximab, Epitumomabcituxetan, Epratuzumab, Erlizumab, Erlizumab, Etaracizumab, Etrolizumab, Evolocumab, Exbivirumab, Fanolesomab, Faralimomab, Farletuzumab, Fasinumab,FBTA05, Felvizumab, Fezakinumab, Ficlatuzumab, Figitumumab, Flanvotumab, Fontolizumab, Foralumab, Foravirumab, Fresolimumab, Fulranumab, Futuximab, Galiximab, Ganitumab, Gantenerumab, Gavilimomab, Gemtuzumabozogamicin, Gemtuzumab, Gevokizumab, Girentuximab, Glembatumumab vedotin, Golimumab, Gomiliximab, Guselkumab, Ibalizumab, Ibritumomab tiuxetan), Icrucumab, Igovomab, IMAB362, Imciromab, Imgatuzumab, Inclacumab, Indatuximabravtansine, Infliximab, Inolimomab, Inotuzumab ozogamicin ozogamicin), Intetumumab, Ipilimumab, Iratumumab, Itolizumab, Ixekizumab, Keliximab, Labetuzumab, Lambrolizumab, Lampalizumab, Lebrikizumab, Lemalesomab, Lerdelimumab, Lexatumumab, Libivirumab, Ligelizumab, Lintuzumab,Lirilumab, Lodelcizumab, Lorvotuzumabmertansine, Lucatumumab, Lumiliximab, Mapatumumab, Margetuximab, Maslimomab, Matuzumab, Mavrilimumab, Mepolizumab, Metelimumab, Milatuzumab zumab), Minretumomab, Mitumomab, Mogamulizumab, Morolimumab, Motavizumab, motavizumab, Moxetumomabpasudotox, Muromonab-CD3, Nacolomabtafenatox, Namilumab, Naptumomabestafenatox, Naretumomab Narnatumab, Natalizumab, Nebacumab, Necitumumab, Nerelimomab, Nesvacumab, Nimotuzumab, Nivolumab, Nofetumomabmerpentan, Ocaratuzumab, Ocrelizumab, Odulimomab, Ofatumumab, Ola Olaratumab, Olokizumab, Omalizumab, Onartuzumab, Ontuxizumab, Oportuzumabmonatox, Oregovomab, Orticumab, Otelixizumab, Otlertuzumab, Oxelumab, Ozanezumab, Ozoralizumab,Pagibaximab, Palivizumab, Panitumumab, Pankomab, Panobacumab, Parsatuzumab, Pascolizumab, Patelizumab, Patritumab, pembrolizumab, Pemtumomab, Perakizumab, Pertuzumab, Pexelizumab, Pidilizumab, Pinatuzumab vedotin, Pintumomab, Placulumab, Polatuzumab vedotin, Ponezumab, Priliximab, Pritoxaximab, Pritumumab, PRO140, Quilizumab, Racotumomab, Radretumab, Rafivirumab, Ramucirumab, Ranibizumab, Raxibacumab, Regavirumab, Reslizumab, Rilotumumab, Rituximab, Robatumumab, Roledumab, Romosozumab, Rontalizumab, Rovezumab (Rovelizumab), Ruplizumab, Samalizumab, Sarilumab, Satumomabpendetide, Secukinumab, Seribantumab, Setoxaximab, Sevirumab, SGN-CD19A, SGN-CD33A, Sibrotuzumab, Sifalimumab, Siltuximab,Simtuzumab, Siplizumab, Sirukumab, Solanezumab, Solitomab, Sonepcizumab, Sontuzumab, Stamulumab, Sulesomab, Suvizumab, Tabalumab, Tacatuzumab tetraxetan, Tadocizumab, Talizumab Talizumab, Tanezumab, Taplitumomab, Patox, Tefibazumab, Telimomabaritox, Tenatumomab, Teneliximab, Teplizumab, Teprotumumab, TGN1412, Ticilimumab, tremelimumab, Tigatuzumab, TNX-650, Atlizumab, Toralizumab, Tositumomab, Tovetumab, Tralokinumab, Trastuzumab, TRBS07, Tregalizumab, Tremelimumab, Tucotuzumabcelmoleukin, Tuvirumab, Ublituximab, Urelumab, Urelumab toxazumab), Ustekinumab, Vantictumab, Vapaliximab, Vatelizumab, Vedolizumab, Veltuzumab, Vepalimomab, Vesencumab, Visilizumab, Volociximab, Vorsetuzumab mafodotin, Votumumab,One or more of Zalutumumab, Zanolimumab, Zatuximab, Ziralimumab, Zolimomab aritox or fragments thereof.

[0158] In some embodiments, the microorganism is selected from one or more of bacteria, viruses, fungi, actinomycetes, rickettsia, mycoplasma, chlamydia, or spirochetes. In some embodiments, the microorganism is selected from probiotics. In some embodiments, the probiotic is selected from one or more of yeast, probiotic spore-forming bacteria, Clostridium butyricum, lactobacillus, bifidobacterium, or actinomycetes.

[0159] ii. Drug components

[0160] The oral dosage forms disclosed herein include a drug component comprising drug particles. In some embodiments, the drug component comprises drug particles and an erodible material. In some embodiments, the drug component comprises a plurality of drug particles uniformly distributed within a second erodible material. The drug component can be formed using a variety of materials having different shapes and sizes.

[0161] In some embodiments, the soluble material mixed with the drug particles has excellent rheological properties, can increase the fluidity of the components in the drug assembly, facilitate extrusion molding, and effectively reduce the printing temperature of the drug assembly.

[0162] In some embodiments, the drug component is a layer.

[0163] In some embodiments, the drug assembly comprises a first drug assembly and a second drug assembly. In some embodiments, the erodible material in the first drug assembly is the same as the erodible material in the second drug assembly. In some embodiments, the erodible material in the first drug assembly is different from the erodible material in the second drug assembly.

[0164] In some embodiments, the drug component has a top surface and a bottom surface, wherein the top surface and the bottom surface are simultaneously exposed to body fluids. In some embodiments, the drug component is a layer having a top surface and a bottom surface. In some embodiments, the top surface of the drug component, or at least a portion thereof, is flat or within a surface tolerance threshold (as measured between two parallel planes).

[0165] In some embodiments, the top or bottom surface of the drug component can have any shape. In some embodiments, the top or bottom surface of the drug component has a capsule shape, a circle, an oval, a bullet shape, an arrow shape, a triangle, a curved triangle, a square, a curved square, a rectangle, a curved rectangle, a diamond shape, a pentagon, a hexagon, an octagon, a half moon shape, an almond shape, or a combination thereof.

[0166] In some embodiments, the top or bottom surface of the drug component (e.g., drug component layer) has a thickness of about 10 mm. 2 to about 400mm 2 , such as about 20 mm 2 to about 200mm 2 , about 20mm 2 to about 100mm 2 , about 20mm 2 to about 60mm 2 or about 30mm 2 to about 50mm 2 In some embodiments, the top or bottom surface of the drug component has a surface area of ​​at least about 20 mm 2 , such as 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 In some embodiments, the top or bottom surface of the drug component has a surface area of ​​less than about 400 mm 2 , such as less than about 400 mm 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 , 28mm2 , 26mm 2 , 24mm 2 , 22mm 2 or 20mm 2 In some embodiments, the top or bottom surface of the drug component has a surface area of ​​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 , 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 The surface area of ​​any one of .

[0167] In some embodiments, the surface area of ​​the top or bottom surface of the drug component exposed to bodily fluid is consistent throughout the thickness of the drug component. For example, as the drug component erodes, the surface exposed to bodily fluid has the same surface area. In some embodiments, the surface area of ​​the top or bottom surface of the drug component exposed to bodily fluid varies at two or more points. For example, as the drug component erodes, the surface exposed to bodily fluid changes, such as increasing and / or decreasing in surface area during erosion. In some embodiments, the shape of the surface exposed to bodily fluid of the drug component is consistent throughout the thickness of the drug component. For example, as the drug component erodes, the surface exposed to bodily fluid has the same shape. In some embodiments, the shape of the surface exposed to bodily fluid of the drug component varies at two or more points. In some embodiments, the bottom surface of the drug component has the same surface area as the top surface of the drug component. In some embodiments, the bottom surface of the drug component has a different surface area than the top surface of the drug component. In some embodiments, the erodible material of the drug component can prevent premature moisture penetration into the drug particles while eroding, thereby avoiding drug crystallization.

[0168] In some embodiments, the top or bottom surface of the drug component (e.g., a drug component layer) has a maximum span dimension of about 5 mm to about 20 mm, such as any one of 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 top or bottom surface of the drug component has a maximum span dimension of at least about 5 mm, such as any one of 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 top or bottom surface of the drug component has a maximum span dimension of less than about 20 mm, such as any one of 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 top or bottom surface of the drug component has a maximum span dimension of about any of 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.

[0169] In some embodiments, the top or bottom surface of the drug component (e.g., drug component layer) has a span dimension perpendicular to the maximum span dimension of about 1 mm to about 15 mm, such as any one of about 2 mm to about 15 mm, about 2 mm to about 6 mm, or about 1 mm to about 5 mm. In some embodiments, the top or bottom surface of the drug component has a span dimension perpendicular to the maximum span dimension of at least about 1 mm, such as any one of 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 top or bottom surface of the drug component has a span dimension perpendicular to the maximum span dimension of less than about 15 mm, such as any one of 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 top or bottom surface of the drug component has a span dimension perpendicular to the maximum span dimension of about any of 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.

[0170] In some embodiments, the top or bottom surface of the drug component (e.g., drug component layer) has a diameter of about 1 mm to about 10 mm, such as about 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm.

[0171] In some embodiments, the drug component (e.g., drug component layer) has a thickness of about 0.1 mm to about 5 mm, such as any one of 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 has a thickness of at least about 0.1 mm, such as at least about any one of 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 has a thickness of less than about 5 mm, such as less than about any of 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 has a thickness of about any of 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.

