JP2023078155A - Dosage forms and use thereof - Google Patents

Abstract

To provide a stable solid pharmaceutical dosage form for oral administration.SOLUTION: A dosage form includes a substrate that forms at least one compartment and a drug content loaded into the compartment. The dosage form is so designed that the active pharmaceutical ingredient of the drug content is released in a controlled manner.SELECTED DRAWING: None

Description

CROSS REFERENCES TO RELATED APPLICATIONS This application is the subject of U.S. Provisional Application No. 62/170,645, filed June 3, 2015, and U.S. Provisional Application No. 62/313, filed March 24, 2016. , 092, the entire disclosures of which are incorporated herein by reference.

The present invention relates generally to pharmaceutical dosage forms and controlled release of biologically active agents, diagnostic agents, reagents, cosmetics, and pesticides/insecticides.

Pharmaceutical products must be manufactured into dosage forms in order to be marketed for use.
Conventional dosage forms typically contain a mixture of active pharmaceutical ingredients and inactive ingredients (excipients) along with other non-reusable materials such as capsule shells. Classes of dosage forms include liquid dosage forms (e.g. solutions, syrups, elixirs, suspensions and emulsions), solid dosage forms (e.g. tablets,
capsules, caplets and gelcaps), and semisolid dosage forms (e.g., ointments and suppositories), of which solid dosage forms are more advantageous for administering drugs with systemic effects by the oral route. is.

Tablets are the most commonly used solid dosage form and offer more benefits from a manufacturing, packaging and shipping standpoint, being easier to identify and swallow. After the tablet is administered to the living body,
It undergoes interactions with the body in exerting its medicinal action. The active pharmaceutical ingredient must be released from the tablet before being absorbed into the blood circulation. The pharmaceutical ingredient then disperses, disintegrates, or dissolves throughout body fluids and tissues. In drug absorption, distribution, metabolism, and excretion processes, dosage form plays a critical role in determining drug release profile and bioavailability. Therefore, there is a continuing need to develop dosage forms that provide controlled drug delivery systems that can provide desired plasma drug levels, reduce side effects, and improve patient compliance.

In one aspect, the present disclosure provides a dosage form that includes a substrate forming at least one compartment and a drug content loaded into the compartment. In some embodiments, the drug content is operably associated with the substrate. In some embodiments,
The drug content is separated from the matrix and is free to move through the compartments.

In some embodiments, the substrate is selected from the group consisting of hydrophilic polymers, hydrophobic polymers, swellable polymers, non-swellable polymers, porous polymers, non-porous polymers, erodible polymers, non-erodible polymers. made from a thermoplastic material that In some embodiments, the thermoplastic material is polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer 57/30/13, polyvinylpyrrolidone-c
o-vinyl acetate (PVP-VA), polyvinylpyrrolidone-polyvinylacetate copolymer (PVP-VA) 60/40, polyvinylpyrrolidone (PVP), polyvinylacetate (PVAc) and polyvinylpyrrolidone (PVP) 80/20, polyethylene glycol-polyvinyl Alcohol graft copolymer 25/75, kollicoat
IR-polyvinyl alcohol 60/40, polyvinyl alcohol (PVA or PV-O
H), polyvinyl acetate (PVAc), poly(butyl methacrylate-co-(2-
dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1, poly(dimethylaminoethyl methacrylate-co-methacrylate), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) , poly(methyl acrylate-co-methyl methacrylate-co
-methacrylic acid) 7:3:1, poly(methacrylic acid-co-methyl methacrylate) 1:
2, poly(methacrylic acid-co-ethyl acrylate) 1:1, poly(methacrylic acid-c
o-methyl methacrylate) 1:1, poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG), hyperbranched polyesteramide, hydroxypropylmethylcellulose phthalate, hypromellose phthalate, hydroxypropylmethylcellulose or hypromellose (HMPC) , hydroxypropyl methylcellulose acetate succinate or hypromellose acetate succinate (HPMCAS), poly(lactide-co-glycolide) (PLGA), carbomer, poly(ethylene-co-vinyl acetate), ethylene-vinyl acetate copolymer, Polyethylene (PE) and Polycaprolactone (PCL), Hydroxylpropylcellulose (HPC), Polyoxyl 40 Hydrogenated Castor Oil, Methylcellulose (MC), Ethylcellulose (EC), Poloxamer, Hydroxypropylmethylcellulose Phthalate (HPMCP), Poloxamer, Hydrogenated Castor Oil and soybean oil, glyceryl palmitostearate, carnauba wax, polylactic acid (PLA), polyglycolic acid (PGA), cellulose acetate butyrate (CAB
), colloidal silicon dioxide, sucrose, glucose, polyvinyl acetate phthalate (PVAP), and combinations thereof.

In some embodiments, the compartments are pie-shaped, cone-shaped, pyramid-shaped,
It has a shape selected from the group consisting of cylindrical, cubic or cuboid, triangular or polygonal prismatic, tetrahedral and combinations thereof.

In some embodiments, the first drug content takes the form of nanoparticles, microneedles, or is a network structure.

In some embodiments, the drug content comprises an active pharmaceutical ingredient (API). In some embodiments, the API is a local anesthetic, antiepileptic and anticonvulsant, anti-Alzheimer's drug, analgesic, antigout, antihypertensive, antiarrhythmic, diuretic, liver disease treatment, Pancreatic drugs, antihistamines, antiallergic drugs, glucocorticoid drugs, hormonal and contraceptive drugs, hypoglycemic drugs, antiosteoporotic drugs, antibiotics, sulfonamides, quinolones and other synthetic antibacterial drugs, antituberculous drugs , antiviral agents, antineoplastic agents, immunomodulators, cosmetic actives and traditional Chinese medicines. In some embodiments, the API is a biologically active agent, diagnostic agent, scientific reagent, cosmetic, or pesticide/insecticide.

In some embodiments, the drug content further comprises excipients. In some embodiments, the excipients are cocoa butter, polyethylene glycol (PEG), sucrose,
made from materials selected from the group consisting of glucose, galactose, fructose, xylose lactose, maltose, trehalose, sorbitol, mannitol, maltodextrin, raffinose, stachyose, fructo-oligosaccharides, water-soluble oligomers and polymers, and combinations thereof. be.

In some embodiments, the compartment has an aperture that is plugged and/or sealed. In some embodiments, the plug is made from porous polymers, erodible polymers, pH sensitive polymers, or natural materials such as shellac. In some embodiments, the plug is made from a material selected from the group consisting of water soluble polymers, erodible or soluble polymers, waxy materials or sugars, or any of the materials described above.

In some embodiments, the dosage form includes a gas-producing component packaged in a first compartment. In some embodiments, the gas generating component is selected from the group consisting of water soluble carbonates, sulfites, bicarbonates, sodium carbonate, sodium bicarbonate, sodium metabisulfite, calcium carbonate, and combinations thereof. It releases carbon dioxide or sulfur dioxide gas on contact with gastric juices. In some embodiments, the gas generating component is a combination of sodium bicarbonate and an organic acid (eg, citric acid, tartaric acid, etc.).

In another aspect, the disclosure provides a dosage form that includes a substrate that forms at least a first compartment and a second compartment. The dosage form includes a first drug content packed in a first compartment and a second drug content packed in a second compartment.

In some embodiments, the first compartment and the second compartment are connected. In some embodiments, the first compartment and the second compartment are not connected.

In some embodiments, the first drug content is the same as the second drug content. In some embodiments, the first drug content is different than the second drug content.

In some embodiments, the first compartment has a first aperture covered with a first plug and the second compartment has a second aperture covered with a second plug. have. In some embodiments, the first plug is more permeable than the second plug. In some embodiments, the first plug erodes faster than the second plug.

In some embodiments, the first compartment is surrounded by a first wall and the second compartment is surrounded by a second wall.

In some embodiments, the first wall is thicker than the second wall. In some embodiments, the first wall is more permeable than the second wall. In some embodiments, the first wall erodes faster than the second wall.

1 shows a conventional dosage form with drug content; FIG. 1B illustrates the release profile upon administration of the dosage form of FIG. 1A to a subject; FIG. FIG. 1B shows plasma drug levels upon administration of the dosage form of FIG. 1A to a subject. FIG. 2 shows plasma drug levels upon administration of a controlled release dosage form having a zero order drug release profile to a subject. FIG. 1 shows an exemplary dosage form having a substrate forming compartments with drug content packed into the compartments. Figure 2B shows the release of API from the dosage form illustrated in Figure 2A. FIG. 1 shows an exemplary dosage form having a substrate forming a compartment with another dosage form packed into the compartment. FIG. 1 shows an exemplary dosage form having a substrate that forms a pie-shaped compartment. FIG. 1 shows an exemplary dosage form having a substrate forming multiple compartments containing openings of varying sizes. FIG. 4 shows an exemplary dosage form having a substrate forming angled compartments. FIG. 1 shows an exemplary dosage form having a matrix forming multiple compartments of different radial sizes. FIG. 3 shows an exemplary dosage form having a matrix forming multiple compartments with different geometries that can be used to modulate the release rate of an API. FIG. 11 shows a cross-section of an exemplary dosage form having pie-shaped compartments. FIG. 1 shows an exemplary dosage form having a matrix forming multiple layers, with drug loading in the form of nanoparticles dispersed between the layers. FIG. 1 shows an exemplary dosage form having a substrate forming compartments with microneedle-shaped drug contents packed into the compartments. FIG. 1 shows an exemplary dosage form having a substrate that forms a compartment filled with drug content. The drug content forms a network structure. The matrix is made of a material that dissolves in 1-5 minutes and the drug content dissolves in seconds. FIG. 8B shows the rapid release of API from the dosage form illustrated in FIG. 8A. FIG. 1 shows an exemplary dosage form having a substrate that forms a cluster of cylindrically-shaped compartments. Each compartment is packed with one drug content. The release of drug content can be controlled by the number and size of compartments. FIG. 3 shows an exemplary dosage form having a substrate that forms three cylindrically shaped compartments. Each compartment is packed with one drug content. Each drug content has a plug that closes the aperture of each compartment. FIG. 1 shows an exemplary dosage form having a multi-layered substrate with drug content embedded in each layer. FIG. 10B shows consistent release of drug content from dosage forms illustrated in FIGS. 10A or 10B. 10B shows plasma drug levels upon administration of a controlled release dosage form illustrated in FIG. 10A or 10B to a subject. FIG. 1 is a workflow schematic showing the use of a three-dimensional printer to prepare patient-specific dosage forms; FIG. FIG. 1 shows an exemplary dosage form having a three-layer substrate with different drug loadings embedded in each layer. Figure 12B illustrates the release of three APIs from the dosage form illustrated in Figure 12A. FIG. 1 shows an exemplary dosage form having a matrix forming three compartments, each of which is loaded with one drug content. The release profile of the drug content can be controlled by the dissolution rate of the drug content. Figure 13B illustrates the release profile of API from the dosage form illustrated in Figure 13A. FIG. 1 shows an exemplary dosage form having a substrate with three pie-shaped segments, with drug content embedded in each segment. FIG. 1 shows an exemplary dosage form having a substrate with three pie-shaped segments wrapped in a shell. Figure 8B shows the release profile of API from the dosage forms illustrated in Figures 8A and 8B. FIG. 1 shows an exemplary dosage form having a base forming compartments filled with drug content. A second API is embedded in the matrix and is released when the matrix dissolves. FIG. 15B shows controlled release of API from the dosage form illustrated in FIG. 15A. FIG. 1 shows an exemplary dosage form having a matrix forming three compartments of cylindrical shape. Each compartment is packed with one drug content. Each drug content has a plug that plugs the opening of each compartment. The release of the drug content of each compartment can be controlled by the permeability, degradability or erodibility of the stopper. Figure 16B shows the release profile of API from the dosage form illustrated in Figure 16A. FIG. 1 shows an exemplary dosage form having a substrate forming four compartments. Each compartment is filled with a drug content. FIG. 3 shows the release of API from dosage forms having a four-segment matrix with embedded drug content. Figure 17B shows controlled release of API from the dosage form illustrated in Figure 17A. FIG. 4 is a schematic diagram showing a drug form having a substrate forming pie-shaped compartments. 18B is a photograph showing the drug release process of the drug form illustrated in FIG. 18A. Figure 18B shows release rate curves for benzoic acid and PEG 8000 from the dosage form of Figure 18A. 1 is a perspective view of a dosage form containing two compartments; FIG. 19B is a cross-sectional view of the dosage form of FIG. 19A. FIG. FIG. 19B shows an exemplary release profile for the dosage form of FIG. 19A. 19B shows another exemplary release profile for the dosage form of FIG. 19A. FIG.

Certain features of the invention (including method steps) are set forth in the foregoing summary of the invention, the detailed description, and the following claims, as well as the accompanying drawings. It is to be understood that the inventive disclosure herein encompasses all possible combinations of such specific features. For example, if a particular feature is disclosed in connection with a particular aspect or embodiment of the invention, or in connection with a particular claim, that feature may be combined with any other particular aspect or embodiment of the invention as far as possible. and/or in connection therewith,
It can also be used in the present invention as a whole.

The term "comprises" and its grammatical equivalents are used herein to mean the optional presence of other ingredients, materials, steps, and the like. for example,
"comprising" (or "which comprises") components A, B, and C
) The article may consist of (ie, include only) components A, B, and C, or may include components A, B, and C as well as one or more other components.

Where a method is described herein that includes two or more specified steps, the specified steps may be performed in any order or simultaneously (unless the context excludes the possibility) can be practiced and the method comprises (unless the context excludes the possibility) before any of the defined steps, between two of the defined steps,
or may include one or more other steps that are performed after all of the specified steps.

When a range of values is stated, each value between the upper and lower values of that range (up to 1/10th of the unit of the lower value unless the context clearly indicates otherwise) and Any other stated or intervening value in the stated range is to be understood to be encompassed within the disclosure, unless there are specifically excluded limits in the stated range. Where the stated range includes one or both of the upper and lower limits, ranges excluding either or both are also included in the disclosure.

The term "at least" followed by a number is used herein to denote the beginning of a range beginning with that number (which can be a range with or without an upper limit, depending on the variable being defined). ). For example, "at least one" means one or more than one. The term "at most" followed by a number is used to denote the end of a range ending with that number (ranges with a lower limit of 1 or 0 or with no lower limit, depending on the variable being defined). can be). For example, "at most 4" means 4 or less than 4, and "at most 40%" means 40% or less than 40%. In the present disclosure, a range is defined as "(first number) to (second number)" or "(first number) to
(second number)", this means a range whose lower limit is the first number and whose upper limit is the second number. For example, 2 to 10 millimeters means a range with a lower limit of 2 millimeters and an upper limit of 10 millimeters.

It will be understood that, where necessary, reference numerals have been repeated among different drawings to indicate corresponding or analogous components for simplicity and clarity of illustration. Moreover, numerous specific details are set forth in order to provide a thorough understanding of the embodiments described herein. However, the embodiments described herein may be practiced without these specific details. In other cases, so as not to obscure the relevant and meaningful functions described,
Methods, procedures and ingredients are not detailed. Also, the description is not considered to limit the scope of the embodiments described herein. It is to be understood that the description and characterization of the embodiments set forth in this disclosure are not to be considered mutually exclusive unless otherwise noted.

Controlled release dosage form
Conventional solid dosage forms, such as compressed tablets, consist of a matrix in which the active drug ingredient is dissolved or embedded (Fig. 1A). Currently, the usual solid dosage form has a first-order drug release profile (
1B), plasma levels of drug rise rapidly to very high levels after administration and then decline exponentially (see FIG. 1C). This has drawbacks such as minimal therapeutic efficacy due to reduced drug levels or possible drug toxicity at high concentrations. This type of drug release does not provide an adequate balance of plasma drug concentrations. The present invention relates to modified or controlled release oral drug delivery systems that provide advantages over conventional systems, including improved patient compliance, selective pharmacology, reduced side effects, and reduced dosing frequency. Controlled release results in prolonged drug delivery and maintenance of plasma levels within a therapeutic window. For example, a drug delivery system exhibiting a zero-order drug release profile (Fig. 1D)
It enables a constant amount of drug release over a long period of time, realizing uniform and sustained drug delivery. As a result, a zero order release profile may be desirable in antibiotic delivery, treatment of hypertension, pain management, antidepressant delivery and many other conditions requiring constant plasma drug levels.

