Delayed-release oral drug dosage form and preparation method therefor

Abstract

A delayed-release oral drug dosage form, and a preparation method related to the oral drug dosage form, such as a three-dimensional printing method.

Description

A delayed-release oral drug dosage form and its preparation method

[0001] Cross-references to related applications

[0002] This application claims priority to PCT / CN2025 / 070805, filed on January 6, 2025, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] In some aspects, this disclosure relates to a delayed-release oral drug dosage form. In other aspects, this disclosure relates to methods of preparation related to the oral drug dosage forms described herein, for example, using three-dimensional printing methods. Background Technology

[0004] Oral administration is the most common route of drug delivery. The process is relatively simple and does not require professional intervention, making it generally easier for patients to accept and adhere to. However, oral administration can be affected by biological, pharmaceutical, and physicochemical barriers, leading to significant individual variability. The ileum can be a site of treatment and / or drug refill; however, its location near the end of the gastrointestinal tract complicates effective oral delivery. For example, ingested oral drug formulations must withstand harsh pH conditions in the stomach, drastically different pH conditions downstream of the stomach, and mechanical stresses imposed by the digestive process before reaching the ileum. All of these factors contribute to reduced drug bioavailability in the ileum, limited availability of deliverable active agents, significant inter-individual variability in drug release, and increased likelihood of systemic side effects due to off-target drug release. Therefore, there remains a need in the art for oral drug formulations capable of precise ileal delivery.

[0005] All references cited in this article, including patent applications and publications, are incorporated herein by reference in their entirety.

[0006] Invention Overview

[0007] In some respects, this article provides an oral drug dosage form configured to release a drug at a desired gastrointestinal location, the oral drug dosage form comprising:

[0008] A drug assembly comprising a first soluble material mixed with a drug; and

[0009] Release the restricted components; among them,

[0010] The release restriction component is configured to restrict the release of the drug from the drug component until the oral drug dosage form begins to release from the drug component from approximately 2 hours to approximately 7 hours after administration to a human individual.

[0011] In some implementations, the glass transition temperature (Tg) of the release limiting component is from about 10°C to about 190°C.

[0012] In some implementations, the melting temperature (Tm) of the release restriction component is from about 30°C to about 200°C.

[0013] In some embodiments, the release limiting component includes a soluble delay member that surrounds the drug component and wherein the soluble delay member prevents the drug component from being eroded.

[0014] In some embodiments, the glass transition temperature (Tg) of the soluble delayed member is from about 10°C to about 190°C.

[0015] In some embodiments, the melting temperature (Tm) of the soluble delay member is from about 30°C to about 200°C.

[0016] In some embodiments, the soluble delay member includes a first matrix comprising a swellable material that swells in an aqueous medium environment.

[0017] In some embodiments, the soluble delay member further includes a second matrix comprising a second soluble material that does not mix with the drug.

[0018] In some embodiments, the first matrix is ​​uniformly mixed with the second matrix.

[0019] In some implementations, the second matrix is ​​soluble in an aqueous medium.

[0020] In some implementations, the second matrix is ​​insoluble in aqueous media.

[0021] In some embodiments, the weight percentage of the first matrix in the soluble delay member is 10% to 100%.

[0022] In some embodiments, the weight ratio of the second matrix in the soluble delay member is 0 to 90%.

[0023] In some embodiments, the first matrix is ​​selected from one or more of the following materials: hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyethylene oxide, polyvinyl alcohol, and methylcellulose.

[0024] In some embodiments, the second matrix is ​​selected from one or more of the following materials: soluble sugars, soluble sugar alcohols, soluble inorganic salts, soluble polymers, insoluble inorganic salts, and insoluble polymers.

[0025] In some embodiments, the second matrix is ​​selected from one or more of the following materials: maltodextrin, polyvinyl alcohol (PVA), microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and mannitol.

[0026] In some embodiments, the second matrix further includes one or more of the following materials: triethyl citrate, tributyl citrate, acetylated triacetic acid, tributyl citrate acetate, butyl stearate, glyceryl monostearate, stearyl alcohol, dibutyl sebacate, diethyl phthalate, dibutyl phthalate, dioctyl phosphate, polyethylene glycol, propylene glycol, glyceryl triacetate, castor oil, polyoxyethylene 40 hydrogenated castor oil, and medium-chain triglycerides.

[0027] In some implementations, the particle size D90 of the second matrix is ​​less than or equal to 600 micrometers.

[0028] In some implementations, the first and second matrices are mixed and then hot-melt extruded.

[0029] In some implementations, the temperature of the hot melt extrusion is from about 30°C to about 200°C.

[0030] In some embodiments, the density of the release-limiting component is 0.5 to 5 mg / mm³. 3 .

[0031] In some embodiments, the release restriction component includes a pH-responsive element configured to dissolve at or above a predetermined pH value.

[0032] In some embodiments, the pH-responsive member surrounds the drug assembly, and wherein the pH-responsive member prevents the drug assembly from being dissolved.

[0033] In some implementations, the pH-responsive component is configured to dissolve at pH values ​​of approximately 5.0 or higher.

[0034] In some embodiments, the release limiting component includes a soluble delay member and a pH-responsive member, the pH-responsive member surrounding the soluble delay member, and wherein the pH-responsive member prevents the soluble delay member from being etched, and wherein the soluble delay member prevents the drug component from being etched.

[0035] In some implementations, the drug is uniformly distributed within the drug component.

[0036] In some embodiments, the drug is distributed in the drug component as an amorphous solid dispersion.

[0037] In some embodiments, the drug component comprises drug particles containing a fourth soluble material mixed with the drug.

[0038] In some embodiments, the pharmaceutical component comprises a lipid-based composition comprising an oil phase mixed with the pharmaceutical product.

[0039] In some embodiments, the lipid-based composition further comprises one or more of a surfactant, a co-surfactant, a stabilizer, and a curing agent.

[0040] In some implementations, the pharmaceutical component comprises a first drug and a second drug.

[0041] In some implementations, the first drug and the second drug are the same.

[0042] In some implementations, the first drug and the second drug are different.

[0043] In some implementations, the drug component comprises a first drug particle and a second drug particle.

[0044] In some embodiments, the first drug particle comprises a fourth soluble material mixed with the first drug, and the second drug particle comprises a fifth soluble material mixed with the second drug.

[0045] In some implementations, the first drug particle and the second drug particle have the same composition.

[0046] In some implementations, the first drug particle and the second drug particle have different compositions.

[0047] In some embodiments, the pharmaceutical component comprises a first lipid-based composition and a second lipid-based composition.

[0048] In some embodiments, the first lipid-based composition and the second lipid-based composition have the same composition.

[0049] In some embodiments, the first lipid-based composition and the second lipid-based composition have different compositions.

[0050] In some implementations, the oral drug dosage form includes multiple drug components.

[0051] In some implementations, the composition of the multiple drug components is identical to that of each other.

[0052] In some implementations, at least two of the plurality of drug components have different compositions from each other.

[0053] In some implementations, the multiple drug components are the same size as each other.

[0054] In some implementations, at least two of the plurality of drug components are of different sizes.

[0055] In some implementations, the pharmaceutical component includes a first pharmaceutical component and a second pharmaceutical component.

[0056] In some embodiments, the first pharmaceutical component comprises a first soluble material mixed with a first pharmaceutical product; and the second pharmaceutical component comprises a third soluble material mixed with a second pharmaceutical product.

[0057] In some embodiments, the first soluble material and the third soluble material control the release of drugs from the first drug component and the second drug component, respectively.

[0058] In some implementations, the first soluble material and the third soluble material are the same.

[0059] In some implementations, the first soluble material and the third soluble material are different.

[0060] In some embodiments, the first drug component includes first drug particles, the first drug particles including a fourth soluble material mixed with the first drug.

[0061] In some embodiments, the second drug component comprises second drug particles, which contain a fifth soluble material mixed with the second drug.

[0062] In some implementations, the first drug and the second drug are the same.

[0063] In some implementations, the first drug and the second drug are different.

[0064] In some implementations, the release restriction component surrounds the first drug component and the second drug component.

[0065] In some implementations, the release-limiting components surrounding the first and second drug components have the same thickness.

[0066] In some implementations, the thickness of the release-limiting components surrounding the first and second drug components is different.

[0067] In some embodiments, the release limiting component includes a soluble delay member that surrounds the first drug component and the second drug component.

[0068] In some implementations, the soluble delay member surrounding the first and second drug components has the same thickness.

[0069] In some implementations, the thickness of the soluble delay member surrounding the first and second drug components is different.

[0070] In some embodiments, the release limiting component includes a pH-responsive member that surrounds the first drug component and the second drug component.

[0071] In some implementations, the pH-responsive components surrounding the first and second drug components have the same thickness.

[0072] In some implementations, the thickness of the pH-responsive member surrounding the first and second drug components is different.

[0073] In some implementations, the release restraint component has a top surface, a side surface, and a bottom surface.

[0074] In some implementations, the top, side, and bottom surfaces have the same thickness.

[0075] In some implementations, the top, side, and bottom surfaces have the same erosion rate.

[0076] In some implementations, the top, side, and bottom surfaces are etched at the same time.

[0077] In some respects, this article provides a method for preparing the oral drug dosage form described herein, the method comprising three-dimensional (3D) printing of the oral drug dosage form.

[0078] In some embodiments, the method includes: distributing materials according to a layer-by-layer model of an oral drug dosage form to print the oral drug dosage form, wherein each layer of the layer-by-layer model is printed by distributing, as needed, the following materials: (a) a drug component comprising a first soluble material mixed with the drug; (b) a soluble delayed member comprising a second soluble material not mixed with the drug; and (c) a pH-responsive member comprising a pH-based enteric material not mixed with the drug.

[0079] In some embodiments, the method includes a method for preparing drug particles: (a) premixing the drug with a fourth soluble material and then filling it in a single-screw or twin-screw extruder; (b) rotating the screw to further extrude the physical mixture while the extruder jacket is heated to a high temperature; (c) melting and kneading the drug and the fourth soluble material, and continuously extruding the melt from the end plate and / or dies of different shapes; (d) pulverizing and sieving.

[0080] In some embodiments, the method includes: distributing materials according to a layer-by-layer model of an oral drug dosage form to print the oral drug dosage form, wherein each layer of the layer-by-layer model is printed by distributing, as needed, the following materials: (a) a drug component comprising a first soluble material mixed with drug particles; (b) a soluble delayed member comprising a second soluble material not mixed with drug particles; and (c) a pH-responsive member comprising a pH-based enteric material not mixed with drug particles.

[0081] In some embodiments, the method includes a method for preparing a lipid-based composition by mixing the components evenly according to the prescribed amounts.

[0082] In some embodiments, the method includes: (a) uniformly mixing the components of a lipid-based composition and loading them into a printhead; (b) dispensing a soluble delay member comprising a second soluble material that is not mixed with the drug and 3D printing to form a cavity; (c) extruding the lipid-based composition into the cavity of the soluble delay member; and (d) 3D printing to seal the soluble delay member. In some embodiments, the method further includes: (e) 3D printing a pH-responsive member of a pH-based enteric material that is not mixed with the drug.

[0083] In some embodiments, the method includes: (a) uniformly mixing the components of the lipid-based composition and loading them into a printhead; (b) dispensing a pH-responsive member of a pH-based enteric material that is not mixed with the drug and 3D printing it to form a cavity; (c) extruding the lipid-based composition into the cavity of the pH-responsive member; and (d) 3D printing the pH-responsive member to seal it.

[0084] In some embodiments, the method includes: distributing materials according to a layer-by-layer model of an oral drug dosage form to print the oral drug dosage form, wherein each layer of the layer-by-layer model is printed by distributing materials as needed to: (a) distributing the drug component; (b) distributing the etchable delay member; (c) injection molding the pH-responsive member; and (d) assembling the drug component and the etchable delay member into the pH-responsive member to form the oral drug dosage form.

[0085] In some embodiments, the method includes a method for preparing a soluble delay component: (a) premixing the components of the soluble delay component and filling them into a single-screw or twin-screw extruder; (b) rotating the screw to further extrude the physical mixture, setting the temperature of different functional blocks in the heating section from the outlet to the inlet, and turning on the heating to prepare the melt; (c) extruding the melt from the nozzle and depositing it layer by layer.

[0086] In some implementations, the heating temperature is from about 30°C to about 190°C.

[0087] In some respects, this paper provides a 3D printing method for oral drug dosage forms, the method comprising: (a) positioning a first print head at a target printing position, the first print head printing layers 1 to N and N+M of a release control component, wherein the N+M layer and the N layer form a cavity; (b) positioning a second print head at the target printing position, the second print head printing a drug component within the cavity; and (c) positioning the first print head at the target printing position, the first print head printing layer O of the release control component; wherein N, M, and O are all positive integers less than or equal to 10.

[0088] In some implementations, the second printhead prints X layers of drug components, where X is a positive integer less than or equal to 5.

[0089] In some embodiments, (b) includes: (b1) positioning a second printhead at the target printing position, the second printhead printing a drug component within the cavity; (b2) positioning a first printhead at the target printing position, the first printhead printing the N+M+K layers of the release control component (K being a positive integer less than or equal to 6), the N+M+K layers forming a cavity with the X layer of the drug component; and (b3) positioning a second printhead at the target printing position, the second printhead printing a drug component within the cavity.

[0090] In some implementations, (b) also includes (b4) repeating (b2) and (b3).

[0091] In some implementations, the O layer is equal to the N layer.

[0092] In some implementations, the printing temperature of the first printhead print release control assembly is from about 30°C to about 200°C.

[0093] In some implementations, the Nth and Oth layers are circular in shape.

[0094] In some implementations, the Mth and Kth layers are annular in shape. Attached Figure Description

[0095] Figures 1A to 1H illustrate schematic diagrams of exemplary oral drug dosage forms provided herein.

[0096] Figures 2A to 2D show various cross-sectional views of the exemplary oral drug dosage forms provided herein.

[0097] Figure 3 shows a photograph of the size measurements of an exemplary oral drug dosage form provided herein.

[0098] Figure 4 shows a surface photograph of an exemplary oral drug dosage form provided herein.

[0099] Figure 5 shows the in vitro dissolution profiles of the exemplary oral drug dosage form provided herein.

[0100] Figure 6 shows the in vivo PK curves of the exemplary oral drug dosage form provided herein.

[0101] Figure 7 illustrates the time-series X-ray images of the exemplary oral drug dosage form provided herein.

[0102] Figure 8 shows the in vitro dissolution profiles of the exemplary oral drug dosage form provided herein.

[0103] Figure 9 shows the in vitro dissolution profiles of the exemplary oral drug dosage forms provided herein.

[0104] Figure 10 illustrates the in vitro dissolution phenomenon of the exemplary oral drug dosage form provided herein.

[0105] Figure 11 illustrates a 3D printing apparatus for preparing the exemplary oral drug dosage form provided herein.

[0106] Figure 12 shows a flowchart of a 3D printing method for preparing an exemplary oral drug dosage form provided herein.

[0107] Figures 13A and 13B show various cross-sectional views of the exemplary oral drug dosage forms provided herein.

[0108] Figure 14 shows the in vitro dissolution profiles of the exemplary oral drug dosage forms provided herein.

[0109] Figure 15 shows the in vitro dissolution profiles of the exemplary oral drug dosage forms provided herein.

[0110] Figure 16 shows the in vitro dissolution profiles of the exemplary oral drug dosage forms provided herein.

[0111] Figure 17 shows the in vitro dissolution profiles of the exemplary oral drug dosage forms provided herein. Detailed Implementation

[0112] In some aspects, this document provides a delayed-release oral drug dosage form comprising: a drug component including a first soluble material mixed with a drug; and a release-limiting component surrounding the drug component and preventing the release of the drug from the oral drug dosage form for approximately 2 hours to approximately 7 hours after administration to a human individual. In some embodiments, the oral drug dosage form is configured to release the drug according to a desired release profile. In some embodiments, the oral drug dosage form is configured such that substantially all (e.g., approximately 100%) of the drug in the oral drug dosage form is released in the ileum of an individual. In some embodiments, the oral drug dosage form is configured to precisely deliver the drug to the ileum for release, avoiding off-target toxicity. In some embodiments, the oral drug dosage form is administered as a single tablet, effectively preventing drug dispersion before reaching the desired gastrointestinal site and reducing inter-individual variability. In some embodiments, the oral drug dosage form is less affected by the pH value within the human individual, reducing inter-individual variability.

[0113] The oral drug dosage forms described herein are based on the inventors’ unique insights and discoveries regarding the design and manufacture of oral drug dosage forms for precise delivery of drugs in the ileum of the gastrointestinal tract. As taught and demonstrated herein, in certain respects, oral drug dosage forms are capable of delivering drugs entirely through the ileum (including complete delivery within a specific area of ​​the ileum), which enables the maximization of the therapeutic effect of certain drugs while minimizing side effects caused by release of the drug in another area of ​​the gastrointestinal tract. For example, when undesirable absorption occurs due to release of the drug in another area of ​​the gastrointestinal tract, corresponding toxicity or side effects may result.

[0114] The oral drug formulations described in this article can precisely deliver the active pharmaceutical ingredient to the desired location and release it in a controlled manner.

[0115] IgA nephropathy (IgAN), sometimes called Berger's disease, is a serious, progressive autoimmune disease of the kidneys, with up to 50% of patients at risk of developing end-stage renal disease (ESRD) within ten to twenty years. Although IgAN is expressed in the kidneys, most scientific research has found that the pathogenesis of IgAN begins in the ileum, the last part of the small intestine before the large intestine. Patches of lymphoid tissue, called Peyer's patches, are mainly found in the ileum, where they produce and secrete IgA antibodies. For patients with advanced IgAN, clinicians can treat them with systemic immunosuppressants, primarily consisting of high-dose systemic corticosteroids such as prednisone, prednisolone, and methylprednisolone. While some published reports suggest these medications can reduce proteinuria, this high dose of systemic corticosteroids is also associated with a wide range of adverse events, including hypertension, weight gain, diabetes, serious infections, and osteoporosis. Therefore, in attempting to meet the current clinical need for effective treatment of IgAN, there is a clear need for new and / or modified treatments for IgAN that utilize effective local therapy with immunosuppressants to reduce or avoid such side effects. The oral dosage forms described in this article can precisely target the ileum, reduce off-target toxicity, increase efficacy, thereby shortening the treatment duration and consequently reducing the amount of medication (e.g., corticosteroids, such as budesonide) ingested by the patient during a treatment cycle, thus reducing or avoiding drug side effects.

[0116] The oral medication formulations described in this article can reduce the size or volume of the medication at the same dosage, making them particularly suitable for patients with dysphagia.

[0117] Therefore, in some aspects, this document provides a delayed-release oral drug dosage form comprising: a drug component including a first soluble material mixable with the drug; and a soluble delay member including a second soluble material not mixable with the drug; wherein the soluble delay member prevents the erosion of the drug component. In some embodiments, the oral drug dosage form is configured to release the drug according to a desired release profile.

[0118] In some aspects, this document provides a delayed-release oral drug dosage form comprising: a drug component including a first soluble material mixed with a drug; a pH-responsive member configured to dissolve at or above a predetermined pH value; wherein the pH-responsive member surrounds the drug component and prevents dissolution of the drug component. In some embodiments, the oral drug dosage form is configured to release the drug according to a desired release profile.

[0119] In some aspects, this document provides a delayed-release oral drug dosage form comprising: a drug component including a first soluble material mixable with the drug; a soluble delay member including a second soluble material not mixable with the drug; and a pH-responsive member configured to dissolve at or above a predetermined pH value; wherein the pH-responsive member surrounds the soluble delay member and prevents dissolution of the soluble delay member, and the soluble delay member prevents dissolution of the drug component. In some embodiments, the oral drug dosage form is configured to release the drug according to a desired release profile.

[0120] In some aspects, this document provides a delayed-release oral drug dosage form comprising: a first drug component comprising a first soluble material mixed with a first drug; a second drug component comprising a third soluble material mixed with a second drug; and a release-limiting component; wherein the first and third soluble materials control the release of the drug from the first and second drug components, respectively, and wherein the release-limiting component surrounds the first and second drug components, preventing the release of the drug from the oral drug dosage form from the oral drug dosage form for approximately 2 hours to approximately 7 hours after administration to a human individual. In some embodiments, the oral drug dosage form is configured to release the drug according to a desired release profile. In some embodiments, the first and second drugs are the same. In some embodiments, the first and second drugs are different. In some embodiments, the first and third soluble materials are the same. In some embodiments, the first and third soluble materials are different. In some embodiments, the first and second drug components have the same dimensions. In some embodiments, the first drug component and the second drug component have different dimensions. In some embodiments, the release-limiting components surrounding the first drug component and the second drug component have the same thickness. In some embodiments, the release-limiting components surrounding the first drug component and the second drug component have different thicknesses.

[0121] In some aspects, this document provides a delayed-release oral drug dosage form comprising: a first drug component comprising a first soluble material mixed with a first drug; a second drug component comprising a third soluble material mixed with a second drug; and a soluble delay member comprising a second soluble material not mixed with the drug; wherein the first and third soluble materials control the release of the drug from the first and second drug components, respectively, and wherein the soluble delay member surrounds the first and second drug components, preventing the release of the drug from the oral drug dosage form from the oral drug dosage form for approximately 2 hours to approximately 7 hours after administration to a human individual. In some embodiments, the oral drug dosage form is configured to release the drug according to a desired release profile. In some embodiments, the first and second drugs are the same. In some embodiments, the first and second drugs are different. In some embodiments, the first and third soluble materials are the same. In some embodiments, the first and third soluble materials are different. In some embodiments, the first drug component and the second drug component have the same dimensions. In some embodiments, the first drug component and the second drug component have different dimensions. In some embodiments, the soluble delay member surrounding the first drug component and the second drug component has the same thickness. In some embodiments, the soluble delay member surrounding the first drug component and the second drug component has different thicknesses.

[0122] In some aspects, this document provides a delayed-release oral drug dosage form comprising: a first drug component comprising a first soluble material mixed with a first drug; a second drug component comprising a third soluble material mixed with a second drug; and a pH-responsive member configured to dissolve at or above a predetermined pH value; wherein the first and third soluble materials control the release of the drug from the first and second drug components, respectively, and wherein the pH-responsive member surrounds the first and second drug components, preventing the release of the drug from the oral drug dosage form from the oral drug dosage form for approximately 2 hours to approximately 7 hours after administration to a human individual. In some embodiments, the oral drug dosage form is configured to release the drug according to a desired release profile. In some embodiments, the first and second drugs are the same. In some embodiments, the first and second drugs are different. In some embodiments, the first and third soluble materials are the same. In some embodiments, the first soluble material and the third soluble material are different. In some embodiments, the first drug component and the second drug component have the same size. In some embodiments, the first drug component and the second drug component have different sizes. In some embodiments, the pH-responsive member surrounding the first drug component and the second drug component has the same thickness. In some embodiments, the pH-responsive member surrounding the first drug component and the second drug component has different thicknesses.