[0172] In some embodiments, the drug component (eg, drug component layer) comprises a top surface and a bottom surface, wherein the thickness measured between the top surface and the bottom surface is substantially uniform, eg, within 20% of an average thickness.

[0173] In some embodiments, the top and bottom surfaces of the medication assembly have the same surface area. In some embodiments, the maximum span dimensions of the top and bottom surfaces of the medication assembly are the same. In some embodiments, the span dimensions perpendicular to the maximum span dimensions of the top and bottom surfaces of the medication assembly are the same. In some embodiments, the diameters of the top and bottom surfaces of the medication assembly are the same. In some embodiments, the top and bottom surfaces of the medication assembly have the same shape.

[0174] In some embodiments, the drug component (eg, drug component layer) includes a side surface.

[0175] In some embodiments, the drug assembly comprises drug particles and an erodible material. In some embodiments, the drug particles are exposed to gastrointestinal fluids based on the erosion of the drug assembly. In some embodiments, the drug particles are exposed to gastrointestinal fluids based on the erosion of the erodible material mixed with the drug particles. In some embodiments, once in contact with the body fluids in a human subject, the drug assembly will be completely eroded within a time period of about 3 hours to about 12 hours, such as about 4 hours to about 8 hours or about 6 hours to about 10 hours. In some embodiments, once in contact with the body fluids in a human subject, the drug assembly will be completely eroded within a time period of at least about 3 hours, such as at least about 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours. In some embodiments, once in contact with the body fluids in a human subject, the drug assembly will be completely eroded within a time period of less than about 12 hours, such as less than about 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, or 3 hours. In some embodiments, upon contact with bodily fluids in a human subject, the drug component is completely eroded within a time period of about any of 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours.

[0176] In some embodiments, the drug component comprises a thermoplastic material, such as a thermoplastic polymer. In some embodiments, the drug component comprises a material comprising any one or more of an erodible thermoplastic material (such as a slow-release erodible material or an immediate-release erodible material), a plasticizer, and other additives (e.g., fillers, binders, lubricants, glidants, effervescent agents, and disintegrants).

[0177] In some embodiments, the erodible thermoplastic material comprises polyvinyl pyrrolidone-co-vinyl acetate (PVP / VA), polyvinyl pyrrolidone, polyethylene oxide (PEO), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, aminoalkyl methacrylate copolymer E, hydroxypropyl methylcellulose acetate succinate or hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), copovidone, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC ), methylcellulose (MC), methacrylic acid copolymer, poly(dimethylaminoethyl methacrylate-co-methacrylate), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammoniumethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly(methacrylic acid-co-methyl methacrylate), poly(methacrylic acid-co-ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), polyethylene glycol-polyvinyl alcohol graft copolymer, methacrylate copolymer and ammonium alkyl methacrylate copolymer.

[0178] In some embodiments, the sustained-release erodible material comprises copovidone, polyvinyl pyrrolidone-co-vinyl acetate (PVP / VA), polyvinyl pyrrolidone, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), methylcellulose (MC), methacrylic acid copolymer, poly(dimethylaminoethyl methacrylate-co-methacrylate), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammoniumethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly(methacrylic acid-co-methyl methacrylate), poly(methacrylic acid-co-ethyl methacrylate), poly(methacrylic acid-co-methyl methacrylate), polyethylene oxide (PEO), polyethylene glycol (PEG), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, Kollicoat Any one or more of IR-polyvinyl alcohol, polyvinyl alcohol (PVA), aminoalkyl methacrylate copolymer E, hydroxypropyl methylcellulose acetate succinate (HPMCAS), methacrylate copolymer, glycerin and ammonium alkyl methacrylate copolymer.

[0179] In some embodiments, the immediate release erodible thermoplastic material comprises copovidone, polyvinyl pyrrolidone-co-vinyl acetate (PVP / VA), polyvinyl pyrrolidone, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), methylcellulose (MC), methacrylic acid copolymer, poly (butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), poly (dimethylaminoethyl methacrylate-co-methacrylate) ), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammoniumethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly(methacrylic acid-co-methyl methacrylate), poly(methacrylic acid-co-ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), polyethylene oxide (PEO), polyethylene glycol (PEG), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, Kollicoat IR-polyvinyl alcohol, polyvinyl alcohol (PVA), aminoalkyl methacrylate copolymer E, hydroxypropyl methylcellulose acetate succinate or hydroxypropyl methylcellulose acetate succinate (HPMCAS), methacrylate copolymers, ammonium alkyl methacrylate copolymers, ethyl cellulose (EC), polyvinyl acetate (PVAc), polyvinyl acetal diethyl amino lactate, and polyvinyl acetal diethyl amino acetate (AEA).

[0180] In some embodiments, the plasticizer includes any one or more of triethyl citrate (TEC), vitamin E polyethylene glycol succinate (TPGS), triacetin, acetylated triethyl citrate, tributyl citrate, o-acetyl tributyl citrate, polyethylene glycol 15-hydroxystearate, PEG-40-hydrogenated castor oil, polyethylene glycol 35-castor oil, dibutyl sebacate, diethyl phthalate, glycerol, methyl 4-hydroxybenzoate, castor oil, oleic acid, triacetin, and polyalkylene glycol.

[0181] In some embodiments, other additives include gum arabic, alginate, alginic acid, aluminum acetate, butyl paraben, butylated hydroxytoluene, citric acid, calcium carbonate, croscarmellose sodium, powdered sugar, colloidal silicon dioxide, cellulose, ordinary or anhydrous calcium phosphate, carnauba wax, corn starch, carboxymethyl cellulose calcium, calcium disodium edetate, calcium hydrogen phosphate dehydrate, cetylpyridinium chloride, calcium hydrogen phosphate, tribasic calcium phosphate, dibasic calcium phosphate, disodium hydrogen phosphate, polydimethylsiloxane, sodium tetraiodofluorescein, ethylenediaminetetraacetic acid (EDTA), gelatin, glycerol monooleate, ferric oxide, ferric oxide, oxygen Any one or more of iron oxide yellow, iron oxide red, lactose, microcrystalline cellulose, magnesium carbonate, magnesium oxide, methylparaben, polysorbate, propyleneparaben, potassium bicarbonate, potassium sorbate, potato starch, phosphoric acid, polyoxyethylene stearate, sodium starch glycolate, pregelatinized starch, croscarmellose sodium, sodium lauryl sulfate, starch, silicon dioxide, sodium benzoate, sucrose, sorbic acid, sodium carbonate, saccharin sodium, sodium alginate, silica gel, sorbitan oleate, sodium chloride, sodium metabisulfite, sodium citrate dehydrate, sodium starch, sodium carboxymethylcellulose, succinic acid, sodium propionate, titanium dioxide and talc.

[0182] iii. Delay component

[0183] The oral dosage forms described herein include a delay component configured to prevent and / or inhibit the release of a drug from the oral dosage form within a desired amount of time after administration of the oral dosage form to a human subject.

[0184] In some embodiments, the delay component does not contain a drug.

[0185] In some embodiments, the delay assembly surrounds the drug assembly. In some embodiments, the delay assembly completely surrounds the drug assembly. In some embodiments, the delay assembly partially surrounds the drug assembly. In some embodiments, the delay assembly surrounds the first drug assembly and the second drug assembly. In some embodiments, the delay assembly surrounds either the first drug assembly or the second drug assembly.

[0186] In some embodiments, the delay component forms a compartment that surrounds the first drug component and / or the second drug component.

[0187] In some embodiments, the delay component forms a first compartment and a second compartment, the first compartment and the second compartment surrounding the first drug component and the second drug component, respectively.

[0188] In some embodiments, the first compartment and the second compartment are in communication.

[0189] In some embodiments, the first compartment and the second compartment are not in communication.

[0190] In some embodiments, the delay assembly comprises an erodible material. In some embodiments, the erodible material of the delay assembly is different from the erodible material of the drug assembly. In some embodiments, the erodible material of the delay assembly is the same as the erodible material of the drug assembly. In some embodiments, the delay assembly comprises a third erodible material that is not mixed with the drug. In some embodiments, the erodible material of the delay assembly, while being eroded, can prevent moisture from prematurely penetrating the drug assembly, thereby avoiding drug crystallization.

[0191] In some embodiments, the delay assembly is configured to have a surface, such as a surface exposed to body fluids during administration of an oral pharmaceutical dosage form to a human subject, having a predetermined shape and surface area. For example, in some embodiments, the delay assembly has a top surface and a bottom surface. In some embodiments, the top surface or the bottom surface of the delay assembly, or at least a portion thereof, is flat or within a surface tolerance threshold (as measured between two parallel planes).

[0192] In some embodiments, the top surface and / or bottom surface of the delay assembly is uneven. In some embodiments, the top surface and / or bottom surface of the delay assembly is printed with a logo (such as a text logo, a graphic logo).

[0193] In some embodiments, the top or bottom surface of the delay assembly can have any shape. In some embodiments, the top or bottom surface of the delay assembly has a shape of a capsule, circle, oval, bullet, arrowhead, triangle, curved triangle, square, curved square, rectangle, curved rectangle, diamond, pentagon, hexagon, octagon, half moon, almond, or a combination thereof.

[0194] In some embodiments, the top or bottom surface of the delay assembly has a thickness of about 10 mm. 2 to about 400mm 2 , such as about 20 mm 2 to about 200mm 2 , about 20mm 2 to about 100mm 2 , about 20mm 2 to about 60mm 2 or about 30mm 2 to about 50mm 2 In some embodiments, the top or bottom surface of the delay assembly has a surface area of ​​at least about 20 mm. 2 , such as 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 In some embodiments, the top or bottom surface of the delay assembly has a surface area of ​​less than about 400 mm 2 , such as less than about 400 mm 2 , 375mm 2 , 350mm 2 , 325mm 2 , 300mm 2 , 275mm 2 , 250mm 2 , 225mm2 , 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 In some embodiments, the top or bottom surface of the delay assembly has a surface area of ​​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 , 33mm2 , 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 The surface area of ​​any one of .