Accordingly, one aspect of the present disclosure provides stable solid pharmaceutical dosage forms for oral administration having a controlled release profile. In some embodiments, the dosage form comprises a substrate forming at least one compartment and a drug content packed into the compartment. The dosage form is designed to allow controlled release of the active pharmaceutical ingredient of the drug content, for example by opening the compartments in a predetermined manner.

A. Substrate As used herein, “substrate” refers to a structure in which the drug is surrounded or embedded. The base of the dosage form of the invention can be of any size and shape suitable for oral administration. In some embodiments, the substrate is about 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm in diameter.
mm, 9 mm, 10 mm, 11 mm, 12 mm flat and round tablets. In some embodiments, the substrate is an oval tablet approximately amm x bmm in size, where a
is 5 to 15 and b is 2 to 10. In some embodiments, the substrate is in the shape of a capsule.

In some embodiments, the substrate is a hydrophilic polymer (e.g., hydroxypropylmethylcellulose (HPMC) and poly(ethylene oxide) (PEO)), a hydrophobic polymer (e.g., ethylcellulose (EC)), a swellable polymer, a non- It is made of a swellable polymer, porous polymer, non-porous polymer, erodible polymer, or non-erodible polymer.

In some embodiments, the dosage form has an integral base. In some embodiments, the substrate consists of several parts, each part being made of the same or different material.

In some embodiments, the substrate is made of a thermoplastic material. In this specification, "
"Thermoplastic material" refers to a material that can be shaped using heat and pressure. In some embodiments, the thermoplastic material can be, for example, a hydrophilic gel-forming material or a hydrophobic material, wherein release of the drug content from the hydrophilic gel-forming material proceeds primarily by diffusion, Release of drug content from hydrophobic materials proceeds primarily by diffusion through pores in the matrix. Polymers, especially cellulose ethers, cellulose esters and/or acrylic resins can be used as hydrophilic thermoplastic materials. Ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic acid and/or their derivatives such as salts, amides or esters thereof are suitable for use as the thermoplastic material. Physiologically acceptable hydrophobic materials known to those skilled in the art can be used as thermoplastic materials, such as mono- or diglycerides of C12-C30 fatty acids and/or C12-C30 fatty alcohols and/or waxes or mixtures thereof. . Substrates prepared from hydrophobic materials such as hydrophobic polymers, waxes, fats, long chain fatty acids, fatty alcohols or corresponding esters or ethers or mixtures thereof are also contemplated.

In some embodiments, the thermoplastic material is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 57/30/13, polyvinylpyrrolidone-co-vinyl acetate (PVP-VA), polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP- VA) 60/40, polyvinylpyrrolidone (PV)
P), polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP) 80/20
, polyethylene glycol-polyvinyl alcohol graft copolymer 25/75, ko
llicoat IR-polyvinyl alcohol 60/40, polyvinyl alcohol (PV
A or PV-OH), poly(vinyl acetate) (PVAc), poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1, poly(dimethylaminoethyl methacrylate- co-methacrylate), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1, poly( methacrylic acid-co-methyl methacrylate) 1:2, poly(methacrylic acid-co-ethyl acrylate) 1:1, poly(methacrylic acid-co-methyl methacrylate) 1:1, poly(ethylene oxide) (
PEO), poly(ethylene glycol) (PEG), hyperbranched polyesteramides, hydroxypropylmethylcellulose phthalate, hypromellose phthalate, hydroxypropylmethylcellulose or hypromellose (HMPC), hydroxypropylmethylcellulose acetate succinate or hypromellose acetate Kucinate (HP
MCAS), poly(lactide-co-glycolide) (PLGA), carbomer, poly(ethylene-co-vinyl acetate), ethylene-vinyl acetate copolymer, polyethylene (PE), and polycaprolactone (PCL), hydroxyl propyl cellulose (HPC ), polyoxyl 40 hydrogenated castor oil, methylcellulose (MC), ethylcellulose (EC), poloxamer, hydroxypropyl methylcellulose phthalate (HPM
CP), poloxamer, hydrogenated castor and soybean oils, glyceryl palmitostearate, carnauba wax, polylactic acid (PLA), polyglycolic acid (PGA), cellulose acetate butyrate (CAB), colloidal silicon dioxide, sucrose, glucose, selected from the group consisting of polyvinyl acetate phthalate (PVAP) and combinations thereof;

Properties and suppliers of various thermoplastic materials are listed in Table 1.

In some embodiments, additive processes such as fused deposition modeling (FDM) can be used to prepare dosage forms from thermoplastic materials. In some embodiments, the substrate can be made by using a three-dimensional printer (3D printer) configured to extrude a thermoplastic material. Typically, a thermoplastic material is melted in a 3D printer and then extruded to form the substrate. In certain embodiments, suitable extruders include, but are not limited to, single or twin screw extruders, wherein temperatures within the extruder range from 50°C to 180°C and 80°C to 140°C. be. Generally, the extrusion process can be carried out at a temperature of 10°C to 40°C above the glass transition (Tg) of the thermoplastic material. Once at a temperature suitable for use in a three dimensional printer, the thermoplastic material can be applied to the three dimensional printing surface. The shape and size of substrates and compartments made of thermoplastic material can be controlled by programming the three-dimensional printing process.

In some embodiments, the material of the matrix can be selected to provide a controlled drug release profile. For example, the substrate is made of a material that has the desired erosion/dissolution rate, permeation rate, so that when administered, the compartment can be opened in a predetermined manner and the drug content can be released from the compartment at the desired rate. released. In some embodiments, the substrate is erodible or soluble and has an embedded active pharmaceutical ingredient (API). As the substrate erodes or dissolves, the API is released.

The release of drug content can also be controlled by adjusting the thickness of the substrate. For example, the substrate forming the compartment is made of a soluble material. The opening of the compartment, and thus the release of the drug content packed therein, can be controlled by adjusting the thickness of the walls surrounding the compartment. The thicker the walls, the slower the compartment opens and the slower the drug content is released.

B. Compartments In certain embodiments, the dosage forms disclosed herein comprise at least one compartment within the matrix. As used herein, "compartment" refers to a space, portion or room that is characterized or divided by a substrate. A compartment can be closed or open (eg, having an aperture or passageway). The compartment may be of any geometry suitable for packing the drug content. In some embodiments, the compartment has a shape selected from the group consisting of pie-shaped, conical, pyramidal, cylindrical, cubic or cuboidal, triangular or polygonal prismatic, tetrahedral and combinations thereof. have.

In some embodiments, including compartments in the dosage form can enhance its retention in the gastrointestinal tract. FIG. 2A illustrates an exemplary dosage form having a substrate forming a compartment filled with drug content. Referring to FIG. 2A, in dosage form 100 compartment 102 is formed by substrate 101 . Drug content 103 is attached to compartment 10 by connecting to the inner wall of compartment 102 .
Packed in 2. Compartment 102 can provide a floating effect to the dosage form, thereby extending its residence time in the stomach or in an aqueous or acidic environment. The residence time is determined by the erosion/dissolution rate of the material of the substrate, A
Sustained release of PI can be provided.

FIG. 3 illustrates another exemplary dosage form with increased retention in the gastrointestinal tract. Referring to FIG. 3, dosage form 200 has a configuration in which compartment 202 contains a second dosage form 203 (eg, a tablet) that moves freely through compartment 202 . The dosage form has a limited residence time in the gastrointestinal tract. The use of a flotation system may allow the dosage form to stay in the stomach, continuously releasing drug in the upper gastrointestinal tract, and maximizing absorption in the small intestine.

In some embodiments, the shape of the compartment is uniquely crafted to allow the drug content to be released at a controlled rate. In some embodiments, the compartment is selected from the group consisting of wedge-shaped, pie-shaped, conical, pyramidal, cylindrical, cubic or cuboidal, triangular or polygonal prismatic, tetrahedral and combinations thereof have a shape.

In one embodiment, the compartments of the dosage form have different geometries. FIG. 4A shows an exemplary dosage form having a substrate that forms a pie-shaped compartment. FIG. 4B shows an exemplary dosage form having a substrate forming multiple compartments containing openings of varying sizes. FIG. 4C shows an exemplary dosage form having a substrate forming angled compartments. FIG. 4D shows an exemplary dosage form having a matrix that forms multiple compartments with different radial sizes.

Compartment geometry can be used to control the release profile of the dosage form. For example, R. A. Lipper and W.J. I. Higuichi described a delivery system that achieves a zero-order release profile illustrated in FIG. FIG. 5 shows a cross-sectional view of a delivery system with pie-shaped compartments. The compartment communicates with the environment through a small opening. The compartments are packed with drug content that dissolves to release the API. The API is then released into the environment through small openings. The drug content dissolution rate is positively correlated with the drug content dissolution boundary (the interface between the drug content and the space of the compartment) area. On the other hand, the diffusion rate of API into the environment is negatively correlated with the diffusion path length λ. As a result, as the drug content dissolves, the dissolution boundary area increases and the dissolution rate of the drug content increases. On the other hand, as the drug content dissolves, the diffusion path length λ increases. Therefore, API released in the compartment must be transported longer lengths to diffuse out of the dosage form. It is envisioned to design dosage forms to achieve zero-order release kinetics (R.A. Lipper and W.I. Higuchi (1977)
, Analysis of theoretical behavior of a p
proposed zero-order drug delivery system.
J. Pharm Sci 66(2): 163-4; Brooke and R.J. J. Washkuhn (1977), Zero-order drug de
livery system: theory and preliminary
Sting. J Pharm Sci. 66(2):159-162).

C. Drug Content As used herein, the term “drug content” includes one or more active ingredients, including active pharmaceutical ingredients (APIs), cosmetics, biological agents, diagnostic agents and reagents for scientific experiments. Refers to composition.

As used herein, API refers to a biologically active ingredient in a pharmaceutical product. In some embodiments, the API is a local anesthetic, an antiepileptic and anticonvulsant, an Alzheimer's drug, an analgesic, an antigout drug, an antihypertensive drug, an antiarrhythmic drug, a diuretic, a liver disease drug, Pancreatic drugs, antihistamines, antiallergic drugs, glucocorticoid drugs, sex hormones and contraceptives, hypoglycemic drugs, antiosteoporotic drugs, antibiotics, sulfonamides, quinolones and other synthetic antibacterial drugs, antituberculous drugs selected from the group consisting of drugs, antiviral agents, antineoplastic agents, immunomodulators, cosmetic actives, traditional Chinese medicine (TCM) and TCM extracts.

In some embodiments, the API is (R)-folitixoline, lidocaine, 1
1-di-deutero-ethyl linoleate, 16-dehydro-pregnenolone, 17β-
Estradiol, 2-iminobiotin, 3,5-diiodothyropropionic acid, 5-fluoro-2-deoxycytidine, 6-mercaptopurine, edtreotide, abacavir, abalone hemocyanin, abamethapyr, avediterol, abemaciclib, abexinostat, abiraterone , acalabrutinib, acamprosate, acamprosate calcium, acarbose, acevirstat, aceclidine, aceclofenac, acehitisin hydrochloride, acemannan, acenoiraminic acid, acetaminophen, acetylcysteine, acetylkitasamycin, acetyl-L-carnitine hydrochloride salt, acetylsalicylic acid, acyclovir, acipimox, acitazanolast, acitretin, acridinium, acridinium bromide, acolbifene, acorafloxacin, acotiamide, acrivastine, actarit, adapalene, adapalene, adefovir dipivoxil, ademetionine, advair, afatinib, afimoxifen, afresertib, agomelatine, aildenafilcitrate, aradrian, aralevonadifloxacin mesylate, arareline acetate, alatrofloxacin mesylate, albendazole, albuterol sulfate, albuterpenoids, alcaftadine , aldoxorubicin, alectinib, alendronate, alendronate sodium, alendronate sodium hydrate, alendronate, alfacalcidol, alfaxalone,
alfentanil, alfuzosin, alisertib, aliskiren, alispolivir, alitretinoin, allantoin, alisartan isoproxil, allopurinol, almotriptan, alogliptin, alogliptin benzoate, alosetron, alpelisib, α-ketoglutarate, α-lipoic acid, α1-anti trypsin, α-cyclodextrin-stabilized sulforaphane, alprazolam, alprostadil, alprostadil alfadex, artiratinib, altretamine, altropane, aluminum sulfate, alvimopan, albocidib, amantadine, amantadine hydrochloride, ambrisentan, ambroxol, ambro xol hydrochloride, amcasertib, amphetamine, amphetamine polystyrenex, amifampridine, amifampridine phosphate, amifostine, amikacin, amiloride, aminolevulinic, aminolevulinic acid, aminolevulinic acid hydrochloride, aminopterin, amiodarone, amicermod, amisulpride, Amitifadine Hydrochloride, Amitriptyline, Amlexanox, Amlodipine, Amlodipine, Amlodipine Besylate, Amlodipine Besylate, Amlodipine Cansylate, Amlodipine Maleate, Amlodipine Nicotinate, Amlodipine Orotate,
ammonium lactate, amodiaquine, amorolfine, amosulalol, amoxicillin,
Amoxicillin hydrate, amphetamine, amphetamine aspartate, amphetamine sulfate, amphotericin B, amphotericin B cholesteryl sulfate, amphotericin B lipid complex, ampicillin sodium, ampiroxicam, amrinone, amrubicin, amtolmetin guacil, anacetrapib, anagliptin, anagrelide , anamorelin, anastrozole, ancrod, androgens, andrographolide,
anecortave, anidulafungin, aniracetam, anistreplase, anlotinib, antazoline, antiandrogens, antineoplaston A-10, antineoplaston AS2-1, anthrofloxacin hydrochloride, anthroquinonol, apabetaron, apalutamide , apatinib mesylate, apazicon, apilimod mesylate, apixaban, apomorphine, apomorphine hydrochloride, apremilast, aprepitant, apricitabine, aramchol, alanidipine, alacertaconazole, alacertaconazole nitrate, arbalclofen, arbalclofen placa Rubil, Arbekacin, Arbekacin Sulfate, Aldeparin Sodium, Alformoterol, Argatroban, Arhalofenate, Arimoclomol, Aripiprazole, Aripiprazole Lauroxyl,
armodafinil, arsenic trioxide, arsenous acid, artefenomer mesylate, artemether,
artemotil, artenimol, alterolane maleate, artesunate, artis [
Artiss], asapiplant, asenapine, asimadoline, astodrimer, astragaloside, asunaprevir, atasiguat, atallen, atazanavir, atazanavir sulfate, atenolol, atomoxetine, atorvastatin, atorvastatin calcium, atorvastatin strontium, atovaquone, atrasentan, atropine, auranofin , auriclosen, avacincaptadpegol sodium, abacopan, avanafil, avathrombopag, avibactam, avibactam sodium, avidinox [AvidinOx], aviptadil, avitinib, avoralstat, axeroplan, axitinib, azacitidine, azacitidine, azacetron , azelaic acid, azelastine,
Azelastine hydrochloride, azelilagon, azelnidipine, azilsartan, azilsartan medoxomil potassium, azilsartan trimethylethanolamine, azimilide, azithromycin, azithromycin lactobionate, aztreonam, aztreonamlysine, azvudine, baclofen, bafetinib, baicalein, baicalin, BAK containing latanoprost, valofloxacin, balsalazide, balsalazide sodium, bambuterol, valasertib, bardoxolone methyl, baricitinib, varnidipine, vasmisanil, vatefenterol succinate, bazedoxifene, beclavvir, beclomethasone dipropionate, beclomethasone dipropionate, bedaquiline, bedoradrine, belinostat, beroranib, berotecan, bempedoic acid, benapenem,
benazepril, bencyclochidium bromide, bendamustine, bendamustine hydrochloride,
Benidipine, Benserazide, Bentamapimod, Benzalkonium Chloride, Benzhydrocodone, Benznidazole, Benzocaine, Benzoyl Peroxide, Benzydamine HCL, Bepotastine, Bepotastine Calcium Dihydrate, Bepotastine Salicylate, Veractant, Beraprost Sodium, Besifloxacin , besifovir, besipirdine, beta-elemen, betahistine, betaine anhydrous, betamethasone, betamethasone butyrate propionate, betamethasone dipropionate, betamethasone valerate, betamipron, betaxolol, betaxolol hydrochloride, betanecol, betrixaban, bevacizumab, bexagliflozin, bexarotene, bezafibrate, biafungin, biapenem, bicalutamide, bisizal, victegravir, biciclor, bilastine, bimatoprost, binimetinib, biotin, vilabresib dihydrate, viscalcitrate potassium, bismuth subgallate, bismuthylecabet, bisnorsimerine , Bisoprolol, Bisoprolol Fumarate, Vitespiramycin, Bixalomer, Bleomycin, Blonanserin,
boammycin hydrochloride, boceprevir, bortezomib, bosentan, bosentan hydrate,
bosutinib, bobactant, brexpiprazole, briciclib sodium, brigatinib, brilacidin, brimapitide, brimonidine, brincidofovir, brinzolamide, brivanib alaninate, brivaracetam, brivudine, brolucizumab, bromazepam, bromfenac, bromfenac sodium, bromocriptine, broncostat, brotizolam, bryostatin-1, bucindolol, bucladesine, budesonide,
Budipine, Buflomedil, Buraquine, Bunazocine, Buparlisib, Bupivacaine, Bupivacaine Hydrochloride, Buprenorphine, Buprenorphine Hydrochloride, Bupropion, Bupropion Hydrochloride, Brixafor, Buserelin Acetate, Buspirone, Buspirone Hydrochloride, Busulfan, Busulfex, Butenafine, Butorphanol Tartrate, Butylphthalide , cabazitaxel, cabergoline, cabotegravir, cabozantinib S-malate, cadazolide, cadrofloxacin, caffeine, caffeine citrate, cafnea, cafsertib hydrochloride, calcipotriol, calcitriol, calcium acetate, calcium fophosphate, calcium levofolinate, Polycarbophil calcium, calfactant, calmangafodipil, calsurf, camicinal, camostat mesylate, camptothecin, canagliflozin, candesartan, candesartan cilexetil, canfosfamide, cangrelor, cannabidiol, capecitabine, capmatinib, capsaicin, captopril, carbamazepine, carbetocin, carbidopa, carbinoxamine, carbocisteine, carboplatin, carbidopa, carfilzomib, cargurumic acid, cariprazine, carisbamate, carmustine, caroteglast-methyl, carteolol, carteolol hydrochloride, carmonam, carvedilol, carvedilol phosphate, caspofungin, catechin, cebranopadol, cediranib, cefaclor, cefadroxil, cefatiamidine, cefazolin sodium pentahydrate, cefcapene, cefdinil, cefditorenpivoxil, cefepime, cefepime dihydrochloride, cefetamethepivoxil hydrochloride, cefiderocol, cefiravancin, cefminox, cefoperazone, cefoperazone sodium, cefoselis, cefotaxime, cefotaxime sodium, cefotiam, cefozopran, cefpirome, cefpodoxime, cefprozil, ceftaroline,
ceftaroline fosamil, ceftazidime, ceftibutene, ceftobiprol medocaryl,
Ceftolozane Sulfate,