[0123] In some aspects, this document provides a delayed-release oral drug dosage form comprising: a first drug component comprising a first soluble material mixed with a first drug; a second drug component comprising a third soluble material mixed with a second drug; a soluble delay member comprising a second soluble material not mixed with the drug; and a pH-responsive member configured to erode at or above a predetermined pH value; wherein the first and third soluble materials control the release of the drug from the first and second drug components, respectively, and wherein the pH-responsive member surrounds the soluble delay member, which in turn surrounds the first and second drug components, preventing erosion of the soluble delay member. In some embodiments, the oral drug dosage form is configured to release the drug according to a desired release profile. In some embodiments, the first and second drugs are identical. In some embodiments, the first drug and the second drug are different. In some embodiments, the first soluble material and the third soluble material are the same. In some embodiments, the first soluble material and the third soluble material are different. In some embodiments, the first drug assembly and the second drug assembly have the same dimensions. In some embodiments, the first drug assembly and the second drug assembly have different dimensions. In some embodiments, the soluble delay member surrounding the first drug assembly and the second drug assembly has the same thickness. In some embodiments, the soluble delay member surrounding the first drug assembly and the second drug assembly has different thicknesses.

[0124] In some aspects, this document provides a delayed-release oral drug dosage form comprising: a drug component including a first drug and a second drug, and a first soluble material mixed with the first drug and the second drug; a release-limiting component surrounding the drug component and preventing the release of the drug from the oral drug dosage form from approximately 2 hours to approximately 7 hours after administration to a human individual. In some embodiments, the oral drug dosage form is configured to release the drug according to a desired release profile. In some embodiments, the first drug and the second drug are the same. In some embodiments, the first drug and the second drug are different.

[0125] In some aspects, this document provides a delayed-release oral drug dosage form comprising: a drug component including a first drug and a second drug, and a first soluble material mixed with the first and second drugs; and a soluble delay member including a second soluble material not mixed with the drugs; wherein the soluble delay member prevents the erosion of the drug component. In some embodiments, the oral drug dosage form is configured to release the drug according to a desired release profile. In some embodiments, the first drug and the second drug are the same. In some embodiments, the first drug and the second drug are different.

[0126] In some aspects, this document provides a delayed-release oral drug dosage form comprising: a drug component including a first drug and a second drug, and a first soluble material mixed with the first drug and the second drug; a pH-responsive member configured to dissolve at or above a predetermined pH value; wherein the pH-responsive member surrounds the drug component, and wherein the pH-responsive member prevents the dissolution of the drug component. In some embodiments, the oral drug dosage form is configured to release the drug according to a desired release profile. In some embodiments, the first drug and the second drug are the same. In some embodiments, the first drug and the second drug are different.

[0127] In some aspects, this document provides a delayed-release oral drug dosage form comprising: a drug component including a first drug and a second drug, and a first soluble material mixed with the first drug and the second drug; a soluble delay member including a second soluble material not mixed with the drug; and a pH-responsive member configured to erode at or above a predetermined pH value; wherein the pH-responsive member surrounds the soluble delay member and prevents erosion of the soluble delay member, and the soluble delay member prevents erosion of the drug component. In some embodiments, the oral drug dosage form is configured to release the drug according to a desired release profile. In some embodiments, the first drug and the second drug are the same. In some embodiments, the first drug and the second drug are different.

[0128] In some embodiments, the drug is uniformly distributed within the drug assembly. In some embodiments, the drug is distributed within the drug assembly as an amorphous solid dispersion.

[0129] In some embodiments, the drug described herein is contained in drug particles. In some embodiments, the drug assembly described herein comprises drug particles containing a soluble material mixed with the drug. In some embodiments, the drug assembly described herein comprises a first drug particle and a second drug particle. In some embodiments, the first drug assembly and the second drug assembly described herein each comprise a first drug particle and a second drug particle, respectively.

[0130] In some embodiments, the medicament described herein is present in a lipid-based composition. In some embodiments, the pharmaceutical component described herein comprises a lipid-based composition comprising an oil phase mixed with the medicament. In some embodiments, the pharmaceutical component described herein comprises a first lipid-based composition and a second lipid-based composition. In some embodiments, the first pharmaceutical component and the second pharmaceutical component described herein each comprise a first lipid-based composition and a second lipid-based composition. In some embodiments, the lipid-based composition described herein is a self-emulsifying drug delivery system (SEDDS).

[0131] In other respects, this document provides commercial batches of any of the oral drug 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 amount of drug in the oral drug dosage form; the weight of the oral drug dosage form; the maximum span dimension of the oral drug dosage form; the span dimension of the oral drug dosage form perpendicular to the maximum span dimension; the diameter of the oral drug dosage form; or the particle size of the drug particles.

[0132] In other respects, this document provides a method for preparing any of the oral drug dosage forms described herein, the method comprising three-dimensional (3D) printing the oral drug dosage form. In some embodiments, the oral drug dosage form includes: a drug component comprising a first soluble material mixed with a drug; and a release-limiting component, wherein the method includes: (a) dispensing the drug component; and (b) dispensing the release-limiting component to form the oral drug dosage form.

[0133] In other respects, this document provides a method for preparing any of the oral drug dosage forms described herein, the method comprising three-dimensional (3D) printing the oral drug dosage form. In some embodiments, the oral drug dosage form comprises: a drug component comprising a first etchable material mixed with a drug; and an etchable delay member comprising a second etchable material not mixed with the drug; wherein the method comprises: (a) dispensing the drug component; and (b) dispensing the etchable delay member to form the oral drug dosage form.

[0134] In other respects, this document provides a method for preparing any of the oral drug dosage forms described herein, the method comprising three-dimensional (3D) printing the oral drug dosage form. In some embodiments, the oral drug dosage form includes: a drug component comprising a first soluble material mixed with a drug; and a pH-responsive member configured to dissolve at or above a predetermined pH value, wherein the method includes: (a) dispensing the drug component; and (b) dispensing the pH-responsive member to form the oral drug dosage form.

[0135] In other respects, this document provides a method for preparing any of the oral drug dosage forms described herein, the method comprising three-dimensionally (3D) printing the oral drug dosage form. In some embodiments, the oral drug dosage form includes: a drug component comprising a first etchable material mixed with a drug; an etchable delay member comprising a second etchable material not mixed with the drug; and a pH-responsive member configured to etch at or above a predetermined pH value, wherein the method includes: (a) dispensing the drug component; (b) dispensing the etchable delay member; and (c) dispensing the pH-responsive member to form the oral drug dosage form.

[0136] In other respects, this document provides a method for preparing any of the oral drug dosage forms described herein, the method comprising three-dimensionally (3D) printing the oral drug dosage form. In some embodiments, the oral drug dosage form includes: a drug component comprising a first soluble material mixed with a drug; and a pH-responsive member configured to dissolve at or above a predetermined pH value, wherein the method includes: (a) dispensing the drug component; (b) injection molding the pH-responsive member; and (c) assembling the drug component into the pH-responsive member to form the oral drug dosage form.

[0137] In other respects, this document provides a method for preparing any of the oral drug dosage forms described herein, the method comprising three-dimensionally (3D) printing the oral drug dosage form. In some embodiments, the oral drug dosage form includes: a drug component comprising a first etchable material mixed with a drug; an etchable delay member comprising a second etchable material not mixed with the drug; and a pH-responsive member configured to etch at or above a predetermined pH value, wherein the method includes: (a) dispensing the drug component; (b) dispensing the etchable delay member; (c) injection molding the pH-responsive member; and (d) assembling the drug component and the etchable delay member into the pH-responsive member to form the oral drug dosage form.

[0138] In other respects, this document provides methods for preparing any of the oral drug dosage forms described herein, the methods further comprising methods for preparing drug particles: (a) premixing the drug with a soluble material and filling it in a single-screw or twin-screw extruder; (b) rotating the screw to further extrude the physical mixture while the extruder jacket is heated to a high temperature; (c) melting and kneading the drug and the soluble material, the melt being continuously extruded from the end plate and / or dies of different shapes; (d) pulverizing and sieving.

[0139] I. Terminology Definition

[0140] For the purposes of interpreting this specification, the following definitions shall apply. In the event of any conflict between any definition set forth below and any reference incorporated herein by reference, the definition set forth herein shall prevail.

[0141] As used herein, the term "treatment" or its equivalents refer to methods for achieving beneficial or desired outcomes, including, for example, relief of symptoms of a disease. For the purposes of this disclosure, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: relief of one or more symptoms caused by a disease, reduction of the severity of one or more symptoms caused by a disease, prevention of an increase in the severity of one or more symptoms caused by a disease, reduction of the dosage of one or more other medications required for the treatment and / or control of a disease, and improvement of quality of life.

[0142] As used herein, the term "individual" refers to a mammal, and includes, but is not limited to, humans, cattle, horses, cats, dogs, rodents, rats, mice, dogs, or primates. In some embodiments, the individual is a human individual.

[0143] As used herein, the terms “comprising,” “having,” “containing,” and “including,” as well as other similar forms and their grammatically equivalent terms, are intended to be equivalent in meaning and are open-ended, meaning that one or more items following any of these words are not intended to be an exhaustive list of those one or more items, nor are they intended to be limited to the one or more items listed. For example, an article of manufacture that “comprising” components A, B, and C may consist of components A, B, and C (i.e., containing only components A, B, and C), or may contain not only components A, B, and C, but also one or more other components. Thus, it is intended to be understood that the terms “comprising” and their similar forms and grammatically equivalent terms include disclosures of embodiments that are “substantially composed of” or “composed of.”

[0144] It should be understood that, unless the context explicitly indicates otherwise, when providing a range of values, every intermediate value (accurate to one-tenth of the lower limit unit) between the upper and lower limits of that range, and any other declared value or intermediate value within that declared range, is also included in this disclosure and is subject to any expressly excluded limit value within the declared range. When a declared range includes one or both limit values, the range excluding any one or both of those included limit values ​​is also included in this disclosure.

[0145] References to “about” values ​​or parameters in this document include (and describe) variations of that value or parameter itself. For example, a description of “about X” includes a description of “X”.

[0146] As used herein, the term “capsule-shaped” or its equivalents refer to an elongated shape comprising two parallel lines and two arcs, wherein the two parallel lines are connected by two arcs when viewed from the front, and includes a circle when viewed from a vertical plane.

[0147] As used herein, the term "particle" or its equivalents refer to particles with an average particle size of 0.1 μm to 1000 μm, and include, but are not limited to, solid, liquid, and semi-solid forms. Solid particles include, but are not limited to, granular and powder forms, while liquid particles include, but are not limited to, droplets and oil droplets. In some embodiments, the particles are in granular form. In some embodiments, the particles are in powder form.

[0148] As used herein, the term "hot melt extrusion" or its equivalents refer to the process of heating and melting components into a liquid or semi-solid state, and then extruding them through a die. In some embodiments, the die refers to a nozzle, syringe nozzle, or other device capable of deforming the melt.

[0149] As used herein (including the appended claims), unless the context clearly indicates otherwise, the singular forms “a,” “or,” and “the” include plural references.

[0150] II. Oral drug dosage forms

[0151] In some aspects, this document provides a delayed-release oral drug dosage form comprising: a drug component including a first soluble material mixable with the drug; and a release-limiting component; wherein the release-limiting component surrounds the drug component and prevents the drug from being released from the oral drug dosage form for about 2 hours to about 7 hours after administration to a human individual. In some embodiments, the release-limiting component includes a soluble delay member comprising a second soluble material not mixable with the drug, the soluble delay member surrounding the drug component. In some embodiments, the release-limiting component includes a pH-responsive member configured to erode at or above a predetermined pH value, the pH-responsive member surrounding the drug component. In some embodiments, the release-limiting component includes a soluble delay member and a pH-responsive member, the pH-responsive member surrounding the soluble delay member, the soluble delay member surrounding the drug component. In some embodiments, the pH-responsive component is etched at or above a predetermined pH value, the predetermined pH value being about 5.0. In some embodiments, the predetermined pH value is about 5.5. In some embodiments, the predetermined pH value is about 6.3. In some embodiments, the drug component comprises one or more drugs. In some embodiments, at least two of the multiple drugs are different from each other. In some embodiments, the delayed-release oral drug dosage form comprises one or more drug components. In some embodiments, the drugs in the multiple drug components are the same. In some embodiments, the drugs in at least two of the multiple drug components are different. In some embodiments, the soluble materials in the multiple drug components are the same. In some embodiments, the soluble materials in at least two of the multiple drug components are different. In some embodiments, the multiple drug components are the same size. In some embodiments, at least two of the multiple drug components are different sizes. In some embodiments, the multiple drug components have the same composition. In some embodiments, at least two of the multiple drug components have different compositions. In some embodiments, the drug is uniformly distributed in the drug component. In some embodiments, the drug is distributed in the drug assembly as an amorphous solid dispersion. In some embodiments, the drug described herein is present in drug particles. In some embodiments, the drug assembly described herein comprises drug particles containing a soluble material mixed with the drug. In some embodiments, the drug assembly described herein comprises a first drug particle and a second drug particle. In some embodiments, the first drug assembly and the second drug assembly described herein each comprise a first drug particle and a second drug particle, respectively.

[0152] The oral drug dosage forms disclosed herein may include various combinations of the components described herein and may be arranged in various configurational arrays. Such components and their configurations for forming oral drug dosage forms are configured to achieve a desired drug release profile. In some cases, such components and configurations are described in a modular manner, and such description is not intended to limit the scope of the oral drug dosage forms covered herein.

[0153] In some embodiments, the oral drug dosage form described herein has a substantially flat top surface and a substantially flat bottom surface. In some embodiments, the thickness measured between the top and bottom surfaces of the oral drug 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.

[0154] In some embodiments, the top and / or bottom surfaces of the oral drug dosage form are not flat. In some embodiments, the top and / or bottom surfaces of the oral drug dosage form are marked with markings (such as text markings or graphic markings).

[0155] In some implementations, the oral drug formulations disclosed herein can reduce the size or volume of the drug at the same dosage, resulting in better patient compliance.

[0156] For illustrative purposes and to facilitate understanding of certain components and their configurations, Figures 1A through 1H provide cross-sectional views of exemplary oral drug dosage forms described herein.

[0157] In some aspects of this disclosure, as shown in FIG1A, an exemplary oral drug dosage form includes a drug component and a release-limiting component. As shown in FIG1A, the drug component has a top surface, a side surface, and a bottom surface, and the release-limiting component has a top surface, a side surface, and a bottom surface. In some embodiments, the release-limiting component surrounds the drug component. The oral drug dosage form of FIG1A is configured such that, upon administration to a human individual and exposure to bodily fluids, the top surface, side surface, and bottom surface of the release-limiting component are simultaneously exposed to and eroded by the bodily fluids. In some embodiments, the top surface, side surface, and bottom surface of the release-limiting component are eroded, and subsequently, the top surface, side surface, and bottom surface of the drug component are simultaneously exposed to bodily fluids and begin to erode. The release-limiting component surface of the oral drug dosage form of FIG1A is dense and non-porous, and upon administration to a human individual and exposure to bodily fluids, a gel layer forms on the first matrix surface and gradually erodes, effectively preventing the crystallization of poorly soluble drugs. In some embodiments, the drug initiation time is adjusted by regulating the composition or thickness of the release-limiting component. For example, increasing the thickness of the release-limiting component can further delay the initial release time of the drug; decreasing the thickness of the release-limiting component can reduce the delayed release time of the drug. In some embodiments, the top, side, and bottom surfaces of the release-limiting component have the same thickness. In some embodiments, the drug is uniformly mixed with a soluble material to form the drug assembly. In some embodiments, the drug is distributed in the drug assembly as an amorphous solid dispersion. In some embodiments, the drug is first mixed with a first soluble material to form drug particles, and then the drug particles are mixed with a fourth soluble material to form the drug assembly.

[0158] In some aspects of this disclosure, as shown in FIG1B, an exemplary oral drug dosage form includes: a drug component comprising a first soluble material mixed with the drug; a soluble etch-delay member comprising a second soluble material not mixed with the drug; and a pH-responsive member configured to etch at or above a predetermined pH value. As shown in FIG1B, the drug component has a top surface, side surfaces, and a bottom surface; the soluble etch-delay member has a top surface, side surfaces, and a bottom surface; and the pH-responsive member has a top surface, side surfaces, and a bottom surface. In some embodiments, the pH-responsive member surrounds the soluble etch-delay member, which in turn surrounds the drug component. The oral drug dosage form of FIG1B is configured such that, upon administration to a human individual and exposure to bodily fluids, the top, side, and bottom surfaces of the pH-responsive member are simultaneously exposed to bodily fluids and etched at or above a predetermined pH value, subsequently exposing the top, side, and bottom surfaces of the soluble etch-delay member to bodily fluids and initiating etch. The top, side, and bottom surfaces of the soluble delay component are etched, subsequently exposing the top, side, and bottom surfaces of the drug assembly to body fluids and initiating etch. The pH-responsive component etches at or above a predetermined pH value, which is approximately 5.0. In some embodiments, the predetermined pH value is approximately 5.5. In some embodiments, the predetermined pH value is approximately 6.3. This pH-responsive component allows the drug to pass completely through the stomach, avoiding the influence of food on drug release.

[0159] In some aspects of this disclosure, as shown in FIG1C, an exemplary oral drug dosage form includes: a drug component comprising a first soluble material mixed with a drug; and a release-limiting component. As shown in FIG1C, the drug component has a top surface, a side surface, and a bottom surface, and the release-limiting component has a top surface, a side surface, and a bottom surface. In some embodiments, the release-limiting component surrounds the drug component. The oral drug dosage form of FIG1C is configured such that, upon administration to a human individual and exposure to bodily fluids, the top surface, side surface, and bottom surface of the release-limiting component are simultaneously exposed to and eroded by the bodily fluids.

[0160] In some aspects of this disclosure, as shown in FIG1D, an exemplary oral drug dosage form includes: a drug component; and a release-limiting component comprising a first matrix and a second matrix. In some embodiments, the first matrix is ​​selected from one or more of the following materials: hydroxypropyl cellulose, hydroxypropyl methylcellulose, and hydroxyethyl cellulose. In some embodiments, the second matrix is ​​selected from one or more of the following materials: soluble sugars, soluble sugar alcohols, soluble inorganic salts, soluble polymers, insoluble inorganic salts, and insoluble polymers. In some embodiments, the second matrix further includes one or more of the following materials: triethyl citrate, tributyl citrate, acetylated triacetic acid, tributyl acetate citrate, butyl stearate, glyceryl monostearate, stearyl alcohol, dibutyl sebacate, diethyl phthalate, dibutyl phthalate, dioctyl phosphate, polyethylene glycol, propylene glycol, triacetic acid glyceride, castor oil, polyoxyethylene 40 hydrogenated castor oil, and medium-chain triglycerides. This second matrix can reduce the printing temperature of the release restriction component during the fabrication process, thus avoiding the impact of high temperature on the component's component stability.

[0161] In some aspects of this disclosure, as shown in FIG1E, an exemplary oral drug dosage form includes: a first drug component comprising a first soluble material mixed with a drug; a second drug component comprising a third soluble material mixed with a drug; and a release-limiting component comprising a first matrix; wherein the first soluble material and the third soluble material respectively control the release of the drug from the first drug component and the second drug component, and wherein the release-limiting component surrounds the first drug component and the second drug component. As shown in FIG1E, the first drug component and the second drug component each have a top surface, a side surface, and a bottom surface, and the release-limiting component has a top surface, a side surface, and a bottom surface. In some embodiments, the release-limiting component surrounds the first drug component and the second drug component. In some embodiments, the release time of the drug in the first drug component and the second drug component is adjusted by adjusting the thickness of the release-limiting component surrounding the first drug component and the second drug component, respectively. In some embodiments, the thickness of the release-limiting component surrounding the first drug component and the second drug component is the same, and the first drug component and the second drug component are simultaneously exposed to body fluids as the top surface, side surface, and bottom surface of the release-limiting component are eroded. In some embodiments, the thickness of the release-limiting component surrounding the first drug component and at the location of the first drug component differs, and the first and second drug components are not simultaneously exposed to body fluids as the top, side, and bottom surfaces of the release-limiting component are eroded. The oral drug dosage form of Figure 1E is configured such that, when administered to a human individual and affected by body fluids, the top, side, and bottom surfaces of the release-limiting component are simultaneously exposed to body fluids and simultaneously eroded.

[0162] In some aspects of this disclosure, as shown in FIG1F, an exemplary oral drug dosage form includes: a first drug component comprising a first soluble material mixed with a first drug; a second drug component comprising a third soluble material mixed with a second drug; and a release-limiting component comprising a first matrix; wherein the first soluble material and the third soluble material respectively control the release of the drug from the first drug component and the second drug component, and wherein the release-limiting component surrounds the first drug component and the second drug component. As shown in FIG1F, the first drug component and the second drug component each have a top surface, a side surface, and a bottom surface, and the release-limiting component has a top surface, a side surface, and a bottom surface. In some embodiments, the release-limiting component surrounds the first drug component and the second drug component. In some embodiments, the release time of the drug in the first drug component and the second drug component is adjusted by adjusting the thickness of the release-limiting component surrounding the first drug component and the second drug component, respectively. In some embodiments, the thickness of the release-limiting component surrounding the first drug component and the second drug component is the same, and the first drug component and the second drug component are simultaneously exposed to body fluids as the top surface, side surface, and bottom surface of the release-limiting component are eroded. In some embodiments, the thickness of the release-limiting component surrounding the first drug component and at the location of the first drug component differs, and the first and second drug components are not simultaneously exposed to body fluids as the top, side, and bottom surfaces of the release-limiting component are eroded. The oral drug dosage form of Figure 1F is configured such that, upon administration to a human individual and exposure to body fluids, the top, side, and bottom surfaces of the release-limiting component are simultaneously exposed to and eroded by body fluids. In some embodiments, the first drug and the second drug are different.

[0163] In some aspects of this disclosure, as shown in FIG1G, an exemplary oral drug dosage form includes: a drug component comprising a first drug and a second drug, and a first soluble material mixed with the first drug and the second drug; and a release-limiting component comprising a first matrix and a second matrix; wherein the release-limiting component surrounds the drug component. As shown in FIG1G, the drug component has a top surface, a side surface, and a bottom surface, and the release-limiting component has a top surface, a side surface, and a bottom surface. The oral drug dosage form of FIG1G is configured such that, upon administration to a human individual and exposure to bodily fluids, the top surface, side surface, and bottom surface of the release-limiting component are simultaneously exposed to bodily fluids and simultaneously eroded. In some embodiments, the top surface, side surface, and bottom surface of the release-limiting component are eroded, subsequently the top surface, side surface, and bottom surface of the drug component are simultaneously exposed to bodily fluids and begin to erode. In some embodiments, the second matrix is ​​selected from one or more of the following materials: soluble sugars, soluble sugar alcohols, soluble inorganic salts, soluble polymers, insoluble inorganic salts, and insoluble polymers. In some embodiments, the second matrix contains a plasticizer. This plasticizer lowers the printing temperature of the release-limiting component during the hot melt extrusion process, avoiding the impact of high temperatures on the component stability of the release-limiting component.

[0164] In some aspects of this disclosure, as shown in FIG1H, an exemplary oral drug dosage form includes: a drug component comprising drug particles, the drug particles comprising a fourth soluble material mixed with the drug; and a first soluble material mixed with the drug particles; and a release-limiting component comprising a first matrix. As shown in FIG1H, the drug component has a top surface, a side surface, and a bottom surface, and the release-limiting component has a top surface, a side surface, and a bottom surface. In some embodiments, the release-limiting component surrounds the drug component. The oral drug dosage form of FIG1H is configured such that, upon administration to a human individual and exposure to bodily fluids, the top surface, side surface, and bottom surface of the release-limiting component are simultaneously exposed to and eroded by the bodily fluids. The fourth soluble material and the first soluble material together control the release of the drug from the drug component.