[0195] In some embodiments, the top or bottom surface of the delay assembly has a maximum span dimension of about 5 mm to about 20 mm, such as any one of 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 top or bottom surface of the delay assembly has a maximum span dimension of at least about 5 mm, such as at least about any one of 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 top or bottom surface of the delay assembly has a maximum span dimension of less than about 20 mm, such as less than any one 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 top or bottom surface of the delay assembly has a maximum span dimension of about any of 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.

[0196] In some embodiments, the top or bottom surface of the delay assembly has a span dimension perpendicular to the maximum span dimension of about 1 mm to about 15 mm, such as any of about 2 mm to about 10 mm, about 2 mm to about 6 mm, or about 1 mm to about 5 mm. In some embodiments, the top or bottom surface of the delay assembly has a span dimension perpendicular to the maximum span dimension of at least about 1 mm, such as at least about any of 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 top or bottom surface of the delay assembly has a span dimension perpendicular to the maximum span dimension of less than about 15 mm, such as 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 top or bottom surface of the delay assembly has a span dimension perpendicular to the maximum span dimension of about any of 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.

[0197] In some embodiments, the delay assembly has a diameter of about 1 mm to about 15 mm, such as any one of about 2 mm to about 10 mm, about 2 mm to about 6 mm, or about 1 mm to about 5 mm. In some embodiments, the top or bottom surface of the delay assembly has a diameter of at least about 1 mm, such as at least about any one of 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 top or bottom surface of the delay assembly has a diameter of less than about 15 mm, such as less than about any one of 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 top or bottom surface of the delay assembly has a diameter of about any of 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.

[0198] In some embodiments, the delay assembly has a thickness of about 0.1 mm to about 5 mm, such as any one of 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 delay assembly has a thickness of at least about 0.1 mm, such as at least about any one of 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 delay assembly has a thickness of less than about 5 mm, such as less than about any of 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 delay assembly has a thickness of about any of 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.

[0199] In some embodiments, the delay assembly includes a top surface and a bottom surface, wherein the thickness measured between the top surface and the bottom surface is substantially uniform, such as within 20% of an average thickness.

[0200] In some embodiments, the top and bottom surfaces of the delay assembly have the same surface area. In some embodiments, the top and bottom surfaces of the delay assembly have the same maximum span dimension. In some embodiments, the top and bottom surfaces of the delay assembly have the same span dimension perpendicular to the maximum span dimension. In some embodiments, the top and bottom surfaces of the delay assembly have the same diameter. In some embodiments, the top and bottom surfaces of the delay assembly have the same shape.

[0201] In some embodiments, the delay assembly includes a side surface.

[0202] In some embodiments, the delay component comprises an erodible material that is not mixed with the drug. In some embodiments, the delay component (e.g., the erodible material of the delay component) comprises a thermoplastic material, such as a thermoplastic polymer. In some embodiments, the delay component comprises any one or more of an erodible thermoplastic material, a plasticizer, and other additives (e.g., a filler, a binder, a lubricant, a glidant, and a disintegrant).

[0203] In some embodiments, the erodible thermoplastic material comprises copolyvidone, polyvinyl pyrrolidone-co-vinyl acetate (PVP / VA), polyvinyl pyrrolidone (PVP), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), methylcellulose (MC), methacrylic acid copolymer, poly (butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), poly (dimethylaminoethyl methacrylate-co-methacrylic acid), any one or more of polyols (e.g., polyols), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammoniumethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly(methacrylic acid-co-methyl methacrylate), poly(methacrylic acid-co-ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), polyethylene oxide (PEO), polyethylene glycol (PEG), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, Kollicoat IR-polyvinyl alcohol, polyvinyl alcohol (PVA), aminoalkyl methacrylate copolymer E, hydroxypropyl methylcellulose acetate succinate or hydroxypropyl methylcellulose acetate succinate (HPMCAS), methacrylate copolymers, ammonium alkyl methacrylate copolymers, ethyl cellulose (EC), polyvinyl acetal diethyl aminolactate, maltodextrin, and polyvinyl acetal diethyl aminoacetate (AEA).

[0204] In some embodiments, the plasticizer includes any one or more of triethyl citrate (TEC), vitamin E polyethylene glycol succinate (TPGS), triacetin, acetylated triethyl citrate, tributyl citrate, o-acetyl tributyl citrate, polyethylene glycol 15-hydroxystearate, PEG-40-hydrogenated castor oil, polyethylene glycol 35-castor oil, dibutyl sebacate, diethyl phthalate, glycerol, methyl 4-hydroxybenzoate, castor oil, oleic acid, triacetin, and polyalkylene glycol.

[0205] In some embodiments, other additives include gum arabic, alginate, alginic acid, aluminum acetate, barium sulfate, butyl paraben, butylated hydroxytoluene, citric acid, calcium carbonate, superphosphate, candelilla wax, croscarmellose sodium, powdered sugar, colloidal silicon dioxide, cellulose, ordinary or anhydrous calcium phosphate, carnauba wax, corn starch, carboxymethyl cellulose calcium, calcium disodium edetate, calcium hydrogen phosphate dehydrate, cetylpyridinium chloride, calcium hydrogen phosphate, tribasic calcium phosphate, dibasic calcium phosphate, disodium hydrogen phosphate, polydimethylsiloxane, sodium tetraiodofluorescein, ethylenediaminetetraacetic acid (EDTA), gelatin, glycerol, glycerol monooleate, ferric oxide, Any one or more of ferric oxide, iron oxide yellow, iron oxide red, lactose, microcrystalline cellulose, magnesium carbonate, magnesium oxide, methylparaben, polysorbate, propyleneparaben, potassium bicarbonate, potassium sorbate, potato starch, phosphoric acid, polyoxyethylene (40) stearate, sodium starch glycolate, pregelatinized starch, cross-linked sodium carboxymethyl cellulose, sodium lauryl sulfate, starch, silicon dioxide, sodium benzoate, sucrose, sorbic acid, sodium carbonate, sodium saccharin, sodium alginate, silica gel, sorbitan oleate, sodium chloride, sodium metabisulfite, sodium citrate, sodium starch, sodium carboxymethyl cellulose, succinic acid, sodium propionate, titanium dioxide and talc.

[0206] In some embodiments, the delay component comprises one or more of hydroxypropyl cellulose (HPC), polyvinyl alcohol (PVA), and triethyl citrate (TEC). In some embodiments, the delay component comprises one or more of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and triethyl citrate (TEC).

[0207] In some embodiments, the delay component has a mass fraction (m 2 ) of hydroxypropyl cellulose of from about 0.1 to about 0.6 based on the weight of the oral dosage form. F In some embodiments, the delay component has a mass fraction (m 2 ) of hydroxypropyl cellulose of at least about 0.1, such as at least about any one of 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, or 0.6, based on the weight of the oral dosage form. FIn some embodiments, the delay component has a mass fraction (m 2 ) of hydroxypropyl cellulose of less than about 0.6, such as less than about any one of 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, based on the weight of the oral dosage form. F In some embodiments, the delay component has a mass fraction (m 2 ) of hydroxypropyl cellulose of about any one of 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, or 0.6, based on the weight of the oral dosage form. F ).

[0208] In some embodiments, the delay component has a mass fraction (m 2 ) of polyvinyl alcohol of from about 0.1 to about 0.6 based on the weight of the oral dosage form. F In some embodiments, the delay component has a mass fraction (m ) of polyvinyl alcohol of at least about 0.1, such as at least about any one of 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, or 0.6, based on the weight of the oral dosage form. F In some embodiments, the delay component has a mass fraction (m ) of polyvinyl alcohol of less than about 0.6, such as less than about any one of 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, based on the weight of the oral dosage form. F In some embodiments, the delay component has a mass fraction (m 2 ) of polyvinyl alcohol of about any one of 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, or 0.6, based on the weight of the oral dosage form. F ).

[0209] In some embodiments, the delay component has a mass fraction (m 2 ) of triethyl citrate of from about 0.01 to about 0.6 based on the weight of the oral dosage form. F In some embodiments, the delay component has a mass fraction (m 2 ) of triethyl citrate of at least about 0.01, such as at least about any one of 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, or 0.6, based on the weight of the oral dosage form. FIn some embodiments, the delay component has a mass fraction (m 2 ) of triethyl citrate of less than about 0.6, such as less than about any one of 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, based on the weight of the oral dosage form. F In some embodiments, the delay component has a mass fraction (m 2 ) of triethyl citrate of about any one of 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, or 0.6, based on the weight of the oral dosage form. F ).

[0210] In some embodiments, the delay component has a mass fraction (m 2 ) of hydroxypropyl methylcellulose of from about 0.01 to about 0.6 based on the weight of the oral dosage form. F In some embodiments, the delay component has a mass fraction (m 2 ) of hydroxypropyl methylcellulose of at least about 0.01, such as at least about any one of 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, or 0.6, based on the weight of the oral dosage form. F In some embodiments, the delay component has a mass fraction (m 2 ) of hydroxypropyl methylcellulose of less than about 0.6, such as less than about any one of 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, based on the weight of the oral dosage form. F In some embodiments, the delay component has a mass fraction (m 2 ) of hydroxypropyl methylcellulose of about any one of 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, or 0.6, based on the weight of the oral dosage form. F ).

[0211] vi. pH-based enteric components

[0212] The oral dosage forms described herein include a pH-based enteric component, such as a pH-based enteric component layer. In some embodiments, the pH-based enteric component comprises more than one layer of pH-based enteric material, such as two layers of pH-based enteric material. In some embodiments, the pH-based enteric component does not contain a drug. In some embodiments, the pH-based enteric component surrounds a delay component. In some embodiments, the pH-based enteric component surrounds a drug component.