ceftriaxone, ceftriaxone sodium, cefuroxime, cefuroxime sodium, celecoxib, celgosivir, celiprolol, celprotect, senestin, senicriviroc, sensavudine, centanafadine, cephalosporins, cerarifimod,
serduratinib, ceritinib, cerium nitrate, cetilistat, cetirizine, cetraxate, cevimeline, chenodeoxycholic acid, clocybutamine, chlorhexidine, chlormadinone acetate, chlorogenic acid, chloroquine, chloroxoquinoline, chlorpheniramine, chlorpheniramine maleate, chlorpheniramine polystyrene, chlorthalidone, chlorthalidone, cholecalciferol, cholic acid, choline alphoscerate,
cholinediepalrestat, choline fenofibrate, ciclesonide, ciclopirox olamine, cyclosporine, cidofovir, cidoxepin, cilastatin, cilazapril, cilnidipine, cilostazol, cimetidine, cinacalcet, cinepazide maleate,
Synhyaluronate sodium, sinitapride tartrate, cipargamin, ciprofibrate, ciprofloxacin, ciprofloxacin hydrochloride, cilaparan tag, circadin, cisatracurium besylate, cisplatin, citalopram, citalopram hydrobromide, citicoline , citrulline, cladribine, clarithromycin, potassium clavulanate, clavulanic acid, clazosentan, clevidipine, clevudine, clindamycin,
clindamycin hydrochloride, clindamycin phosphate, clioquinol, clobazam, clobetasol propionate, clobetasol propionate form, clodronic acid, clofarabine, clofazimine, clomipramine, clomipramine hydrochloride, clonazepam, clonidine, clonidine hydrochloride, clopidogrel, clopidogrel besylate,
clopidogrel bisulfate, clopidogrel camsylate, clopidogrel hydrogen sulfate, clopidogrel napadisylate, clopidogrel resinate, clotrimazole, clozapine, cobamamide, cobicistat, cobimetinib, cobiprostone, codeine, codeine polystyrene, colchicine, cholecalciferol, colesevelam, cholestilan, colforsin daropate, colfosceryl palmitate, colistin metasodium, conivaptan, copanlisib, copper histidine, cortexolone 17α-propionate, cocitecan, clenolanib, clidanimod sodium, crisabolol, crizotinib, crofelemer, chloribulin, cromoglycate, cromolyn sodium, cutamethine dihydrochloride, cyanocobalamin, cyclidine lactate, cyclobenzaprine hydrochloride, cyclophosphamide, cyclophosphamide monohydrate, cyclosporine, cyproterone,
cyproterone acetate, cytarabine, cytarabine ocphosphate, dabigatran etexilate, dabrafenib, daclatasvir, dacomitinib, dalbavancin, dalcetrapib, dalfampridine, dalfopristin, dalteparin sodium, danaparoid sodium, danazol, danilixin, danoprevir, dantrolene sodium ,
Danusertib, dapaconazole, dapagliflozin, dapagliflozin propanediol, dapiprazole, dapivirin, dapoxetine, daprodustat, dapsone, darifenacin, darinaparsin, darunavir, dasabvir, dasatinib, dasotraline, daunorubicin, decitabine, decuplate, defactinib, deferasirox, deferiprone , deferoxamine mesylate, deflazacort, defflexifol, delafloxacin, delamanid, delapril, delapril hydrochloride, delavirdine, denibulin, deoxyandrographolide, dermatan sulfate, desflurane, desipramine hydrochloride, desloratadine, desmopressin, desmopressin acetate, desogestrel, Desonide, desvenlafaxine, deuxdextromethorphan hydrobromide, deuteporfin, deuterated levodopa, deuterated venlafaxine, deutetrabenazine, dexamethasone, dexamethasone acetate, dexamethasone cipesylate, dexamethasone palmitate , dexamethasone sodium phosphate, dexamphetamine, dexanabinol, dexferm, dexketoprofen trometamol, dexlansoprazole, dexmedetomidine, dexmethylphenidate, dexpramipexole, dexrazoxane, dexsotalol, dextroamphetamine saccharate, dextroamphetamine Sulfate, dextromethorphan, dextromethorphan hydrobromide, dextropropoxyphene, diacerein, diamorphine hydrochloride, dianhydrogalactitol, diazepam, diazoxidecholine, diclofenac, diclofenac potassium, diclofenac sodium, diclofenamide, dicycloplatin , didanosine, dienogest, difluprednate, digoxin, dihomo-γ-linolenic acid, dihydroergocristine, dihydroergotamine, dihydroergotamine mesylate, diltiazem, diltiazem hydrochloride, dimesna, dimethyl fumarate, dimiracetam, dinoprostone, diphenylcyclopropenone, dipraglulant , dipyridamole, diquafosol tetrasodium, dirithromycin, disfentone sodium, disulfiram,
dithranol, d-methadone, docarpamine, docetaxel, dociparstat, docosanol, dofetilide, dolasetron, dolutegravir, domperidone, donafenib tosylate, donepezil, donepezil hydrochloride, dopamine, doravirine, doripenem, dorzolamide, dorzolamide hydrochloride, dosmalmate , doxacrium chloride, doxazosin, doxazosin mesylate, doxepin hydrochloride, doxercalciferol, doxfluridine, doxofylline, doxorubicin, doxorubicin hydrochloride, doxycycline, doxycycline hycrate, doxylamine succinate, dronabinol, dronedarone, drospirenone, droxidopa , D-tagatose, duloxetine, duloxetine hydrochloride, dutasteride, duvelisib, ebastine, evelconazole, ebselen, ecavet, econazole nitrate, ecopipam, edaravone, ediboxetine, ednerpic maleate, edoxaban, efatuazone, efavirenz, efinaco Nazol, eflornithine, efonidipine hydrochloride, egualen sodium, eicosapentaenoic acid monoglyceride, elafibranol, elagolix, eramipretide, elvasvir, eldecalcitol, eleclazine, elescromol sodium, eletriptan, eliglustat tartrate, elobixibat, Eltrombopag, Elxadrine Dihydrochloride, Elvitegravir, Emdogain, Emedastine, Emeramide, Emixustat, Emodepside, Empagliflozin, Emlicasan, Emtricitabine, Enalapril, Enalapril Maleate, Enacidenib, Ensenicline, Enclomiphencitrate, Encorafenib, Endo xifene, enovosalm, enoxa singleconate, enoxaparin sodium, enprostil, entacapone, entasovrin, entecavir, entecavir maleate, entinostat, entospretinib, entrectinib, enzalutamide, enzastaurin, epacadostat, epalrestat, eperisone, Epetrabolol, ephedrine sulfate, epinastine hydrochloride, epinephrine, epirubicin, epirubicin hydrochloride, episulvan, epitinib, eplerenone, epoprostenol, epristeride, eprodisate, eprosartan, eptaplatin, eravacycline, erdafitinib, erdosteine, eribulin mesylate , erlotinib, ertapenem, erteverel, ertugliflozin, erythromycin, erythromycin assistrate, erythromycin stinoplate, escitalopram, esketamine, esketamine hydrochloride, eslicarbazepine acetate, esmolol hydrochloride, esomeprazole, esomeprazole magnesium, esomeprazole strontium, esomeprazole, estetrol, estradiol, estradiol acetate, estradiol cypionate, estradiol valerate, estradiol, estrogen, esveraprost sodium, eszopiclone, etamicastat, ethambutol hydrochloride, etaselen, ethinyl estradiol , calcium salt of ethyl hydrogen fumarate, magnesium salt of ethyl hydrogen fumarate, zinc salt of ethyl hydrogen fumarate, ethinyl estradiol, etidronic acid, etimicin sulfate, ethinotecampegol, etizolam, etodolac, etonogestrel, etoposide , etoposide phosphate, etoricoxib, etravirine, etripamil, oipatiline, ebenamide hydrochloride, everolimus, evofosfamide, evogliptin, exemestane, exendin (9-39), exeporphinium chloride, ezatiostat, ezetimibe, eztromide, fadolmidine, fadrozole, fardapre vir, falecalcitriol, famciclovir, famitinib, famotidine, fampridine, faropenem,
Facitibant chloride, fasoracetam, fasudil, fasudil hydrochloride, fasudil mesylate, favipiravir, febarbamate, febuxostat, fedovapagon, felbamate, felbinactrometamol, felodipine, femitra, fenfluramine hydrochloride, phenobam, fenofib Fenofibric Acid, Fenoldopam, Fenoterol, Fenretinide, Fentanyl, Fentanyl Citrate, Fenticonazole, Fermagat, Ferric Citrate, Ferric Maltol, Fermoxitol, Fesoterodine Fumarate, Fevipiprant, Fexini Dazol, fexofenadine, fibrin sealant, fibrinogen, fibrinogen sealant, fidaxomycin, filanesib, filgotinib, filocyclovir, fimaporfin, fimasartan, finafloxacin, finafloxacin hydrochloride, finasteride, finelenone, fingolimod , fipamezole, filtecampegol, flecainide, fleroxacin, flibanserin, flomoxef,