[0165] As disclosed herein, components of oral drug dosage forms can be configured in a variety of shapes and sizes. Unless otherwise specified, references to certain shapes, sizes, and measurements reflect the oral drug dosage form prior to administration to a human individual (e.g., prior to the dissolution of any component of the oral drug dosage form).

[0166] i. Drug components

[0167] The oral drug dosage forms disclosed herein include drug components containing a drug. In some embodiments, the drug component includes a soluble material containing the drug. A variety of materials with different shapes and sizes can be used to form the drug component.

[0168] In some implementations, the drug component is a layer.

[0169] In some embodiments, the pharmaceutical assembly includes a first pharmaceutical assembly and a second pharmaceutical assembly. In some embodiments, the soluble material in the first pharmaceutical assembly is the same as the soluble material in the second pharmaceutical assembly. In some embodiments, the soluble material in the first pharmaceutical assembly is different from the soluble material in the second pharmaceutical assembly.

[0170] 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, the bottom surface, or at least a portion thereof of the drug component is flat or within a surface tolerance threshold (e.g., measured between two parallel planes).

[0171] In some embodiments, the drug assembly has a top surface, a side surface, and a bottom surface, wherein the top surface, the side surface, and the bottom surface are simultaneously exposed to body fluids. In some embodiments, the drug assembly is a layer having a top surface, side surface, and bottom surface. In some embodiments, the top surface, bottom surface, or at least a portion thereof of the drug assembly is flat or within a surface tolerance threshold (e.g., measured between two parallel planes).

[0172] In some embodiments, the top or bottom surface of the drug component may have any shape. In some embodiments, the top or bottom surface of the drug component has a capsule shape, a circle, an oval shape, a bullet shape, an arrow shape, a triangle, an arc triangle, a square, an arc square, a rectangle, an arc rectangle, a rhombus, a pentagon, a hexagon, an octagon, a crescent shape, an almond shape, or a combination thereof.

[0173] In some embodiments, the top or bottom surface of the drug component (e.g., a drug component layer) has a thickness of approximately 10 mm. 2 Approximately 400mm 2 Such as approximately 20mm 2 Approximately 200mm 2 Approximately 20mm 2 Approximately 100mm 2 Approximately 20mm 2 Approximately 60mm 2 or about 30mm 2 approximately 50mm 2The surface area of ​​either of the components. 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 22mm 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 The surface area of ​​either of the components. In some embodiments, the top or bottom surface of the drug component has a surface area of ​​less than about 400 mm². 2 Such as less than about 400mm 2 375mm 2350mm 2 325mm 2 300mm 2 275mm 2 250mm 2 225mm 2 200mm 2 190mm 2 180mm 2 170mm 2 160mm 2 150mm 2 140mm 2 130mm 2 120mm 2 110mm 2 100mm 2 95mm 2 90mm 2 85mm 2 80mm 2 75mm 2 70mm 2 65mm 2 60mm 2 58mm 2 56mm 2 54mm 2 52mm 2 50mm 2 48mm 2 46mm 2 44mm 2 42mm 2 40mm 2 38mm 2 36mm 2 34mm 2 32mm 2 30mm 2 28mm 2 26mm 2 24mm 2 22mm 2 Or 20mm 2 The surface area of ​​either of the components. In some embodiments, the top or bottom surface of the drug component has approximately 20 mm². 2 21mm 2 22mm 2 23mm 2 24mm 2 25mm 2 26mm 2 27mm2 、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 2325mm 2 350mm 2 375mm 2 Or 400mm 2 The surface area of ​​any one of them.

[0174] In some embodiments, the surface area of ​​the top or bottom surface of the drug component exposed to the body fluid is consistent across the entire thickness of the drug component. For example, as the drug component dissolves, the surface exposed to the body fluid has the same surface area. In some embodiments, the surface area of ​​the top or bottom surface of the drug component exposed to the body fluid differs at two or more points. For example, as the drug component dissolves, the surface exposed to the body fluid changes, such as increasing and / or decreasing in surface area during the dissolution of the drug component. In some embodiments, the shape of the surface of the drug component exposed to the body fluid is consistent across the entire thickness of the drug component. For example, as the drug component dissolves, the surface exposed to the body fluid has the same shape. In some embodiments, the shape of the surface of the drug component exposed to the body fluid differs 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.

[0175] 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 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 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 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 any one of about 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm.

[0176] In some embodiments, the top or bottom surface of the drug component (e.g., a drug component layer) has a span dimension perpendicular to the maximum span size, such as about 1 mm to about 15 mm, 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 size, such as at least about 1 mm, such as 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 size, such as less than about 15 mm, such as 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, which is any one 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.

[0177] In some embodiments, the top or bottom surface of the drug component (e.g., the 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, or 10 mm.

[0178] In some embodiments, the drug component (e.g., a drug component layer) has a thickness of about 0.1 mm to about 5 mm, such as 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 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 any of the following: 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 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.

[0179] In some embodiments, the drug component (e.g., a drug component layer) includes a top surface and a bottom surface, wherein the thickness measured between the top surface and the bottom surface is substantially uniform, for example, within 20% of the average thickness.

[0180] In some embodiments, the top and bottom surfaces of the drug assembly have the same surface area. In some embodiments, the maximum span dimensions of the top and bottom surfaces of the drug assembly are the same. In some embodiments, the span dimensions perpendicular to the maximum span dimensions of the top and bottom surfaces of the drug assembly are the same. In some embodiments, the top and bottom surfaces of the drug assembly have the same diameter. In some embodiments, the top and bottom surfaces of the drug assembly have the same shape.

[0181] In some implementations, the drug component (e.g., a drug component layer) includes side surfaces.

[0182] In some embodiments, drug release into gastrointestinal fluids is based on the erosion of the drug component. In some embodiments, upon contact with bodily fluids in a human individual, the drug component is completely eroded within a timeframe of approximately 3 hours to approximately 12 hours, such as approximately 4 hours to approximately 8 hours or approximately 6 hours to approximately 10 hours. In some embodiments, upon contact with bodily fluids in a human individual, the drug component is completely eroded within a timeframe of at least approximately 3 hours, such as at least approximately 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours. In some embodiments, upon contact with bodily fluids in a human individual, the drug component is completely eroded within a timeframe of less than approximately 12 hours, such as less than approximately 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, or 3 hours. In some implementations, once in contact with bodily fluids in a human individual, the drug component is completely dissolved within a timeframe of approximately 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours.

[0183] In some embodiments, the pharmaceutical component has 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 pharmaceutical dosage form. In some embodiments, the pharmaceutical component has a 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 pharmaceutical component has a 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 pharmaceutical component has a mass fraction of any one of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%.

[0184] In some embodiments, the amount of drug in the pharmaceutical component is from 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 drug in the pharmaceutical component is about 1 mg or more, such as any one of about 3 mg or more, about 4 mg or more, about 5 mg or more, about 6 mg or more, about 7 mg or more, about 8 mg or more, about 9 mg or more, about 10 mg or more, about 11 mg or more, about 12 mg or more, about 13 mg or more, about 14 mg or more, about 15 mg or more, about 16 mg or more, about 17 mg or more, about 18 mg or more, about 19 mg or more, about 20 mg or more, about 21 mg or more, about 22 mg or more, about 23 mg or more, about 24 mg or more, or about 25 mg or more. In some embodiments, the amount of drug in the pharmaceutical component is about 25 mg or less, such as about 24 mg or less, about 23 mg or less, about 22 mg or less, about 21 mg or less, about 20 mg or less, about 19 mg or less, about 18 mg or less, about 17 mg or less, about 16 mg or less, about 15 mg or less, about 14 mg or less, about 13 mg or less, about 12 mg or less, about 11 mg or less, about 10 mg or less, about 9 mg or less, about 8 mg or less, about 7 mg or less, about 6 mg or less, about 5 mg or less, about 4 mg or less, or about 3 mg or less. In some embodiments, the amount of drug in the drug component is any one of about 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.

[0185] In some embodiments, the drug in the pharmaceutical component of the oral pharmaceutical dosage form described herein can be any drug. In some embodiments, the drug is selected from one or more of small molecule compounds, peptides, proteins, nucleic acids, antibodies, or microorganisms. In some embodiments, the pharmaceutically active material is selected from one or more of small molecule compounds, peptides, and proteins.

[0186] In some embodiments, the drug is uniformly dispersed in the first soluble material in the form of an amorphous solid dispersion (ASD).

[0187] In some embodiments, the drug component comprises drug particles containing a fourth soluble material mixed with the drug, the drug particles being uniformly dispersed in a first soluble material.

[0188] In some embodiments, the small molecule compound is selected from tofacitinib, lidocaine, ethyl 11-di-deuterated linoleate, 16-dehydropregnenolone, 3,5-diiodothyronine, 5-fluoro-2-deoxycytidine, 6-mercaptopurine, abacavir, abiraterone, acampolic acid, acarbose, acetaminophen, aceclofenac, acetonitrile, acetaminophen, acetylcysteine, acetyl-L-carnitine, acetylsalicylic acid, acyclovir, acilimex, azastaxate, adecyl bromide, azithromycin, acobifen, acotiamide, avasine, acetalide, adapalene, adefovir dipivoxil, afatinib, agomelatine, edenafil, relinylpyridinium acetate, aratrovafloxacin, albendazole, salbutamol sulfate, aclatadine, alendronate, alfacalcidol, and alfa... Salon, Alfentanil, Alfuzosin, Alistilide, Alivitaic Acid, Alisartan Medoxem, Allogestrinone, Allopurinol, Amotriptan, Alogliptin, Alosetron, Alphaketon Glutaric Acid, Lipoic Acid, Alprazolam, Alprostadil, Hexamethylmelamine, Aluminum Sulfate, Avimopan, Amantadine, Ambesentan, Ambroxol, Amphetamine, Divinylbenzene Sulfonate, Amipridine, Amifostine, Amikacin, Amiloride, Amacetyl, Lippropionic Acid, Ampterin, Amiodarone, Amisulpride, Amitriptyline, Amexanol, Amlodipine, Ammonium Lactate, Amodiaquine, Amorolfen, Amsulon, Amoxicillin, Amphetamine, Ampicillin, Ampicillin, Amoxicillin, Amoxicillin ... Natrozole, Anclozole, Andrographolide, Anacotazone, Annifenidine, Piracetam, Aniprase, Anlotinib, Antazoline, Androquinolone, Apatinib, Apixaban, Apomorphine, Aprepitant, Aripipridine, Aredipine, Abekarin, Afortrol, Argatroban, Aripiprazole, Modafinil, Arsenic acid, Artemether, Artemisininol, Penicillium Artesunate, Asenapine, Asimadolin, Astragaloside A, Anavipiravir, Atazanavir, Atenolol, Atomoxetine, Atorvastatin, Atorvaquinone, Atrasentan, Atropine, Adenofenofi, Avabactam, Axitinib, Azacitidine, Cytidine, Azasetron, Azelaic acid, Azelastine, Azeldipine, Azilsartan, Azilite, Aztreonam, Azvudine Baclofen, Baflutinib, Baicalin, Balofacin, Balsalazide, Bambuterol, Baricitinib, Barnidipine, Badoxifene, Beclomethasone Dipropionate, Beclomethasone Dipropionate, Bedroxil, Belotecone, Benazepril, Benzoquine Bromide, Bendamustine, Bennidipine, Benserazide, Benzalkonium Chloride, Benznidazole, Benzocaine, Benzoyl Peroxide, Benzymetamine, Betahistine, Betasine Lacontan, Beprost, Besifloxacin, Besifovir, Besipyridine, β-Olefin, Betahistine, Betaine, Betamethasone, Betamilone, Betalol, Carbamoylcholine, Urapcholine, Betrixiban, Bevacizumab, Besalodin, Bezafibrate, Biapenem, Bicalutamide, Bicyclol, Bifidobacterium, Birastine, Bimatoprost, Bismuth Gallate, IcabetBisoprolol, Bisoprolol, Bleomycin, Brenaseline, Boprevir, Bortezomib, Bosentan, Bosutinib, Bofacryan, Buripiperazole, Brimonidine, Pirimethasone, Brividan, Bovril, Bromzepam, Brofenac, Bromocriptine, Brotizolam, Buxinolol, Bradioxane, Budesonide, Butadiazine, Butodralil, Bunazosin, Bupivacaine, Buprenorphine, Bupropion, Bupropion, Bulixafor, Butorphanone, Busulfan, Butenafine, Butorphanol, Butophthalamide, Cabazitaxel, Cabergoline, Cabozantinib, Cardural, Caffeine, Calcipotriol, Calcitriol, Carmostat, Camptothecin, Canagliflozin, Candesartan, Cangrelox, Capecitabine, Captopril, Carbamazepine Carbetocin, Carbidopa, Carbidopa, Carbisacodyl, Carboplatin, Carbidopa, Carfenomib, Carboglutamate, Calira, Carmustine, Carteolol, Carrumonam, Carvedilol, Caspofungin, Catechol, Sildenafil, Cefaclor, Cefadroxil, Cefalothin, Cefcarpine, Cefdinir, Ceftoranil, Cefepime, Cefotaxime Cefminox, Cefoperazone, Cefotaxime, Cefotiam, Cefazolin, Cefpirome, Cefpodoxime, Cefprozil, Cefuroxime, Ceftazidime, Ceftazidime, Ceftazidime, Cefotolide, Ceftriaxone, Cefuroxime, Celecoxib, Sigosvir, Celirolol, Ceritinib, Cetirizine, Cetirizine, Cetrimonyl ester, Cevimeline, Chenodeoxycholic acid Chlorpheniramine, chlorogenic acid, chlorpheniramine, chlorthalidone, cholecalciferol, cholic acid, choline phosphate, choline fenofibrate, cicsolone, ciclopirox olamine, cyclosporine, cidofovir, cidosepine, cilastatin, cilazapril, cilnidipine, cilostazol, cimetidine, cinnacalcet, cinipazide, cilnidazole, ciprofloxacin, ciprofloxacin, atracurium, cisplatin, citalopram, cytidine diphosphate choline, citrulline, cladribine, clarithromycin, clavulanic acid, clarsentan, clovidipine, clavudine, clootriol, clobazine, clobetasol, clodextrin, clofazimine, clomipramine, clonazepam, clonidine, clopidogrel, clotrimazole, clozapine, adenosylcobalamin, crobitetide, codeine, colchicine, cholecalciferol, colesvelan, colesti Lan, Coufsell, Conivrevatan, 11-Deoxycortisone-17α-vinylpropionic acid, Crimod, Crizotinib, Cromolyn, Cyanocobalamin, Cyclobenzaline, Cyclophosphamide, Cyclosporine, Cyproterone acetate, Cytarabine, Dabigatran etexilate, Darafenib, Daclatasvir, Dacomitinib, Dapavancin, Dacetroprol, Aminopyridine, Dafopridin, Danazol, Dantrolene, Darussalam, Dapivacain, Dapoxetine, Daphendipine, Dafenacin, Darunavir, Dasabuvir, Dasatinib, Dasorubicin, Decitabine, Larosx, Defocole, Delafloxacin, Deimadil, Delapril, Deraviridine, Denibulin, Deoxyandrographolide, Desflurane, Desipramine, Loratadine, Desmopressin, Desogestrel, DesonideDextromethorphan, dextromethorphan, verteporphan, levodopa, venlafaxine, dexamethasone, dexamethasone octanoate, dextromethorphan, dextromethorphan iron, dextromethorphan tromethamine, dextromethorphan lansoprazole, dextrometomid, methylphenidate, dextromethorphan, sotalol, dextromethorphan sucrose, dextromethorphan, dextromethorphan propoxyphene, diacerein, diacetylmorphine Epioxidized lactol, diazepam, diazoxide choline, diclofenac, diclofenac, diclofenac, dicycloplatin, didanofen, phenobarbital, difluprednisolone, digoxin, linolenic acid, dihydroergotin, dihydroergotamine, diltiazem, demetriox, dimethyl fumarate, delecane, dinoprostone, diphenylcyclopropenone, dipyridamole, tobramycin, disufenone, disulfiram, anthraquinone, dexamethasone Ketones, Docarbazide, Docetaxel, Glycoside, Dofelith, Dolastron, Dulutevir, Domperidone, Sorafenib, Donepezil, Dopamine, Doripenem, Dozole, Dosmaester, Docuronium Chloride, Doxazosin, Doxepin Hydrochloride, Ducalcidol, Deoxyfluorouridine, Doxophylline, Doxorubicin, Doxycycline, Doxylamine Succinate, Drolynol, Dronedarone, Drolynol Spiroquinone, Drolidone, D-tagagose, Duloxetine, Dutasteride, Ebastine, Eberconazole, Ibusecrol, Icarbet, Isconazole, Icopipan, Edaravone, Eduxaban, Efavirenz, Ifluconazole, Elonisen, Efodipine, Etiguanylamine, Eicosapentaenoic acid glyceride, Olaragogueli, Idicalcitol, Ilisimor, Iritriptan, Eltrombopag, Etiham Ticavir, Emesine, Ipalgliflozin, Enricacin, Emtricitabine, Enalapril, Enclomiphene, Tamoxifen, Enoxacin, Enprost, Entacapone, Entecavir, Entenolol, Enzalutamide, Epalrestat, Eperisone, Ephedrine, Epirubicin, Epirubicin, Epipitinib, Eplerenone, Epriprostol, Eprexol, Irroxine Dexamethasone, Iprosartan, Etoposide, Erdostatin, Eribulin, Erlotinib, Ertapenem, Erythromycin, Escitalopram, Eketamine, Ketamine, Eslicarbazepine, Esmolol, Esomeprazole, Estradiol, Estradiol, Eszopiclone, Etsopiclone, Ethambutol, Ethylenesylestradiol, Ethylfumaric acid, Ethinylestradiol, Etidrotic acid, Etimicicin, Etizolam, Etodole, Etogestene, Etoposide, Etocoxib, Etravirine, Isorhein, Everolimus, Exemestane, Ezetimibe, Fatrazole, Fluorotrichume, Famotidine, Ampicillin, Faropenem, Fasocilan, Fasudil, Favipiravir, Fibram, Febuxostat, Tromethamine, Felodipine, Fenfluramine, Fenofibrate, Fenofibrate Pan, Fennoteukol, Feniveran, Fentanyl, Fenteconazole, Ferric Citrate, Ferric Maltol, Fexoril, Fexonitrile, Fexofenadine, Femmasartan, Finafloxacin, Finasteride, Fingolimod, Flucainide, Fluroxacin, Flubancelin, Fluoxetine, Fluuridine, Fluconazole, Fludarabine, Flumazenil, Flunisolone, Fluocinolone Acetonide, Fluoxetine, FluoxetineFlupyridine, flurbiprofen, fluoroerythromycin, fluticasone, flutramazole, fluvastatin, fluvoxamine, folic acid, folinic acid, metoprolol, formetastatin, formoterol, furopycin, fusanavir, fosapirate, fluconazole, fosfomycin, fosinopril, phosphatidylcholine, fosfopromycin, fosfotoxin, propofol, formustin, fulvastatin, fruquintinib, fodostatin, fulvestrant, furosemide Fusidic acid, gabapentin, gabapentin ennacarbi, gabexate, gadobutrol, gadofosamide, galantamine, gallium nitrate, gambogia, ganexoloxone, ganirilac, galafloxacin, gatifloxacin, gefitinib, gemcitabine, gemfibrozil, gemimifloxacin, gentamicin, gentiopicroside, gepiperone, gestadienone, gestrinone, timolol, glatiramer, glibenclamide Gliclazide, Glimepiride, Glipizide, Glucophosphamide, Glutamine, Glycerin, Glyceryl sulfadiazine, Glycyrrhizic acid, Golomod, Gogliptin, Granisetron, Guaifenesin, Guanimelis, Guanifaxin, Guanilimus, Halometasol, Halofantrol, Halometasone, Hyaluronic acid, Hydrochlorothiazide, Hydrocodone, Hydrocortisone, Hydromorphone, Hydroxycobalamin, Hydroxyurea, Hydroxychloroquine, Hydroxyprogesterone hexanoate, Hypericin, Epaturon, Ibrutinib, Ibuprofen, Ibutilide, Epimedium, Elaprin, Eicosapentaenoic acid, Ethyleicosapentaenoic acid, Icotinib, Idebenone, Idole, Ifetroxan, Elaprin, Iprazosin, Ipoprostol, Imatinib, Midazoline, Midapril, Imipenem, Imiquimod Aristocort, Incadronate, Indacaterol, Indapamide, Indrolidine, Indinavir, Indisetron, Indomethacin, Indolamin, Enalapril, Iggliflozin, Ipratropium, Ipratropium bromide, Etacarin, Irbesartan, Irinotecan, Irinotecan sulfosuccinate, Ilofofen, Esopridine, Isoflurane, Isoniazid, Unoprostone isopropyl ester, Isosorbide dinitrate, Isotretinoin Chrysanthemum, Isotretinoin, Iradipine, Itratheline, Itopride, Itraconazole, Ivabradine, Ixaspiron, Ketamine, Ketoconazole, Ketoprofen, Ketoprofen, Ketoxalate, Lycium chinense B, Lacidipine, Laclodamide, Lactitol, Lafluolimus, Lafutidine, Lamivudine, Lamotrigine, Landilolol, Nanaminavir, Lanoconazole, Lansoprazole, Lanthanum Carbonate, Lapatinib, Laquimod, Lasoxifene, Latanoprost, Leadipasvir, Leflunomide, Lenalidomide, Lentinan, Lercadipine, Lecanidipine, Leprilin, Letrozole, Leucine, Leuprorelin, Levasalbutamol, Levamisole, Levaamlodipine, Levetiracetam, Levabupivacaine, Lecarbastine, Lecarnitine, Levocetirizine, Levodopa, Levofloxacin, Levodopa 18-Methylnorethindrone, Levonorgestrel, Levo-18-methylnorethindrone butyrate, Levobenzylidene hydrochloride, Levo-ornidazole, L-glutamine, Lidocaine, Limonene hydrochloride, Limaprost, Liraristine, Linezolid, Isosorbide dinitrate, Liranaftate, Lisinopril, Rhodenafil, Lofexidine, Lomefloxacin, Lomerizine, Clonidamine, Lopinavir, LoratadineLorazepam, Lornoxicam, Losartan, Losartan Potassium, Clotiprenor, Lovastatin, Loxoprofen, Levapraziquantel, Clomecoxib, Sulfamiron, Magnesium Isoglycyrrhizinate, Mancozeb, Mannidipine, Mannitol, Malawiro, Maribavir, Masaratetinib, Mebendazole, Nitrogen Mustard, Mecobalamin, Medroxyprogesterone, Meloxicam, Memantine, Tetraene-Menaquinone, McPaklin, Adipine, P-methoxyphenol, Mercaptophenone, Mercaptopurine, Meropenem, Mesalazine, Metacavir, Metadoxine, Analgin, Metadacone, Ergobenzyl Ester, Metformin, Methadone, Mezalazole, Methotrexate, Methoxyflurane, Methylvalerate, Methylnaltrexone, Methylphenidate, 6-Methylhydroprednisolone, Methylprednisolone Acetate Propylester, Methylene Blue, Methyltyrosine, Metoclopramide, Metoprolol Metronidazole, Mepiridone, Mibeprazole, Miconazole, Midazolam, Midodrine, Midotaurin, Mifepristone, Miglitol, Milnapril, Milrinone, Mitefocin, Milnapril, Minocycline, Minodrine, Minoxidil, Mirabelon, Milonafil, Mirtazapine, Misoprostol, Miglinide, Mitoxantrone, Mivodiol, Mizolastine, Mizoribine, Moclobemide Modafinil, doxycycline, modepapan, moxipril, mofenzolate, morpholinone, mometasone furoate, glycyrrhizic acid, monobenzone, luminol, monoterpene perillol, montelukast, moricizine, tigecycline, morpholinone, morphine glucuronic acid, mosapride, moxifloxacin, moxifloxacin, mozavaptane, mupirocin, mycophenolate moxifloxacin, myristyl nicotinate, nabumetone, N-acetylcysteine, naflufloxacin, naldolol, nalnatifen, nabuphen, nalfurafen, naloxone, naloxone, nandrolone decanoate, naphazoline, naproxen, naproxen, nalabolic acid ... Nemonoxacin, Neostigmine, Nepatantan, Nepafenamide, Napistat, Lenatinib, Neridronic Acid, Netilmicin, Netutopeptide, Nevirapine, Niacin, Nicardipine, Nicergoline, Nicorandil, Nifedipine, Nicotine, Niclosamide, Nifedipine, Nifedipine, Nifedipine, Niferulic, Nifedipine, Niferulic Acid, Niclosamide, Nilotinib, Nirutimibe, Nivadipine Nimesulide, Nimodipine, Moroxydazole, Nisodipine, Nizoralide, Nitixinone, Nifedipine, Nitroglycerin, Nizatidine, Loratroxetine, Norgestrel, Norgestrel, Norepinephrine, Norethindrone, Norfloxacin, Norgestrel, Obeticholic Acid, Otinidin, Succinyloctahydroacrylidine, Ofloxacin, Olanzapine, Olaparib, Orlistat, Olmesartan, Indidatate Loperamide, Olotaterol, Olopatadine, Oprerinone, Osalazine, Otepra, Ogliptin, Omeprazole, Omoconazole, Onassidone, Ondansetron, Opipiperazine, Methylphenidate, Oxyphenidate, Orlistat, Ornithine Phenylacetic Acid, Onoprost, Oseltamivir, Osipamifen, Oxaliplatin, Oxaloacetic Acid, Oxazepam, OxcarbazepineOmphendazole, Piracetam, Oxybutynin, Oxycodone, Oxymethazoline, Oxymorphine, Oxytocin, Ozagrel, Ozefloxacin, Paclitaxel, Paliperidone, Pamifloxacin, Palonosetron, Parovatin, Panipenem, Pabistat, Pantoprazole, Acetaminophen, Parecoxib, Paricalcitol, Palripalvir, Paroggliflozin, Baromomycin, Paroxetine, Partopilone Pazopanib, Pazufloxacin, Perbiprofen, Pemetrexed, Pyriproxyfen, Pyriproxyfen potassium, Pyriproxyfen, Penciclovir, Long-acting Tonol, Pentamidine, Pentiacic acid, Pentostatin, Hexonexobromine, Peramivir, Perampanel, Aminopyrene, Perfluoropentane, Perfluorooctylammonium bromide, Pergolide, Perifoxane, Perindopril, Piperipirone, Fenclofen, Phenoxybenzamine Hydrochloride, Fen Topiramate, Phenytoin, Phentolamine, Phenytoin, Sapelelin, Pidotimod, Pircicarbide, Pimoben, Piamethoxam, Pioglitazone, Piperidone, Pipercuronium, Piperacillin, Piperquine, Piracetam, Pirarubicin, Pirfenidone, Pirometrox, Pirotinib, Piroxicam, Pitavastatin, Pisantrol, Proconazole, Procarbazine, Procarbazine, Pornalione, Pordafil, Pomalidomide, Panatinib, Porfenib, Posaconazole, Clavulanic acid, Paradefovir, Prodefovir, Aminopterin, Pramipexole, Pramipexole, Procetista, Prasugrel, Pravastatin, Prazosin, Prednisolone, Prednisolone, Prednisolone, Pregabalin, Premicaine, Procaterol, Prochlorpromazine, Progesterone Progesterone, chlorguanidine, promethazine, propafenone, propafenone, propofol, propranolol, propranolol, prucalocarboxamide, prulifloxacin, Prussian blue, pseudoephedrine, puerarin, praquitinib, pyrazinamide, pyridoxine, pyridoxine, ethirimol, diquinopyridine, cyclophosphamide, quazepam, quetiapine, quinapril, quinidine, quinine, quinzatinib, rabeprazole, caldotril, ladotril Raloxifene, Raloxifene, Naloxifen, Raltitravir, Raltitrexed, Ramatroban, Ramipril, Ramipril, Ramosetron, Ranitidine, Ranolazine, Rasagiline, Rebapamide, Reboxetine, Ibuprofen, Naproxen, Glycolone bromide, Diclofenac, Mebendazole, Progesterone, Zoledronic acid, Regorafenib, Remifentanil, Repaglinide, Repiroxide, Ambroxol Zanoxetine, Chloramphenicol, Butylamine, Guanabenzyl, Chlorpheniramine, Masindole, Naltrexone, Nitixinone, Retigabin, Rosiglitazone, Resimod, Repaglin, Retamorin, Retigabin, Retinoic Acid, Revarazine, Rhein, Ribavirin, Rifabutin, Rifampin, Rifamycin, Rifapentine, Rifaximin, Relapadine, Rilpivirine, Rilpivirine Hydrochloride, Riluzole, Rimesocone, Resigludec, Riociguat, Risedronate, Risperidone, Ritonavir, Rivaroxaban, Ridestigmine, Rizatriptan, Roflumilast, Rotamycin, Rorapiron, Ropinikol, Ropivacaine, Rosiglitazone, Rosuvastatin, Rotigotine, Roxithromycin, Rubotecan, Ruffamide, Lufluxacin, Rupatadine, RuxolitinibLevofloxacin, Sacubitril, Salfedipine, Salbutamol, Salicylic Acid, Salmeterol, Salvastatin, 3-Formamide-4-hydroxycyclopropylmethylhydroxymorphone, Amlodipine, Sapropterin, Saquinavir, Cicatinib, Sargrelate, Saxagliptin, Scopolamine, Secnidazole, Selegiline, Selmetinib, Cetrastex, Ciladasil, Sertaconazole, Sertaconazole Nitric acid, sertraline, sesquiterpenes, sevelamer, sevoflurane, sibutramine, sildenafil, sirodoxine, cimiprovir, simvastatin, cenotecan, sibormod, sirolimus, sitafloxacin, sitagliptin, civelex, cizonan, cisofilan, cizonose, modafinil, sobuzosen, aescin, benzoic acid, cromoglycine, glycyrrhizin, guarenin Acids, Hyaluronic Acid, Ibandronic Acid, Hydroxybutyric Acid, Phenylacetic Acid, Phenylacetic Acid, Pyruvic Acid, Sofosbuvir, Solifenacin, Sorafenib, Sorbitol, Sparfloxacin, Ropril, Stavudine, Statilonine, Statipentine, Strontium Ranelate, Sutalan Zinc, Sugan Glucoside, Sulbactam, Susoxime, Methoxypyrazine, Sulfasalazine, Surufatinib, Sumatriptan, Sunitinib, Methoxysulfamethoxazole Tadalafil, Suramin Sodium, Verapamil, Rilpivirine, Tacalcitol, Tercoccal, Taclopramide, Tacrolimus, Tadalafil, Chlorfenapyridine, Tafenoxate, Tarapofen, Talicrix, Tatirelin, Tamibarbitine, Tamoxifen, Tamsulosin, Tapentadone, Talinexin, Tasmegone, Taquimod, Tazarotin, Tazobactam, Telbipenem, Tecoviride, Tidemazine Miconazole, Tetracycline, Tegafur, Teicoplanin, Telpivir, Tellatinib, Telbivudine, Tetracycline, Telmisartan, Temopril, Temoporfin, Temozolomide, Sirolimus, Terlilitine, Tenofovir, Tenoxicam, Teprenone, Terazosin, Terbinafine, Terlifluramide, Tersofensine, Tetracycline, Tetrathiomolybdate, Tetracycline Hydrozoline, Tetrahydronaphthylazolin, Thalidomide, Thifenofene, Thiotepa, Ticargrel, Ticlopidine, Tigecycline, Tiludromic acid, Timolol, Timolol maleate, Tinidazole, Metronidazole, Tiaconazole, Thiopronine, Tiotropium bromide, Tiperidine, Tipepidine, Tipepidine, Tipepidine, Tipepiril, Tiranavir, Tirazamine, Tirazat, Tirofiban, Oxcarbazepine, Tirofiban, Zanidin, Tobramycin, Tocoxol, Tofacitinib, Toggliflozin, Tocapone, Tolimide, Topazolone, Tolterodine, Tovapron, Tonaboxa, Topiramate, Topiprothiolane, Topiramate, Toremifene, Toseldoxacin, Tosufloxacin, Trabectin, Tramadol, Trametinib, Tramectin, Tranilast, Trazodone, Trazodone Gliptin, Sosoxan, Retinoic Acid, Triamcinolone, Triazolam, Trichlorothiazide, Tricepirimidine, Triclobendazole, Triclocarban, Trientine, Tralostane, Trimebutine, Trimeprogesterone, Trimethoprim, Tropisetron, Trascarbamine, Travafloxacin, Traxipitol, Tobbutol, Taladipine, Ubenimex, Umendeceno, Udinellafil, Ulinastatin, UlinastatinUbetasol, Urapidil, Valacyclovir, Valdecoxib, Valganciclovir, Pentorubicin, Valsartan, Vandetanil, Varanoslin, Vardenafil, Varniclone, Vestrugide, Verafenib, Venlafaxine, Verapamil, Phenylexin, Venakalan, Vertepofen, Vesneridone, Vesneridone, Vicagrelor, Vigabatrin, Vilanterol, Verazordine, Vildagliptin, Voriconazole, Vorinostat, Volticils The following are pharmaceutically acceptable salts, esters, prodrugs, limetavir, ozenafil, zafirlukast, zalcitabine, zaleplon, zaltoprofen, zanamivir, zidovudine, ziprasidone, levofenpril, zoledronic acid, zolmitriptan, zolpidem, zonisamide, zopiclone, zotiprine, zucacetin, zuclothiasol, tofapastatin, or one or more of their pharmaceutically acceptable salts, esters, prodrugs, hydrates, deuterated compounds, or stereoisomers.