[0213] Enteric-coated components based on pH are configured to dissolve at or above the desired pH value. As understood in the art, different regions of the human gastrointestinal tract have different pH environments. Using such enteric-coated components based on pH helps control the dissolution of the components of the oral dosage form described herein, up to the desired location of the gastrointestinal tract. In some embodiments, the enteric-coated components based on pH dissolve at a pH of about 5.5 to about 8, such as about 5.5 to about 7.5 and about 6 to about 7, at a pH value between any one of these. In some embodiments, the pH-based enteric component erodes at a pH of about 5.5, such as about any of 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.

[0214] In some embodiments, the enteric component of pH can be formed with a variety of materials having different shapes and sizes. In some embodiments, the enteric component based on pH is the enteric material layer based on pH. In some embodiments, the enteric component based on pH is configured to have a surface, such as being exposed to the surface of body fluid during the oral pharmaceutical dosage form application to human individuals, and this surface has a predetermined shape and surface area. As based on the surface of body fluid when being exposed to, the surface based on the enteric component of pH (such as the enteric component layer based on pH) can have any shape. In some embodiments, this surface has the shape of capsule-shaped, circle, oval, bullet-shaped, arrow-shaped, triangle, arcuate triangle, square, arcuate square, rectangle, arcuate rectangle, rhombus, pentagon, hexagon, octagon, half moon, almond or their combination.

[0215] In some embodiments, the pH-based enteric component (such as a pH-based enteric component layer) comprises a thermoplastic material, such as a thermoplastic polymer. In some embodiments, the pH-based enteric component (such as a pH-based enteric component layer) comprises a material including any one or more of a matrix material, a plasticizer, or other additives (e.g., a filler, a binder, a lubricant, a glidant, and a disintegrant).

[0216] In some embodiments, the pH-based enteric component material comprises one or more of the following: stearic acid, copovidone, polyvinyl pyrrolidone-co-vinyl acetate, polyvinyl pyrrolidone-polyvinyl acetate copolymer, cross-linked polyvinyl pyrrolidone, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methylcellulose, methacrylic acid copolymer, polymethacrylic acid-co-ethyl acrylate, polybutyl methacrylate-co-(2-dimethylaminoethyl methacrylate-dimethylaminoethyl methacrylate), poly(dimethylaminoethyl methacrylate-methacrylic acid-co-methacrylate), poly(ethyl acrylate-trimethylaminoethyl methacrylate chloride), poly(methyl acrylate-methacrylic acid-methacrylic acid-methyl methacrylate), polymethacrylic acid-methyl methacrylate, polyethylene glycol, polyethylene 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 hydroxypropyl methylcellulose acetate succinate, methacrylate copolymer, ammonium alkyl methacrylate copolymer, ethylcellulose, polyvinyl acetate and polyvinyl pyrrolidone, polyvinyl acetal diethylamino lactate, polyvinyl acetal diethylamino lactate, maltitol, lactose monohydrate, xylitol, isomalt, sucrose, glucose, dextran 70 or maltose.

[0217] In some embodiments, the plasticizer includes any one or more of triethyl citrate (TEC), vitamin E polyethylene glycol succinate (TPGS), triacetin, acetylated triethyl citrate, tributyl citrate, o-acetyl tributyl citrate, polyethylene glycol 15-hydroxystearate, PEG-40-hydrogenated castor oil, polyethylene glycol 35-castor oil, dibutyl sebacate, diethyl phthalate, glycerol, methyl 4-hydroxybenzoate, castor oil, oleic acid, triacetin, and polyalkylene glycol.

[0218] In some embodiments, other additives include gum arabic, alginate, alginic acid, aluminum acetate, butyl paraben, butylated hydroxytoluene, citric acid, calcium carbonate, croscarmellose sodium, powdered sugar, colloidal silicon dioxide, cellulose, ordinary or anhydrous calcium phosphate, carnauba wax, corn starch, carboxymethyl cellulose calcium, calcium disodium edetate, calcium hydrogen phosphate dehydrate, cetylpyridinium chloride, calcium hydrogen phosphate, tribasic calcium phosphate, dibasic calcium phosphate, disodium hydrogen phosphate, polydimethylsiloxane, sodium tetraiodofluorescein, ethylenediaminetetraacetic acid (EDTA), gelatin, glycerol monooleate, ferric oxide, ferric oxide, oxygen Any one or more of iron oxide yellow, iron oxide red, lactose, microcrystalline cellulose, magnesium carbonate, magnesium oxide, methylparaben, polysorbate, propyleneparaben, potassium bicarbonate, potassium sorbate, potato starch, phosphoric acid, polyoxyethylene stearate, sodium starch glycolate, pregelatinized starch, croscarmellose sodium, sodium lauryl sulfate, starch, silicon dioxide, sodium benzoate, sucrose, sorbic acid, sodium carbonate, saccharin sodium, sodium alginate, silica gel, sorbitan oleate, sodium chloride, sodium metabisulfite, sodium citrate dehydrate, sodium starch, sodium carboxymethylcellulose, succinic acid, sodium propionate, titanium dioxide and talc.

[0219] v.Add-ons

[0220] In some embodiments, the oral dosage form includes additional components, such as 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 decorative 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, the additional component is a label, such as: a company name, abbreviation, or logo; a drug label or drug name (such as a drug brand name and / or drug chemical name or abbreviation); a drug quantity or strength; an identifying barcode, or any combination thereof.

[0221] III. Commercial batches

[0222] In some aspects, provided herein are commercial batches of at least about 1000 oral pharmaceutical dosage forms described herein. In some embodiments, a commercial batch comprises 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 any one of 100,000 oral pharmaceutical dosage forms described herein.

[0223] In some embodiments, the commercial batch has a standard deviation of about 0.1 or less, e.g., about 0.05 or less, for one or more of: the average particle size of the drug particles; the amount of drug in the oral pharmaceutical dosage form; the weight of the oral pharmaceutical dosage form; the maximum span dimension of the oral pharmaceutical dosage form and the span dimension of the oral pharmaceutical dosage form perpendicular to the maximum span dimension, or the diameter of the oral pharmaceutical dosage form.

[0224] IV. Methods for Preparing Oral Pharmaceutical Dosage Forms

[0225] In some aspects, provided herein are methods of preparing the oral dosage forms described herein. In some embodiments, the preparation method comprises three-dimensional (3D) printing technology to form at least one component or a portion thereof of the components of the oral dosage forms described herein.

[0226] In some embodiments, the pharmaceutical particles described herein are prepared by hot melt extrusion (HME).

[0227] In some embodiments, a method for preparing the drug particles described herein is provided, comprising: (a) premixing a drug with a first erodible material and then loading the mixture into a single-screw or twin-screw extruder; (b) rotating the screws to further extrude the physical mixture while simultaneously heating the extruder interlayer to a predetermined temperature; (c) thoroughly mixing the drug and the first erodible material, and continuously extruding the mixture through an end plate and a die of various shapes; and (d) pulverizing and sieving. In some embodiments, the drug described herein is uniformly distributed in the drug particles in the form of an amorphous solid dispersion.

[0228] In some embodiments, a method for three-dimensional (3D) printing an oral dosage form described herein is provided, the method comprising dispensing materials according to a layer-by-layer model of the oral dosage form to print the oral dosage form, wherein each layer of the layer-by-layer model is printed by dispensing the following materials as needed: (a) a drug component comprising drug particles and a second erodible material; and (b) a delay component comprising a third erodible material not mixed with the drug. In some embodiments, the method further comprises generating a layer-by-layer model of the oral dosage form. In some embodiments, the dispensing is performed via melt extrusion deposition (MED). In some embodiments, the dispensing of each material is performed by a different print head.

[0229] In some embodiments, a method for three-dimensional (3D) printing an oral dosage form described herein is provided, the method comprising dispensing materials according to a layer-by-layer model of the oral dosage form to print the oral dosage form, wherein each layer of the layer-by-layer model is printed by dispensing the following materials as needed: (a) a drug component comprising drug particles and a second erodible material; (b) a pH-based enteric component comprising a pH-based enteric material that is not mixed with the drug. In some embodiments, the method further comprises generating a layer-by-layer model of the oral dosage form. In some embodiments, the dispensing is performed via hot melt extrusion deposition (MED). In some embodiments, the dispensing of each material is performed by a different print head.

[0230] In some embodiments, a method for three-dimensional (3D) printing an oral dosage form described herein is provided, the method comprising dispensing materials according to a layer-by-layer model of the oral dosage form to print the oral dosage form, wherein each layer of the layer-by-layer model is printed by dispensing the following materials as needed: (a) a drug component comprising drug particles and a second erodible material; (b) a delay component comprising a third erodible material not mixed with the drug; (c) a pH-based enteric component comprising a pH-based enteric material not mixed with the drug. In some embodiments, the method further comprises generating a layer-by-layer model of the oral dosage form. In some embodiments, the dispensing is performed via hot melt extrusion deposition (MED). In some embodiments, the dispensing of each material is performed by a different print head.

[0231] In some embodiments, step (a) utilizes low-temperature printing. In some embodiments, the low-temperature printing temperature is about 30-120°C. In some embodiments, the low-temperature printing temperature is about 30-110°C. In some embodiments, the low-temperature printing temperature is about 30-100°C. In some embodiments, the low-temperature printing temperature is about 35-120°C. In some embodiments, the low-temperature printing temperature is about 35-110°C. In some embodiments, the low-temperature printing temperature is about 35-100°C.

[0232] In some embodiments, step (a) is performed using melt extrusion deposition (MED). In some embodiments, step (a) is performed using semi-solid extrusion.