Floxuridine, fluazolepari, fluconazole, fludarabine, flumatinib, flumazenil, flunisolide, fluocinolone acetonide, fluocinonide, fluorapasin, fluorouracil, fluoxetine, fluoxetine hydrochloride, flupirtine, flurbiprofen, flurbiprofen axetil, flurbi profen sodium, flurithromycin, fluticasone, fluticasone furoate, fluticasone propionate,
flutrimazole, fluvastatin, fluvoxamine, folic acid, folinate, folium ginkgo, fomepizole, fonadelpar, fondaparinux sodium, foretinib, formestane, formoterol, formoterol fumarate, forodecin, fosamprenavir, fosaprepitant, fosbre tabulin, fosbretabrine disodium, fosfluconazole, fosfomycin, fosfomycin disodium, fosfomycin trometamol, fosinopril, fosinopril sodium, fosmidomycin, fosphenytoin, fospropofol, fosravuconazole, fostamatinib, fostemsavir tromethamine, fotagliptin benzoate, fotemustine, frovatriptan, fluquintinib, fudosteine, fulvestrant, funapide, furosemide, fusidic acid,
gabapentin, gabapentin enacarbyl, gabexate mesylate, gacyclidine, gadobutrol, gadoversetamide, disodium gadoxetate, galantamine, galeterone, galidesivir, gallium nitrate, garnisertib, gamboginic acid, ganaxolone, ganciclovir, ganetespib, ganilelix acetate, garenoxacin, gatifloxacin , gatifloxacin mesylate, gedatricib, gefitinib, gemcaben, gemcitabine, gemcitabine hydrochloride, gemfibrozil, gemifloxacin, gemigliptin, gemigliptin tartrate, genistein, gentamicin, gentiopicrin, gepirone, jepotidacin, gestodene, gestrinone, timolol maleate, gilteritinib , gimeracil, ginsenosides CK, ginsenoside Rg3, gibinostat, glasdigeb, glatiramer acetate, glecaprevir, glesatinib glycolate, glibenclamide, gliclazide, glimepiride, glipizide, glufosfamide, glutamine, glutathionarsenoxide, glycerol phenylbutyrate , glycopyrronium, glycopyrronium bromide, glycopyrronium tosylate, glycyrrhizic acid, ganglioside, golotimod, gosogliptin, granisetron, granisetron hydrochloride, glazoprevir, guaifenesin, guaimesal, guanfacine, gusperimus trihydrochloride, Haemophilus influenzae, halobetasol Propionate, Halofantrine, Halomethasone, Heron, Hematoporphyrin, Hemealginate, Hemocoagulase Actus, Heparin,
Herbiron, hethrombopag, hextend, higenamine hydrochloride, histamine dihydrochloride, HPPH photosensitizer, human apotransferrin, human plasminogen, huperzine A, sodium hyaluronate, hydralazine hydrochloride, hydrochlorothiazide, hydrocodone, hydrocodone Bitartolate, Hydrocodone Polystyrene, Hydrocortisone, Hydrogen Peroxide, Hydromorphone, Hydromorphone Hydrochloride, Hydroxocobalamin, Hydroxycarbamide, Hydroxychloroquine, Hydroxyprogesterone Caproate,
Hydroxysafrole Yellow A, Hilastane, Hypericin, Hipestoxide, Ibandronate, Ibandronic Acid, Iberogast N, Ivodutant, Ibrutinib, Ibudilast, Ibuprofen, Ibutilide, Ibutilide Fumarate, Icaritin, Iclaprim, Icosubate, Icosapent, Icosapentethyl, Icosapentethyl ester,
icotinib hydrochloride, idalopirdine, idasanutrin, idebenone, idelalisib, idoxuridine, idlonoxyl, ifetroban, ifetroban sodium, iguratimod, ilansoprazole, ilaprazole, iloperidone, iloprost, iloprost betadexclathrate, imatinib, imatinib mesylate, Imeglimin, Imidafenacin, Imidapril, Imidazole Salicylate, Imidol Hydrochloride, Imigliptin Dihydrochloride, Imipenem, Imiquimod, Imisopasem Manganese, Imrecoxib, Incadronic Acid, Incobotulinum Toxin, Indacaterol, Indacaterol Maleate, Indapamide, Indeloxazine, Indimitecan, Indinavir, Indisetron, Indomethacin, Indolamine, Indothecan, Indoxymod, Ricecalcitol, Infigratinib, Ingavirin, Ingenol Mebutate, Inhaled Sodium Nitrite, Ferric Carboxymaltose, Inosine, Intepil din, iodiconazole,
Ipatasertib dihydrochloride, ipragliflozin, ipratropium, ipratropium bromide, iptacarim, irbesartan, irinotecan, irinotecan hydrochloride, irinotecan closophate, irofulven, iron isomaltoside 1000, iron protein succinate, irosstat, irsogladine maleate, isabco Nazonium chloride/sulfate, isodibut, isoflurane, isoniazid, isopropyl unoprostone, isosorbide dinitrate, isosorbide mononitrate, isosteviol, isothiafluzine, isotretinoin, isradipine, istaloxime, istradefylline, itacitinib, itopride hydrochloride, itraconazole , ivabradine hemisulfate, ivabradine hydrochloride, ivacaftor, ivermectin, ivosidenib, aflibercept, ixabepilone, ixazomib citrate, kallikrein, kangbeide, ketamine, ketanserin, ketoconazole, ketoprofen, ketorolac, ketorolac tromethamine , ketotifen, quevetrin, cucoamine B mesylate, L-4-chlorokynurenine, lacidipine, lacosamide, lactitol, ladarixin, ladostigil, laflunimus, lafutidine, lamivudine, lamotrigine, landiolol, landiolol hydrochloride, laninamivir octanoate, lanoconazole, lansoprazole, lanthanum carbonate, lapatinib, laquinimod, lalomustine, lasmiditane, lasofoxifene, latanoprost, latanoprostenbunod, lauflumide, ledipasvir, lefamulin, leflunomide, lemborexant, lenalidomide, lentinan, lentinansul phate, lentinanviral, lenvatinib mesylate,
lercanidipine, lesinurad, leteprinim, letermovir, letrozole, leucine,
leuprorelin acetate, levalbuterol, levalbuterol hydrochloride, levamisole, levamlodipine, levamlodipine besylate, levamlodipine maleate, levetiracetam, levobupivacaine, levocabastine, levocabastine hydrochloride, levocarnitine,
levocetirizine dihydrochloride, levodopa, levodoxazocin mesylate, levofloxacin,
levotoconazole, levomilnacipran, levonadifloxacin arginine salt, levonorgestrel, levonorgestrel butanoate, levo-fencinonate hydrochloride, levonidazole, levorphanol, levosimendan, levothyroxine sodium, levotus ], L-glutamine, lidocaine, lifitegrast, ligustrazine hydrochloride, limaprost, linagliptin, linezolid, liothyronine, liothyronine sodium, lipobean, liposomal curcumin, lipoteichoic acid, lilanaphtate, lisdexamphetamine, lisinopril, lisofylline, lisuride hydrogen maleate, lithium citrate, lithium succinate, lixivaptan, lobaplatin, lobeglitazone, lodenafil carbonate, lofexidine, lomefloxacin, lomerizine, lomerizine dihydrochloride, lomitapide, lonafarnib, lonidamine, loperamide, loperamide oxide, lopinavir, loratadine, lorazepam, lorcaserin, loridipron [lorediplon], lorlatinib, L-ornithine-L-aspartate, lornoxicam, losartan, losartan potassium, rosmapimod, loteprednol etabonate, lovastatin, loxapine, loxoprofen, L-praziquantel, lubiprostone, lucanthone, lucerastat
], lucinactant, rusitanib hydrochloride, luliconazole, lumacaftor, lumateperone toluene sulfonate, lumefantrin, lumiracoxib, lunacalcipol, lurasidone, lurbinectedin, luseogliflozin hydrate, lustrombopag, lysine acetylsalicylate , masimorelin, macitentan, mafenide, magnesium carbonate, magnesium isoglycyrrhizinate, mangafodipir, manidipine, manidipine dihydrochloride, mannitol, maraviroc, marivavir, marizomib,
masilukast, macitinib, mavoglurant, maxacalcitol, mebendazole, mebiphon, mecamylamine, mecamylamine hydrochloride, mechlorethamine, mecobalamin, medroxyprogesterone, medroxyprogesterone acetate, mefloquine, megestrol, megestrol acetate, mace osuri [ meisuoshuli], melevodopa, meloxicam, melphalan, melphalan flufenamide hydrochloride, memantine, memantine hydrochloride, menadione sodium sulfite, menatetrenone, mepacrine, mequinol, mercaptamine, mercaptamine bitartrate, mercaptamine hydrochloride, mercaptopurine, merestinib , meropenem, merotocin, mesalamine, mesalazine, metacavir, metadoxine, metamizole sodium, metaxalone, metergoline, metformin, metformin hydrochloride, methadone, methazolamide, methotrexate, methoxyflurane, methyl aminolevulinate hydrochloride, methylnaltrexone bromide, methylnaltrexone, methylphenidate, methylphenidate hydrochloride, methylprednisolone, methylprednisolone aceponate,

methylthioninium chloride, metyrosine, metoclopramide, metoprolol, metoprolol succinate, metrifonate, metronidazole, metyrapone, mexiletine, mibefradil, miconazole, miconazole nitrate, midazolam, midazolam hydrochloride, midodrine, midostaurin, mifamurtide, mifepristone, miglastat, miglitol, miglustat, milnacipran, milrinone, miltefosine, minaprine, minocycline, minocycline hydrochloride, minodronic acid, minoxidil, mirabegron, miriplatin hydrate, milodenafil, milodenafil hydrochloride, mirogabalin, mirtazapine, misoprostol, mitiglinide, mitomycin , mitoxantrone, mitoxantrone hydrochloride, mibotyrate, mizolastine, mizoribine, mocetinostat dihydrobromide, moclobemide, modafinil, doxycycline, mozipafant, moexipril, mofezolac, molidustat, molindone hydrochloride, momerotinib, Mometasone, monepantel, monoammonium glycyrrhizinate, monobenzone, monosodium α-luminol, monoterpene perillyl alcohol, montelukast, montelukast sodium, montmorillonite, moracidin, morinidazole, morphine, morphine glucuronide, morphinepitavastatin, morphine sulfate, morphothiazine mesi mosapride, motrimod, moxidectin, moxifloxacin, moxifloxacin hydrochloride, moxonidine, moxonidine hydrochloride, mozavaptan, mpafostat sodium, mupirocin, mycobactovir, mycophenolate mofetil, myristyl nicotinate , nabilone, nabiximols, nabumetone, N-
Acetylcysteine, Nacisterine, Nadifloxacin, Nadolol, Nadroparin Calcium, Naftifine Hydrochloride, Naftopidil, Nalbuphine, Nalbuphine Sebacate,
naldemedine, nalfuraphine, nalmefene, naloxegol, naloxone, naloxone hydrochloride, naltrexone, naltrexone hydrochloride, narzotane, nandrolone decanoate, napabucasin, naphazoline, naphthoquine, naproxen, naproxen sodium, nacotinib mesylate, naratriptan, narulaprevir, naspacu [ nasapaque]
, nasalplase, nastorazepide calcium, nateglinide, navamepent, nazartinib, nebivolol, necparanib
ranib], nedaplatin, nedocromil, nerarabine, nelfinavir, nerotanserin, nemonapride, nemonoxacin, neoandrographolide, neosaxitoxin, neostigmine methylsulfate, nepazutant, nepafenac, nepicastat, nepolong [nepolong], neramexane, neratinib, neridronic acid, netarsudil [ netarsud
il], netilmicin, netupitant, nevirapine, niacin, nicardipine, nicergoline, nicorandil, nicotiflorin, nicotine, nicotinic acid, nixamide, nifedipine, nifekalant, nifeviroc, nifurtimox, nifluzide,
nikcomycin, nilotinib, nilutamide, nilvadipine, nimesulide, nimodipine, nimorazole, ningetinib, nintedanib, niraparib, nisoldipine,
nitazoxanide, nitisinone, nitrendipine, nitric oxide, nitroglycerin, nitroglycerin, nizatidine, nokxaban, noratrexed, nomegestrol acetate, norelgestromin, norepinephrine, norethindrone, norethindrone acetate, norethindrone enanthate, norethisterone, norethisterone acetate, norfloxacin, norgestimate, noribogaine, norursodeoxycholic acid, obeticholic acid, octenidine, octohydroaminoacridine succinate, octreotide, octreotide hydrochloride, odalasvir, odanakatib, odiparcil, ofloxacin, olanzapine, olaparib , olesoxime, oliceridine, olmesartan, olmesartan cilexetil, olmesartan medoxomil, olodaterol, olodaterol hydrochloride, olopatadine, olopatadine hydrochloride, olpurinone, olsalazine, oltipraz, omacetaxine mepesuccinate, omadacycline, omarigliptin, omaveloxolone , ombitasvir, omecamtivemecarbir, omega-3 carboxylic acid, omeprazole, omigapil, omoconazole, onarespib, onapristone, ondansetron, onderoplan, opicapone, opipramol, methylphenidate, oricinoside, orlotimod, oritavancin, orlistat , ornithine phenylacetate, ornoprostil, ortataxel, orteronel, orthovisc, orbepitant, oseltamivir, osilodrostat, osimertinib, Osiris Phleu
m pretense], ospemifene, oteracil potassium, otesecconazole, oxaliplatin, oxaloacetate, oxandrolone, oxazepam, oxcarbazepine, oxfendazole, sodium glutathione oxide, oxracetam, oxybutynin, oxybutynin hydrochloride, oxycodone, oxycodone hydrochloride salt, oxymetazoline, oxymetazoline hydrochloride, oxymorphone, oxytocin, ozagrel, ozagrel hydrochloride, ozagrel sodium, ozanimod, ozenoxacin, paclitaxel, paclitaxel polygumex, paclitinib, palbociclib, paliperidone, paliperidone palmitate,
palmidrol, palonosetron, palovarotene, disodium pamidronate, pancrelipase, panipenem, panobinostat, pantoprazole, paracetamol, parecoxib, paricalcitol, paritaprevir, parnaparin sodium, parogleril,
paromomycin, paroxetine, paroxetine hydrochloride 0.5hydrate, paroxetine mesylate, patiromer calcium, patupilone, pazopanib, pazufloxacin, pazufloxacin mesylate, pefcalcitol, peficitinib, pegylated apo-filgrastim, perbiprofen, pemafibrate, pemetrexed sodium, pemirolast,
pemirolast potassium, pemirolast sodium, penciclovir, penehiclidine hydrochloride, pentamidine, calcium trisodium pentetate, zinc trisodium pentetate,
Pentetrazole, sodium pentosan polysulfate, pentostatin, pentoxifylline, peramivir, perampanel, perclozone, peretinoin, perfrenapent, perflubron emulsion, perfluorooctyl bromide, pergolide, perhexyline maleate, perifosine, perindopril, perindopril arginine, Perospirone, pevonedistat, pexidartinib, PhagoBioDerm, phenchlobenpyrrone, phenethyl isothiocyanate, phenoxybenzamine hydrochloride, phentermine, phentermine hydrochloride, phentolamine mesylate, phenylbutyrate, phenylephrine, phenylephrine hydrochloride, phenytoin, phosphazide, pibrentasvir, picibanil, piclorib, picropodophylline, pidotimod, pilocarpine, pilocarpine hydrochloride, pilsicainide, pimasertib hydrochloride, pimavanserin, pimecrolimus, pimobendan, pinocembrin, pinometostat, pioglitazone, pioglitazone hydrochloride, pipamperon , pipecuronium, piperacillin, piperacillin sodium, piperaquine, piperaquine phosphate, piperidone hydrochloride, piperine, piperphentonamine, piracetam, pirarubicin, pirfenidone, pirmenol, piromelatine, pirotinib, piroxicam, piroxicam betadex, pitavastatin , pitavastatin calcium, pitlisanth, pixantrone, plazomycin, pleconaril, plelixafo, plinabulin, pocapavir [po
capavir], hydromorphone, podophilox, polaprezinc, pormacoxib, polydatin, polyoxidonium, pomagretad methionyl, pomalidomide, ponatinib, ponesimod, porfimer sodium, posaconazole, posiphen,
potassium bicarbonate, potassium citrate, potassium clavulanate, poziotinib, pracinostat, pradefovir, pralatrexate, pramipexole, pramiracetam, pranlukast, pranlukast hydrate, prasterone, prasugrel, pravastatin,
prazosin, prednimustine, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisone, pregabalin, prenpro, presatovir, pretomanide, previdersin, plexasertib, pridopidine, prilocaine, priterivir, procaterol hydrochloride, prochlorperazine , prochlorperazine maleate, profezyme
, progesterone, progestogen, progestogen dienogest, proguanil, promethazine, promitil, propafenone, propagermanium, propofol, propranolol, propranolol hydrochloride, prostat, proxodolol,
prucalopride, prulifloxacin, prurisol, insoluble prussian blue, pseudoephedrine, pseudoephedrine hydrochloride, puerarin, pkitinib mesylate, pyrazinamide, pyridoxamine dihydrochloride, pyridoxine hydrochloride, pyrimethamine,
pyronaridine, pyrroltinib maleate, quazepam, quetiapine fumarate, quetiapine, quinagolide hydrochloride, quinapril hydrochloride, quinidine sulfate, quinine sulfate, quinupristine, xinostat, quizartinib dihydrochloride, rabeprazole,
rabeprazole sodium, rabeximod, racecadotril, radezolid, radtinib,
ralfinamide, larimetinib, lalinepag, raloxifene, raltegravir, raltitrexed, ramatroban, ramelteon, ramipril, ramosetron,