[0189] 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, adrenaline, GLP-1 receptor agonist, semaglutide, liraglutide, dulaglutide, exenatide, octreotide, teriparatide, vancomycin, linaclotide, purcanatide, vorciclosporine, taterelin, acetaminophen, masimoretin, and glucagon-like peptide-2 (GLP-2) analogs (e.g., teduglutide).

[0190] In some embodiments, the protein is selected from proteins relevant to the pharmaceutical, agricultural, 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 factor (TNF), and enzymes. In some embodiments, the protein is selected from asparaginase, glutamate, 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, growth hormone-inhibiting factor, colony-stimulating factor (CSF), coagulation factors, tumor necrosis factor, interferon, gastrointestinal peptides, and vasoactive intestinal peptide (VIP). One or more of the following: incretin peptide (CCK), gastrin, secretin, hormones, pancreatic enzymes, superoxide dismutase, thyrotropin-releasing hormone (TRH), thyroid-stimulating hormone, luteinizing hormone, luteinizing hormone-releasing hormone (LHRH), tissue plasminogen activator, receptor antagonist (IL-1RA), leptin, auxin, granulocyte-monocyte colony-stimulating factor (GM-CSF), adenosine deaminase, uricase, asparaginase, human chorionic gonadotropin, heparin, atrial natriuretic peptide, hemoglobin, retroviral vector, relaxin, cyclosporine, oxytocin, ankylosing spore repeat protein, and affinity protein.

[0191] In some embodiments, nucleic acids refer to oligomers or polymers comprising at least two linked nucleotides or nucleotide derivatives, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) linked together by phosphodiester bonds or other phosphate esters. In some embodiments, nucleic acids include DNA molecules and RNA molecules. In some embodiments, nucleic acids may be single-stranded or double-stranded, and may be cDNA.

[0192] In some embodiments, the antibody is selected from abagovomab, abciximab, actoxumab, adalimumab, adecatumumab, aducanumab, afelimomab, afutuzumab, and alacizumab. pegol), ALD518, Alemtuzumab, Alirocumab, Altumomab penetate, Amatuximab, Anatumomab mafenatox, Anifrolumab, Anrukinzumab, Apolizumab, Arcitumomab, Aselizumab, Atinumab, Atlizumab Atorumab, Bapineuzumab, Basiliximab, Bavituximab, Bectumomab, Belimumab, Benralizumab, Bertilimumab, Besilesomab, Bevacizumab, Bezlotoxumab, Biciromab, Bimagrumab, Bivatuzumab Mertansine, Blinatumomab, Blosozzumab, Brentuximab vedotin, Briakinumab, Brodalumab, Canakinumab, Cantuzumab mertansine, Cantuzumabravtansine, Caplacizumab, Capromab pendetide, Carlumab, CatuxomabcBR96-doxorubicin immunoconjugate, cedelizumab, cetholizumabpegol, cetuximab, citatuzumab, cixutumumab, clazakizumab, claliximab, clivatuzumabtetraxetan, 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, Ertumaxomab, Etaracizumab, Etrolizumab, Evolocumab, Exbivirumab, Fanolesomab, Faralimomab, Farletuzumab, FasimumabFBTA05, Felvizumab, Fezakinumab, Ficlatuzumab, Figitumumab, Flanvotumab, Fontolizumab, Foralumab, Foravirumab, Fresolimumab, Fulranumab, Futuximab, Galiximab, Ganitumab Gatainerumab, Gavilimomab, Gemtuzumab / Ozogamicin, Gemtuzumab, Gevokizumab, Girentuximab, Glembatumumab / Vedotin, Golimumab, Gomiliximab, Guselkumab, Ibalizumab, Ibritumomab tiuxetan, Icrucumab, Igovomab, IMAB362, Imciromab, Imgatuzumab, Inclacumab, Indatuximabravtansine, Infliximab, Inolimomab, Inotuzumab ozogamicin), Intetumumab, Ipilimumab, Iratumumab, Itolizumab, Ixekizumab, Keliximab, Labetuzumab, Lambrrolizumab, Lampalizumab, Lebrikizumab, Lemalesomab, Lerdelimumab, Lexatumumab, Livivirumab, Ligelizumab, LintuzumabLirilumab, Lodelcizumab, Lorvotuzumab mertansine, Lucatumumab, Lumiliximab, Mapatumumab, Margetuximab, Maslimomab, Matuzumab, Mavrilimumab, Mepolizumab, Metelimumab, Milazumab zumab), Minretumomab, Mitumomab, Mogamulizumab, Morolimumab, Motavizumab, Moxetumomabpasudotox, Muromonab-CD3, Nacolomabtafenatox, Namilumab, Naaptumomabestafenatox, Naril 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, OzoralizumabPagibaximab, Palivizumab, Panitumumab, Pankocumab, Panobacumab, Parsatuzumab, Pascolizumab, Pateclizumab, 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, Rovezizumab (Rovelizumab), Ruplizumab, Samalizumab, Sarilumab, Satumomabpendetide, Secukinumab, Seribantumab, Setoxaximab, Sevirumab, SGN-CD19A, SGN-CD33A, Sibrotuzumab, Sifalimumab, SiltuximabSimtuzumab, Siplizumab, Sirukumab, Solanezumab, Solitomab, Sonepcizumab, Sontuzumab, Stamulumab, Sulesomab, Suvizumab, Tabalumab, Tacatuzumabtetraxetan, Tadocizumab, Talizumab Talizumab, Tanezumab, Tapitumoumab, Tefibazumab, Telimomabaritox, Tenatumomab, Teneliximab, Teplizumab, Teprotumumab, TGN1412, Ticilimumab, Tremelimumab, Tigatuzumab, TNX-650, Torres Atlizumab, Toralizumab, Tositumomab, Tovetumab, Tralokinumab, Trastuzumab, TRBS07, Tregalizumab, Tremelimumab, Tucotuzumabcelmoleukin, Tuvirumab, Ublituximab, Urelumab, Urizumab toxazumab, Ustekinumab, Vantictumab, Vapaliximab, Vatelizumab, Vedolizumab, Veltuzumab, Vepalimomab, Vesencumab, Visilizumab, Volociximab, Vorsetuzumabmafodotin, VotumumabZalutumumab, Zanomimab, Zatuximab, Ziralimumab, Zolimomab aritox, or one or more fragments thereof.

[0193] In some embodiments, the microorganism is selected from one or more of bacteria, viruses, fungi, actinomycetes, rickettsiae, 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 yeasts, probiotic spores, Clostridium butyricum, lactobacillus, bifidobacteria, or actinomycetes.

[0194] In some embodiments, the pharmaceutical component comprises a thermoplastic material, such as a thermoplastic polymer. In some embodiments, the pharmaceutical component comprises one or more of a material including soluble thermoplastic materials (such as sustained-release or immediate-release soluble materials), plasticizers, and other additives (such as fillers, binders, lubricants, flow aids, and disintegrants).

[0195] In some embodiments, the soluble thermoplastic material includes polyvinylpyrrolidone-co-vinyl acetate (PVP-VA), polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone (PVPP), polyethylene oxide (PEO), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyvinylcaprolactam-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), and hydroxypropyl methylcellulose (HP). MC), methylcellulose (MC), hydroxyethylcellulose (HEC), methacrylic acid copolymer, poly(dimethylaminoethyl methacrylate-co-methacrylate), poly(ethyl acrylate-co-methyl methacrylate-trimethylammonium ethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly(methacrylate-co-methyl methacrylate), poly(methacrylate-co-methyl methacrylate), poly(methacrylate-co-ethyl acrylate), poly(methacrylate-co-methyl methacrylate), polyethylene glycol-polyvinyl alcohol graft copolymer, methacrylate copolymer and ammonium alkyl methacrylate copolymer.

[0196] In some embodiments, the slow-release soluble etchable materials include copovidone, polyvinylpyrrolidone-co-vinyl acetate (PVP-VA), polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone (PVPP), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), methylcellulose (MC), hydroxyethyl cellulose (HEC), methacrylic acid copolymers, poly(dimethylaminoethyl methacrylate-co-methacrylate), poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride), poly(methyl acrylate-methyl methacrylate-co-methacrylate), poly(methyl methacrylate-co-methyl methacrylate), poly(methyl methacrylate-co-ethyl methacrylate), poly(methyl methacrylate-co-methyl methacrylate), polyethylene oxide (PEO), polyethylene glycol (PEG), polyvinyl caprolactam-vinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, Kollicoat The first one or more of IR-polyvinyl alcohol, polyvinyl alcohol (PVA), aminoalkyl methacrylate copolymer E, hydroxypropyl methylcellulose succinate (HPMCAS), methacrylate copolymer, glycerol, poloxamer and ammonium alkyl methacrylate copolymer.

[0197] In some embodiments, the readily-release soluble thermoplastic material includes copovidone, polyvinylpyrrolidone-co-vinyl acetate (PVP-VA), polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone (PVPP), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), methylcellulose (MC), hydroxyethyl cellulose (HEC), methacrylic acid copolymer, poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate), poly(dimethyl methacrylate) The following are included in the list of poly(ethyl acrylate-co-methyl methacrylate), poly(ethyl acrylate-co-methyl methacrylate-trimethylammonium ethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methyl methacrylate), poly(methyl methacrylate-co-methyl methacrylate), poly(methyl methacrylate-co-methyl methacrylate), poly(methyl methacrylate-co-ethyl acrylate), poly(methyl methacrylate-co-methyl methacrylate), polyethylene oxide (PEO), polyethylene glycol (PEG), polyvinyl caprolactam-vinyl 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 copolymer, ammonium alkyl methacrylate copolymer, ethyl cellulose (EC), polyvinyl acetate (PVAc), diethyl polyvinyl acetal aminolactic acid and diethyl polyvinyl acetal aminoacetate (AEA)

[0198] In some embodiments, the plasticizer includes any one or more of triethyl citrate (TEC), vitamin E polyethylene glycol succinate (TPGS), glyceryl acetate, acetylated triethyl citrate, tributyl citrate, o-acetylated tributyl citrate, polyethylene glycol 15-hydroxystearate, PEG-40-hydrogenated castor oil, polyethylene glycol 35-castor oil, dibutyl sebacate, diethyl phthalate, glycerin, methyl 4-hydroxybenzoate, castor oil, oleic acid, glyceryl triacetate, N,N-diethylpropynylamine (DEP), and polyalkylene glycols.

[0199] In some implementations, other additives include gum arabic, alginate, alginic acid, aluminum acetate, butylparaben, butylated hydroxytoluene, citric acid, calcium carbonate, croscarmellose sodium, powdered sugar, colloidal silica, cellulose, ordinary or anhydrous calcium phosphate, carnauba wax, corn starch, calcium carboxymethyl cellulose, calcium disodium EDTA, dehydrated calcium hydrogen phosphate, hexadecylpyridine chloride, calcium hydrogen phosphate, ternary calcium phosphate, dibasic calcium phosphate, disodium hydrogen phosphate, polydimethylsiloxane, sodium tetraiodofluorescein, EDTA, gelatin, glyceryl monooleate, ferric oxide, ferric oxide, and oxygen. Ferric yellow, ferric oxide red, lactose, microcrystalline cellulose, magnesium carbonate, magnesium oxide, methylparaben, polysorbate, propylene glycol, potassium bicarbonate, potassium sorbate, potato starch, phosphoric acid, polyoxyethylene stearate, sodium carboxyacetic acid starch, 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, dehydrated sorbitan oleate, sodium chloride, sodium metabisulfite, dehydrated sodium citrate, sodium starch, sodium carboxymethyl cellulose, succinic acid, sodium propionate, titanium dioxide, and talc.

[0200] In some embodiments, the pharmaceutical component comprises budesonide, VA64, and triethyl citrate. In some embodiments, the pharmaceutical component comprises about 10% budesonide, about 75% VA64, and about 15% triethyl citrate, based on the weight of the pharmaceutical component.

[0201] ii. Drug granules

[0202] The oral drug dosage forms disclosed herein include particles containing a drug. In some embodiments, the drug particles may optionally be in powder form. In some embodiments, the drug particles comprise a soluble material uniformly mixed with the drug. In some embodiments, the drug particles comprise a soluble material containing the drug. Drug particles can be formed using a variety of materials with different shapes and sizes (including materials having a range of drug mass fractions).

[0203] In some embodiments, the drug particles are selected from one or more of solid, liquid, or semi-solid forms. In some embodiments, the drug particles are in solid form. In some embodiments, the drug particles are selected from one or more of granular or powder forms.