[0233] As used herein, "printing," "three-dimensional printing," "3D printing," "additive manufacturing," or their equivalents refer to methods for producing three-dimensional objects (e.g., oral dosage forms) layer by layer using a digital design. The basic process of three-dimensional printing has been described in U.S. Patents 5,204,055; 5,260,009; 5,340,656; 5,387,380; 5,503,785; and 5,633,021. Other U.S. patents and patent applications related to 3D printing include: U.S. Patents 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. Publication Nos. 2002 / 0015728; 2002 / 0106412; 2003 / 0143268; 2003 / 0198677; and 2004 / 0005360. The contents of the aforementioned U.S. patents and patent applications are hereby incorporated by reference in their entirety. In some embodiments, additive manufacturing techniques are used to produce the oral pharmaceutical dosage forms described herein. In some embodiments, layer-by-layer techniques are used to produce the oral pharmaceutical dosage forms described herein. Since 3D printing can process a range of pharmaceutical materials and can locally control both composition and structure, it is well suited for manufacturing oral pharmaceutical dosage forms with complex geometry and composition according to the present invention.

[0234] In some embodiments, when referring to, for example, a drug component layer, a layer refers to a configuration of a component of an oral pharmaceutical 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 printing packing density. In some embodiments, the layer (e.g., a drug component layer or a delay component layer) includes a plurality of printed layers between about 5 printed layers and about 2500 printed layers, such as between about 10 printed layers and about 2500 printed layers, about 25 printed layers and about 100 printed layers, about 50 printed layers and about 200 printed layers, about 100 printed layers and about 200 printed layers, about 150 printed layers and about 250 printed layers, about 200 printed layers and about 250 printed layers, about 500 printed layers and about 1000 printed layers, or about 2000 printed layers and about 2400 printed layers. In some embodiments, the thickness of the printed layer is no more than about 5 mm, such as no more than about any of 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. In some embodiments, the thickness of the printed layer is about any of 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.

[0235] In some embodiments, the oral dosage forms described herein are 3D printed using an extrusion method. In some embodiments, the method of 3D printing includes using a twin-screw extrusion method. In the extrusion process, material is extruded from an automatically driven print head through a print nozzle. Unlike adhesive deposition that requires a powder bed, the extrusion method can be printed on any substrate. Various materials can be extruded for three-dimensional printing, including thermoplastic materials, pastes and colloidal suspensions, silicones and other semi-solids disclosed herein. One extrusion printing method is hot melt extrusion deposition (MED), which uses material extruded from a print head to print layers of material to form components of the oral dosage form. Another common type of extrusion printing method is fused deposition modeling, which uses solid polymer filaments for printing.

[0236] In some embodiments, 3D printing is performed using melt extrusion deposition (MED). In some embodiments, the hot melt extrusion deposition technique involves preparing the material to be dispensed (e.g., preparing a powder in a hot melt extruder) and then feeding the material into a MED printhead. The MED printhead then dispenses the material to form the oral dosage form in an additive manner (layer-by-layer deposition). In some embodiments, each material of the oral dosage form, such as the drug component and the delay component, is dispensed by a different MED printhead.

[0237] In some embodiments, the methods herein for preparing the oral dosage forms described herein further comprise providing a tracking marker. In some embodiments, the methods comprise: providing a tracking marker; imaging an individual; and designing an oral dosage form based on the imaging location and the tracking marker state. In some embodiments, the tracking marker comprises an erodible material. In some embodiments, the tracking marker comprises an insoluble material. In some embodiments, the tracking marker is selected from one or more of a tracking ring, a tracking strip, a tracking layer, or a tracking block. In some embodiments, the tracking marker is detected via an imaging technique. In some embodiments, the imaging is an X-ray imaging technique. In some embodiments, the imaging location is selected from one or more of the stomach, small intestine, or large intestine. In some embodiments, the final form of the oral dosage form will not include a tracking strip, and such a tracking strip is only required during the design phase to ensure correctly positioned drug delivery.

[0238] In some embodiments, the hot melt extrusion deposition 3D printing technology includes: (a) preparing component materials by melt extrusion, wherein the components are selected from one or more of a drug component, a delay component, a pH-based enteric component, and / or a tracking marker; and (b) printing an oral pharmaceutical dosage form. In some embodiments, the hot melt extrusion deposition 3D printing technology also includes preparing a print head for printing.

[0239] The oral dosage forms and components thereof described herein can be printed on a commercial scale. For example, in some embodiments, the methods disclosed herein can be used to 3D print 10,000 to 100,000 units of oral dosage forms per hour. In some embodiments, the methods disclosed herein can be used to 3D print 10,000 to 100,000 oral dosage forms per hour. In some embodiments, the methods disclosed herein can be used to 3D print 10,000 to 100,000 dosage units per hour. In some embodiments, the methods disclosed herein can be used to 3D print 10,000 to 100,000 dosage units per hour.

[0240] Example

[0241] Example 1

[0242] This example illustrates the design, production, and testing of an oral dosage form described herein that contains a fixed amount of a drug, apixaban, with a desired drug release profile.

[0243] Figure 1B provides a schematic diagram of an oral pharmaceutical dosage form. The dimensions and component compositions of the prepared dosage form are shown in Table 1A and Table 1B, and a schematic diagram of the oral pharmaceutical dosage form is shown in Figure 2A.

[0244] As shown in FIG1B , an oral dosage form includes: a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles uniformly distributed within the second erodible material, the drug particles comprising a first drug and the first erodible material; and a delay component comprising a third erodible material that is not mixed with the drug; wherein the delay component surrounds the drug component and wherein the delay component prevents release of the drug from the oral dosage form within about 0.5 hours to about 7 hours after administration of the oral dosage form to a human subject. After administration, the delay component is exposed to gastrointestinal fluids and the delay component begins to erode. The delay component erodes, exposing a surface of the drug component, causing the surface of the drug component to erode. As the drug component erodes, the drug particles are exposed to gastrointestinal fluids, and the drug is released from the drug particles. The disclosure provided herein also encompasses oral dosage forms having one or more tracking strips. Such tracking strips are useful in developing and optimizing oral dosage forms. For example, after administration, imaging of the subject (such as using X-rays) can be used to determine the location of erosion of the drug dosage form. After development and optimization of the oral dosage form, these tracking strips may no longer be needed. Table 1A and Table 1B provide detailed information on the oral dosage form shown in FIG. 2 .

[0245] Table 1A Composition of the oral dosage form shown in Figure 2

[0246] Table 1B Dimensions of the oral dosage forms shown in Figure 2

[0247] The preparation process of oral drug dosage form is:

[0248] (1) Preparation of drug granules: Apixaban was uniformly mixed with HPMC E5 and VA64; the mixture was added to a twin-screw extruder, and the screw speed was adjusted to extrude the drug granules;

[0249] (2) Material mixing of drug components: The drug particles were uniformly mixed with PEG4000 and PEG20000; the mixture was added to a twin-screw extruder, and the screw speed was adjusted to mix the materials;

[0250] (3) Mixing the materials of the delay assembly: Add the weighed materials into the pulverizer and mix; add the mixture into the twin-screw extruder, adjust the screw speed, and mix the materials;

[0251] (4) 3D printing steps: distribute the materials of the drug component and the delay component into different nozzles respectively; set the temperature of the 3D printer, turn on the heating, and perform 3D printing. The temperature of each component is as follows:

[0252] The oral drug dosage form was subjected to an in vitro dissolution test, and the in vitro dissolution study was as follows: referring to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931-Method), 0.05 mol / L phosphate buffer (54.44 g of potassium dihydrogen phosphate and 7.1 g of sodium hydroxide were taken, 8000 mL of water was added to dissolve, and the pH value was adjusted to 6.8 ± 0.05 with 0.2 mol / L sodium hydroxide) 900 mL was used as the dissolution medium, the speed was 100 revolutions per minute, and the operation was carried out in accordance with the law. At the established sampling points, 2 mL of the solution was taken respectively, filtered with a 0.8 μm filter membrane, and then tested by HPLC. The in vitro dissolution curve is shown in Figure 3.

[0253] Example 2

[0254] This example illustrates the design, production, and testing of an oral dosage form described herein that contains a fixed amount of a drug, apixaban, with a desired drug release profile.

[0255] Figure 1B provides a schematic diagram of an oral pharmaceutical dosage form. The dimensions and component compositions of the prepared dosage form are shown in Tables 2A and 2B, and a schematic diagram of the oral pharmaceutical dosage form is shown in Figure 2A.

[0256] As shown in FIG1B , an oral dosage form includes: a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles uniformly distributed within the second erodible material, the drug particles comprising a first drug and the first erodible material; and a delay component comprising a third erodible material that is not mixed with the drug; wherein the delay component surrounds the drug component and wherein the delay component prevents release of the drug from the oral dosage form within about 0.5 hours to about 7 hours after administration of the oral dosage form to a human subject. After administration, the delay component is exposed to gastrointestinal fluids and the delay component begins to erode. The delay component erodes, exposing a surface of the drug component, causing the surface of the drug component to erode. As the drug component erodes, the drug particles are exposed to gastrointestinal fluids, and the drug is released from the drug particles. The disclosure provided herein also encompasses oral dosage forms having one or more tracking strips. Such tracking strips are useful in developing and optimizing oral dosage forms. For example, after administration, imaging of the subject (such as using X-rays) can be used to determine the location of erosion of the drug dosage form. After development and optimization of the oral dosage form, these tracking strips may no longer be needed. Tables 2A and 2B provide detailed information on the oral dosage form shown in FIG. 2 .