Ranitidine, ranitidine bismuth citrate, ranolazine, rasagiline, ravidasvir hydrochloride, raxatrigine, rebamipide, levastinib, reboxetine, reboxetine mesylate, recilisib sodium, recoflavone, redaporfin, ibuprofen, naproxen, glycopyrro bromide, lefametinib, regorafenib, relebactam, lelenopride, relugolix, lemeglulant, remifentanil, remifentanil hydrochloride, remimazolam, remimazolam tosylate, remogliflozin etabonate, repaglinide, reparixin, repirinast, amlexanox, chlorcic Lysine hydrochloride, bucillamine, guanabenz, mazindol, naltrexone, nitisinone, ondansetron, facetoperan, retigabine,
rosiglitazone, sodium phenylbutyrate, resiniferatoxin, resiquimod, resminostat, resveratrol, retagliptin, retapamulin, retigabine, retinoic acid, retosiban, revaprazan, levefenacin, reviparin sodium, rhein, rhenium 186 etidronate, ribavirin, ribociclib, licorinostat, lisinirazole, ridostin, rifabutin, rifampicin, rifamycin, rifapentin, rifaximin, rigosertib sodium, rilapradib, rilpivirine, rilpivirine hydrochloride, riluzole, rimantadine, rimepolid, rimexolone, riociguat, lipasdil hydrochloride hydration drug, risedronate sodium, risperidone, ritonavir, rivaroxaban, rivastigmine, ribipansel sodium, rizatriptan, rizatriptan benzoate, rmulation, rociletinib, roflumilast, rokitamycin, lorapitant, romurtide, ronakarelet, roneparstat [ roneparstat], ronopterin, ropinirole, ropinirole hydrochloride, ropivacaine, rose bengal sodium, rosiglitazone, rosiglitazone maleate, rosiglitazone sodium, rosafuroxin, rosuvastatin, rosuvastatin calcium, rotigotine, robatirelin, roxadustat, roxi thromycin,
rubitecan, rucaparib phosphate, rufinamide, rufloxacin, rupatadine, ruxolitinib, disodium S-(-)-ornidazole phosphate, sabarubicin,
Sacubitril, Safinamide, Salbutamol, Salbutamol Sulfate, Salicylic Acid, Salmeterol, Salmeterol Xinafoate, Salubrinal, Salvicin, Samarium (153Sm) Lexidronam, Samidorphan, S-Amlodipine Nicotinate, Sapacitabine, Sapropterin, Sapropterin Dihydrochloride, Saquinavir, salacatinib, salecycline, saloglitazar, sarpogrelate hydrochloride, savolitinib
tinib], saxagliptin, scopolamine, scorpion venom, omega-3 polyunsaturated fatty acids, secnidazole, segesterone acetate, selegiline, selegiline hydrochloride, cerepressin, selexipag, seliciclib, selinexol, sericistat, selumetinib, cerulanpanel, cepranolon [sepranolone], seratrodast, serlopitant, sertaconazole, sertaconazole nitrate, sertindole, sertraline, sertraline hydrochloride, setipiprant, sevelamer carbonate, sevelamer hydrochloride, seviteronel [sevite]
ronel], sevoflurane, sevuparin sodium [sevuparin sodium], sibutramine maleate, sibutramine mesylate, sildenafil, sildenafil citrate, silibinin dihydrogen succinate, cilmitasertib [si
lmitasertib], silodosin, silver sulfadiazine, simeprevir, cimecan hydrochloride,
Cimotinib hydrochloride, simvastatin, sinotecean, siponimod, sirolimus, sitafloxacin, sitagliptin, sitagliptin phosphate, sivelestat, schizophyllan, smilagenin, S-modafinil, sobuzoxan, sodium esinate, sodium ascorbate, sodium benzoate, sodium bicarbonate , sodium cromoglycate, sodium gluconate ferric salt complex, glycididazole sodium,
Sodium guarenate, sodium hyaluronate, sodium ibandronate, sodium nitrate, sodium nitrite, sodium oxybate, sodium phenylacetate, sodium phenylbutyrate, sodium polysulfionate, sodium plasterone sulfate, sodium pyruvate, sodium taurocholate , sodium thiosulfate, sodium zirconium cyclic silicate, sofosbuvir, sofpironium bromide, solabegron, solifenacin, solithromycin, sonidezib, sonolisib, sofocarpine, sophoridine hydrochloride, sorafenib, sorbitol, sotagliflozin, sotirimod, sotras taurine, sotylize, sovaprevir, sparfloxacin, sparsentan, pebrutinib, spirapril, spironolactone, squalamine, stannsoporfin, stavudine, S-tenatoprazole, stepronin, stiripentol, streptozocin, strontium malonate, strontium ranelate , succinic acid, sucralfate, sucroferric oxyhydroxide, sufentanil, suftalane zinc, sugammadex, sulbactam, sulbactam sodium, sulcardine sulfate, sulfamethoxypyrazine, sulfasalazine, sulfatinib, sulfonylurea, sulforaphane,
sulfotashinone sodium, sulindac, sulodexide, sulfamethoxazole, sultiam, sumatriptan, sumatriptan succinate, sunitinib, sunstone, suplasyn, suplatast tosylate, suramin sodium, verapamil hydrochloride,
rilpivirine, stezolide, suvorexant, tacalcitol, tacrine, tacrolimus, tadalafil, tafamidis, tafenoquine, tafluprost, tafoxiparin sodium, taladesib, talaporfin, talazoparib, talipexole, taltirelin, tamibarotene, tamoxifen, tamsulosin, tamsulosin hydrochloride , tandospirone, tanespimycin, tapentadol, tarafenacin, tarenflurbil, tarloxotinib bromide, tacerisib, tasimelteon, tasquinimod, tababolol, tavirermide, tazarotene, tazemetostat, tazobactam, tazobactam sodium, tebipenempivoxil, tecarfarin, tecovirimat, tektrigenin sodium sulfonate, tedisamil, tedizolid phosphate, tefinostat, tegafur, tegacerod, teicoplanin, telaprevir, telapristone acetate, teratinib, telbivudine, telithromycin, telmisartan, telotristatetiprate, temanogrel, temocapril, temoporfin, temozolomide, temsirolimus, tenalisib
, tenapanol, teneligliptin, tenofovir, tenofovir alafenamide, tenofovir dipivoxil fumarate, tenofovir disoproxil aspartate, tenofovir disoproxil fumarate, tenoxicam, tepotinib, teprenone, terameprocol, terazosin, terbinafine, terbinafine hydrochloride, terguride, teriflunomide, tesevatinib, tesofensine, testosterone, testosterone undecanoate, tetrabenazine, tetracaine, tetracaine hydrochloride, tetrahydrocannabidiol, tetrathiomolybdate, tetrizoline, tezacaftor, thalidomide, theliatinib , theophylline, therapeutic
], thiazide, thienorphine hydrochloride, thiotepa, thrombin, thromboredactin, thyroxine, tiagabine, tianeptine, tibolone, ticagrelor, ticlopidine, tigecycline, disodium tiludronate, timolol, timolol maleate, tindamax, tinidazole, tinzaparin sodium, tioconazole, thiopronin, tiotropium bromide, tiotropium bromide monohydrate, tipelukast, tipepidine hibenzate, tipifarnib, tipiracil hydrochloride, tipranavir, tirapazamine, tiracemtib, tirazad, tirofiban, tirofiban hydrochloride, tivantinib,
tivozanib, tizanidine, tobramycin, tocofersolan, tocolatinate, tofacitinib, tofogliflozin, tolcapone, trimidone, tolperisone, tolterodine, tolterodine tartrate, tolvaptan, tonaversat, topiramate, topiroxostat, topotecan, topotecan hydrochloride, torasemide, trefolant, toremifene, tosedostat, tosufloxacin, totrombopag, tozadenant, trabectedin, travodenosone, tradipitant, tramadol, tramadol hydrochloride, trametinib, trandolapril, tranexamic acid, tranilast, transcrocetinate sodium, transepithelial riboflavin, trantinterol hydrochloride, travoprost, trazodone, trehalose, trelagliptin succinate, treosulfan, treprostinil, treprostinyl diolamine, tretinoin, triamcinolone acetonide, triapine,
triazolam, tribendimidine, trichlormethiazide, triciribine, triclabendazole, triclocarban, trientine hydrochloride, trifarotene,
trifluridine, triflusal, triheptanoin, trilostane, trimebutine 3-
thiocarbamoyl-benzenesulfonate, trimebutine tosylate, trimegestone,
trimethoprim, trimetrexate, trinitrate, tripotassium dicitratobismuthate, trophinetide, tropicamide, tropisetron, trospium chloride, trovafloxacin, troxipide, tucatinib, tulobuterol, tylerdipine hydrochloride , ubenimex, ubidecarenone, ubrogepant, udenafil, ulinastatin, ulipristal, urixertinib, urobetasol, umeclidinium, umeclidinium bromide, upamostat
, euprosertib, uracil, urapidil, uridine triacetate, uroacitide [ur
oacitides], ursodeoxycholic acid, ursolic acid, vaborbactam, vadastat, valacyclovir, valacyclovir hydrochloride, valbenazine, valdecoxib, valganciclovir, valomaciclovir stearate, valproic acid, valrubicin, valsartan, valsartan trisodium 2.5-hydrate thing,

vancomycin, vancomycin hydrochloride, vandetanib, vaniprevir, vanoxerine,
vapendavir, vardenafil hydrochloride, varenicline, varisena
ena], vallitinib, vatiquinone, vavelta, veliparib, velpatasvir, vercetrag, vemurafenib, venetoclax, venlafaxine, venlafaxine hydrochloride, bepoloxamer, verapamil, verapamil hydrochloride, verdinexol [verdinex
or], veregen, vericiguat, verinurad, vernakalant, vernakalant hydrochloride, verosudil, verteporfin, verbecestat, verbulin, vesatrimod, vesnarinone, vibegron, vicagrel, vigabatrin, vilanterol, vilanterol trifena Tate, vilaprisan, vilazodone, vildagliptin, vincristine sulfate, vinflunine, vinorelbine, vinpocetine, bintaforide, viralym-C, vismodegib, bistusertib, vitamin E nicotinicate, visomitin, voglibose, vorasertib, voli xibat potassium ethanolate hydrate, vonoprazan fumarate, vorapaxal, voriconazole, vorinostat, vortioxetine, vortioxetine hydrobromide, bolsaloxine, voxilaprevir, warfarin, xemilofiban, yimitasvir, yonkenafil, zavofloxacin, zafirlukast, zalcitabine, zaleplon, zaltoprofen, zamicastat
, Zanamivir, Zemistatin, Z-Endoxifene Hydrochloride, Zibotentan, Didebactam, Zidovudine, Zileuton, Zinc Acetate, Dinostatin Stimaramer, Ziprasidone, Zofenopril, Zogenix, Zoledronate D, L-Lysine Monohydrate, Zoledronate Dihydrochloride selected from the group consisting of sodium, zoledronic acid, zoliflodacin, zolmitriptan, zolpidem, zolpidem tartrate, zonisamide, zopiclone, zotepine, zucapsaicin, zuclopenthixol, and zretinol acetate.

In some embodiments, the traditional Chinese medicine is Abelmoschi Corolla, Abri Herba,
Abutili Semen, Acanthopanacis Cortex Acanthopanacis Senticosi Radix Et Rhizoma S
eu Caulis, Acanthopanax Extract, Achilleae Herba, Achyranthis Bidentatae Radix,
Aconiti Kusnezoffii Folium, Aconiti Kusnezoffii Radix Cocta, Aconiti Kusnezoffii
Radix, Aconiti Lateralis Radix Praeparata, Aconiti Radix Cocta, Aconiti Radix,
Acori Calami Rhizoma, Acori Tatarinowii Rhizoma, Adenophorae Radix, Aesculi Seme
n, Agkistrodon, Agrimoniae Herba, Ailanthi Cortex, Ajugae Herba, Akebiae Caulis
, Akebiae Fructus, Albiziae Cortex, Albiziae Flos, Alismatis Rhizoma, Allii Macr
ostemonis bulbus, Allii Sativi Bulbus, Allii Tuberosi Semen, Aloe, Alpiniae Kats
umadai Semen, Alpiniae Officinarum Rhizoma, Alpiniae Oxyphyllae Fructus, Alumen
, Amomi Fructus Rotundus, Amomi Fructus, Ampelopsis Radix, Andrographis Herba, A
ndrographolides, Anemarrhenae Rhizoma, Anemones Raddeanae Rhizoma, Angelicae Dah
uricae Radix, Angelicae Pubescentis Radix, Angelicae Sinensis Radix, Anisi Stell
ati Fructus, Apocyni Veneti Folium, Aquilariae Lignum Resinatum, Arcae Concha, A
rctii Fructus, Ardisiae Crenatae Radix, Ardisiae Japonicae Herba, Arecae Pericar
pium, Arecae Semen Tostum, Arecae Semen, Arisaema Cum Bil, Arisaematis Rhizoma P
reparatum, Arisaematis Rhizoma, Aristolochiae Fructus, Aristolochiae Herba, Arme
niacae Semen Amarum, Arnebiae Radix, Artemisiae Annuae Herba, Artemisiae Argyi F
olium, Artemisiae Scopariae Herba, Asari Radix Et Rhizoma, Asiatic Moonseed Root
Extract, Asini Corii Colla, Asparagi Radix, Aspongopus, Asteris Radix Et Rhizom
a, Astragali Complanati Semen, Astragali Radix Praeparata Cum Melle, Astragali R
adix, Atractylodis Macrocephalae Rhizoma, Atractylodis Rhizoma, Aucklandiae Radi
x, Aurantii Fructus Immaturus, Aurantii Fructus, Bambusae Caulis In Taenias, Bam
busae Concretio Silicea, Baphicacanthis Cusiae Rhizoma Et Radix, Belamcandae Rhi
zoma, Belladonna Extract, Belladonna Liquid Extract, Belladonnae Herba, Benincas
ae Exocarpium, Benzoinum, Berberidis Radix, Bergeniae Rhizoma, Bergenin, Bistort
ae Rhizoma, Bletillae Rhizoma, Bolbostematis Rhizoma, Bombyx Batryticatus, Born
eolum Syntheticum, Borneolum, Bovis Calculus Artifactus, Bovis Calculus Sativus
, Bovis Calculus, Breviscapine, Broussonetiae Fructus, Bruceae Fructus, Bubali C
ornu, Buddlejae Flos, Bufonis Venenum, Bungarus Parvus, Bupleuri Radix, Calamine
, Callicarpae Caulis Et Folium, Callicarpae Formosanae Folium, Callicarpae Macro
phyllae folium, Calomelas, Campsis Flos, Canarii Fructus, Canavaliae Semen, Cann
abis Fructus, Capsici Fructus, Carotae Fructus, Carpesii Fructus, Carthami Flos
, Caryophylli Flos, Caryophylli Fructus, Cassiae Semen, Castor Oil, Catechu, Cel
osiae Cristatae Flos, Celosiae Semen, Centella Total Glucosides, Centellae Herba
, Centipedae Herba, Cera Chinensis, Cera Flava, Cervi Cornu Degelatinatum, Cervi
Cornu Pantotrichum, Cervi Cornu, Cervi Cornus Colla, Chaenomelis Fructus, Chang
ii Radix, Chebulae Fructus Immaturus, Chebulae Fructus, Chelidonii Herba, Chines
Angelica Liquid Extract, Chloriti Lapis, Choerospondiatis Fructus, Chrysanthem
i Flos, Chrysanthemi Indici Flos, Chuanxiong Rhizoma, Cibotii Rhizoma, Cicadae P
eriostracum, Cichorii Herba, Cichorii Radix, Cimicifugae Rhizoma, Cinnabaris, Ci
nnamomi Cortex, Cinnamomi Ramulus, Cinnamon Oil, Cirsii Herba, Cirsii Japonici H
erba Carbonisata, Cirsii Japonici Herba, Cissampelotis Herba, Cistanches Herba,
Citri Exocarpium Rubrum, Citri Fructus, Citri Grandis Exocarpium, Citri Reticula
tae Pericarpium Viride, Citri Reticulatae Pericarpium, Citri Reticulatae Semen,
Citri Sarcodactylis Fructus, Clematidis Armandii Caulis, Clematidis Radix Et Rhi
zoma, Clinopodii Herba, Cnidii Fructus, Codonopsis Radix, Coicis Semen, Commelin
ae Herba, Conyzae Herba, Coptidis Rhizoma, Cordyceps, Corni Fructus, Corydalis B
ungeanae Herba, Corydalis Decumbentis Rhizoma, Corydalis Rhizoma, Crataegi Foliu
m, Crataegi Fructus, Cremastrae Pseudobulbus, Pleiones Pseudobulbus, Crinis Carbo
nisatus, Croci Stigma, Crotonis Fructus, Crotonis Semen Pulveratum, Curculiginis
Rhizoma, Curcumae Longae Rhizoma, Curcumae Radix, Curcumae Rhizoma, Cuscutae Se
men, Cyathulae Radix, Cyclovirobuxine, Cynanchi Atrati Radix Et Rhizoma, Cynanch
i Paniculati Radix Et Rhizoma, Cynanchi Stauntonii Rhizoma Et Radix, Cynomorii H
erba, Cyperi Rhizoma, Dahurian Rhododendron Leaf Oil, Dalbergiae Odoriferae Lign
um, Daturae Flos, Dendrobii Caulis, Dendrobii Officinalis Caulis, Descurainiae S
emenlepidii Semen, Desmodii Styracifolii Herba, Dianthi Herba, Dichroae Radix, D
ictamni Cortex, Dioscorea Panthaicae Rhizoma, Dioscoreae Hypoglaucae Rhizoma, Di
oscoreae Nipponicae Rhizoma, Dioscoreae Rhizoma, Dioscoreae Spongiosae Rhizoma,
Dipsaci Radix, Draconis Sanguis, Drynariae Rhizoma, Dryopteridis Crassirhizomati
s Rhizoma Carbonisatum, Dryopteridis Crassirhizomatis Rhizoma, Echinopsis Radix
, Ecliptae Herba, Entadae Semen, Entianae Rhodanthae Herba, Ephedrae Herba, Ephe
drae Radix Et Rhizoma, Epimedii Folium, Epimedii Wushanensis Folium, Equiseti Hi
emalis Herba, Erigerontis Herba, Eriobotryae Folium, Eriocauli Flos, Erodii Herb
a Geranii Herba, Erycibes Caulis, Eucalyptus Oil, Eucommiae Cortex, Eucommiae Fo
lium, Euodiae Fructus, Eupatorii Herba, Eupatorii Lindleyani Herba, Euphorbiae E
bracteolatae Radix, Euphorbiae Hirtae Herba, Euphorbiae Humifusae Herba, Euphorb
iae Pekinensis Radix, Euphorbiae Semen Pulveratum, Euphorbiae Semen, Eupolyphaga
Steleophaga, Euryales Semen, Fagopyri Dibotryis Rhizoma, Farfarae Flos, Ferulae
Resina, Fibraureae Caulis, Fibriuretinin, Fluoritum, Foeniculi Fructus, Forsyth
iae Fructus, Fraxini Cortex, Fritillariae Cirrhosae Bulbus, Fritillariae Hupehen
sis Bulbus, Fritillariae Pallidiflorae Bulbus, Fritillariae Thunbergii Bulbus, F
ritillariae Ussuriensis Bulbus, Galangae Fructus, Galla Chinensis, Galli Gigerii
Endothelium Corneum, Ganoderma, Capillary Wormwood Extract, Gardeniae Fructus Pr
aeparatus, Gardeniae Fructus, Gastrodiae Rhizoma, Gecko, Gei Herba, Gendarussae
Herba, Genkwa Flos, Gentianae Macrophyllae Radix, Gentianae Radix Et Rhizoma, Gi
Ginger Liquid Extract, Ginkgo Folium, Ginkgo Leaves Extract, Ginkgo Semen, Ginseng
Folium, Ginseng Radix Et Rhizoma Rubra, Ginseng Radix Et Rhizoma, Glabrous Sarc
andra Extract, Glechomae Herba, Gleditsiae Fructus Abnormalis, Gleditsiae Sinens
is Fructus, Gleditsiae Spina, Glehniae Radix, Glycyrrhizae Radix Et Rhizoma Prae
Parata Cum Melle, Glycyrrhizae Radix Et Rhizoma, Gossampini Flos, Granati Perica
rpium, Gypsum Fibrosum, Gypsum Ustum, Haematitum, Haliotidis Concha, Halitum, Ha
lloysitum Rubrum, Hawthorn Leave Extract, Hedysari Radix Praeparata Cum Melle, H
edysari Radix, Hibisci Mutabilis Folium, Hippocampus, Hippophae Fructus, Hirudo
, Homalomenae Rhizoma, Hordei Fructus Germinatus, Houttuyniae Herba, Hydrargyri
Oxydum Rubrum, Hyoscyami Semen,