[0204] In some embodiments, the average particle size of the drug particles is from 0.1 μm to 1000 μm. In some embodiments, the average particle size of the drug particles is from 1 μm to 800 μm. In some embodiments, the average particle size of the drug particles is from 10 μm to 500 μm. In some embodiments, the average particle size of the drug particles is from 100 μm to 500 μm, for example, 150 μm, 200 μm, 350 μm, 400 μm, or 450 μm. In some embodiments, the average particle size of the drug particles is from 10 μm to 100 μm, for example, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, or 90 μm. In some embodiments, the average particle size of the drug particles is from 500 μm to 900 μm, for example, 550 μm, 600 μm, 650 μm, 700 μm, 750 μm, 800 μm, or 850 μm. In some embodiments, the drug particles have a particle size distribution of less than about 0.35. In some embodiments, the drug particles have a particle size distribution of from about 0.1 to about 0.3, such as a particle size distribution of any one of about 0.15, 0.2, or 0.25.

[0205] In some embodiments, the soluble material in the drug particles is selected from one or more of drug dispersing materials, fillers, binders, lubricants, disintegrants, or plasticizers. In some embodiments, the drug dispersing material comprises an expandable polymer impregnated with a drug, for example, such that the drug is released from the drug dispersing material upon expansion. In some embodiments, the drug dispersing material comprises any one or more of cellulose acetate phthalate (CAP), quaternary ammonium methacrylate copolymer, poly(lactide-co-glycolic acid) (PLGA), ethylene-vinyl acetate copolymer, polyethylene (PE), polycaprolactone (PCL), polylactic acid (PLA), cellulose acetate butyrate (CAB), cellulose acetate (CA), polyvinyl acetate (PVAc), diethyl polyvinyl acetal glycine (AEA), poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), ethyl cellulose (EC), polyvinyl acetate (PVAc), polyvinylpyrrolidone (PVP), and crosspovidone.

[0206] In some embodiments, the filler is selected from one or more of copovidone (PVP / VA), polyvinyl alcohol (PVA), polyethylene glycol (PEG), polyvinylpyrrolidone (VA), hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), lactose, mannitol, sorbitol, xylitol, erythritol, sucrose, starch, microcrystalline cellulose, dicalcium phosphate, or dextrin. In some embodiments, the binder is selected from one or more of gum arabic, starch, amylopectin, gelatin, ethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, or dextrin. In some embodiments, the lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, sodium stearate fumarate, polyethylene glycol, or silica. In some embodiments, the disintegrant is selected from one or more of crospovidone, low-substituted hydroxypropyl cellulose, crospovidone carboxymethyl cellulose, partially pregelatinized starch, or sodium carboxymethyl starch. In some embodiments, the plasticizer is selected from one or more of the following: triethyl citrate (TEC), vitamin E polyethylene glycol succinate (TPGS), glyceryl acetate, acetylated triethyl citrate, tributyl citrate, o-acetylated 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, triacetylated glycerol, and polyalkylene glycols.

[0207] In some embodiments, the drug particles comprise a first drug particle and a second drug particle. In some embodiments, the first drug particle is an immediate-release particle. In some embodiments, the first drug particle is a sustained-release particle. In some embodiments, the first drug particle is a delayed-release particle. In some embodiments, the second drug particle is an immediate-release particle. In some embodiments, the second drug particle is a sustained-release particle. In some embodiments, the second drug particle is a delayed-release particle.

[0208] In some embodiments, based on the weight of the oral drug dosage form, 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%. 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 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%.

[0209] In some embodiments, the amount of drug in the drug particles is from 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 drug in the drug particles is about 1 mg or more, such as any one of about 3 mg or more, about 4 mg or more, about 5 mg or more, about 6 mg or more, about 7 mg or more, about 8 mg or more, about 9 mg or more, about 10 mg or more, about 11 mg or more, about 12 mg or more, about 13 mg or more, about 14 mg or more, about 15 mg or more, about 16 mg or more, about 17 mg or more, about 18 mg or more, about 19 mg or more, about 20 mg or more, about 21 mg or more, about 22 mg or more, about 23 mg or more, about 24 mg or more, or about 25 mg or more. In some embodiments, the amount of drug in the drug particles is about 25 mg or less, such as about 24 mg or less, about 23 mg or less, about 22 mg or less, about 21 mg or less, about 20 mg or less, about 19 mg or less, about 18 mg or less, about 17 mg or less, about 16 mg or less, about 15 mg or less, about 14 mg or less, about 13 mg or less, about 12 mg or less, about 11 mg or less, about 10 mg or less, about 9 mg or less, about 8 mg or less, about 7 mg or less, about 6 mg or less, about 5 mg or less, about 4 mg or less, or about 3 mg or less. In some embodiments, the amount of drug in the drug particles is any one of about 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.

[0210] iii. Lipid-based compositions

[0211] The oral drug dosage forms described herein include lipid-based compositions containing a drug. In some embodiments, the lipid-based compositions described herein are self-emulsifying formulations.

[0212] In some embodiments, the lipid-based composition comprises an oil phase.

[0213] In some embodiments, the oil phase is selected from one or more of the following: caprylic / capric acid mono- and diglycerides, linoleic acid mono- and glycerides, medium-chain triglycerides, triacetic acid glycerides, propylene glycol monocaprylate, propylene glycol dicaprylate, glyceryl dispalmitate stearate, glyceryl mono- and distearate, glyceryl distearate, propylene glycol monolaurate, polyglyceryl oleate, stearate, glyceryl monooleate, glyceryl monocapric acid mono- and glycerides, isopropyl myristate, isopropyl palmitate, ethyl linoleate, ethyl oleate, corn oil, soybean oil, olive oil, oleic acid, and linoleic acid.

[0214] In some embodiments, the oil phase has a mass fraction of 10% to 90% based on the weight of the lipid-based composition. In some embodiments, the oil phase has a mass fraction of 20% to 80%. In some embodiments, the oil phase has a mass fraction of 30% to 70%. In some embodiments, the oil phase has a mass fraction of 40% to 60%. In some embodiments, the oil phase has a mass fraction of 45% to 55%.

[0215] In some embodiments, the lipid-based composition further comprises one or more of a surfactant, a co-surfactant, a stabilizer, and a curing agent.

[0216] In some embodiments, the surfactant is selected from one or more of the following: polyoxyethylene ether-35 castor oil, polyoxyethylene ether-40 hydrogenated castor oil, caprylic / capric acid PEG-glycerol ester, polyoxyethylene castor oil, lauroyl polyoxyethylene-32 glycerol ester, polyethylene glycol-32 stearate, stearoyl polyoxyethylene glycerol ester, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene dehydrated sorbitan fatty acid ester, phospholipids, polyethylene glycol-15 hydroxystearate, coconut oil C8 / C10 polyethylene glycol glycerol ester, vitamin E polyethylene glycol succinate, and polysorbate.

[0217] In some embodiments, the surfactant has a mass fraction of 10% to 90% based on the weight of the lipid-based composition. In some embodiments, the surfactant has a mass fraction of 20% to 80%. In some embodiments, the surfactant has a mass fraction of 30% to 70%. In some embodiments, the surfactant has a mass fraction of 40% to 60%. In some embodiments, the surfactant has a mass fraction of 45% to 55%.

[0218] In some embodiments, the co-surfactant is selected from one or more of polyethylene glycol, diethylene glycol monoethyl ether, caprylic / capric acid glyceride mono- and diglycerides, glycerol, ethanol, propylene glycol, isopropanol, propylene glycol monolaurate, polyglycerol oleate, oleoyl polyoxyethylene glyceride, lauroyl polyoxyethylene 6 glyceride, linoleoyl polyoxyethylene 6 glyceride, and propylene glycol monocaprylate.

[0219] In some embodiments, the co-surfactant has a mass fraction of 10% to 90% based on the weight of the lipid-based composition. In some embodiments, the co-surfactant has a mass fraction of 20% to 80%. In some embodiments, the co-surfactant has a mass fraction of 30% to 70%. In some embodiments, the co-surfactant has a mass fraction of 40% to 60%. In some embodiments, the co-surfactant has a mass fraction of 45% to 55%.

[0220] In some embodiments, the stabilizer is selected from one or more of sodium dodecyl sulfate, sodium dodecyl sulfonate, D-alpha tocopherol, polyethylene glycol succinate, Tween, castor oil, hydrogenated castor oil, polyethylene glycol 15-hydroxystearate, poloxamer, hydroxypropyl β-cyclodextrin, polyvinyl alcohol, copovidone, povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, and sodium carboxymethyl cellulose.

[0221] In some embodiments, the stabilizer has a mass fraction of 10% to 90% based on the weight of the lipid-based composition. In some embodiments, the stabilizer has a mass fraction of 20% to 80%. In some embodiments, the stabilizer has a mass fraction of 30% to 70%. In some embodiments, the stabilizer has a mass fraction of 40% to 60%. In some embodiments, the stabilizer has a mass fraction of 45% to 55%.

[0222] In some embodiments, the curing agent is selected from one or more of fumed silica, calcium carbonate, lactose, mannitol, talc, microcrystalline cellulose, sodium carboxymethyl starch, modified starch, activated carbon, montmorillonite, polyvinylpyrrolidone, hydroxypropyl methylcellulose, gum arabic, magnesium stearate, calcium stearate, glyceryl monostearate, and magnesium aluminum silicate.

[0223] In some embodiments, the curing agent has a mass fraction of 10% to 90% based on the weight of the lipid-based composition. In some embodiments, the curing agent has a mass fraction of 20% to 80%. In some embodiments, the curing agent has a mass fraction of 30% to 70%. In some embodiments, the curing agent has a mass fraction of 40% to 60%. In some embodiments, the curing agent has a mass fraction of 45% to 55%.

[0224] iv. Release the limiting component

[0225] The oral drug formulations described herein include a release-limiting component configured to prevent and / or inhibit the release of a drug from the oral drug formulation within a desired amount of time after administration to a human individual.

[0226] In some implementations, the release restriction component does not contain a drug.

[0227] In some implementations, the release limiting component includes a soluble delay member.

[0228] In some implementations, the release restriction component includes a pH-responsive element.

[0229] In some embodiments, the release limiting component includes a soluble delay member and a pH-responsive member, the pH-responsive member at least partially surrounding the soluble delay member.

[0230] In some embodiments, the release limiting component surrounds the drug component. In some embodiments, the release limiting component completely surrounds the drug component. In some embodiments, the release limiting component partially surrounds the drug component. In some embodiments, the release limiting component prevents the drug component from dissolving. In some embodiments, as the release limiting component dissolves, the drug component is exposed to body fluids, and the drug begins to be released from the drug component.

[0231] In some embodiments, the release restriction component comprises a soluble material. In some embodiments, the soluble material of the release restriction component is different from the soluble material of the drug component. In some embodiments, the soluble material of the release restriction component is the same as the soluble material of the drug component. In some embodiments, the release restriction component comprises a second soluble material that does not mix with the drug. In some embodiments, the soluble material of the release restriction component gels upon being etched to prevent premature water penetration into the drug component and avoid drug crystallization. In some embodiments, the glass transition temperature (Tg) of the release restriction component is from about 10°C to about 190°C. In some embodiments, the glass transition temperature (Tg) of the release restriction component is from about 10°C to about 150°C. In some embodiments, the glass transition temperature (Tg) of the release restriction component is from about 10°C to about 130°C. In some embodiments, the glass transition temperature (Tg) of the release restriction component is from about 30°C to about 150°C. In some embodiments, the glass transition temperature (Tg) of the release-limiting component is from about 30°C to about 130°C. In some embodiments, the glass transition temperature (Tg) of the release-limiting component is from about 50°C to about 100°C. In some embodiments, the melting temperature (Tm) of the release-limiting component is from about 30°C to about 200°C. In some embodiments, the melting temperature (Tm) of the release-limiting component is from about 30°C to about 150°C. In some embodiments, the melting temperature (Tm) of the release-limiting component is from about 30°C to about 130°C. In some embodiments, the melting temperature (Tm) of the release-limiting component is from about 50°C to about 100°C. The release-limiting component described herein is stable during melt deposition, minimizing or avoiding impurities in the components of the release-limiting component due to thermal instability.

[0232] In some embodiments, the release-limiting component is configured to have a surface, such as a surface exposed to bodily fluids during administration of an oral drug dosage form to a human individual, having a predetermined shape and surface area. For example, in some embodiments, the release-limiting component has a top surface and a bottom surface. In some embodiments, the top surface or bottom surface of the release-limiting component, or at least a portion thereof, is flat or within a surface tolerance threshold (e.g., measured between two parallel planes). In some embodiments, the release-limiting component has a top surface, side surfaces, and a bottom surface. In some embodiments, the top surface, side surfaces, and bottom surface are simultaneously exposed to bodily fluids.

[0233] In some embodiments, the top and / or bottom surfaces of the release restraint component are not flat. In some embodiments, the top and / or bottom surfaces of the release restraint component are marked with markings (such as text markings or graphic markings).

[0234] In some embodiments, the top or bottom surface of the release restraint component may have any shape. In some embodiments, the top or bottom surface of the release restraint component may have a capsule shape, a circle, an ellipse, a bullet shape, an arrow shape, a triangle, an arc triangle, a square, an arc square, a rectangle, an arc rectangle, a rhombus, a pentagon, a hexagon, an octagon, a crescent shape, an almond shape, or a combination thereof.

[0235] v. Dissolvable delay component

[0236] The release-limiting components described herein include soluble delay members configured to prevent and / or inhibit the release of a drug from the oral drug formulation within a desired amount of time after administration to a human individual.

[0237] In some implementations, the soluble delay component does not contain a drug.

[0238] In some embodiments, the soluble delay member surrounds the drug assembly. In some embodiments, the soluble delay member completely surrounds the drug assembly. In some embodiments, the soluble delay member partially surrounds the drug assembly. In some embodiments, the soluble delay member prevents the drug assembly from being eroded. In some embodiments, as the soluble delay member erodes, the drug assembly is exposed to body fluids, and the drug begins to be released from the drug assembly.

[0239] In some embodiments, the soluble delay member comprises a first matrix that swells in an aqueous medium. In some embodiments, the first matrix forms a gel layer upon contact with bodily fluids. In some embodiments, the surface of the soluble delay member composed of the first matrix is ​​substantially non-porous or dense, and upon contact with bodily fluids, the gel layer appears only on the bodily fluid-contact surface of the soluble delay member. In some embodiments, the gel layer dissolves in the bodily fluids. In some embodiments, the soluble delay member, while being dissolved, prevents premature penetration of moisture into the drug component, thus avoiding drug crystallization.

[0240] In some embodiments, the soluble delay member further includes a second matrix comprising a second soluble material that is not miscible with the drug. In some embodiments, the first matrix and the second matrix in the soluble delay member are uniformly mixed. In some embodiments, the second matrix in the soluble delay member is soluble in an aqueous medium. In some embodiments, the second matrix begins to dissolve after the first matrix comes into contact with body fluids. In some embodiments, the second matrix dissolves faster at higher pH values ​​than at lower pH values. In some embodiments, the solubility of the second matrix decreases at pH values ​​less than 5.0. In some embodiments, the dissolution rate of the second matrix is ​​higher than that of the first matrix. In some embodiments, the dissolution of the second matrix accelerates the dissolution of the first matrix. In some embodiments, the weight percentage of the first matrix in the soluble delay member is 10% to 100%, and the weight percentage of the second matrix is ​​0% to 90%.

[0241] In some embodiments, the particle size D90 of the second matrix is ​​less than or equal to 600 micrometers. In some embodiments, the particle size D90 of the second matrix is ​​less than or equal to 550 micrometers. In some embodiments, the particle size D90 of the second matrix is ​​less than or equal to 500 micrometers. In some embodiments, the particle size D90 of the second matrix is ​​less than or equal to 450 micrometers. In some embodiments, the particle size D90 of the second matrix is ​​less than or equal to 400 micrometers. In some embodiments, the particle size D90 of the second matrix is ​​less than or equal to 350 micrometers. In some embodiments, the particle size D90 of the second matrix is ​​less than or equal to 300 micrometers. In some embodiments, the particle size D90 of the second matrix is ​​less than or equal to 250 micrometers. In some embodiments, the particle size D90 of the second matrix is ​​less than or equal to 200 micrometers. In some embodiments, the particle size D90 of the second matrix is ​​less than or equal to 150 micrometers.

[0242] In some embodiments, the second matrix of the soluble erosion delay member comprises a water-soluble material or a water-insoluble material. In some embodiments, the water-soluble material is selected from soluble sugars, soluble sugar alcohols, soluble inorganic salts, and soluble polymers.

[0243] In some implementations, the soluble polysaccharide or soluble sugar alcohol material includes trehalose, galactose, lactose, oligosaccharides, sorbitol, sucrose, mannose, maltose, chitosan, raffinose, cyclodextrin, maltodextrin, sorbitol, xylitol, mannitol, maltitol, lactitol, sugar anhydride, fructose syrup, and dextran.

[0244] In some implementation schemes, soluble inorganic salt materials include silicon dioxide, titanium dioxide, kaolin, barium sulfate, sodium chloride, talc, anhydrous calcium bicarbonate, anhydrous calcium hydrogen phosphate, calcium alginate, and calcium carbonate.

[0245] In some implementations, the soluble polymeric materials include PVA, PEG, PEO, PVP, PVP-VA, poloxamer, polyvinyl alcohol-polyethylene glycol copolymer, EC, croscarmellose sodium, carboxymethyl starch sodium, ethyl methacrylate copolymer, croscarmellose, microcrystalline cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.

[0246] In some embodiments, the second matrix of the soluble delay member includes a plasticizer. In some embodiments, the plasticizer is selected from triethyl citrate, tributyl citrate, acetylated triacetic acid, tributyl acetate, butyl stearate, glyceryl monostearate, stearyl alcohol, dibutyl sebacate, diethyl phthalate, dibutyl phthalate, dioctyl phosphate, polyethylene glycol, propylene glycol, glyceryl triacetate, castor oil, polyoxyethylene 40 hydrogenated castor oil, and medium-chain triglycerides.

[0247] In some embodiments, the first and second matrices of the soluble delay member are uniformly mixed and then hot-melt extruded. In some embodiments, the first and second matrices of the soluble delay member are mixed, pulverized, heated to about 10°C to about 190°C, and then extruded. In some embodiments, the glass transition temperature (Tg) of the soluble delay member is about 10°C to about 190°C. In some embodiments, the melting temperature (Tm) of the soluble delay member is about 30°C to about 200°C. The soluble delay member described herein is stable during melt deposition, minimizing or avoiding impurities in the components of the soluble delay member due to thermal instability.

[0248] In some embodiments, the soluble delay member comprises a soluble material. In some embodiments, the soluble material of the soluble delay member is different from the soluble material of the drug component. In some embodiments, the soluble material of the soluble delay member is the same as the soluble material of the drug component. In some embodiments, the soluble delay member comprises a second soluble material that does not mix with the drug.

[0249] In some embodiments, the soluble delay member is configured to have a surface, such as a surface exposed to bodily fluids during administration of an oral drug dosage form to a human individual, having a predetermined shape and surface area. For example, in some embodiments, the soluble delay member has a top surface and a bottom surface. In some embodiments, the top surface or bottom surface of the soluble delay member, or at least a portion thereof, is flat or within a surface tolerance threshold (e.g., measured between two parallel planes). In some embodiments, the soluble delay member has a top surface, side surfaces, and a bottom surface. In some embodiments, the top surface, side surfaces, and bottom surface are simultaneously exposed to bodily fluids. In some embodiments, the top surface, side surfaces, and bottom surface have the same thickness. In some embodiments, the top surface, side surfaces, and bottom surface have the same density. In some embodiments, the top surface, side surfaces, and bottom surface have the same erosion rate. In some embodiments, the density of the soluble delay member is from about 0.5 to about 5 mg / mm². 3 In some embodiments, the density of the soluble delay element is about 1 to about 2 mg / mm². 3 In some implementations, the density of the soluble delay element is approximately 1, 2, 3, 4, or 5 mg / mm². 3 In some implementations, the density of the soluble delay element is approximately 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, or 1.9 mg / mm². 3 .

[0250] In some embodiments, the top and / or bottom surfaces of the soluble delay member are not flat. In some embodiments, the top and / or bottom surfaces of the soluble delay member are marked with markings (such as text markings or graphic markings).

[0251] In some embodiments, the top or bottom surface of the soluble delay member may have any shape. In some embodiments, the top or bottom surface of the soluble delay member may have a capsule shape, a circle, an ellipse, a bullet shape, an arrow shape, a triangle, an arc triangle, a square, an arc square, a rectangle, an arc rectangle, a rhombus, a pentagon, a hexagon, an octagon, a crescent shape, an almond shape, or a combination thereof.

[0252] In some embodiments, the top or bottom surface of the soluble delay member has approximately 10 mm of surface area. 2 Approximately 400mm 2 Such as approximately 20mm 2 Approximately 200mm 2 Approximately 20mm 2 Approximately 100mm 2 Approximately 20mm 2 Approximately 60mm 2 or about 30mm 2approximately 50mm 2 The surface area of ​​either of them. In some embodiments, the top or bottom surface of the soluble delay member has at least about 20 mm. 2 Such as at least about 22mm 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 The surface area of ​​either of them. In some embodiments, the top or bottom surface of the soluble delay member has a surface area of ​​less than about 400 mm. 2 Such as less than about 400mm2 375mm 2 350mm 2 325mm 2 300mm 2 275mm 2 250mm 2 225mm 2 200mm 2 190mm 2 180mm 2 170mm 2 160mm 2 150mm 2 140mm 2 130mm 2 120mm 2 110mm 2 100mm 2 95mm 2 90mm 2 85mm 2 80mm 2 75mm 2 70mm 2 65mm 2 60mm 2 58mm 2 56mm 2 54mm 2 52mm 2 50mm 2 48mm 2 46mm 2 44mm 2 42mm 2 40mm 2 38mm 2 36mm 2 34mm 2 32mm 2 30mm 2 28mm 2 26mm 2 24mm 2 22mm 2 Or 20mm 2 The surface area of ​​either of them. In some embodiments, the top or bottom surface of the soluble delay member has approximately 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 、275mm2 300mm 2 325mm 2 350mm 2 375mm 2 Or 400mm 2 The surface area of ​​any one of them.

[0253] In some embodiments, the top or bottom surface of the soluble delay member has a maximum span dimension of about 5 mm to about 20 mm, such as 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 soluble delay member has a maximum span dimension of at least about 5 mm, such as 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 soluble delay member has a maximum span dimension of less than about 20 mm, such as 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 soluble delay member has a maximum span dimension of any one of about 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm or 20 mm.

[0254] In some embodiments, the top or bottom surface of the etchable delay member has a span dimension perpendicular to the maximum span size, such as about 1 mm to about 15 mm, including 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 etchable delay member has a span dimension perpendicular to the maximum span size, such as at least about 1 mm, including any one of 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 etchable delay member has a span dimension perpendicular to the maximum span size, such as less than about 15 mm, including any one 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 soluble delay member has a span dimension perpendicular to the maximum span dimension, which is any one 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.

[0255] In some embodiments, the soluble delay member has a diameter of about 1 mm to about 15 mm, such as 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 soluble delay member has a diameter of at least about 1 mm, such as 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 soluble delay member has a diameter of less than about 15 mm, such as 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 soluble delay member has a diameter of any one 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.