[0257] Table 2A Composition of the oral dosage form shown in Figure 2

[0258] Table 2B Dimensions of the oral dosage forms shown in Figure 2

[0259] The preparation process of oral drug dosage form is:

[0260] (1) Preparation of drug granules: Apixaban was uniformly mixed with HPMC E5 and VA64; the mixture was added to a twin-screw extruder, and the screw speed was adjusted to extrude the drug granules;

[0261] (2) Material mixing of drug components: uniformly mix drug particles and PEG20000; add the mixture to a twin-screw extruder, adjust the screw speed, and mix the materials;

[0262] (3) Mixing the materials of the delay assembly: Add the weighed materials into the pulverizer and mix; add the mixture into the twin-screw extruder, adjust the screw speed, and mix the materials;

[0263] (4) 3D printing steps: distribute the materials of the drug component and the delay component into different nozzles respectively; set the temperature of the 3D printer, turn on the heating, and perform 3D printing. The temperature of each component is as follows:

[0264] The oral drug dosage form was subjected to an in vitro dissolution test, and the in vitro dissolution study was as follows: referring to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931-Method), 0.05 mol / L phosphate buffer (54.44 g of potassium dihydrogen phosphate and 7.1 g of sodium hydroxide were taken, 8000 mL of water was added to dissolve, and the pH value was adjusted to 6.8 ± 0.05 with 0.2 mol / L sodium hydroxide) 900 mL was used as the dissolution medium, the speed was 100 revolutions per minute, and the operation was carried out in accordance with the law. At the established sampling points, 2 mL of the solution was taken respectively, filtered with a 0.8 μm filter membrane, and then tested by HPLC. The in vitro dissolution curve is shown in Figure 4.

[0265] Example 3

[0266] This example illustrates the design, production, and testing of an oral dosage form described herein that contains a fixed amount of a drug, apixaban, with a desired drug release profile.

[0267] Figure 1B provides a schematic diagram of an oral dosage form. The dimensions and component compositions of the prepared dosage form are shown in Tables 3A and 3B, and a schematic diagram of the oral dosage form is shown in Figure 2A.

[0268] As shown in FIG1B , an oral dosage form includes: a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles uniformly distributed within the second erodible material, the drug particles comprising a first drug and the first erodible material; and a delay component comprising a third erodible material that is not mixed with the drug; wherein the delay component surrounds the drug component and wherein the delay component prevents release of the drug from the oral dosage form within about 0.5 hours to about 7 hours after administration of the oral dosage form to a human subject. After administration, the delay component is exposed to gastrointestinal fluids and the delay component begins to erode. The delay component erodes, exposing a surface of the drug component, causing the surface of the drug component to erode. As the drug component erodes, the drug particles are exposed to gastrointestinal fluids, and the drug is released from the drug particles. The disclosure provided herein also encompasses oral dosage forms having one or more tracking strips. Such tracking strips are useful in developing and optimizing oral dosage forms. For example, after administration, imaging of the subject (such as using X-rays) can be used to determine the location of erosion of the drug dosage form. After development and optimization of the oral dosage form, these tracking strips may no longer be needed. Tables 3A and 3B provide detailed information on the oral dosage form shown in FIG. 2 .

[0269] Table 3A Composition of the oral dosage form shown in Figure 2

[0270] Table 3B Dimensions of the oral dosage forms shown in Figure 2

[0271] The preparation process of oral drug dosage form is:

[0272] (1) Preparation of drug granules: Apixaban was uniformly mixed with HPMC E5 and VA64; the mixture was added to a twin-screw extruder, and the screw speed was adjusted to extrude the drug granules;

[0273] (2) Material mixing of drug components: The drug particles were uniformly mixed with PEG20000 and PEO 100W; the mixture was added to a twin-screw extruder, and the screw speed was adjusted to mix the materials;

[0274] (3) Mixing the materials of the delay assembly: Add the weighed materials into the pulverizer and mix; add the mixture into the twin-screw extruder, adjust the screw speed, and mix the materials;

[0275] (4) 3D printing steps: distribute the materials of the drug component and the delay component into different nozzles respectively; set the temperature of the 3D printer, turn on the heating, and perform 3D printing. The temperature of each component is as follows:

[0276] The oral dosage form was subjected to an in vitro dissolution test, and the in vitro dissolution study was as follows: referring to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931-Method), 0.05 mol / L phosphate buffer (54.44 g of potassium dihydrogen phosphate and 7.1 g of sodium hydroxide were taken, 8000 mL of water was added to dissolve, and the pH value was adjusted to 6.8 ± 0.05 with 0.2 mol / L sodium hydroxide) 900 mL was used as the dissolution medium, the speed was 100 revolutions per minute, and the operation was carried out in accordance with the law. At the established sampling points, 2 mL of the solution was taken respectively, filtered with a 0.8 μm filter membrane, and then tested by HPLC. The in vitro dissolution curve is shown in Figure 5.

[0277] Example 4

[0278] This example illustrates the design, production, and testing of an oral dosage form described herein that contains a fixed amount of a drug, apixaban, with a desired drug release profile.

[0279] Figure 1B provides a schematic diagram of an oral dosage form. The dimensions and component compositions of the prepared dosage form are shown in Tables 4A and 4B, and a schematic diagram of the oral dosage form is shown in Figure 2A.

[0280] As shown in FIG1B , an oral dosage form includes: a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles uniformly distributed within the second erodible material, the drug particles comprising a first drug and the first erodible material; and a delay component comprising a third erodible material that is not mixed with the drug; wherein the delay component surrounds the drug component and wherein the delay component prevents release of the drug from the oral dosage form within about 0.5 hours to about 7 hours after administration of the oral dosage form to a human subject. After administration, the delay component is exposed to gastrointestinal fluids and the delay component begins to erode. The delay component erodes, exposing a surface of the drug component, causing the surface of the drug component to erode. As the drug component erodes, the drug particles are exposed to gastrointestinal fluids, and the drug is released from the drug particles. The disclosure provided herein also encompasses oral dosage forms having one or more tracking strips. Such tracking strips are useful in developing and optimizing oral dosage forms. For example, after administration, imaging of the subject (such as using X-rays) can be used to determine the location of erosion of the drug dosage form. After development and optimization of the oral dosage form, these tracking strips may no longer be needed. Tables 4A and 4B provide detailed information on the oral dosage form shown in FIG. 2 .

[0281] Table 4A Composition of the oral dosage form shown in Figure 2

[0282] Table 4B Dimensions of the oral dosage forms shown in Figure 2

[0283] The preparation process of oral drug dosage form is:

[0284] (1) Preparation of drug granules: Apixaban was uniformly mixed with HPMC E5 and VA64; the mixture was added to a twin-screw extruder, and the screw speed was adjusted to extrude the drug granules;

[0285] (2) Material mixing of drug components: The drug particles were uniformly mixed with PEG20000 and PEO 100W; the mixture was added to a twin-screw extruder, and the screw speed was adjusted to mix the materials;

[0286] (3) Mixing the materials of the delay assembly: Add the weighed materials into the pulverizer and mix; add the mixture into the twin-screw extruder, adjust the screw speed, and mix the materials;

[0287] (4) 3D printing steps: distribute the materials of the drug component and the delay component into different nozzles respectively; set the temperature of the 3D printer, turn on the heating, and perform 3D printing. The temperature of each component is as follows:

[0288] The oral dosage form was subjected to an in vitro dissolution test, and the in vitro dissolution study was as follows: referring to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931-Method), 0.05 mol / L phosphate buffer (54.44 g of potassium dihydrogen phosphate and 7.1 g of sodium hydroxide were taken, 8000 mL of water was added to dissolve, and the pH value was adjusted to 6.8 ± 0.05 with 0.2 mol / L sodium hydroxide) 900 mL was used as the dissolution medium, the speed was 100 revolutions per minute, and the operation was carried out in accordance with the law. At the established sampling points, 2 mL of the solution was taken respectively, filtered with a 0.8 μm filter membrane, and then tested by HPLC. The in vitro dissolution curve is shown in Figure 6.

[0289] Example 5

[0290] This example illustrates the design, production, and testing of an oral dosage form described herein that contains a fixed amount of a drug, budesonide, with a desired drug release profile.

[0291] Figure 1A provides a schematic diagram of an oral pharmaceutical dosage form. The dimensions and component compositions of the prepared dosage form are shown in Tables 5A and 5B, and a schematic diagram of the oral pharmaceutical dosage form is shown in Figure 7.

[0292] As shown in Figure 1A, an oral pharmaceutical dosage form includes: a drug component, the drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles are uniformly distributed in the second erodible material, and the drug particles comprise a first drug and a first erodible material. After administration, as the drug component erodes, the drug particles are exposed to gastrointestinal fluid, and the drug is released from the drug particles. The disclosure provided herein also encompasses oral pharmaceutical dosage forms having one or more tracking strips, such as those used in the development and optimization of oral pharmaceutical dosage forms. For example, after administration, imaging of an individual (such as using X-rays) can be used to determine the location of erosion of the pharmaceutical dosage form. After the oral pharmaceutical dosage form is developed and optimized, these tracking strips may no longer be needed. Tables 5A and 5B provide detailed information on the oral pharmaceutical dosage form shown in Figure 7.

[0293] Table 5A Composition of the oral dosage form shown in Figure 7

[0294] Table 5B Dimensions of the oral dosage forms shown in Figure 7

[0295] The preparation process of oral drug dosage form is:

[0296] (1) Preparation of drug granules: Budesonide and VA64 were uniformly mixed; the mixture was added to a twin-screw extruder, and the screw speed was adjusted to extrude the drug granules;

[0297] (2) Material mixing of drug components: uniformly mix drug particles and PEG20000; add the mixture to a twin-screw extruder, adjust the screw speed, and mix the materials;

[0298] (3) 3D printing step: Distribute the material of the drug component into the nozzle; set the temperature of the 3D printer, turn on the heating, and perform 3D printing. The temperature of each component is as follows:

[0299] The oral dosage form was subjected to an in vitro dissolution test. The in vitro dissolution study was as follows: referring to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0931-1), 900 mL of pH 6.8 phosphate buffer containing 0.05 mol / LTW80 was used as the dissolution medium, the speed was 100 revolutions per minute, and the operation was carried out in accordance with the law. At the established sampling points, 2 mL of the solution was taken, filtered with a 0.45 μm filter membrane, and then tested by HPLC. The in vitro dissolution curve is shown in Figure 8.