Hyperici Perforati Herba, Ilicis Chinensis Folium, Ilicis Cornutae Folium, Ilici
s Rotundae Cortex, Ulicii Cortex, Impatientis Semen, Imperatae Rhizoma, Indigo N
aturalis, Inulae Flos, Inulae Herba, Inulae Radix, Iridis Tectori Rhizoma, Isati
dis Folium, Isatidis Radix, Juglandis Semen, Jujubae Fructus, Junci Medulla, Kad
surae Caulis, Kaempferiae Rhizoma, Kaki Calyx, Kansui Radix, Knoxiae Radix, Koch
iae Fructus, Lablab Semen Album, Laggerae Herba, Lagotidis Herba, Laminariae Tha
llus Eckloniae Thallus, Lamiophlomis Herba, Lasiosphaera Calvatia, Leonuri Fruct
us, Leonuri Herba, Leonurus Liquid Extract, Licorice Extract, Licorice Liquid Ex
tract, Ligustici Rhizoma Et Radix, Ligustri Lucidi Fructus, Lilii Bulbus, Limoni
tum, Linderae Radix, Lini Semen, Liquidambaris Fructus, Liquidambaris Resina, Li
riopes Radix, Litchi Semen, Litseae Fructus, Lobeliae Chinensis Herba, Longan Ar
illus, Lonicerae Flos, Lonicerae Japonicae Caulis, Lonicerae Japonicae Flos, Lop
hatheri Herba, Luffae Fructus Retinervus, Lycii Cortex, Lycii Fructus, Lycopi He
rba, Lycopodii Herba, Lygodii Spora, Lysimachiae Herba, Lysionoti Herba, /-Borne
olum, /-Menthol, Magnetitum, Magnoliae Flos, Magnoliae Officinalis Cortex, Magnolia
liae Officinalis Flos, Mahoniae Caulis, Malvae Fructus, Manis Squama, Mantidis O
OTheca, Margarita, Margaritifera Concha, Marsdeniae Tenacissimae Caulis, Mel, Me
lanteritum, Meliae Cortex, Melo Semen, Menispermi Rhizoma, Menthae Haplocalycis
Herba, Meretricis Concha, Cyclinae Concha, Micae Lapis Aureus, Microctis Folium,
Mirabilitum Praeparatum, Momordicae Semen, Mori Cortex, Mori Folium, Mori Fructu
s, Mori Ramulus, Morindae Officinalis Radix, Moschus, Moslae Herba, Moutan Corte
x, Mume Flos, Mume Fructus, Murrayae Folium Et Cacumen, Mylabris, Myristicae Sem
en, Myrrha, Nardostachyos Radix Et Rhizoma, Natrii Sulfas Exsiccatus, Natrii Sul
fas, Nelumbinis Folium, Nelumbinis Plumula, Nelumbinis Receptaculum, Nelumbinis
Rhizomatis Nodus, Nelumbinis Semen, Nelumbinis Stamen, Nigellae Semen, Notoginse
ng Radix Et Rhizoma, Notoginseng Total Saponins, Notoginseng Triol Saponins, Not
opterygii Rhizoma Et Radix, Ocimum Gratissimum Oil, Olibanum, Omphalia, Ophicalc
itum, Ophiopogonis Radix, Orostachyis Fimbriatae Herba, Oroxyli Semen, Oryzae Fr.
uctus Germinatus, Osmundae Rhizoma, Ostreae Concha, Paeoniae Radix Alba, Paeonia
e Radix Rubra, Panacis Japonici Rhizoma, Panacis Majoris Rhizoma, Panacis Quinqu
efolii Radix, Papaveris Pericarpium SI, Paridis Rhizoma, Patchouli Oil, Pegaeoph
yti Radix Et Rhizoma, Peppermint Oil, Perillae Caulis, Perillae Folium, Perillae
Fructus, Periplocae Cortex, Persicae Ramulus, Persicae Semen, Peucedani Decursi
vi Radix, Peucedani Radix, Pharbitidis Semen, Phellodendri Amurensis Cortex, Phe
llodendri Chinensis Cortex, Pheretima, Phragmitis Rhizoma, Phyllanthi Fructus, P
hysalis Calyx Seu Fructus, Physochlainae Radix, Phytolaccae Radix, Picrasmae Ram
ulus Et Folium, Picriae Herba, Picrorhizae Rhizoma, Pinelliae Rhizoma Praeparatu
m Cum Alumine, Pinelliae Rhizoma Praeparatum Cum Zingibere Et Alumine, Pinelliae
Rhizoma Praeparatum, Pinelliae Rhizoma, Pini Lignum Nodi, Pini Pollen, Piperis
Fructus, Piperis Kadsurae Caulis, Piperis Longi Fructus, Plantaginis Herba, Plan
taginis Semen, Platycladi Cacumen, Platycladi Semen, Platycodonis Radix, Pogoste
monis Herba, Polygala Liquid Extract, Polygalae Japonicae Herba, Polygalae Radix
, Polygonati Odorati Rhizoma, Polygonati Rhizoma, Polygoni Avicularis Herba, Pol
ygoni Cuspidati Rhizoma Et Radix, Polygoni Multiflori Caulis, Polygoni Multiflor
i Radix Praeparata, Polygoni Multiflori Radix, Polygoni Orientalis Fructus, Poly
goni Perfoliati Herba, Polygoni Tinctorii Folium, Polyporus, Poria, Poriae Cutis
, Portulacae Herba, Potentillae Chinensis Herba, Potentillae Discoloris Herba, P
Owerdered Buffalo Horn Extract, Prinsepiae Nux, Propolis, Prunellae Spica, Pruni
Semen, Psammosilenes Radix, Pseudolaricis Cortex, Pseudostellariae Radix, Psora
leae Fructus, Pterocephali Herba, Puerariae Lobatae Radix, Puerariae Thomsonii
Radix, Pulsatillae Radix, Pyritum, Pyrolae Herba, Pyrrosiae Folium, Quisqualis F
ructus, Rabdosiae Rubescentis Herba, Ranae Oviductus, Ranunculi Ternati Radix, R
aphani Semen, Realgar, Rehmanniae Radix Praeparata, Rehmanniae Radix, Rhapontici
Radix, Rhei Radix Et Rhizoma, Rhodiolae Crenulatae Radix Et Rhizoma, Rhododendr
i Daurici Folium, Rhododendri Mollis Flos, Rhubarb Extract, Rhubarb Liquid Extra
ct, Ricini Semen, Rosae Chinensis Flos, Rosae Laevigatae Fructus, Rosae Rugosae
Flos, Rubi Fructus, Rubiae Radix Et Rhizoma, Saigae Tataricae Cornu, Salvia Tota
l Phenolic Acids, Salviae Miltiorrhizae Radix Et Rhizoma, Sanguisorbae Radix, Sa
ntali Albi Lignum, Saposhnikoviae Radix, Sappan Lignum, Sarcandrae Herba, Sargas
sum, Sargentodoxae Caulis, Sauropi Folium, Saururi Herba, Saussureae Involucrata
e Herba, Schisandrae Chinensis Fructus, Schisandrae Sphenantherae Fructus, Schiz
onepetae Herba Carbonisata, Schizonepetae Herba, Schizonepetae Spica Carbonisata
, Schizonepetae Spica, Scolopendra, Scorpio, Scrophulariae Radix, Scutellaria Ex
tract, Scutellariae Barbatae Herba, Scutellariae Radix, Sedi Herba, Selaginellae
Herba, Semiaquilegiae Radix, Senecionis Scandentis Hebra, Sennae Folium, Sepiae
Endoconcha, Serpentis Periostracum, Sesame Oil, Sesami Semen Nigrum, Setariae F
ructus Germinatus, Siegesbeckiae Herba, Silybi Fructus, Sinapis Semen, Sinomenii
Caulis, Sinopodophylli Fructus, Siphonostegiae Herba, Siraitiae Fructus, Smilac
is Chinae Rhizoma, Smilacis Glabrae Rhizoma, Sojae Semen Germanatum, Sojae Semen
Nigrum, Sojae Semen Praeparatum, Solidaginis Herba, Sophorae Flavescentis Radix
, Sophorae Flos, Sophorae Fructus, Sophorae Tonkinensis Radix Et Rhizoma, Sparga
nii Rhizoma, Spatholobi Caulis, Spiceleaf Kernel Oil, Spirodelae Herba, Stachyur
i Medulla Helwingiae Medulla, Stalactitum, Star Anise Oil, Stauntoniae Caulis Et
Folium, Stellariae Radix, Stemonae Radix, Stephaniae Tetrandrae Radix, Sterculi
ae Lychnophorae Semen, Strychni Semen Pulveratum, Strychni Semen, Styrax, Suis F
ellis Pulvis, Sulfur, Swertiae Herba, Swertiae Mileensis Herba, Syngnathus, Syri
ngae Cortex, Talci Pulvis, Talcum, Tamaricis Cacumen, Tanshinones, Taraxaci Herb
a, Taxilli Herba, Tea-Seed Oil, Terminaliae Belliricae Fructus, Testudinis Carap
acis Et Plastri Colla, Testudinis Carapax Et Plastrum, Tetrapanacis Medulla, Thl
aspi Herba, Thunberg Fritillary Liquid Extract, Tinosporae Radix, Totalal Ginseno
side Of Ginseng Stems And Leaves, Toosendan Fructus, Torreyae Semen, Total Ginse
noside Ginseng Root, Toxicodendri Resina, Trachelospermi Caulis Et Folium, Trach
ycarpi Petiolus, Tribuli Fructus, Trichosanthis Fructus, Trichosanthis Pericarpi
um, Trichosanthis Radix, Trichosanthis Semen Tostum, Trichosanthis Semen, Trigon
ellae Semen, Trionycis Carapax, Tsaoko Fructus, Turpentine Oil, Turpiniae Folium
, Typhae Pollen, Typhonii Rhizoma, Uncariae Ramulus Cum Uncis, Vaccariae Semen,
Valerianae Jatamansi Rhizoma Et Radix, Verbenae Herba, Vespae Nidus, Vignae Seme
n, Violae Herba, Visci Herba, Vitex Oil, Viticis Fructus, Viticis Negundo Folium
, Vladimiriae Radix, Weeping Forsythia Extract, Wenyujin Rhizoma Concisum, Xanth
ii Fructus, Zanthoxyli Pericarpium, Zanthoxyli Radix, Zaocys, Zedoary Turmeric O
il, Zingiberis Rhizoma Praeparatum, Zingiberis Rhizoma Recens, Zingiberis Rhizom
a, Ziziphi Spinosae Semen.

In some embodiments, the drug content further comprises a vehicle. The medium can be associated with the API, ie the medium is in physical contact with the API. In some embodiments, the API is embedded in media. In some embodiments, the API is distributed within the medium. In some embodiments, the medium is made of thermoplastic materials disclosed herein.

In some embodiments, the vehicle is cocoa butter, polyethylene glycol (PE
G), sucrose, glucose, galactose, fructose, xylose lactose,
A water-soluble excipient selected from the group consisting of maltose, trehalose, sorbitol, mannitol, maltodextrin, raffinose, stachyose, fructooligosaccharides and combinations thereof. In some embodiments, the substrate further comprises a plasticizer.

The drug content can have any shape and size suitable for being packed into the compartment.

In some embodiments, the drug content is operably linked to the compartment by covalent bonds, non-covalent interactions or via linkers. Thus, the drug content and matrix can be made separately and attached by covalent or non-covalent interactions. In some embodiments, the dosage form is made by manufacturing the drug content and substrate in a single step using 3D printing methods.

In some embodiments, the drug content is formed in the shape of a compressed tablet, oval tablet, pill, or capsule. In some embodiments, the shape of the drug content matches the shape of the compartment. For example, when the compartment is pie-shaped, the drug content is also pie-shaped, eg, to occupy the compartment.

In some embodiments, the drug content is in the form of nanoparticles illustrated in FIG.
The drug content can be mixed with a solution in which the API is dissolved or suspended. then
The solution is atomized/sprayed onto the printing layer during three-dimensional printing of the dosage form. Once the solution containing the drug content has dried, the drug content is dispersed in the dosage form. Nanoparticles have a large surface area, which translates into a high dissolution rate.

The size of the nanoparticles ranges in size from 1 nm to 900 nm (preferred size is 10
0-800 nm, 100-700 nm, 100-600 nm, 100-500 nm, 10
0-400 nm, 100-300 nm, 100-200 nm, 1 nm, 2 nm, 3 nm,
4 nm, 5 nm, 6 nm, 7 nm, 8 nm, 9 nm, 10 nm, 11 nm, 12 nm, 1
3 nm, 14 nm, 15 nm, 16 nm, 17 nm, 18 nm, 19 nm, 20 nm, 1
00nm, 200nm, 300nm, 400nm, 500nm, 600nm, 700nm
, 800 nm, 900 nm). Nanoparticle size can be controlled by choosing appropriate synthetic methods and/or systems. To obtain nanoparticles within the desired size range, the synthesis conditions can be appropriately controlled or modified, e.g., to achieve desired solution concentrations or desired cavity ranges (a detailed review can be found e.g.
, Controlled Synthesis of Nanoparticles
in microheterogeneous systems, Published
by Springer, 2006).

In some embodiments, the drug content is in the form of microneedles illustrated in FIG. Microneedles are printed with or inserted into the dosage form during three-dimensional printing of the dosage form. Microneedles can be composed of sugar, PLGA polymer or API or combinations thereof. Microneedles can help the API to penetrate the patient's circulatory system when administered parenterally or enterally.