[0256] In some embodiments, the soluble delay member has a thickness of about 0.1 mm to about 5 mm, such as about 0.2 mm to about 2 mm, about 0.5 mm to about 1.5 mm, or about 0.6 mm to about 1.4 mm. In some embodiments, the soluble delay member has a thickness of at least about 0.1 mm, such as at least about 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.2 mm, 2.4 mm, 2.6 mm, 2.8 mm, 3.0 mm, 3.2 mm, 3.4 mm, 3.6 mm, 3.8 mm, 4.0 mm, 4.2 mm, 4.4 mm, 4.6 mm, 4.8 mm, or 5 mm. In some embodiments, the soluble delay member has a thickness of less than about 5 mm, such as less than about 4.8 mm, 4.6 mm, 4.4 mm, 4.2 mm, 4.0 mm, 3.8 mm, 3.6 mm, 3.4 mm, 3.2 mm, 3.0 mm, 2.8 mm, 2.6 mm, 2.4 mm, 2.2 mm, 2.0 mm, 1.9 mm, 1.8 mm, 1.7 mm, 1.6 mm, 1.5 mm, 1.4 mm, 1.3 mm, 1.2 mm, 1.1 mm, 1.0 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, or 0.1 mm. In some embodiments, the soluble delay member has a thickness of about 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.

[0257] In some embodiments, the soluble delay member includes a top surface and a bottom surface, wherein the thickness measured between the top surface and the bottom surface is substantially consistent, for example, within 20% of the average thickness.

[0258] In some embodiments, the top and bottom surfaces of the soluble delay member have the same surface area. In some embodiments, the maximum span dimensions of the top and bottom surfaces of the soluble delay member are the same. In some embodiments, the span dimensions perpendicular to the maximum span dimensions of the top and bottom surfaces of the soluble delay member are the same. In some embodiments, the top and bottom surfaces of the soluble delay member have the same diameter. In some embodiments, the top and bottom surfaces of the soluble delay member have the same shape.

[0259] In some implementations, the soluble delay member includes a side surface.

[0260] In some embodiments, the soluble delay member comprises a soluble material that is not miscible with the drug. In some embodiments, the soluble delay member (e.g., the soluble material of the soluble delay member) comprises a thermoplastic material, such as a thermoplastic polymer. In some embodiments, the soluble delay member comprises one or more of a soluble thermoplastic material, a plasticizer, and other additives (e.g., fillers, binders, lubricants, flow aids, and disintegrants).

[0261] In some embodiments, the soluble thermoplastic material includes copovidone, polyvinylpyrrolidone-co-vinyl acetate (PVP-VA), polyvinylpyrrolidone (PVP), cross-linked polyvinylpyrrolidone (PVPP), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), methylcellulose (MC), hydroxyethyl cellulose (HEC), methacrylic acid copolymer, poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate), poly(dimethyl methacrylate-co-methyl methacrylate), etc. The following are included in the list of poly(ethyl methacrylate-co-methyl methacrylate-trimethylammonium ethyl methacrylate chloride), poly(methyl methacrylate-co-methyl methacrylate-co-methyl methacrylate), poly(methyl methacrylate-co-methyl methacrylate), poly(methyl methacrylate-co-methyl methacrylate), poly(ethyl methacrylate-co-ethyl methacrylate), poly(methyl methacrylate-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 copolymer, ammonium alkyl methacrylate copolymer, ethyl cellulose (EC), diethyl polyvinyl acetal aminolactic acid and diethyl polyvinyl acetal aminoacetate (AEA).

[0262] In some embodiments, the plasticizer includes any one or more of triethyl citrate (TEC), vitamin E polyethylene glycol succinate (TPGS), glyceryl acetate, acetylated triethyl citrate, tributyl citrate, o-acetylated tributyl citrate, polyethylene glycol 15-hydroxystearate, PEG-40-hydrogenated castor oil, polyethylene glycol 35-castor oil, dibutyl sebacate, diethyl phthalate, glycerin, methyl 4-hydroxybenzoate, castor oil, oleic acid, glyceryl triacetate, N,N-diethylpropynylamine (DEP), and polyalkylene glycols.

[0263] In some implementations, other additives include gum arabic, alginate, alginic acid, aluminum acetate, barium sulfate, butylparaben, butylated hydroxytoluene, citric acid, calcium carbonate, superphosphate, candelilla wax, croscarmellose sodium carboxymethyl cellulose, powdered sugar, colloidal silica, cellulose, ordinary or anhydrous calcium phosphate, carnauba wax, corn starch, calcium carboxymethyl cellulose, calcium disodium EDTA, dehydrated dicalcium phosphate, hexadecylpyridine chloride, dicalcium phosphate, ternary calcium phosphate, dibasic calcium phosphate, disodium hydrogen phosphate, polydimethylsiloxane, sodium tetraiodofluorescein, EDTA, gelatin, glycerin, glyceryl monooleate, ferric oxide, ferric oxide yellow, and oxidized iron oxide. Iron oxide red, lactose, microcrystalline cellulose, magnesium carbonate, magnesium oxide, methylparaben, polysorbate, propylene glycol, potassium bicarbonate, potassium sorbate, potato starch, phosphoric acid, polyoxyethylene (40) stearate, sodium carboxyacetic acid starch, 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, talc, poloxamer, polyvinyl alcohol-polyethylene glycol copolymer, cyclodextrin and maltodextrin, any one or more of these.

[0264] In some embodiments, the soluble etch-delaying member comprises one or more of hydroxypropyl cellulose (HPC), polyvinyl alcohol (PVA), and triethyl citrate (TEC). In some embodiments, the soluble etch-delaying member comprises one or more of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and triethyl citrate (TEC). In some embodiments, the soluble etch-delaying member comprises one or more of hydroxypropyl cellulose (HPC), maltodextrin, and triethyl citrate (TEC).

[0265] In some embodiments, based on the weight of the oral pharmaceutical dosage form, the soluble delay member has a mass fraction (m) of hydroxypropyl cellulose of about 0.1 to about 0.6. FIn some embodiments, based on the weight of the oral pharmaceutical dosage form, the soluble delay member has a mass fraction (m) of hydroxypropyl cellulose 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. F In some embodiments, based on the weight of the oral pharmaceutical dosage form, the soluble delay member has a hydroxypropyl cellulose mass fraction (m) of less than about 0.6, such as less than any one of about 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1. F In some embodiments, based on the weight of the oral pharmaceutical dosage form, the soluble delay member has a hydroxypropyl cellulose mass fraction (m) of about 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, or 0.6. F ).

[0266] In some embodiments, based on the weight of the oral pharmaceutical dosage form, the soluble delay member has a polyvinyl alcohol mass fraction (m) of about 0.1 to about 0.6. F In some embodiments, based on the weight of the oral pharmaceutical dosage form, the soluble delay member has a polyvinyl alcohol mass fraction (m) 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. F In some embodiments, based on the weight of the oral pharmaceutical dosage form, the soluble delay member has a polyvinyl alcohol mass fraction (m) of less than about 0.6, such as less than any one of about 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1. F In some embodiments, based on the weight of the oral pharmaceutical dosage form, the soluble delay member has a polyvinyl alcohol mass fraction (m) of about 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, or 0.6. F ).

[0267] In some embodiments, based on the weight of the oral pharmaceutical dosage form, the soluble delay member has a mass fraction (m) of triethyl citrate of about 0.01 to about 0.6. FIn some embodiments, based on the weight of the oral pharmaceutical dosage form, the soluble delay member has a mass fraction (m) of triethyl citrate of at least about 0.01, such as at least about 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. F In some embodiments, based on the weight of the oral pharmaceutical dosage form, the soluble delay member has a triethyl citrate mass fraction (m) of less than about 0.6, such as less than any of about 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. F In some embodiments, based on the weight of the oral pharmaceutical dosage form, the soluble delay member has a triethyl citrate mass fraction (m) of about 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. F ).

[0268] In some embodiments, based on the weight of the oral pharmaceutical dosage form, the soluble delay member has a mass fraction (m) of hydroxypropyl methylcellulose of about 0.01 to about 0.6. F In some embodiments, based on the weight of the oral pharmaceutical dosage form, the soluble delay member has a mass fraction (m) of hydroxypropyl methylcellulose of at least about 0.01, such as at least about 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. F In some embodiments, based on the weight of the oral pharmaceutical dosage form, the soluble delay member has a mass fraction (m) of hydroxypropyl methylcellulose less than about 0.6, such as less than any one of about 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. FIn some embodiments, based on the weight of the oral pharmaceutical dosage form, the soluble delay member has a mass fraction (m) of hydroxypropyl methylcellulose of about 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. F ).

[0269] In some embodiments, the soluble delay member has a maltodextrin mass fraction (m) of about 0.1 to about 0.6, based on the weight of the oral pharmaceutical dosage form. F In some embodiments, based on the weight of the oral pharmaceutical dosage form, the soluble delay member has a maltodextrin mass fraction (m) of at least about 0.1, such as at least about 0.2, 0.3, 0.4, 0.5, or 0.6. F In some embodiments, based on the weight of the oral pharmaceutical dosage form, the soluble delay member has a maltodextrin mass fraction (m) of less than about 0.6, such as less than any one of about 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1. F In some embodiments, based on the weight of the oral pharmaceutical dosage form, the soluble delay member has a maltodextrin mass fraction (m) of about 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, or 0.6. F ).

[0270] In some embodiments, the soluble etch-delay member comprises hydroxypropyl cellulose, maltodextrin, and triethyl citrate. In some embodiments, based on the weight of the soluble etch-delay member, the soluble etch-delay member comprises about 65% hydroxypropyl cellulose, about 25% maltodextrin, and about 10% triethyl citrate.

[0271] vi. pH-responsive components

[0272] The release-limiting components described herein include pH-responsive members, such as pH-responsive member layers. In some embodiments, the pH-responsive member comprises more than one layer of a pH-based enteric material, such as two layers of a pH-based enteric material. In some embodiments, the pH-responsive member does not contain a drug. In some embodiments, the pH-responsive member surrounds a soluble delay member, which in turn surrounds a drug component. In some embodiments, the pH-responsive member prevents erosion of the soluble delay member, and the soluble delay member prevents erosion of the drug component. In some embodiments, the pH-responsive member surrounds the drug component. In some embodiments, the pH-responsive member prevents erosion of the drug component.

[0273] pH-responsive components are configured to dissolve at or above a desired pH value. As understood in the art, different regions of the human gastrointestinal tract have different pH environments. Using such pH-responsive components helps control the dissolution of this component in oral drug formulations described herein, down to the desired location in the gastrointestinal tract, avoiding the influence of food and achieving precise drug release. In some embodiments, the pH-responsive component dissolves at a pH value between about 5.5 and about 8, such as between about 5.5 and about 7.5 and between about 6 and about 7. In some embodiments, the pH-responsive component dissolves at or above a pH value of about 5.5, such as about 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.

[0274] A variety of materials with different shapes and sizes can be used to form pH-responsive components. In some embodiments, the pH-responsive component is a layer of pH-based enteric material. In some embodiments, the pH-responsive component is configured to have a surface, such as a surface exposed to bodily fluids during administration of an oral drug dosage form to a human individual, having a predetermined shape and surface area. The surface of the pH-responsive component (such as a pH-responsive component layer) can have any shape, as based on the surface exposed to bodily fluids during administration. In some embodiments, the surface has shapes such as capsule-shaped, circular, elliptical, bullet-shaped, arrow-shaped, triangular, arc-triangular, square, arc-square, rectangular, arc-rectangular, rhomboid, pentagonal, hexagonal, octagonal, crescent-shaped, almond-shaped, or combinations thereof.

[0275] In some embodiments, the pH-responsive component (such as a pH-responsive component layer) comprises a thermoplastic material, such as a thermoplastic polymer. In some embodiments, the pH-responsive component (such as a pH-responsive component layer) comprises a material including one or more of a matrix material, a plasticizer, or other additives (such as fillers, binders, lubricants, flow aids, and disintegrants).

[0276] In some embodiments, the pH-responsive component material includes one or more of the following: stearic acid, copovidone, polyvinylpyrrolidone-co-vinyl acetate, polyvinylpyrrolidone-polyvinyl acetate copolymer, crosslinked povidone, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose or hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methylcellulose, methacrylic acid copolymer, poly(ethyl methacrylate-co-ethyl acrylate), poly(butyl methacrylate-co-(2-dimethylaminoethyl methacrylate-dimethylaminoethyl methacrylate), poly(dimethylaminoethyl methacrylate-methacrylate-co-methyl methacrylate), poly(ethyl acrylate-trimethylaminoethyl methacrylate chloride), poly(methyl acrylate-methacrylate-methyl methacrylate-methyl methacrylate), poly(methyl methacrylate-methyl methacrylate), polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, Kollicoat IR-polyvinyl alcohol, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, hydroxypropyl methylcellulose acetate succinate or hydroxypropyl methylcellulose acetate succinate, methacrylate copolymer, ammonium alkyl methacrylate copolymer, ethyl cellulose, polyvinyl acetate and polyvinylpyrrolidone, polyvinyl acetal diethylaminolactic acid ester, polyvinyl acetal diethylaminolactic acid ester, maltitol, lactose monohydrate, xylitol, isomaltitol, sucrose, glucose, dextran 70 or maltose.

[0277] In some embodiments, the plasticizer includes any one or more of triethyl citrate (TEC), vitamin E polyethylene glycol succinate (TPGS), glyceryl acetate, acetylated triethyl citrate, tributyl citrate, o-acetylated tributyl citrate, polyethylene glycol 15-hydroxystearate, PEG-40-hydrogenated castor oil, polyethylene glycol 35-castor oil, dibutyl sebacate, diethyl phthalate, glycerin, methyl 4-hydroxybenzoate, castor oil, oleic acid, glyceryl triacetate, N,N-diethylpropynylamine (DEP), and polyalkylene glycols.

[0278] In some implementations, other additives include gum arabic, alginate, alginic acid, aluminum acetate, butylparaben, butylated hydroxytoluene, citric acid, calcium carbonate, croscarmellose sodium, powdered sugar, colloidal silica, cellulose, ordinary or anhydrous calcium phosphate, carnauba wax, corn starch, calcium carboxymethyl cellulose, calcium disodium EDTA, dehydrated calcium hydrogen phosphate, hexadecylpyridine chloride, calcium hydrogen phosphate, ternary calcium phosphate, dibasic calcium phosphate, disodium hydrogen phosphate, polydimethylsiloxane, sodium tetraiodofluorescein, EDTA, gelatin, glyceryl monooleate, ferric oxide, ferric oxide, and oxygen. Ferric yellow, ferric oxide red, lactose, microcrystalline cellulose, magnesium carbonate, magnesium oxide, methylparaben, polysorbate, propylene glycol, potassium bicarbonate, potassium sorbate, potato starch, phosphoric acid, polyoxyethylene stearate, sodium carboxyacetic acid starch, 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, dehydrated sorbitan oleate, sodium chloride, sodium metabisulfite, dehydrated sodium citrate, sodium starch, sodium carboxymethyl cellulose, succinic acid, sodium propionate, titanium dioxide, and talc.

[0279] vii. Add-ons

[0280] In some embodiments, the oral drug dosage form includes an additional component, 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 colored 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 trademark name and / or drug chemical name or abbreviation); drug quantity or strength; an identification barcode, or any combination thereof.

[0281] III. Commercial Batch

[0282] In some aspects, this document provides commercial batches of at least about 1,000 oral drug dosage forms described herein. In some embodiments, a commercial batch includes any one of at least about 250, 500, 750, 1,000, 2,500, 5,000, 7,500, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000, or 100,000 oral drug dosage forms described herein.

[0283] In some implementations, the commercial batch has a standard deviation of about 0.1 or less, for example about 0.05 or less, for one or more of the following: the amount of drug in the oral dosage form; the weight of the oral dosage form; the maximum span size of the oral dosage form; the span size of the oral dosage form perpendicular to the maximum span size; the diameter of the oral dosage form; or the particle size of the drug particles.

[0284] IV. Methods for preparing oral drug dosage forms

[0285] In some aspects, this document provides methods for preparing the oral drug dosage forms described herein. In some embodiments, the preparation method includes three-dimensional (3D) printing of at least one component or a portion thereof of the components forming the oral drug dosage forms described herein.

[0286] In some embodiments, a method for three-dimensionally (3D) printing the oral drug dosage form described herein is provided, the method comprising dispensing materials according to a layer-by-layer model of the oral drug dosage form to print the oral drug dosage form, wherein each layer of the layer-by-layer model is printed by dispensing, as needed, the following materials: (a) a drug component comprising a first soluble material mixed with a drug; (b) a soluble delayed member comprising a second soluble material not mixed with the drug; and (c) a pH-responsive member comprising a pH-based enteric material not mixed with the drug. In some embodiments, the method further includes generating a layer-by-layer model of the oral drug dosage form. In some embodiments, dispensing is performed via melt extrusion deposition (MED). In some embodiments, the dispensing of the various materials is performed by different printheads. In some embodiments, the drug described herein is uniformly distributed in the drug component as an amorphous solid dispersion.

[0287] In some embodiments, a method is provided for preparing any of the oral drug dosage forms described herein, the method comprising three-dimensionally (3D) printing the oral drug dosage form. In some embodiments, the oral drug dosage form includes: a drug component comprising a first soluble material mixed with a drug; and a pH-responsive member configured to dissolve at or above a predetermined pH value, wherein the method includes: (a) dispensing the drug component; (b) injection molding the pH-responsive member; and (c) assembling the drug component into the pH-responsive member to form the oral drug dosage form.

[0288] In some embodiments, a method is provided for preparing any of the oral drug dosage forms described herein, the method comprising three-dimensionally (3D) printing the oral drug dosage form. In some embodiments, the oral drug dosage form comprises: a drug component comprising a first etchable material mixed with a drug; a etchable delay member comprising a second etchable material not mixed with the drug; and a pH-responsive member configured to etch at or above a predetermined pH value, wherein the method comprises: (a) dispensing the drug component; (b) dispensing the etchable delay member; (c) injection molding the pH-responsive member; and (d) assembling the drug component and the etchable delay member into the pH-responsive member to form the oral drug dosage form.

[0289] In some embodiments, a method for three-dimensionally (3D) printing the oral drug dosage form described herein is provided, the method comprising dispensing materials according to a layer-by-layer model of the oral drug dosage form to print the oral drug dosage form, wherein each layer of the layer-by-layer model is printed by dispensing, as needed, the following materials: (a) a drug component comprising a first etchable material mixed with drug particles; (b) a etch-delayed member comprising a second etchable material not mixed with the drug; and (c) a pH-responsive member comprising a pH-based enteric material not mixed with the drug. In some embodiments, the method further includes generating a layer-by-layer model of the oral drug dosage form. In some embodiments, dispensing is performed via melt extrusion deposition (MED). In some embodiments, the dispensing of the various materials is performed by different printheads. In some embodiments, the drug particles described herein comprise a etchable material mixed with the drug.

[0290] In some embodiments, a method is provided for preparing any of the oral drug dosage forms described herein, the method comprising three-dimensionally (3D) printing the oral drug dosage form. In some embodiments, the oral drug dosage form includes: a drug component comprising a first soluble material mixed with drug particles; and a pH-responsive member configured to dissolve at or above a predetermined pH value, wherein the method includes: (a) dispensing the drug component; (b) injection molding the pH-responsive member; and (c) assembling the drug component into the pH-responsive member to form the oral drug dosage form.

[0291] In some embodiments, a method is provided for preparing any of the oral drug dosage forms described herein, the method comprising three-dimensionally (3D) printing the oral drug dosage form. In some embodiments, the oral drug dosage form comprises: a drug component comprising a first soluble material mixed with drug particles; a soluble etch-delay member comprising a second soluble material not mixed with the drug; and a pH-responsive member configured to etch at or above a predetermined pH value, wherein the method comprises: (a) dispensing the drug component; (b) dispensing the soluble etch-delay member; (c) injection molding the pH-responsive member; and (d) assembling the drug component and the soluble etch-delay member into the pH-responsive member to form the oral drug dosage form.

[0292] In some embodiments, the drug particles described herein are prepared by hot melt extrusion (HME). In some embodiments, a method for preparing the drug particles described herein is provided, comprising: (a) premixing the drug with a soluble material and then filling it in a single-screw or twin-screw extruder; (b) rotating the screw to further extrude the physical mixture while the extruder jacket is heated to a high temperature; (c) melting and kneading the drug and soluble material, and continuously extruding the melt from a final plate and dies of different shapes; and (d) pulverizing and sieving. In some embodiments, the drug described herein is uniformly distributed in the drug particles as an amorphous solid dispersion.

[0293] In some embodiments, the lipid-based composition described herein is prepared by mixing the components evenly according to the prescribed amounts.

[0294] In some embodiments, a method for any of the oral drug dosage forms described herein includes: (a) uniformly mixing the components of a lipid-based composition and loading them into a printhead; (b) dispensing a soluble delay member comprising a second soluble material that is not mixed with the drug and 3D printing to form a cavity; (c) extruding the lipid-based composition into the cavity of the soluble delay member; and (d) 3D printing to seal the soluble delay member. In some embodiments, the method further includes: (e) 3D printing a pH-responsive member of a pH-based enteric material that is not mixed with the drug.

[0295] In some embodiments, the method includes: (a) uniformly mixing the components of the lipid-based composition and loading them into a printhead; (b) dispensing a pH-responsive member of a pH-based enteric material that is not mixed with the drug and 3D printing it to form a cavity; (c) extruding the lipid-based composition into the cavity of the pH-responsive member; and (d) 3D printing the pH-responsive member to seal it.

[0296] In some implementations, the pH-responsive component is fabricated using injection molding.

[0297] As used herein, “printing,” “3D printing,” “additive manufacturing,” or equivalent terms refer to a method of producing three-dimensional objects (e.g., oral pharmaceutical dosage forms) layer by layer using digital design. The basic process of 3D 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; 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 incorporated herein by reference in their entirety. In some embodiments, additive manufacturing techniques are used to produce the oral drug dosage forms described herein. In some embodiments, layer-by-layer techniques are used to produce the oral drug dosage forms described herein. Because 3D printing can handle a range of pharmaceutical materials and can simultaneously and locally control composition and structure, it is well-suited for manufacturing oral pharmaceutical dosage forms with complex geometries and compositions according to the present invention.

[0298] In some embodiments, when referring to, for example, a drug component layer, a layer refers to the configuration of a component of an oral drug dosage form and may comprise multiple printed layers of the same material. In some embodiments, the layers have a predetermined infill density, such as a 3D printing infill density. In some embodiments, the layers (e.g., a drug component layer or a soluble delayed component layer) comprise multiple printed layers between about 5 printed layers and about 2500 printed layers, for example, 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 implementations, the thickness of the printed layer does not exceed about 5 mm, such as not exceeding any one of about 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 implementations, the thickness of the printed layer is any one of approximately 5 mm, 4 mm, 3 mm, 2 mm, 1 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, 0.1 mm, 0.09 mm, 0.08 mm, 0.07 mm, 0.06 mm, 0.05 mm, 0.04 mm, 0.03 mm, 0.02 mm, or 0.01 mm.

[0299] In some embodiments, the oral drug dosage forms described herein are 3D printed using extrusion. In some embodiments, the 3D printing method includes the use of a twin-screw extrusion method. In the extrusion process, material is extruded from an automatically driven printhead through a print nozzle. Unlike binder deposition, which requires a powder bed, extrusion methods can print on any substrate. A wide variety of materials can be extruded for 3D printing, including the thermoplastics, pastes and colloidal suspensions, silicones, and other semi-solids disclosed herein. One extrusion printing method is melt extrusion deposition (MED), which uses material extruded from a printhead to print layers of material to form components of an oral drug dosage form. Another common type of extrusion printing method is fused deposition modeling, which uses solid polymer filaments for printing.