[0300] Example 6

[0301] This example illustrates the design, production, and testing of an oral dosage form described herein that contains a fixed amount of a drug, budesonide, with a desired drug release profile.

[0302] Figure 1B provides a schematic diagram of an oral dosage form. The dimensions and component compositions of the prepared dosage form are shown in Tables 6A and 6B, and a schematic diagram of the oral dosage form is shown in Figure 9A.

[0303] As shown in FIG1B , an oral dosage form includes: a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles uniformly distributed within the second erodible material, the drug particles comprising a first drug and the first erodible material; and a delay component comprising a third erodible material that is not mixed with the drug; wherein the delay component surrounds the drug component and wherein the delay component prevents release of the drug from the oral dosage form within about 0.5 hours to about 7 hours after administration of the oral dosage form to a human subject. After administration, the delay component is exposed to gastrointestinal fluids and the delay component begins to erode. The delay component erodes, exposing a surface of the drug component, causing the surface of the drug component to erode. As the drug component erodes, the drug particles are exposed to gastrointestinal fluids, and the drug is released from the drug particles. The disclosure provided herein also encompasses oral dosage forms having one or more tracking strips. Such tracking strips are useful in developing and optimizing oral dosage forms. For example, after administration, imaging of the subject (such as using X-rays) can be used to determine the location of erosion of the drug dosage form. After development and optimization of the oral dosage form, these tracking strips may no longer be needed. Tables 6A and 6B provide detailed information on the oral dosage form shown in FIG. 9 .

[0304] Table 6A Composition of the oral dosage form shown in Figure 9

[0305] Table 6B Dimensions of the oral dosage forms shown in Figure 9

[0306] The preparation process of oral drug dosage form is:

[0307] (1) Preparation of drug granules: Budesonide and VA64 were uniformly mixed; the mixture was added to a twin-screw extruder, the screw speed was adjusted, and the drug granules were prepared by extrusion;

[0308] (2) Material mixing of drug components: uniformly mix drug particles and PEG20000; add the mixture to a twin-screw extruder, adjust the screw speed, and mix the materials;

[0309] (3) Mixing the materials of the delay assembly: Add the weighed materials into the pulverizer and mix; add the mixture into the twin-screw extruder, adjust the screw speed, and mix the materials;

[0310] (4) 3D printing steps: distribute the materials of the drug component and the delay component into different nozzles respectively; set the temperature of the 3D printer, turn on the heating, and perform 3D printing. The temperature of each component is as follows:

[0311] The oral dosage form was subjected to an in vitro dissolution test. The in vitro dissolution study was as follows: referring to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0931-1), 900 mL of pH 6.8 phosphate buffer containing 0.05 mol / LTW80 was used as the dissolution medium, the speed was 100 revolutions per minute, and the operation was carried out in accordance with the law. At the established sampling points, 2 mL of the solution was taken, filtered with a 0.45 μm filter membrane, and then tested by HPLC. The in vitro dissolution curve is shown in Figure 10.

[0312] Example 7

[0313] This example illustrates the design, production, and testing of an oral dosage form described herein that contains a fixed amount of a drug, budesonide, with a desired drug release profile.

[0314] Figure 1G provides a schematic diagram of an oral dosage form. The dimensions and component compositions of the prepared dosage form are shown in Tables 7A and 7B, and a schematic diagram of the oral dosage form is shown in Figure 11A.

[0315] As shown in FIG1G , an oral dosage form includes: a drug component comprising a plurality of drug particles and a second erodible material; the plurality of drug particles are uniformly distributed within the second erodible material, the drug particles comprising a first drug and the first erodible material; and a pH-based enteric component comprising a third erodible material that is not mixed with the drug; wherein the pH-based enteric component surrounds the drug component, and wherein the pH-based enteric component prevents the drug from being released from the oral dosage form within about 1 hour to about 7 hours after administration of the oral dosage form to a human subject. After administration, the pH-based enteric component is exposed to gastrointestinal fluid, and the pH-based enteric component begins to erode. The pH-based enteric component erodes, then exposes a surface of the drug component, causing the surface of the drug component to erode. As the drug component erodes, the drug particles are exposed to gastrointestinal fluid, and the drug is released from the drug particles. The disclosure provided herein also encompasses oral pharmaceutical dosage forms having one or more tracking strips that are useful in developing and optimizing oral pharmaceutical dosage forms. For example, after administration, imaging of an individual (such as using X-rays) can be used to determine the location of erosion of the pharmaceutical dosage form. After developing and optimizing the oral pharmaceutical dosage form, these tracking strips may no longer be needed. Tables 7A and 7B provide detailed information on the oral pharmaceutical dosage form shown in Figure 11.

[0316] Table 7A Composition of the oral dosage form shown in Figure 11

[0317] Table 7B Dimensions of the oral dosage forms shown in Figure 11

[0318] The preparation process of oral drug dosage form is:

[0319] (1) Preparation of drug granules: Budesonide and PVP / VA64 were uniformly mixed; the mixture was added to a twin-screw extruder, and the screw speed was adjusted to extrude the drug granules;

[0320] (2) Material mixing of drug components: uniformly mix drug particles and poloxamer 407; add the mixture to a twin-screw extruder, adjust the screw speed, and mix the materials;

[0321] (3) 3D printing step: Distribute the material of the drug component into the nozzle; set the temperature of the 3D printer, turn on the heating, and perform 3D printing. The temperature of each component is as follows:

[0322] (4) Preparation of pH-based enteric-soluble component: adding the weighed materials into a mold to form a pH-based enteric-soluble component;

[0323] (5) Preparation of oral drug dosage form: The drug component is assembled with the pH-based enteric component, and a gap is present between the drug component and the pH-based enteric component.

[0324] The oral drug dosage form was subjected to an in vitro dissolution test, and the in vitro dissolution study was as follows: referring to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931-Method), 900 mL of 0.1 mol / L hydrochloric acid was used as the dissolution medium, the speed was 100 revolutions per minute, and after 2 hours, the sample was taken out, and 900 mL of 0.05% Tween 80 pH 6.8 phosphate buffer preheated to 37 ° C in advance was used as the dissolution medium, the speed was 100 revolutions per minute, and the operation was carried out in accordance with the law. At the established sampling points, 2 mL of the solution was taken respectively, filtered with a 0.45 μm filter membrane, and then tested by HPLC. The in vitro dissolution curve is shown in Figure 12.

[0325] Example 8

[0326] This example illustrates the design, production, and testing of an oral dosage form described herein that contains a fixed amount of a drug, budesonide, with a desired drug release profile.

[0327] Figure 1J provides a schematic diagram of an oral pharmaceutical dosage form. The dimensions and component compositions of the prepared dosage forms are shown in Tables 8A and 8B.

[0328] As shown in FIG1J , an oral dosage form includes: a first drug component comprising a plurality of drug particles and a second erodible material, the plurality of drug particles being uniformly distributed within the second erodible material; a second drug component comprising a plurality of drug particles and a fourth erodible material, the plurality of drug particles being uniformly distributed within the fourth erodible material; and a delay component comprising a third erodible material that is not mixed with the drug; wherein the second erodible material and the fourth erodible material control the release of the drug from the first and second drug components, respectively, and wherein the delay component surrounds the first drug component but does not surround the second drug component, and the delay component prevents the drug from being released from the oral dosage form within about 0.5 hours to about 7 hours after administration of the oral dosage form to a human subject. After administration, as the second drug component erodes, the drug particles in the second drug component are exposed to gastrointestinal fluid, and the drug is released from the drug particles. Simultaneously, after administration, the delay component is exposed to gastrointestinal fluid and begins to erode. The delay component dissolves, and then the surface of the drug component is exposed, so that the surface of the first drug component dissolves. As the first drug component dissolves, the drug particles in the first drug component are exposed to the gastrointestinal fluid, and the drug is released from the drug particles. The disclosure provided herein also encompasses oral pharmaceutical dosage forms with one or more tracking strips, which are used to develop and optimize oral pharmaceutical dosage forms. For example, after administration, imaging of an individual (such as using X-rays) can be used to determine the dissolution location of the pharmaceutical dosage form. After developing and optimizing the oral pharmaceutical dosage form, these tracking strips may no longer be needed. Tables 8A and 8B provide detailed information on the oral pharmaceutical dosage form.

[0329] Table 8A Composition of oral dosage form

[0330] Table 8B Dimensions of Oral Dosage Forms

[0331] The preparation process of oral drug dosage form is:

[0332] (1) Preparation of drug granules: Budesonide and VA64 were uniformly mixed; the mixture was added to a twin-screw extruder, and the screw speed was adjusted to extrude the drug granules;

[0333] (2) Material mixing of the first drug component: uniformly mix the drug particles and PEG20000 according to the prescribed amount; add the mixture to a twin-screw extruder, adjust the screw speed, and mix the materials;

[0334] (3) Material mixing of the second drug component: The drug particles and PEG20000 were uniformly mixed according to the prescribed amount; the mixture was added to the twin-screw extruder, and the screw speed was adjusted to mix the materials;

[0335] (4) Mixing the materials of the delay assembly: Add the weighed materials into the pulverizer and mix; add the mixture into the twin-screw extruder, adjust the screw speed, and mix the materials;

[0336] (5) 3D printing step: distribute the materials of the first drug component, the delay component, and the second drug component into different nozzles respectively; set the temperature of the 3D printer, turn on the heating, and perform 3D printing. The temperature of each component is as follows:

[0337] The oral drug dosage form was subjected to an in vitro dissolution test. The in vitro dissolution study was as follows: referring to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0931-Method 1), 900 mL of pH 6.8 phosphate buffer containing 0.05 mol / LTW80 was used as the dissolution medium, the rotation speed was 100 revolutions per minute, and the operation was carried out in accordance with the law.

[0338] Example 9

[0339] This example illustrates the design, production, and testing of an oral dosage form described herein that contains a fixed amount of a drug, budesonide, with a desired drug release profile.