In some embodiments, the drug content forms a network. As shown in FIG. 8A, the dosage form has a substrate that forms a compartment filled with drug content. The drug loading has a matrix forming a network structure. The framework structure of the tablet is 1 to 1
Made of a material that dissolves in 0 minutes, the substrate is 2-60 seconds, preferably 2, 5, 10, 1
Dissolve in 5, 20, 25, 30, 35, 40, 45, 50, 55, 60 seconds. As shown in Figure 8B, the dosage form can release the API seconds after being administered.

The drug loading can be made using additive methods such as Fused Deposition Modeling (FDM). In some embodiments, the drug content can be made by using a three-dimensional printer (3D printer) that is configured to extrude the mixture of API and excipients. The API can be melted and homogeneously mixed with the melted substrate prior to extrusion. Alternatively, solid APIs (eg, powders) can be mixed and dispersed in a molten matrix prior to extrusion. In general, the extrusion process reduces the glass transition (Tg
) and close to the melting point of the API.
Once at a temperature suitable for use in a three-dimensional printer, the substrate can be applied to the three-dimensional printing surface. The shape and size of the drug content can be controlled by programming the three-dimensional printing process. In some embodiments, drug content is fabricated in the same process as the substrate. In some embodiments, the drug content is fabricated prior to fabrication of the substrate and loaded into the compartment during or after the substrate is fabricated.

In some embodiments, when the drug content is loaded into the compartment, it is associated with, eg, embedded in or secured to, the substrate. In some embodiments, the drug content is separable from the substrate once the compartment is loaded.

D. Controlled Release The dosage forms disclosed herein can provide different release profiles after oral administration. In some embodiments, the dosage form provides a constant release profile, pulsatile or delayed delivery, or non-linear drug release. In some embodiments, the dosage form achieves zero-order release kinetics.

A suitable release profile can benefit several drug therapeutic regimens. For example, pulsatile release profiles provide controlled absorption, reduced peak-to-trough ratios, targeted drug release to specific regions within the gastrointestinal tract, and absorption independent of feeding state, thus resulting in tolerability. can be used to prevent side effects, reduce side effects, and improve patient compliance, and is desirable for treating diseases such as ADHD. In another example, a release profile of an initial dose followed by a maintenance dose may be good for treating chronic conditions such as hypertension and diabetes.

Some of the mechanisms by which release profiles are controlled using the dosage forms disclosed herein have been described above. For example, by manipulating the exposed area of a matrix that erodes slowly and consistently over time, a drug content embedded in the matrix can slowly deliver a constant amount of drug over time. Additionally, the release profile can be controlled by the size of the compartment opening and/or the geometry of the compartment.

In some embodiments, the release profile can be controlled by the design of compartments having apertures that are plugged or blocked. Stoppers are made of water-soluble, porous, or erodible materials or pH-sensitive materials or hydrophobic materials that are subject to friction as the dosage form passes through the gastrointestinal tract. When the dosage form is administered to a subject, the plug dissolves, permeates or erodes, thus releasing the drug content from the compartment. The release profile of the drug content can be controlled by selecting a plug of appropriate erosion/dissolution or permeation rate. Alternatively, the drug content release profile can be controlled by utilizing the shape and/or size of the plug (eg, rod shape of appropriate length). The release profile can also be controlled by the number of compartments. FIG. 9 illustrates an exemplary dosage form having a substrate that forms a cluster of cylindrical compartments on either side of the dosage form. Each compartment is filled with a drug content. Each compartment has an aperture closed by a rod-shaped plug. Plugs have different dissolution rates. Depending on plug size, shape and dissolution rate, API persistence,
Continuous, simultaneous, sequential or pulsed release can occur.

FIG. 10A shows an exemplary dosage form that achieves a sequential release profile. Figure 10
Referring to A, dosage form 700 has a substrate 701 forming three compartments 702-704 of cylindrical shape. Each compartment is packed with drug contents of the same API. Each compartment has an aperture closed by a bar-shaped plug 705-707. The plugs are made of the same material but have different lengths. Therefore, dissolve the plug,
The amount of time it takes to open the compartment and release the drug content varies. Figure 10
As illustrated in C, the shortest plug dissolves first and API is released from the first compartment. When the API in the first compartment is completely released, the intermediate length plug dissolves and the API is released from the second compartment. When the API in the second compartment is completely released, the third plug dissolves and the API is released from the third compartment. As a result, the plasma drug level reaches a first peak as the drug content of the first compartment is released. AP released from the first compartment
As I begins to be excreted, plasma drug levels begin to decline (see Figure 10D). Before the plasma drug level falls below the critical level (horizontal line, below which the drug becomes ineffective), the API is released from the second compartment and the plasma drug level rises again. When the API released from the second compartment reaches a second peak and begins to be excreted, the third compartment plug dissolves, opening the compartment. As a result, plasma API levels above critical levels are maintained for extended periods of time, benefiting several diseases.

A sequential release pattern can also be achieved by another exemplary dosage form in which several drug contents are bundled in layers as illustrated in FIG. 10B. The synchronous dissolution of each layer allows the API to be released in a sustained manner, resulting in A as shown in Figure 10C.
A continuous and sustained release of PI is achieved. In some embodiments, upon administration of the dosage form, the outer layer of the dosage form immediately dissolves, releasing the embedded drug content. but,
The layers sandwiched in the middle do not dissolve or dissolve much more slowly because the outer layers occlude the interface with the environment. Dissolution of the outer layers exposes the middle sandwiched layers and facilitates their dissolution, thus achieving the sequential release profile illustrated in FIG. 10C.

In some embodiments, the dosage form includes a gas-producing component packaged in a first compartment. In some embodiments, the gas generating components are organic acids and carbonates, sulfites, bicarbonates, sodium carbonate, sodium bicarbonate, sodium metabisulfite,
It is selected from the group consisting of calcium carbonate, and combinations thereof, which releases carbon dioxide or sulfur dioxide gas upon contact with gastric juices. When the substrate dissolves, permeates or erodes in the stomach, the gas-producing components are exposed to an acidic environment, or water permeates the compartment, inducing a reaction between the acid and sodium bicarbonate to release gas. It develops and releases the drug content while effervescent.

The dosage forms disclosed herein may include one or more drug inclusions in at least partially timed-release form. Timed release is achieved with the aid of conventional materials and methods known to those skilled in the art.
For example, by embedding the API in a time-release matrix/substrate or applying one or more time-release coatings. Timed release can control API release such that administration of the dosage form twice or once a day is sufficient. This is particularly advantageous when sustained levels of the active compound are required, for example to combat pain.

In some embodiments, the dosage form is intended to release the active ingredient immediately in the oral cavity. One example includes the oral cavity, or the sublingual region is chosen.

In some embodiments, the drug form is glycerin monostearate, semi-synthetic triglyceride derivatives, semi-synthetic glycerides, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyvinylpyrrolidone, gelatin, magnesium stearate, stearin known to those skilled in the art, preferably selected from the group consisting of acids, sodium stearate, talcum, sodium benzoate, boric acid and colloidal silica, fatty acids, substituted triglycerides, glycerides, polyoxyalkylene glycols and derivatives thereof. It further contains conventional auxiliary substances.

Dosage form manufacturing
The controlled release dosage forms disclosed herein can be manufactured using any suitable method. In some embodiments, dosage forms are manufactured using three-dimensional printing (3D printing).

3D printing, as used herein, refers to the method of manufacturing 3D objects layer-by-layer from a digital design. The basic 3D printing method is US Pat. No. 5,204,055;
5,260,009; 5,340,656; 5,387,380; 5,5
03,785; and 5,633,021. Other US patents and applications related to 3D printing include US Pat. Nos. 5,490,962;
518,690; 5,869,170; 6,530,958; 6,280,
771; 6,514,518; 6,471,992; 8,828,411; U.S. Patent Application Publication Nos. 2002/0015728;
003/0143268; 2003/0198677; 2004/000536
No. 0 is mentioned. A detailed description of 3D printing can be found in the patents and applications listed above.

Various 3D printing methods have been developed for dosage form manufacturing in terms of raw materials, equipment and solidification. These 3D printing methods include binder attachment (L Gibson et al., (
2015) Additive Manufacturing Technologies:
3D Printing, Rapid Prototyping, and Dir
ect Digital Manufacturing. 2 ed. Spring
W. er, New York; E. Katstra et al., (2000) Oral
Dosage forms fabricated by three dimensions
onal printing, J.; Control Release 66: 1-
9; E. Katstra et al., (2001) Fabrication of c.
omplex oral delivery forms by three dime
National printing, Dissertation in Materi
als Science and Engineering, Massachusse
H. tts Institute of Technology; Lipson et al.
(2013) Fabricated: The New World of 3Dp
Rinting, John Wiley & Sons, Inc. G.; Jon
athan, A.; Karim (2016) 3D printing in pha
rmaceutics: a new tool for designing cus
Tomized drug delivery systems, Int. J. P.
harm. 499: 376-394), material injection (G. Jonath
an, A. Karim (2016) 3D printing in pharma
ceutics: a new tool for designing custom
sized drug delivery systems, Int. J. Phar
m. 499: 376-394), extrusion (L Gibson et al., (201
5) Additive Manufacturing Technologies: 3D
Printing, Rapid Prototyping, and Direct
Digital Manufacturing. 2 ed. Springer,
New York), and photopolymerization (FP Melchels et al., (
2010) A review on stereolithography and
its application in biomedical engineering
g. Biomaterials 31: 6121-30).

In some embodiments, the dosage forms disclosed herein are manufactured using an extrusion method. In the extrusion process, the material is extruded through a nozzle driven by a robot. Unlike binder deposition, which requires a powder bed, extrusion methods can print on any substrate. A variety of 3D printing materials can be extruded, including thermoplastic materials, pastes and colloidal suspensions, silicones and other semi-solids disclosed herein. One common type of extrusion printing is Fused Lamination, which uses solid polymer filaments to print. In the fused deposition process, a gear train forces a filament into a heated nozzle assembly for extrusion (L Gibson et al. (2015) Additive Manfac
Turing Technologies: 3D Printing, Rapid
Prototyping, and Direct Digital Manufacture
uring. 2 ed. See Springer, New York).

Manufacturing instructions for a print job can be generated in a variety of ways, including direct coding, derivation from a solid CAD model, or other means specific to the 3D printing machine's computer interface and application software. These instructions contain information about the number and spatial arrangement of the droplets, and each length dimension (X
, Y, Z) and general printing parameters such as fluid volume or mass per droplet. Given a set of materials, these parameters can be adjusted to improve the quality of the structures produced. The overall decomposition of the structure produced is determined by powder particle size, fluid droplet size, printing parameters,
and material properties.

3D printing is well suited for the fabrication of dosage forms with complex geometries and compositions according to the present invention, as it can handle a variety of pharmaceutical materials and locally control their composition and structure.

Using 3D printing methods to manufacture dosage forms also facilitates personalized medicine. Personalized medicine refers to the stratification of patient populations based on biomarkers to aid in treatment decisions and personalized drug formulation design. Modifying a digital design is easier than modifying a physical device. Also, small-scale automated 3D printing can have negligible operating costs. Thus, 3D printing can make multiple individualized small batches economically feasible, and engineered individualized dosage forms can enable improved compliance.

Personalized dosage forms can adjust the amount of drug delivered based on the patient's mass and metabolism. 3D-printed dosage forms can ensure accurate dosing in growing children and enable personalized administration of highly potent drugs. In personalization form,
All of a patient's medications may be combined into a single daily dose, thus improving patient compliance with medications.

FIG. 11 illustrates a method of manufacturing individualized dosage forms utilizing 3D printing. Various clinical test results are available for each patient, including weight, age, metabolic indices and genomic biomarkers. Input clinical trial results into computer software. The information is combined with physician prescribing and pharmacokinetic models to design specific doses and combination dosage forms. The instructions are then sent to a 3D printer to manufacture the designed dosage form and administer it to the patient.

Controlled release of multiple drugs
The dosage forms and methods disclosed herein can be used to control the release of two or more drugs in order to optimize the combination in some therapeutic regimens. For example, a tablet for treating hypercholesterolemia can be designed to provide immediate release of atorvastatin calcium and prolonged release of nicotinic acid. In another example, non-steroidal anti-inflammatory drugs (NSAIDs) for pain relief provide sustained release of NSAIDs and rapid release of H2 receptor antagonists to prevent NSAID-induced mucosal damage. can be designed.

In some embodiments, the substrate forms multiple compartments, each filled with a drug content. In some embodiments, multiple compartments are concatenated. In some embodiments, multiple compartments are unconnected. In some embodiments, the drug contents loaded into different compartments are the same. In some embodiments, the drug contents loaded into different compartments are different. Dosage forms can be designed to provide simultaneous or sequential release of multiple drug contents to exert a synergistic therapeutic effect.

FIG. 12A shows an exemplary dosage form capable of simultaneously releasing APIs. Figure 1
Referring to 2A, dosage form 800 comprises three stacked layers 801-803, each of which is imbedded with a different drug content. As illustrated in FIG. 12B, when dosage form 800 is administered, the drug content is released simultaneously as the layers dissolve, but at different rates.

FIG. 13A shows another exemplary dosage form with a simultaneous release profile. Referring to FIG. 13A, dosage form 900 includes three cylindrical compartments 901-903, which are filled with three drug contents. Each drug content contains an API embedded in a different dissolution rate matrix. As illustrated in FIG. 13B, when dosage form 900 is administered, the three APIs are released simultaneously but at different rates as the drug content matrix dissolves. The release rate of API can also be controlled by the shape of the compartment or the size of the compartment opening.

Figures 14A and 14B show another exemplary dosage form with simultaneous release profiles of three APIs. Referring to FIG. 14A, dosage form 1000 has three pie-shaped segments 10
01-1003, in which the drug content is embedded. As illustrated in FIG. 14C, the drug content is released simultaneously as the segments dissolve, and the release rate of the drug content can be controlled by the dissolution rate of the segments. Referring to FIG. 14B, dosage form 1100 includes three pie-shaped segments 1101-1103 that are encased by a shell 1104 that dissolves more slowly than the segments. The release rate of the drug content embedded in the segments is determined by the shell 1104 being in segments 1101-1103
decreases as it closes the interface with the environment.

FIG. 15A shows an exemplary dosage form with two API sequential release profiles. Referring to FIG. 15A, dosage form 1200 includes substrate 1201 forming a compartment filled with drug content 1202 . Substrate 1201 includes a first API and drug content 1202 includes a second API. As illustrated in Figure 15B, the first API releases as the substrate dissolves when the dosage form is administered. The second API does not release until the matrix has dissolved to expose the drug content, providing a sequential release profile for the API.

FIG. 16A shows another exemplary dosage form with a sequential release profile. Figure 16
Referring to A, dosage form 1300 has a base 1301 forming three cylindrical compartments 1302-1304 that are filled with three drug contents. Compartments 1302-1304 have apertures blocked by rod-shaped plugs having different lengths and/or dissolution rates. As illustrated in FIG. 16B, API is progressively released as the plugs progressively dissolve, opening the compartments.

FIG. 17A shows exemplary dosage forms with simultaneous or sequential release profiles. Referring to Figure 17A, dosage form 1400 has a substrate comprising four segments 1701-1704 having different dissolution rates. In some embodiments, as illustrated in FIG. 17B, drug content is embedded in segments 1701-1704 and is released upon dissolution of the matrix. In some embodiments, each segment includes a compartment filled with drug content. As illustrated in Figure 17C, the drug content is released sequentially as the matrix dissolves.

[Example 1]
This example demonstrates the design of a dosage form with a controlled release profile.

As shown in Figure 18A, the dosage form comprised a flat tablet base forming a pie-shaped compartment. The substrate was made of PEG8000. Benzoic acid was used as the module drug content.