[0300] In some embodiments, 3D printing is performed via melt extrusion deposition (MED). In some embodiments, melt extrusion deposition technology involves preparing a material to be dispensed (e.g., preparing a powder in a melt extruder) and then feeding that material into a MED printhead. The MED printhead then dispenses the material in an additive (layer-by-layer deposition) manner to form an oral drug dosage form. In some embodiments, the various materials of the oral drug dosage form, such as drug components and soluble delay members, are dispensed by different MED printheads.

[0301] In some embodiments, the hot melt extrusion deposition 3D printing technology includes: (a) preparing component materials by hot melt extrusion of component materials, wherein these components are selected from one or more of pharmaceutical components, soluble delayed components, pH-responsive components, and / or tracking markers; and (b) printing oral pharmaceutical dosage forms. In some embodiments, the hot melt extrusion deposition 3D printing technology also includes preparing a printhead for printing.

[0302] In some embodiments, the soluble retardant member described herein is prepared by melt extrusion deposition (MED). In some embodiments, a method for preparing the soluble retardant member described herein is provided, comprising: (a) premixing the components of the soluble retardant member and filling them into a single-screw or twin-screw extruder; (b) rotating the screw to further extrude the physical mixture, setting the temperatures of different functional blocks in the heating section from the outlet to the inlet, and activating heating to prepare the melt; and (c) extruding the melt from the nozzle and depositing it layer by layer. In some embodiments, the heating temperature is from about 30°C to about 190°C. In some embodiments, the heating temperature is from about 60°C to about 120°C. In some embodiments, the heating temperature is about 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, 170°C, 180°C, or 190°C. In some embodiments, the heating temperature is about 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, or 120°C. In some embodiments, the screw speed is about 10 to about 80 rpm. In some embodiments, the screw speed is about 20 to about 70 rpm. In some embodiments, the screw speed is about 30 to about 60 rpm. In some embodiments, the screw speed is about 10 rpm, 20 rpm, 30 rpm, 40 rpm, 50 rpm, 60 rpm, 70 rpm, or 80 rpm. In some embodiments, the screw speed is about 30 rpm, 40 rpm, 50 rpm, or 60 rpm.

[0303] In some respects, as shown in Figure 11, this paper provides a 3D printing device for oral drug dosage forms, including: a first print head for printing a first printing material; a second print head for printing a second printing material; a carrier plate on which a target printing position is set; and a motion stage for moving the position of the carrier plate.

[0304] In some aspects, as shown in Figure 12, this paper provides a 3D printing method for oral drug dosage forms, the method comprising: (a) positioning a first print head at a target printing position, the first print head printing a first printing material to form layers 1 to N (step a1 in the figure) and layer N+M (step a2 in the figure) of a release control component, wherein the N+M layer and the N layer form a cavity; (b) positioning a second print head at the target printing position, the second print head printing a second printing material within the cavity to form a drug component; (c) positioning the first print head at the target printing position, the first print head printing the first printing material to form layer O of the release control component; wherein N, M, and O are all positive integers less than or equal to 10. In some embodiments, N, M, and O are independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, respectively. In some embodiments, N and O are the same. In some embodiments, N and O are different.

[0305] In some embodiments, the second printhead prints X layers of drug components, where X is a positive integer less than or equal to 5. In some embodiments, X is a positive integer less than or equal to 3. In some embodiments, X is selected from 1, 2, 3, 4, and 5. In some embodiments, X is selected from 1, 2, and 3.

[0306] In some embodiments, step (b) includes: (b1) positioning a second printhead at the target printing position, the second printhead printing a drug component within the cavity; (b2) positioning a first printhead at the target printing position, the first printhead printing the N+M+K layers of the release control component (K being a positive integer less than or equal to 6), the N+M+K layers forming a cavity with the X layer of the drug component; and (b3) positioning a second printhead at the target printing position, the second printhead printing a drug component within the cavity. In some embodiments, K is selected from 1, 2, 3, 4, 5, and 6.

[0307] In some implementations, step (b) further includes (b4) repeating b2 and b3.

[0308] In some implementations, the O layer is equal to the N layer.

[0309] In some implementations, the printing temperature of the first printhead print release control assembly is from about 30°C to about 200°C.

[0310] In some implementations, the Nth and Oth layers are circular in shape.

[0311] In some implementations, the Mth and Kth layers are annular in shape.

[0312] In some embodiments, the method for preparing the oral drug dosage form described herein further includes setting a tracking marker. In some embodiments, the method includes: setting the tracking marker; imaging an individual; and designing the oral drug dosage form based on the imaging location and the status of the tracking marker. In some embodiments, the tracking marker comprises a soluble 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 X-ray imaging. 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 drug dosage form will not contain a tracking strip, and such a tracking strip is only required during the design phase to ensure proper positioning of drug delivery. In some embodiments, the tracking marker comprises barium sulfate as an imaging material. In some embodiments, the tracking marker comprises one or more of barium sulfate (BaSO4), polyvinylpyrrolidone (VA64), and triethyl citrate (TEC). In some implementations, the tracking markers (e.g., tracking strips, tracking rings) contain about 60% barium sulfate, about 32% VA64, and about 8% triethyl citrate, based on the weight of the tracking markers.

[0313] In some embodiments, the pH-responsive components described herein are fabricated using injection molding. The drug components or soluble etch-delay components described herein are fabricated using the 3D printing method described herein. The fabricated components are assembled to form the oral drug dosage form described herein.

[0314] The oral drug dosage forms and components described herein are commercially scalable. For example, in some embodiments, the methods disclosed herein can be used to 3D print 10,000 to 100,000 oral drug dosage forms per hour. In some embodiments, the methods disclosed herein can be used to 3D print 10,000 to 100,000 oral drug dosage forms per hour. In some embodiments, the methods disclosed herein can be used to 3D print 10,000 to 100,000 dose units per hour. In some embodiments, the methods disclosed herein can be used to 3D print 10,000 to 100,000 dose units per hour.

[0315] Example

[0316] Example 1

[0317] This embodiment illustrates the design, manufacture, and testing of the oral drug dosage form described herein. The oral drug dosage form comprises a fixed amount of a drug with a desired drug release profile, namely budesonide.

[0318] Figure 1A provides a schematic diagram of an oral drug dosage form. The component composition and dimensions of the prepared dosage form are shown in Tables 1A and 1B, and a schematic diagram of the oral drug dosage form is shown in Figure 2A.

[0319] As shown in Figure 1A, an oral drug dosage form includes: a drug component comprising a first soluble material mixed with a drug; and a soluble delay member comprising a second soluble material not mixed with the drug; wherein the soluble delay member surrounds the drug component, and wherein the soluble delay member prevents the release of the drug from the oral drug dosage form within approximately 2 hours to approximately 7 hours after administration to a human individual. The drug is mixed with the first soluble material in powder form and uniformly dispersed within the drug component. Upon administration, the soluble delay member is exposed to gastrointestinal fluid, and the soluble delay member begins to erode. The soluble delay member erodes, subsequently exposing the surface of the drug component, causing the surface of the drug component to erode, and the drug is released from the drug component. As shown in Figure 2A, the oral drug dosage form may include tracking features, such as tracking strips and / or rings. Such tracking features are used in the development and optimization of oral drug formulations. For example, after administration, imaging of the individual (such as using X-rays) can be used to determine the location of dissolution in the drug formulation or the release of the drug from the drug component. After the oral drug formulation has been developed and optimized, these tracking features may no longer be needed. In such embodiments, portions of the tracking features may be replaced by a material embedded therein and / or may be further modified, such as adjusting one or more drug component characteristics (e.g., surface area, thickness, drug mass fraction) to indicate that the tracking features are no longer present.

[0320] The composition of oral drug dosage forms shown in Table 1A and Figure 2A

[0321] The soluble etch-delay component comprises hydroxypropyl cellulose, maltodextrin, and triethyl citrate; the tracking feature (e.g., tracking strip, tracking ring) comprises barium sulfate, VA64, and triethyl citrate; and the pharmaceutical component comprises budesonide, VA64, and triethyl citrate. In some embodiments, based on the weight of the soluble etch-delay component, the soluble etch-delay component comprises about 65% hydroxypropyl cellulose, about 25% maltodextrin, and about 10% triethyl citrate; based on the weight of the tracking feature, the tracking feature (e.g., tracking strip, tracking ring) comprises about 60% barium sulfate, about 32% VA64, and about 8% triethyl citrate; and based on the weight of the pharmaceutical component, the pharmaceutical component comprises about 10% budesonide, about 75% VA64, and about 15% triethyl citrate.

[0322] Table 1B and Figure 2A show the dimensions of oral drug dosage forms.

[0323] The preparation process is as follows:

[0324] (1) Material mixing of drug components: After pulverizing and sieving budesonide, it is uniformly mixed with VA64 and triethyl citrate; the mixture is added to a twin-screw extruder, and the screw speed is adjusted to mix the materials.

[0325] (2) Material mixing of soluble delay components: Add the weighed material to the pulverizer and mix; add the mixture to the twin-screw extruder, adjust the screw speed and mix the material;

[0326] (3) Material mixing in the tracking feature section: Add the weighed material to the pulverizer and mix; add the mixture to the twin-screw extruder, adjust the screw speed, and mix the material.

[0327] (4) 3D printing steps: Distribute the materials for the drug component, the soluble delay component, and the tracking feature into different nozzles; set the 3D printer temperature, turn on the heating, and perform 3D printing. The temperatures of each component are as follows:

[0328] The size of the oral medication dosage form was measured and compared with that of capsule No. 1. The measurement results are shown in Figure 3, indicating that the oral medication dosage form described in this paper has a smaller size and better patient compliance. Electron microscopy at 100x magnification was used to take photographs, as shown in Figure 4, revealing the dense surface of the oral medication dosage form described in this paper.

[0329] In vitro dissolution testing was performed on the oral drug dosage form. The in vitro dissolution rate study was conducted as follows: Following the method for determination of dissolution and release (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931-1), 900 mL of pH 6.8 phosphate buffer containing 0.05 wt% Tween 80 was used as the dissolution medium, and the rotation speed was 100 rpm. At predetermined sampling points, 2 mL of solution was collected, filtered through a 0.45 μm filter membrane, and then analyzed by HPLC. The resulting in vitro dissolution curves are shown in Figure 5. For each time point of the dissolution curve, the data points are based on the average of six repeated measurements, and the standard deviation is provided using error bars.

[0330] Clinical trials were conducted to perform pharmacokinetic (PK) and X-ray studies. Twelve healthy subjects (appropriate male-to-female ratio) were enrolled in a randomized, open-label, single-dose, two-sequence, four-cycle, fully replicated crossover trial design. Enrolled subjects maintained a uniform diet one day prior to the first cycle of administration and fasted for at least 10 hours the night before the trial. On the morning of the day of administration, a blank blood sample was collected, and the subjects, on an empty stomach, took one tablet of the test formulation (as described in this article, refer to Tables 1A and 1B, Figure 2) or one tablet of the control formulation (budesonide enteric-coated capsules, trade name: [trade name missing]) with 240 mL of water. Specification: 4mg. Swallow the tablet whole; do not break or chew it.

[0331] Venous blood samples were collected from all subjects before administration (within 1 hour before administration) and at 0.50h, 1.00h, 1.50h, 2.00h, 2.50h, 3.00h, 3.50h, 4.00h, 4.50h, 5.00h, 5.50h, 6.00h, 7.00h, 8.00h, 9.00h, 10.00h, 16.00h, 24.00h, 36.00h, and 48.00h after administration. Approximately 4 mL of blood was collected at each point. The PK parameters are shown in Table 2, and the PK curves of the tested oral drug dosage forms are provided in Figure 6.

[0332] Table 2. PK parameters measured in healthy subjects administering oral drug formulations containing budesonide.

[0333] Pharmacokinetic results reflect the delayed-release characteristics of the oral drug formulation in this study, including the absorption T values ​​(ranges) for both the oral drug formulation and the control formulation. lag The values ​​were 2.5 (2.0-4.0) and 4.5 (3.0-7.0), respectively, which confirms the ileal release characteristics of the oral drug formulations in this study.

[0334] Subjects who received the test formulation underwent abdominal X-ray examinations at 2.0 h ± 0.5 h, 3.0 h ± 0.5 h, 4.0 h ± 0.5 h, 5.0 h ± 0.5 h, and 6.0 h ± 0.5 h post-administration to confirm the drug status of the test formulation and to assess gastrointestinal localization. One subject was selected, and the resulting X-ray image is shown in Figure 7. Each X-ray image indicates the capture time, the onset of drug release, and the completion of drug release.

[0335] X-ray images showed that the release location / time was consistent with the predicted PK parameters of the oral drug formulation presented in this paper. The oral drug formulation described in this paper allows for precise control of drug release and accurate delivery of the drug to the ileum.

[0336] Example 2

[0337] This embodiment illustrates the design, manufacture, and testing of the oral drug dosage form described herein. The oral drug dosage form comprises a fixed amount of a drug with a desired drug release profile, namely budesonide.

[0338] Figure 1A provides a schematic diagram of the oral drug dosage form. The component composition and dimensions of the prepared dosage form are shown in Tables 3A and 3B.

[0339] As shown in Figure 1A, an oral drug dosage form includes: a drug component comprising a first soluble material mixed with a drug; and a soluble delay member comprising a second soluble material not mixed with the drug; wherein the soluble delay member surrounds the drug component, and wherein the soluble delay member prevents the release of the drug from the oral drug dosage form within approximately 2 hours to approximately 7 hours after administration to a human individual. The drug is mixed with the first soluble material in powder form and uniformly dispersed within the drug component. Upon administration, the soluble delay member is exposed to gastrointestinal fluid, and the soluble delay member begins to erode. The soluble delay member erodes, subsequently exposing the surface of the drug component, causing the surface of the drug component to erode, and releasing the drug from the drug component.

[0340] The composition of oral drug dosage forms shown in Table 3A and Figure 1A

[0341] Table 3B shows the dimensions of oral drug dosage forms in Figure 1A.

[0342] In vitro dissolution testing was performed on the oral drug dosage form. The in vitro dissolution rate study was conducted as follows: Following the method for determination of dissolution and release (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931-1), 900 mL of pH 6.8 phosphate buffer containing 0.05 wt% Tween 80 was used as the dissolution medium, and the rotation speed was 100 rpm. At predetermined sampling points, 2 mL of solution was collected, filtered through a 0.45 μm filter membrane, and then analyzed by HPLC. The obtained in vitro dissolution curves are shown in Figure 8.

[0343] Example 3

[0344] This embodiment illustrates the design, manufacture, and testing of the oral drug dosage form described herein. The oral drug dosage form comprises a fixed amount of a drug with a desired drug release profile, namely budesonide.

[0345] The component composition and dimensions of the prepared dosage form are shown in Tables 4A and 4B. The oral drug dosage form includes: a drug component comprising a first soluble material mixed with a drug; and a pH-responsive member configured to dissolve at or above a predetermined pH value. The drug is mixed with the first soluble material in powder form and uniformly dispersed within the drug component. Upon administration, the pH-responsive member is exposed to gastrointestinal fluid, initiating dissolution. The pH-responsive member dissolves, subsequently exposing the surface of the drug component, which then dissolves, releasing the drug from the drug component.

[0346] Table 4A Composition of Oral Drug Dosage Forms

[0347] Table 4B Dimensions of Oral Drug Dosage Forms

[0348] In vitro dissolution testing was performed on the oral drug dosage form. The in vitro dissolution rate study was conducted as follows: Following the method for determining dissolution and release (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931-1), 900 mL of 0.1N HCl was used as the dissolution medium at a rotation speed of 75 rpm. After 2 hours, the solution was transferred to 900 mL of pH 6.8 phosphate buffer containing 0.05 wt% Tween 80 as the dissolution medium at a rotation speed of 75 rpm, and the procedure was repeated. At predetermined sampling points, 2 mL of solution was collected, filtered through a 0.45 μm filter membrane, and analyzed by HPLC. The obtained in vitro dissolution curves are shown in Figure 9.

[0349] Example 4

[0350] This embodiment illustrates the design, manufacture, and testing of the oral drug dosage form described herein. The oral drug dosage form comprises a fixed amount of a drug with a desired drug release profile, namely budesonide.

[0351] The soluble etch-delaying component of Example 1 was replaced, and the composition and size of other components were the same as in Example 1. The preparation method was the same as in Example 1, and tablets 5 and 6 were prepared. The composition of the soluble etch-delaying component of tablets 5 and 6 and the weight ratio between each component are shown in Table 5.

[0352] Table 5. Composition of the soluble delay component in tablets 5 and 6.

[0353] The in vitro dissolution phenomenon of the oral drug dosage forms was observed. The in vitro dissolution rate study was conducted as follows: Following the method for determining dissolution and release (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II), 900 mL of pH 6.8 phosphate buffer containing 0.05 wt% Tween 80 was used as the dissolution medium, and the rotation speed was 75 rpm. The procedure was performed according to the method. A schematic diagram of the dissolution process is shown in Figure 10. It can be seen that the soluble etch-delay component of tablets 5 and 6 gelled upon contact with the aqueous medium.

[0354] Example 5

[0355] This embodiment illustrates the design, manufacture, and testing of the oral drug dosage form described herein. The oral drug dosage form comprises a fixed amount of a drug with a desired drug release profile, namely budesonide.

[0356] Figures 13A and 13B provide schematic diagrams of oral drug dosage forms. The component composition and dimensions of the prepared dosage forms are shown in Tables 6A and 6B.

[0357] As shown in Figures 13A and 13B, an oral drug dosage form includes: a drug component comprising a first soluble material mixed with a drug; and a soluble delay member comprising a second soluble material not mixed with the drug; wherein the soluble delay member surrounds the drug component, and wherein the soluble delay member prevents the release of the drug from the oral drug dosage form within approximately 2 hours to approximately 7 hours after administration to a human individual. The drug is mixed with the first soluble material in powder form and uniformly dispersed within the drug component. Upon administration, the soluble delay member is exposed to gastrointestinal fluid, and the soluble delay member begins to erode. The soluble delay member erodes, subsequently exposing the surface of the drug component, causing the surface of the drug component to erode, and releasing the drug from the drug component.

[0358] The composition of oral drug dosage forms shown in Table 6A, Figure 13A, and Figure 13B

[0359] The drug component consists of budesonide, hydroxypropyl cellulose (SSL), and poloxamer, with each component accounting for 20:40:40 of the total weight of the drug component. The soluble etch-delay component consists of triethyl citrate, hydroxypropyl cellulose (JF), and microcrystalline cellulose, with each component accounting for 45:45:10 of the total weight of the etch-delay component.

[0360] Table 6B shows the dimensions of oral drug dosage forms as shown in Figures 13A and 13B.

[0361] The preparation process is as follows:

[0362] (1) Preparation of drug component intermediates by melt extrusion: The active drug and excipients are added to a mixer according to the prescription ratio and mixed evenly. The temperature of the conical twin-screw extruder is set to 60-60-60 (°C). After the set temperature is reached, the mixed powder is added to the extruder and melt extruded to obtain the drug component intermediate.

[0363] (2) Preparation of soluble delay component intermediate by melt extrusion: Add the excipients to the mixer according to the soluble delay component formula, mix evenly, set the temperature of the conical twin-screw extruder to 130-130-130, and after the set temperature is reached, add the mixed powder to the extruder and melt extrude to obtain the soluble delay component intermediate.

[0364] (3) 3D printing: Print oral drug dosage forms. Set the printing head temperature of the drug component to 60-60-60-60 for preheating and the printing head temperature of the soluble delay component to 90-100-110-110 for preheating. Once the temperature is reached, use the intermediate filler of the drug component and the intermediate filler of the soluble delay component respectively. After confirming the output flow rate of the printing head, load the printing code to produce oral drug dosage forms.

[0365] In vitro dissolution testing was conducted on the oral drug dosage form. The in vitro dissolution study was conducted as follows: The dissolution and release determination method (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0931, Method I) was used. A fixed sieve (20-mesh, 15mm diameter, 5mm height circular sieve) was used as the dissolution medium. 900ml of 0.1mol / L hydrochloric acid solution was used as the dissolution medium. The temperature was 37℃±0.5℃, and the rotation speed was 100 rpm. The procedure was followed, and samples were taken after 2 hours. The dissolution amount should not exceed 10% of the labeled amount.

[0366] Take the test sample after 2 hours of acid dissolution and transfer it to a dissolution vessel. Use 900 ml of 0.2 mol / L sodium phosphate buffer (accurately weigh approximately 49.18 g of anhydrous sodium phosphate, dissolve in 1500 ml of water, shake well, measure 1500 ml, add 4500 ml of 0.1 mol / L hydrochloric acid solution, add approximately 3 g of Tween 80, shake well, and adjust the pH to 6.8 ± 0.05 with hydrochloric acid or sodium hydroxide solution if necessary) as the dissolution medium. The temperature should be 37℃ ± 0.5℃, and the rotation speed should be 100 rpm. Follow the procedure. The obtained in vitro dissolution curve is shown in Figure 14.

[0367] Example 6

[0368] This embodiment illustrates the design, manufacture, and testing of the oral drug dosage form described herein. The oral drug dosage form comprises a fixed amount of a drug with a desired drug release profile, namely budesonide.

[0369] Figures 13A and 13B provide schematic diagrams of oral drug dosage forms. The component composition and dimensions of the prepared dosage forms are shown in Tables 7A and 7B.

[0370] As shown in Figures 13A and 13B, an oral drug dosage form includes: a drug component comprising a first soluble material mixed with a drug; and a soluble delay member comprising a second soluble material not mixed with the drug; wherein the soluble delay member surrounds the drug component, and wherein the soluble delay member prevents the release of the drug from the oral drug dosage form within approximately 2 hours to approximately 7 hours after administration to a human individual. The drug is mixed with the first soluble material in powder form and uniformly dispersed within the drug component. Upon administration, the soluble delay member is exposed to gastrointestinal fluid, and the soluble delay member begins to erode. The soluble delay member erodes, subsequently exposing the surface of the drug component, causing the surface of the drug component to erode, and releasing the drug from the drug component.

[0371] The composition of oral drug dosage forms shown in Table 7A, Figure 13A, and Figure 13B

[0372] The drug component consists of budesonide and PVP-VA64, with a ratio of budesonide:PVP-VA64 = 10:90; the soluble retardant component consists of triethyl citrate (TEC), hydroxypropyl cellulose (HPC JF), and hydroxypropyl cellulose (HPC SSL), with a ratio of HPC JF:HPC SSL:TEC = 45:45:10.

[0373] Table 7B shows the dimensions of oral drug dosage forms as shown in Figures 13A and 13B.

[0374] The preparation process is as follows:

[0375] (1) Preparation of drug component intermediates by melt extrusion: The active drug and excipients are added to the mixer according to the prescription ratio and mixed evenly. The temperature of the conical twin-screw extruder is set to 120-170-180-180-180-180-180-180 (°C). After the set temperature is reached, the mixed powder is added to the extruder and melt extruded to obtain the drug component intermediate.

[0376] (2) Preparation of soluble delay component intermediate by melt extrusion: Add the excipients to the mixer according to the soluble delay component formula, mix evenly, set the temperature of the conical twin-screw extruder to 120-120-120, and after the set temperature is reached, add the mixed powder to the extruder and melt extrude to obtain the soluble delay component intermediate.