[0340] Figure 1K provides a schematic diagram of an oral pharmaceutical dosage form. The dimensions and component compositions of the prepared dosage forms are shown in Tables 9A and 9B.

[0341] As shown in FIG1K , an oral dosage form includes a first drug component comprising a plurality of drug particles and a second erodible material, wherein the plurality of drug particles are uniformly distributed within the second erodible material; and a second drug component comprising a plurality of drug particles and a fourth erodible material, wherein the plurality of drug particles are uniformly distributed within the fourth erodible material; wherein the second erodible material and the fourth erodible material control the release of the drug from the first drug component and the second drug component, respectively. After administration, as the first and second drug components erode, the drug particles in the first and second drug components are exposed to gastrointestinal fluids, and the drug is released from the drug particles. The disclosure provided herein also encompasses oral dosage forms having one or more tracking strips. Such tracking strips are useful in developing and optimizing oral dosage forms. For example, after administration, imaging of a subject (such as using X-rays) can be used to determine the location of erosion of the drug dosage form. After development and optimization of the oral dosage form, these tracking strips may no longer be necessary. Tables 9A and 9B provide detailed information on the oral dosage form.

[0342] Table 9A Composition of oral dosage form

[0343] Table 9B Dimensions of Oral Dosage Forms

[0344] The preparation process of oral drug dosage form is:

[0345] (1) Preparation of drug granules: Budesonide and VA64 were uniformly mixed; the mixture was added to a twin-screw extruder, and the screw speed was adjusted to extrude the drug granules;

[0346] (2) Material mixing of the first drug component: uniformly mix the drug particles and PEG20000 according to the prescribed amount; add the mixture to a twin-screw extruder, adjust the screw speed, and mix the materials;

[0347] (3) Material mixing of the second drug component: The drug particles and PEG20000 were uniformly mixed according to the prescribed amount; the mixture was added to the twin-screw extruder, and the screw speed was adjusted to mix the materials;

[0348] (4) 3D printing step: the materials of the first drug component and the second drug component are respectively distributed in different nozzles; the temperature of the 3D printer is set, the heating is turned on, and 3D printing is performed. The temperature of each component is as follows:

[0349] The oral drug dosage form was subjected to an in vitro dissolution test. The in vitro dissolution study was as follows: referring to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0931-Method 1), 900 mL of pH 6.8 phosphate buffer containing 0.05 mol / LTW80 was used as the dissolution medium, the rotation speed was 100 revolutions per minute, and the operation was carried out in accordance with the law.

Claims

1. A controlled-release oral pharmaceutical dosage form, characterized in that The oral drug dosage form includes: a drug component comprising a plurality of drug particles and a second erodible material; The plurality of drug particles are uniformly distributed in the second erodible material, the drug particles comprising a first drug; wherein the second erodible material controls release of the drug from the oral drug dosage form within a desired amount of time after administration of the oral drug dosage form to a human subject.

2. An oral pharmaceutical dosage form according to claim 1, characterized in that The drug particles include a first erodible material uniformly mixed with a first drug.

3. An oral pharmaceutical dosage form according to any one of claims 1 to 2, characterized in that The second erodible material has a melting point of about 30-120°C.

4. An oral pharmaceutical dosage form according to any one of claims 1 to 3, characterized in that The second erodible material has a glass transition temperature (Tg) in the range of about -60°C to 80°C.

5. An oral pharmaceutical dosage form according to any one of claims 1 to 4, characterized in that The viscosity of the second erodible material at a temperature between Tm and (Tm+30° C.) of the second erodible material is about 100-50,000 Pa·s.

6. An oral pharmaceutical dosage form according to any one of claims 1 to 5, characterized in that The drug component has a viscosity of about 100-50,000 Pa·s at a temperature between Tm and (Tm+30° C.) of the second erodible material.

7. An oral pharmaceutical dosage form according to any one of claims 1 to 6, characterized in that The oral dosage form comprises a delay member comprising a third erodible material that is not mixed with the drug.

8. An oral pharmaceutical dosage form according to claim 7, characterized in that The delay component surrounds the drug component, and wherein the delay component prevents release of the drug from the oral dosage form within about 0.5 hours to about 7 hours after administration of the oral dosage form to a human subject.

9. An oral pharmaceutical dosage form according to any one of claims 1 to 8, characterized in that The oral dosage form comprises a pH-based enteric component configured to erode at or above a predetermined pH value.

10. An oral pharmaceutical dosage form according to claim 9, characterized in that The pH-based enteric component surrounds the drug component, and wherein the pH-based enteric component prevents release of the drug from the oral dosage form within about 1 hour to about 7 hours after administration of the oral dosage form to a human subject.

11. An oral pharmaceutical dosage form according to claim 9, characterized in that The pH-based enteric component surrounds the delay component, the pH-based enteric component prevents erosion of the delay component, and wherein the delay component prevents erosion of the drug component.

12. An oral pharmaceutical dosage form according to any one of claims 1 to 11, characterized in that The drug particles include first drug particles and second drug particles.

13. An oral pharmaceutical dosage form according to claim 12, characterized in that The first drug particles include a first drug and a first erodible material mixed with the first drug; the second drug particles include a second drug and a fifth erodible material mixed with the second drug.

14. An oral pharmaceutical dosage form according to claim 13, characterized in that The first erodible material and the fifth erodible material are the same.

15. An oral pharmaceutical dosage form according to claim 13, characterized in that The first erodible material and the fifth erodible material are different.

16. An oral pharmaceutical dosage form according to any one of claims 12 to 15, characterized in that The first drug particles and / or the second drug particles further contain a third drug, and the third drug is uniformly mixed with the drug and the erodible material therein.

17. An oral pharmaceutical dosage form according to any one of claims 1 to 11, characterized in that The drug particles further include a second drug, and the first drug, the second drug and the first erodible material are uniformly mixed.

18. An oral pharmaceutical dosage form according to any one of claims 1 to 17, characterized in that The drug component includes a first drug component and a second drug component.

19. An oral pharmaceutical dosage form according to claim 18, characterized in that The first drug component comprises a second erodible material mixed with drug particles, and the second drug component comprises a fourth erodible material mixed with drug particles, wherein the second erodible material and the fourth erodible material control the release of the drug in the first drug component and the second drug component, respectively.

20. An oral pharmaceutical dosage form according to claim 19, characterized in that The second erodible material and the fourth erodible material are the same.

21. An oral pharmaceutical dosage form according to claim 19, characterized in that The second erodible material and the fourth erodible material are different.

22. An oral pharmaceutical dosage form according to any one of claims 19 to 21, characterized in that The drug particles are selected from one or more of first drug particles and second drug particles.

23. An oral pharmaceutical dosage form according to any one of claims 18 to 22, characterized in that The first drug component and the second drug component are in contact.

24. An oral pharmaceutical dosage form according to any one of claims 18 to 22, characterized in that The first drug component and the second drug component are not in contact.

25. An oral pharmaceutical dosage form according to claim 24, characterized in that An intermediate component is included between the first drug component and the second drug component.

26. An oral pharmaceutical dosage form according to any one of claims 18 to 25, characterized in that The delay assembly surrounds the first and second drug assemblies.

27. An oral pharmaceutical dosage form according to any one of claims 18 to 25, characterized in that The delay component surrounds the first drug component or the second drug component.

28. An oral pharmaceutical dosage form according to any one of claims 18 to 27, characterized in that The delay component forms a compartment that surrounds the first drug component and / or the second drug component.

29. An oral pharmaceutical dosage form according to any one of claims 18 to 28, characterized in that The delay assembly forms a first compartment and a second compartment, the first compartment and the second compartment surrounding the first drug assembly and the second drug assembly, respectively.

30. An oral pharmaceutical dosage form according to claim 29, characterized in that The first compartment and the second compartment are in communication.

31. An oral pharmaceutical dosage form according to claim 29, characterized in that The first compartment and the second compartment are not in communication.

32. An oral pharmaceutical dosage form according to any one of claims 26 to 31, characterized in that The delay component surrounding the first drug component and the second drug component has the same thickness.

33. An oral pharmaceutical dosage form according to any one of claims 26 to 31, characterized in that The delay component surrounding the first drug component and the second drug component has different thicknesses.

34. An oral pharmaceutical dosage form according to any one of claims 1 to 33, characterized in that The drug is distributed in the drug particles in the form of an amorphous solid dispersion.

35. An oral pharmaceutical dosage form according to any one of claims 1 to 34, characterized in that The average particle size of the drug particles is 0.1 μm to 1000 μm.

36. A method for preparing an oral pharmaceutical dosage form according to any one of claims 1 to 35, characterized in that: The method includes three-dimensional (3D) printing the oral pharmaceutical dosage form.

37. A method for preparing the oral pharmaceutical dosage form according to claim 36, characterized in that: The method includes a method for preparing the drug component: mixing drug particles with a second soluble material, and preparing the drug component through 3D printing technology.

38. A method for preparing an oral pharmaceutical dosage form according to any one of claims 36 to 37, characterized in that: The method includes a method for preparing drug particles: (a) premixing a first drug and a first erodible material and then filling the mixture into a single-screw or twin-screw extruder; (b) rotating the screw to push the physical mixture for further extrusion while heating the extruder interlayer to a preset temperature; (c) fully mixing the first drug and the first erodible material and continuously extruding them from an end plate and / or a mold of different shapes; and (d) pulverizing and screening.

39. A method for preparing an oral pharmaceutical dosage form according to any one of claims 36 to 38, characterized in that: The method includes dispensing materials according to a layer-by-layer model of an oral pharmaceutical dosage form to print the oral pharmaceutical dosage form, wherein each layer of the layer-by-layer model is printed by dispensing the following materials as needed: (a) a drug component comprising drug particles and a second erodible material; (b) a delay component comprising a third erodible material not mixed with the drug; and (c) a pH-based enteric component comprising a pH-based enteric material not mixed with the drug.

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