The release profile of benzoic acid from the dosage forms was measured as follows. pH8
was prepared as a _solubilizer for _benzoic acid. The 120 μg/mL benzoic acid solution was serially diluted to 30 μg/mL, 15 μg/m, 7.5 μg/m, 3.75 μg/mL, and 1.875 μg/mL solutions and their absorbance at 226 nm was determined by Measured using a UV spectrophotometer. The resulting values were processed by linear regression to generate a calibration curve for benzoic acid concentration with the formula y=0.0599x+0.0347. To determine the amount of benzoic acid released, the dosage form was dissolved in degassed pH 8 Na ₂ HPO ₄ solution at 37° C.±0.5° C. and centrifuged at 100 rpm. From the solution, 5 mL of solution was taken at each time point to determine the concentration of benzoic acid, and 5 mL of dissolving agent was added back to the solution. The collected solutions were filtered through a 0.45 μm membrane and then transferred to a UV spectrophotometer to measure absorbance at 226 nm. The percentage of released benzoic acid was calculated using the following formula.

式中、Ｃ_ｎは測定された濃度を意味し、Ｖ_ｔは全溶液体積を意味し、Ｖ_ｓは試料体積を意
味し、Ｑ_{ｂｅｎｚｏｉｃ ａｃｉｄ}は剤形中の安息香酸の量を意味する。

where C _n means the measured concentration, V _t means the total solution volume, V _s means the sample volume, and Q _{benzoic acid} means the amount of benzoic acid in the dosage form.

The following method is used to measure the release of PEG8000. To generate a PEG8000 standard curve, 0.1275 g of PEG8000 standard sample was dissolved in water in a 25 mL volumetric flask. Transfer 1 mL, 2 mL, 5 mL and 10 mL each to a 10 mL volumetric flask and dilute with water to prepare the control solution. Inject 50 μl of the control solution into the liquid chromatography (three Waters Ultrahydrogel™ 120/
250/500 connected in series, flow rate 0.5 ml/min, temperature 40° C., measured with a differential refractometer). Areas of volume were measured and used as the y-axis. The log number of control solution concentration was used as the x-axis. A standard curve for PEG8000 was generated with the formula y=1.024x+8.918. The percentage of PEG800 released was calculated using the following formula.

式中、Ｃ_ｎは測定された濃度を意味し、Ｖ_ｔは溶液体積を意味し、Ｖ_ｓは試料体積を意味
し、Ｑ_{ＰＥＧ８０００}は剤形中のＰＥＧ８０００の量を意味する。

where C _n means the measured concentration, V _t means the solution volume, V _s means the sample volume, and Q _PEG8000 means the amount of PEG8000 in the dosage form.

Results: As illustrated in Figure 18C, the release profile of benzoic acid Broo
ke and R. J. Model profile by Washkuhn (Zero-Ord
er Drug Delivery System: Theory and Prel
iminary Testing, J Pharm Sci. , 1977, 66:
159-162) and was controlled by the interface. Thus, the dosage forms disclosed herein allow for controlled release profiles to be designed.

[Example 2]
This example demonstrates the design of dosage forms that control the release of drug content from different compartments.

Dosage Design: Two dosage forms were manufactured using a hot melt layering process. The base of the dosage form is Copovidone (Kollidon® VA64) 72%, PEG 1500 18% and S
Made with oluplus® 10%. The drug content consisted of 30% moxifloxacin hydrochloride, 70% PEG1000. A schematic of the dosage form is shown in Figures 19A and 19B. Referring to FIGS. 19A and 19B, dosage form 1600 included substrate 1601 forming two compartments 1602 and 1603 . The compartments were enclosed by walls 1604 and 1605, respectively. In the first dosage form, the two compartments were enclosed by walls of thickness 0.75 mm and 1.5 mm respectively. second
, the two compartments are 0.75 mm and 2.25 mm thick, respectively.
was surrounded by a wall of

To detect the release of the drug content, the dosage form was added to 900 ml of pH 6.8 phosphate buffer.
00 rpm. The UV absorbance of the buffer was assayed to determine the release of drug content.

The results of the release assay are shown in Figures 19C and 19D. As shown in Figure 19C, addition of the first dosage form to the buffer for 20 minutes opened the first compartment and released the drug content in the first compartment. The second compartment did not open until 40 minutes after adding the dosage form to the buffer. The results for the second dosage form are shown in Figure 19D,
For the second dosage form, the second compartment did not open until 60 minutes after adding the dosage form to the buffer. Therefore, the release profile of the dosage form can be controlled by the thickness of the walls surrounding the compartments.

Although the principles of the invention have been described in connection with specific embodiments, it is to be clearly understood that these descriptions are made by way of example only and are not intended to limit the scope of the invention. should. The material disclosed herein has been presented for purposes of illustration and description.
It is not intended to be exhaustive or to limit the disclosure to the precise forms set forth. Many modifications and variations will be apparent to those skilled in the art. The various embodiments and various modifications best describe the principles and practical applications of the disclosed embodiments in the described technical field and thereby lend themselves to particular uses contemplated by others skilled in the art. Disclosures have been selected and explained in order to provide an understanding of It is intended that the scope of the disclosure be defined by the claims set forth below and their equivalents.

Claims (52)

a substrate forming a compartment;
a drug content packed in compartments. 2. The dosage form of claim 1, wherein the drug content is operably associated with the substrate. 2. The dosage form of claim 1, wherein the drug content is separate from the matrix. 2. The dosage form of claim 1, wherein the substrate is made from at least one thermoplastic material. 4. The thermoplastic material is selected from the group consisting of hydrophilic polymers, hydrophobic polymers, swelling polymers, non-swelling polymers, porous polymers, non-porous polymers, eroding polymers, non-eroding polymers. The dosage form described in . a thermoplastic material
Polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer 57/30/13, polyvinylpyrrolidone-co-vinylacetate (PVP-
VA), polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60
/40, polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP) 80/20, polyethylene glycol-polyvinyl alcohol graft copolymer 25/75, kollicoat IR-polyvinyl alcohol 60
/40, polyvinyl alcohol (PVA or PV-OH), poly (vinyl acetate)
(PVAc), poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1, poly(dimethylaminoethyl methacrylate-co-methacrylate), poly(ethyl acrylate- co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1
, poly(methacrylic acid-co-methyl methacrylate) 1:2, poly(methacrylic acid-c
o-ethyl acrylate) 1:1, poly(methacrylic acid-co-methyl methacrylate)
1:1, poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG)
, hyperbranched polyesteramides, hydroxypropylmethylcellulose phthalate, hypromellose phthalate, hydroxypropylmethylcellulose or hypromellose (H
MPC), hydroxypropyl methylcellulose acetate succinate or hypromellose acetate succinate (HPMCAS), poly(lactide-co-glycolide)
(PLGA), carbomer, poly(ethylene-co-vinyl acetate), ethylene-vinyl acetate copolymer, polyethylene (PE), and polycaprolactone (PCL).
), hydroxyl propyl cellulose (HPC), polyoxyl 40 hydrogenated castor oil, methyl cellulose (MC), ethyl cellulose (EC), poloxamer, hydroxypropyl methyl cellulose phthalate (HPMCP), poloxamer, hydrogenated castor oil and soybean oil,
from glyceryl palmitostearate, carnauba wax, polylactic acid (PLA), polyglycolic acid (PGA), cellulose acetate butyrate (CAB), colloidal silicon dioxide, sucrose, glucose, polyvinyl acetate phthalate (PVAP), and combinations thereof 5. The dosage form of claim 4, selected from the group consisting of: 2. The compartment of claim 1, wherein the compartment has a shape selected from the group consisting of pie-shaped, conical, pyramidal, cylindrical, cubic or cuboidal, triangular or polygonal prismatic, tetrahedral and combinations thereof. dosage form. 2. The dosage form of claim 1, wherein the drug content is in the form of nanoparticles. 2. The dosage form of claim 1, wherein the drug content is in the form of microneedles. 2. The dosage form according to claim 1, wherein the drug content forms a network structure or a porous structure. 2. The dosage form of claim 1, wherein the drug content comprises an active pharmaceutical ingredient (API). Local anesthetics, pain management drugs, sleep disorder drugs, antiepileptic drugs and anticonvulsants, Alzheimer's disease drugs, analgesics, antigout drugs, antihypertensive drugs, antiarrhythmic drugs, diuretics, liver disease drugs , pancreatic disease therapeutics, GI disease therapeutics, CNS disease therapeutics, antihistamines, antiallergic drugs, glucocorticoids, hormones and contraceptives, hypoglycemic drugs, anti-osteoporotic drugs, antibiotics, sulfonamides, quinolones, and other synthetic antibacterial, antituberculous, antiviral,
12. The dosage form according to claim 11, selected from the group consisting of antineoplastic drugs, immunomodulators, veterinary drugs, cosmetic active substances, traditional Chinese medicines and extracts of traditional Chinese medicines. 12. The dosage form of Claim 11, wherein the drug content comprises a vehicle having a faster erosion/dissolution rate than the API. 12. The dosage form of claim 11, wherein the drug content further comprises at least one excipient. excipients include cocoa butter, polyethylene glycol (PEG), sucrose, glucose, galactose, fructose, xylose lactose, maltose, trehalose,
15. The dosage form of claim 14, made from water-soluble materials selected from the group consisting of sorbitol, mannitol, maltodextrin, raffinose, stachyose, fructo-oligosaccharides, and combinations thereof. 2. The dosage form of claim 1, wherein the compartment has an aperture blocked by a plug. 17. The dosage form of claim 16, wherein the stopper is made from a material selected from the group consisting of water-soluble polymers, erodible or soluble polymers, wax-like materials, sugars, or combinations thereof. 2. The dosage form of claim 1, further comprising a gas generating component packed in the compartment. the gas generating component is selected from the group consisting of water-soluble carbonates, sulfites, bicarbonates, sodium carbonate, sodium bicarbonate, sodium metabisulfite, calcium carbonate, and combinations thereof; 18. The dosage form of claim 17, which releases carbon dioxide or sulfur dioxide gas upon contact with. a substrate forming at least a first compartment and a second compartment;
A dosage form comprising a first drug content loaded in a first compartment and a second drug content loaded in a second compartment. Claim 20, wherein the first compartment and the second compartment are connected
The dosage form described in . Claim 2, wherein the first compartment and the second compartment are unconnected.
The dosage form according to 0. 21. The dosage form of claim 20, wherein the first drug content is the same as the second drug content. 21. The dosage form of claim 20, wherein the first drug content is different than the second drug content. a first compartment having a first aperture covered by a first plug;
3. The compartment of claim 2 has a second aperture covered with a second plug.
The dosage form according to 0. 26. The dosage form of claim 25, wherein the first stopper is longer than the second stopper. Claim 25, wherein the first plug has a first permeation rate and the second plug has a second permeation rate.
The dosage form described in . 28. The dosage form of claim 27, wherein the first permeation rate is the same as the second permeation rate. 28. The dosage form of claim 27, wherein the first permeation rate is higher than the second permeation rate. the first plug having a first erosion/dissolution rate and the second plug having a second erosion/dissolution rate;
26. A dosage form according to claim 25. 31. The dosage form of claim 30, wherein the first erosion/dissolution rate is the same as the second erosion/dissolution rate. 31. The dosage form of claim 30, wherein the first erosion/dissolution rate is higher than the second erosion/dissolution rate. A first compartment is bounded by a first wall and a second compartment is bounded by a second
21. The dosage form of claim 20, which is enclosed by a wall of . 34. The dosage form of claim 33, wherein the first wall is thicker than the second wall. 34. The dosage form of claim 33, wherein the first wall is more permeable than the second wall. 34. The dosage form of claim 33, wherein the first wall erodes/dissolves faster than the second wall. A dosage form comprising two or more stacked matrix layers,
A dosage form wherein at least one of two or more matrix layers is each loaded with at least one drug content. 38. The dosage form of claim 37, wherein the two or more matrix layers are separable from each other. 38. The dosage form of claim 37, wherein two or more matrix layers are made from at least one thermoplastic material. at least one thermoplastic material is selected from the group consisting of hydrophilic polymers, hydrophobic polymers, swellable polymers, non-swellable polymers, porous polymers, non-porous polymers, erodible polymers, non-erodible polymers; 40. A dosage form according to claim 39. at least one thermoplastic material is polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft copolymer 57/30/13, polyvinylpyrrolidone-co-vinylacetate (PVP-VA), polyvinylpyrrolidone-polyvinylacetate copolymer (PVP-VA) 60/ 40, polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP) 80/20, polyethylene glycol-polyvinyl alcohol graft copolymer 25/75, kollicoa
t IR-polyvinyl alcohol 60/40, polyvinyl alcohol (PVA or PV
—OH), poly(vinyl acetate) (PVAc), poly(butyl methacrylate-co
-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2
: 1, poly(dimethylaminoethyl methacrylate-co-methacrylic acid ester), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1, poly(methacrylic acid-co-methyl methacrylate) 1:2, poly(methacrylic acid-co-ethyl acrylate) 1:1, poly(methacrylic acid-co-methyl methacrylate) 1:1, poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG), hyperbranched polyesteramides, hydroxypropylmethylcellulose phthalate, hypromellose phthalate, hydroxypropylmethylcellulose or hypromellose (HMPC), hydroxypropylmethylcellulose acetate succinate or hypromellose acetate succinate (HPMCAS),
Poly(lactide-co-glycolide) (PLGA), carbomer, poly(ethylene-co
-vinyl acetate), ethylene-vinyl acetate copolymer, polyethylene (PE)
, and polycaprolactone (PCL), hydroxyl propyl cellulose (HPC),
Polyoxyl 40 hydrogenated castor oil, methylcellulose (MC), ethylcellulose (EC)
, Poloxamer, Hydroxypropyl Methylcellulose Phthalate (HPMCP), Poloxamer, Hydrogenated Castor and Soybean Oils, Glyceryl Palmitostearate, Carnauba Wax, Polylactic Acid (PLA), Polyglycolic Acid (PGA), Cellulose Acetate Butyrate (CAB), Colloids 40. The dosage form of claim 39 selected from, but not limited to, the group consisting of silicon dioxide, sucrose, glucose, polyvinyl acetate phthalate (PVAP), and combinations thereof. 38. The dosage form of claim 37, wherein the drug content is in the form of nanoparticles. 38. The dosage form of claim 37, wherein the drug content is in the form of microneedles. 38. The dosage form of claim 37, wherein the drug content forms a network or porous structure. 38. The dosage form of claim 37, wherein the drug content comprises an active pharmaceutical ingredient (API). Local anesthetics, pain management drugs, sleep disorder drugs, antiepileptic drugs and anticonvulsants, Alzheimer's disease drugs, analgesics, antigout drugs, antihypertensive drugs, antiarrhythmic drugs, diuretics, liver disease drugs , pancreatic disease therapeutics, GI disease therapeutics, CNS disease therapeutics, antihistamines, antiallergic drugs, glucocorticoids, hormones and contraceptives, hypoglycemic drugs, antiosteoporotic drugs, antibiotics, sulfonamides, quinolones, and other synthetic antibacterial, antituberculous, antiviral,
46. The dosage form according to claim 45, selected from the group consisting of antineoplastic drugs, immunomodulators, veterinary drugs, cosmetic active substances, traditional Chinese medicines and extracts of traditional Chinese medicines. 38. The dosage form of claim 37, wherein each matrix layer further comprises at least one excipient. excipients include cocoa butter, polyethylene glycol (PEG), sucrose, glucose, galactose, fructose, xylose lactose, maltose, trehalose,
48. The dosage form of claim 47 made from water-soluble materials selected from the group consisting of sorbitol, mannitol, maltodextrin, raffinose, stachyose, fructo-oligosaccharides, and combinations thereof. 38. The dosage form of claim 37, wherein the two or more matrix layers have different thicknesses. 38. The dosage form of claim 37, wherein two or more matrix layers have different erosion/dissolution rates. 38. The dosage form of claim 37, wherein the two or more matrix layers are configured such that each of the at least one loaded drug content is released in aqueous solution according to a predetermined release profile. Two or more matrix layers, a first matrix layer loaded with a first drug content and a second drug content loaded and positioned outwardly of the first matrix layer, thus the second and a second matrix layer from which the drug content is released prior to the first drug content.

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