[0377] (3) 3D printing: Print oral drug dosage forms. Set the printing head temperature of the drug component to 145-155-155-160 for preheating and the printing head temperature of the soluble delay component to 100-120-120-130 for preheating. After reaching the temperature, use the intermediate filler of the drug component and the intermediate filler of the soluble delay component respectively. After confirming the output flow rate of the printing head, load the printing code to produce oral drug dosage forms.

[0378] In vitro dissolution testing was performed on the oral drug dosage form. The in vitro dissolution rate study was conducted as follows: The dissolution and release rate determination method (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0931, Method I) was followed, using 900 ml of pH 6.8 sodium phosphate buffer as the dissolution medium, at a temperature of 37℃ ± 0.5℃, and a rotation speed of 100 rpm. The resulting in vitro dissolution curve is shown in Figure 15.

[0379] Example 7

[0380] This embodiment illustrates the design, manufacture, and testing of the oral drug dosage form described herein. The oral drug dosage form comprises a fixed amount of a drug with a desired drug release profile, namely budesonide.

[0381] Figures 13A and 13B provide schematic diagrams of oral drug dosage forms. The component composition and dimensions of the prepared dosage forms are shown in Tables 8A and 8B.

[0382] As shown in Figures 13A and 13B, an oral drug dosage form includes: a drug component comprising a first soluble material mixed with a drug; and a soluble delay member comprising a second soluble material not mixed with the drug; wherein the soluble delay member surrounds the drug component, and wherein the soluble delay member prevents the release of the drug from the oral drug dosage form within approximately 2 hours to approximately 7 hours after administration to a human individual. The drug is mixed with the first soluble material in powder form and uniformly dispersed within the drug component. Upon administration, the soluble delay member is exposed to gastrointestinal fluid, and the soluble delay member begins to erode. The soluble delay member erodes, subsequently exposing the surface of the drug component, causing the surface of the drug component to erode, and releasing the drug from the drug component.

[0383] The composition of oral drug dosage forms shown in Table 8A, Figure 13A, and Figure 13B

[0384] The drug component consists of budesonide and PVP-VA64, with a composition of budesonide:PVP-VA64 = 10:90; the soluble retardant component consists of triethyl citrate (TEC), hydroxypropyl cellulose (HPC JF), and hydroxypropyl methylcellulose (HPMC K100LV), with a composition of HPC JF:HPMC K00LV:TEC = 45:45:10.

[0385] Table 8B shows the dimensions of oral drug dosage forms as shown in Figures 13A and 13B.

[0386] The preparation process is as follows:

[0387] (1) Preparation of drug component intermediates by melt extrusion: The active drug and excipients are added to the mixer according to the prescription ratio and mixed evenly. The temperature of the conical twin-screw extruder is set to 120-170-180-180-180-180-180-180 (°C). After the set temperature is reached, the mixed powder is added to the extruder and melt extruded to obtain the drug component intermediate.

[0388] (2) Preparation of soluble delay component intermediate by melt extrusion: Add the excipients to the mixer according to the soluble delay component formula, mix evenly, set the temperature of the conical twin-screw extruder to 120-120-120, and after the set temperature is reached, add the mixed powder to the extruder and melt extrude to obtain the soluble delay component intermediate.

[0389] (3) 3D printing: Print oral drug dosage forms. Set the printing head temperature of the drug component to 145-155-155-160 for preheating and the printing head temperature of the soluble delay component to 100-120-120-130 for preheating. After reaching the temperature, use the intermediate filler of the drug component and the intermediate filler of the soluble delay component respectively. After confirming the output flow rate of the printing head, load the printing code to produce oral drug dosage forms.

[0390] In vitro dissolution testing was performed on the oral drug dosage form. The in vitro dissolution rate study was conducted as follows: The dissolution and release rate determination method (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0931, Method I) was followed, using 900 ml of pH 6.8 sodium phosphate buffer as the dissolution medium, a temperature of 37℃ ± 0.5℃, and a rotation speed of 100 rpm. The resulting in vitro dissolution curve is shown in Figure 16.

[0391] Example 8

[0392] This embodiment illustrates the design, manufacture, and testing of the oral drug dosage form described herein. The oral drug dosage form comprises a fixed amount of a drug with a desired drug release profile, namely budesonide.

[0393] Figures 13A and 13B provide schematic diagrams of oral drug dosage forms. The component composition and dimensions of the prepared dosage forms are shown in Tables 9A and 9B.

[0394] As shown in Figures 13A and 13B, an oral drug dosage form includes: a drug component comprising a first soluble material mixed with a drug; and a soluble delay member comprising a second soluble material not mixed with the drug; wherein the soluble delay member surrounds the drug component, and wherein the soluble delay member prevents the release of the drug from the oral drug dosage form within approximately 2 hours to approximately 7 hours after administration to a human individual. The drug is mixed with the first soluble material in powder form and uniformly dispersed within the drug component. Upon administration, the soluble delay member is exposed to gastrointestinal fluid, and the soluble delay member begins to erode. The soluble delay member erodes, subsequently exposing the surface of the drug component, causing the surface of the drug component to erode, and releasing the drug from the drug component.

[0395] The composition of oral drug dosage forms shown in Table 9A, Figure 13A, and Figure 13B

[0396] The drug component consists of budesonide, PVP-VA64, and triethyl citrate (TEC), with the weight ratio of each component being budesonide:PVP-VA64:triethyl citrate (TEC) = 10:75:15. The soluble etch-delay component consists of triethyl citrate (TEC), hydroxypropyl cellulose (HPC JF), and mannitol, with the weight ratio of each component being HPC JF:mannitol:TEC = 65:32:3.

[0397] Table 9B shows the dimensions of oral drug dosage forms in Figures 13A and 13B.

[0398] The preparation process is as follows:

[0399] (1) Preparation of drug component intermediates by melt extrusion: The active drug and excipients are added to the mixer according to the prescription ratio and mixed evenly. The temperature of the conical twin-screw extruder is set to 120-170-180-180-180-180-180-180 (°C). After the set temperature is reached, the mixed powder is added to the extruder and melt extruded to obtain the drug component intermediate.

[0400] (2) Preparation of soluble delay component intermediate by melt extrusion: Add the excipients to the mixer according to the soluble delay component formula, mix evenly, set the temperature of the conical twin-screw extruder to 120-120-120, and after the set temperature is reached, add the mixed powder to the extruder and melt extrude to obtain the soluble delay component intermediate.

[0401] (3) 3D printing: Print oral drug dosage forms. Set the printing head temperature of the drug component to 145-155-155-160 for preheating and the printing head temperature of the soluble delay component to 100-120-120-130 for preheating. After reaching the temperature, use the intermediate filler of the drug component and the intermediate filler of the soluble delay component respectively. After confirming the output flow rate of the printing head, load the printing code to produce oral drug dosage forms.

[0402] In vitro dissolution testing was conducted on the oral drug dosage form. The in vitro dissolution rate study was as follows: The dissolution and release rate determination method (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0931, Method I) was used. A fixed sieve (20-mesh, 15mm diameter, 5mm height circular sieve) was used. 900ml of 0.1mol / L hydrochloric acid solution was used as the dissolution medium. The temperature was 37℃±0.5℃, and the rotation speed was 100 rpm. The procedure was followed, and samples were taken after 2 hours. The dissolution rate should not exceed 10% of the labeled amount.

[0403] Take the test sample after 2 hours of acid dissolution and transfer it to a dissolution vessel. Use 900 ml of 0.2 mol / L sodium phosphate buffer (accurately weigh approximately 49.18 g of anhydrous sodium phosphate, dissolve in 1500 ml of water, shake well, measure 1500 ml, add 4500 ml of 0.1 mol / L hydrochloric acid solution, add approximately 3 g of Tween 80, shake well, and adjust the pH to 6.8 ± 0.05 with hydrochloric acid or sodium hydroxide solution if necessary) as the dissolution medium. The temperature should be 37℃ ± 0.5℃, and the rotation speed should be 100 rpm. Follow the procedure. The obtained in vitro dissolution curve is shown in Figure 17.

Claims

1. An oral drug dosage form, characterized in that, Its configuration allows for the release of drugs at the desired gastrointestinal location. The oral drug dosage forms include: A pharmaceutical assembly comprising a first soluble material mixed with a pharmaceutical agent; and Release the restricted components; among them, The release restriction component is configured to restrict the release of the drug from the drug component until the oral drug dosage form begins to release from the drug component from approximately 2 hours to approximately 7 hours after administration to a human individual.

2. An oral drug dosage form as described in claim 1, characterized in that, The glass transition temperature (Tg) of the release restriction component is from about 10°C to about 190°C.

3. An oral drug dosage form as described in claim 1 or 2, characterized in that, The melting temperature (Tm) of the release restriction component is from about 30°C to about 200°C.

4. An oral drug dosage form as described in any one of claims 1 to 3, characterized in that, The release restriction component includes a soluble delay member that surrounds the drug component and wherein the soluble delay member prevents the drug component from being dissolved.

5. An oral drug dosage form as described in claim 4, characterized in that, The glass transition temperature (Tg) of the soluble delay member is from about 10°C to about 190°C.

6. An oral pharmaceutical dosage form as described in any one of claims 4 to 5, characterized in that, The melting temperature (Tm) of the soluble delay component is about 30°C to about 200°C.

7. An oral pharmaceutical dosage form as described in any one of claims 4 to 6, characterized in that, The soluble erosion delay member includes a first matrix comprising a swellable material that swells in an aqueous medium environment.

8. An oral pharmaceutical dosage form as described in any one of claims 4 to 7, characterized in that, The soluble etching delay member further includes a second matrix comprising a second soluble etching material that does not mix with the drug.

9. An oral pharmaceutical dosage form as described in claim 8, characterized in that, The first matrix and the second matrix are mixed uniformly.

10. An oral pharmaceutical dosage form as described in any one of claims 7 to 9, characterized in that, The weight ratio of the first matrix in the soluble etch delay member is 10% to 100%.

11. An oral pharmaceutical dosage form as described in any one of claims 8 to 10, characterized in that, The weight ratio of the second matrix in the soluble etch-delay member is 0 to 90%.

12. An oral pharmaceutical dosage form as described in any one of claims 7 to 11, characterized in that, The first matrix is ​​selected from one or more of the following materials: hydroxypropyl cellulose, hydroxypropyl methylcellulose, and hydroxyethyl cellulose.

13. An oral pharmaceutical dosage form as described in any one of claims 8 to 12, characterized in that, The second matrix is ​​selected from one or more of the following materials: soluble sugars, soluble sugar alcohols, soluble inorganic salts, soluble polymers, insoluble inorganic salts, and insoluble polymers.

14. An oral pharmaceutical dosage form as described in any one of claims 8 to 13, characterized in that, The second matrix comprises one or more of the following materials: triethyl citrate, tributyl citrate, acetylated triacetic acid, tributyl citrate acetate, butyl stearate, glyceryl monostearate, stearyl alcohol, dibutyl sebacate, diethyl phthalate, dibutyl phthalate, dioctyl phosphate, polyethylene glycol, propylene glycol, glyceryl triacetate, castor oil, polyoxyethylene 40 hydrogenated castor oil, medium-chain triglycerides, maltodextrin, polyvinyl alcohol, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and mannitol.

15. An oral pharmaceutical dosage form as described in any one of claims 8 to 14, characterized in that, The particle size D90 of the second matrix is ​​less than or equal to 600 micrometers.

16. An oral pharmaceutical dosage form as described in any one of claims 7 to 15, characterized in that, The first and second matrices are mixed and then hot-melted and extruded.

17. An oral pharmaceutical dosage form as described in claim 16, characterized in that, The temperature of the hot melt extrusion is from about 30°C to about 200°C.

18. An oral pharmaceutical dosage form as described in any one of claims 1 to 17, characterized in that, The density of the release-limiting component is approximately 0.5 to approximately 5 mg / mm³. 3 .

19. An oral pharmaceutical dosage form as described in any one of claims 1 to 18, characterized in that, The release restriction component includes a pH-responsive element configured to dissolve at or above a predetermined pH value.

20. An oral pharmaceutical dosage form as described in claim 19, characterized in that, The pH-responsive component is configured to dissolve at pH values ​​of approximately 5.0 and above.

21. An oral pharmaceutical dosage form as described in any one of claims 19 to 20, characterized in that, The pH-responsive member surrounds the drug assembly, and wherein the pH-responsive member prevents the drug assembly from dissolving.

22. An oral pharmaceutical dosage form as described in any one of claims 1 to 21, characterized in that, The release restriction component includes a soluble delay member and a pH-responsive member, the pH-responsive member surrounding the soluble delay member, wherein the pH-responsive member prevents the soluble delay member from being eroded, and wherein the soluble delay member prevents the drug component from being eroded.

23. An oral pharmaceutical dosage form as described in any one of claims 1 to 22, characterized in that, The drug is uniformly distributed within the drug assembly.

24. An oral pharmaceutical dosage form as described in any one of claims 1 to 23, characterized in that, The drug is distributed in the drug component in the form of an amorphous solid dispersion.

25. An oral pharmaceutical dosage form as described in any one of claims 1 to 24, characterized in that, The drug component comprises drug particles, the drug particles comprising a fourth soluble material mixed with the drug.

26. An oral pharmaceutical dosage form as described in any one of claims 1 to 25, characterized in that, The pharmaceutical component comprises a lipid-based composition, the lipid-based composition comprising an oil phase mixed with the pharmaceutical product.

27. An oral pharmaceutical dosage form as described in any one of claims 1 to 26, characterized in that, The lipid-based composition further comprises one or more of surfactants, co-surfactants, stabilizers, and curing agents.

28. An oral pharmaceutical dosage form as described in any one of claims 1 to 27, characterized in that, The pharmaceutical component comprises a first drug and a second drug.

29. An oral pharmaceutical dosage form as described in claim 28, characterized in that, The first drug and the second drug are the same.

30. An oral pharmaceutical dosage form as described in claim 28, characterized in that, The first drug and the second drug are different.

31. An oral pharmaceutical dosage form as described in any one of claims 1 to 30, characterized in that, The drug component comprises a first drug particle and a second drug particle.

32. An oral pharmaceutical dosage form as described in claim 31, characterized in that, The first drug particle contains a fourth soluble material mixed with the first drug, and the second drug particle contains a fifth soluble material mixed with the second drug.

33. An oral pharmaceutical dosage form as described in any one of claims 31 to 32, characterized in that, The first drug particle and the second drug particle have the same composition.

34. An oral pharmaceutical dosage form as described in any one of claims 31 to 32, characterized in that, The first drug particle and the second drug particle have different compositions.

35. An oral pharmaceutical dosage form as described in any one of claims 1 to 26, characterized in that, The pharmaceutical component comprises a first lipid-based composition and a second lipid-based composition.

36. An oral pharmaceutical dosage form as described in any one of claims 1 to 35, characterized in that, The first lipid-based composition and the second lipid-based composition have the same composition.

37. An oral pharmaceutical dosage form as described in any one of claims 1 to 35, characterized in that, The first lipid-based composition and the second lipid-based composition have different compositions.

38. An oral pharmaceutical dosage form as described in any one of claims 1 to 37, characterized in that, The oral drug dosage form includes multiple drug components.

39. An oral pharmaceutical dosage form as described in claim 38, characterized in that, The composition of the plurality of drug components is identical to that of each other.

40. An oral pharmaceutical dosage form as described in claim 38, characterized in that, At least two of the plurality of drug components have different compositions from each other.

41. An oral pharmaceutical dosage form as described in any one of claims 38 to 40, characterized in that, The multiple drug components are all the same size.

42. An oral pharmaceutical dosage form as described in any one of claims 38 to 40, characterized in that, At least two of the plurality of drug components have different dimensions from each other.

43. An oral pharmaceutical dosage form as described in any one of claims 1 to 42, characterized in that, The drug component includes a first drug component and a second drug component.

44. An oral pharmaceutical dosage form as described in claim 43, characterized in that, The first drug component includes a first soluble material mixed with a first drug; the second drug component includes a third soluble material mixed with a second drug.

45. An oral pharmaceutical dosage form as described in claim 44, characterized in that, The first soluble and the third soluble materials respectively control the release of drugs from the first and second drug components.

46. ​​An oral pharmaceutical dosage form as described in claim 45, characterized in that, The first soluble and the third soluble material are the same.

47. An oral pharmaceutical dosage form as described in claim 45, characterized in that, The first soluble and the third soluble materials are different.

48. An oral pharmaceutical dosage form as described in any one of claims 43 to 47, characterized in that, The first drug component includes first drug particles, and the first drug particles include a fourth soluble material mixed with the first drug.

49. An oral pharmaceutical dosage form as described in any one of claims 43 to 48, characterized in that, The second drug component includes second drug particles, and the second drug particles include a fifth soluble material mixed with the second drug.

50. An oral pharmaceutical dosage form as described in any one of claims 44 to 49, characterized in that, The first drug and the second drug are the same.

51. An oral pharmaceutical dosage form as described in any one of claims 44 to 49, characterized in that, The first drug and the second drug are different.

52. An oral pharmaceutical dosage form as described in any one of claims 43 to 51, characterized in that, The release restriction component surrounds the first drug component and the second drug component.

53. An oral pharmaceutical dosage form as described in any one of claims 43 to 52, characterized in that, The release restriction components surrounding the first and second drug components have the same thickness.

54. An oral pharmaceutical dosage form as described in any one of claims 43 to 52, characterized in that, The thickness of the release restriction components surrounding the first and second drug components is different.

55. An oral pharmaceutical dosage form as described in any one of claims 43 to 54, characterized in that, The release restriction component includes a soluble delay member that surrounds the first drug component and the second drug component.

56. An oral pharmaceutical dosage form as described in claim 55, characterized in that, The soluble delay members surrounding the first and second drug components have the same thickness.

57. An oral pharmaceutical dosage form as described in claim 55, characterized in that, The thickness of the soluble delay member surrounding the first and second drug components is different.

58. An oral pharmaceutical dosage form as described in any one of claims 43 to 57, characterized in that, The release restriction component includes a pH-responsive element that surrounds the first drug component and the second drug component.

59. An oral pharmaceutical dosage form as described in claim 58, characterized in that, The pH-responsive components surrounding the first and second drug components have the same thickness.

60. An oral pharmaceutical dosage form as described in claim 58, characterized in that, The pH-responsive components surrounding the first and second drug components have different thicknesses.

61. An oral pharmaceutical dosage form as described in any one of claims 1 to 60, characterized in that, The release restraint component has a top surface, a side surface, and a bottom surface.

62. An oral drug dosage form as described in claim 61, characterized in that, The top, side, and bottom surfaces have the same thickness.

63. An oral pharmaceutical dosage form as described in any one of claims 61 to 62, characterized in that, The top, side, and bottom surfaces have the same erosion rate.

64. An oral pharmaceutical dosage form as described in any one of claims 61 to 63, characterized in that, The top, side, and bottom surfaces all have the same etch time.

65. A method for preparing an oral pharmaceutical dosage form as described in any one of claims 1 to 64, characterized in that, The method includes three-dimensional (3D) printing of the oral drug dosage form.

66. A method for preparing an oral drug dosage form as described in claim 65, characterized in that, The method includes: distributing materials according to a layer-by-layer model of an oral drug dosage form to print the oral drug dosage form, wherein each layer of the layer-by-layer model is printed by distributing, as needed, the following materials: (a) a drug component comprising a first soluble material mixed with the drug; and (b) a soluble delay member comprising a second soluble material not mixed with the drug.

67. A method for preparing an oral drug dosage form as described in claim 66, characterized in that, The method further includes: (c) a pH-responsive component comprising a pH-based enteric material that does not mix with the drug.

68. A method for preparing an oral pharmaceutical dosage form as described in any one of claims 65 to 67, characterized in that, The method includes a method for preparing drug particles: (a) premixing the drug with a fourth soluble material and then filling it in a single-screw or twin-screw extruder; (b) rotating the screw to further extrude the physical mixture while the extruder jacket is heated at high temperature; (c) melting and kneading the drug and the fourth soluble material, and continuously extruding the melt from the end plate and / or dies of different shapes; (d) pulverizing and sieving.

69. A method for preparing an oral drug dosage form as described in claim 65, characterized in that, The method includes: distributing materials according to a layer-by-layer model of an oral drug dosage form to print the oral drug dosage form, wherein each layer of the layer-by-layer model is printed by distributing the following materials as needed: (a) a drug component comprising a first soluble material mixed with drug particles; and (b) a soluble delay member comprising a second soluble material not mixed with drug particles.

70. A method for preparing an oral drug dosage form as described in claim 69, characterized in that, The method further includes: (c) a pH-responsive component comprising a pH-based enteric material that does not mix with the drug particles.

71. A method for preparing an oral drug dosage form as described in claim 65, characterized in that, The method includes: distributing materials according to a layer-by-layer model of an oral drug dosage form to print the oral drug dosage form, wherein each layer of the layer-by-layer model is printed by distributing materials as needed to: (a) distributing the drug component; (b) distributing the etchable delay member; (c) injection molding the pH-responsive member; and (d) assembling the drug component and the etchable delay member into the pH-responsive member to form the oral drug dosage form.

72. A method for preparing an oral pharmaceutical dosage form as described in any one of claims 66 to 71, characterized in that, The method includes a method for preparing a soluble delay component: (a) premixing the components of the soluble delay component and filling them into a single-screw or twin-screw extruder; (b) rotating the screw to further extrude the physical mixture, setting the temperature of different functional blocks in the heating section from the discharge port to the feed port respectively, and turning on the heating to prepare the melt; (c) extruding the melt from the nozzle and depositing it layer by layer.

73. A method for preparing an oral drug dosage form as described in claim 72, characterized in that, The heating temperature is from about 30°C to about 190°C.

74. A 3D printing method for an oral drug dosage form, characterized in that, The method includes: (a) positioning a first printhead at a target printing position, wherein the first printhead prints layers 1 to N and N+M of a release control component, wherein layers N+M and N form a cavity; (b) positioning a second printhead at the target printing position, wherein the second printhead prints a drug component within the cavity; and (c) positioning the first printhead at the target printing position, wherein the first printhead prints layer O of the release control component; wherein N, M, and O are all positive integers less than or equal to 10.

75. The 3D printing method as described in claim 74, characterized in that, The second printhead prints X layers of drug components, where X is a positive integer less than or equal to 5.

76. The 3D printing method according to any one of claims 74 to 75, characterized in that, The step (b) includes: (b1) positioning a second printhead at the target printing position, wherein the second printhead prints a drug component within the cavity; (b2) positioning a first printhead at the target printing position, wherein the first printhead prints the N+M+K layers of the release control component (K being a positive integer less than or equal to 6), wherein the N+M+K layers and the X layer of the drug component form a cavity; and (b3) positioning a second printhead at the target printing position, wherein the second printhead prints a drug component within the cavity.

77. The 3D printing method as described in claim 76, characterized in that, The (b) further includes (b4) repeating (b2) and (b3).

78. The 3D printing method according to any one of claims 74 to 77, characterized in that, The O layer is equal to the N layer.

79. The 3D printing method according to any one of claims 74 to 78, characterized in that, The printing temperature of the first printhead print release control assembly is approximately 30°C to approximately 200°C.

80. The 3D printing method according to any one of claims 74 to 79, characterized in that, The Nth and Oth layers are circular in shape.

81. The 3D printing method according to any one of claims 74 to 80, characterized in that, The Mth and Kth layers are circular in shape.

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