CN109431965B

CN109431965B - Pharmaceutical dosage forms and uses thereof

Info

Publication number: CN109431965B
Application number: CN201810705441.XA
Authority: CN
Inventors: 李霄凌
Original assignee: Triastek Inc
Current assignee: Triastek Inc
Priority date: 2015-06-03
Filing date: 2016-06-03
Publication date: 2022-04-08
Anticipated expiration: 2036-06-03
Also published as: CN113133980A; CN113171350B; CN106236715A; CN108653221A; CN113081991A; CN109431965A; CN113171350A; CN106236715B; CN113081991B; CN206120771U; CN206120770U; CN109432039A; CN108721242B; CN109432039B; CN108721242A; CN108653221B

Abstract

The present disclosure provides a stable solid pharmaceutical dosage form for oral administration. The pharmaceutical dosage form includes a base forming a compartment therein; and a drug matrix contained in the compartment. The design of the pharmaceutical dosage form allows for the controlled release of the pharmaceutically active ingredient in the pharmaceutical matrix.

Description

Pharmaceutical dosage forms and uses thereof

This application is a divisional application of the chinese patent application having application number 201610395483.9 filed on day 2016, 6, 3, entitled "pharmaceutical dosage forms and uses thereof," which claims priority from us provisional patent application having application number 62/170,645 filed on day 2015, 6, 3, and us provisional patent application having application number 62/313,092 filed on day 2016, 3, 24, which is incorporated herein by reference in its entirety.

Technical Field

The present invention relates generally to a pharmaceutical dosage form and controlled release of bioactive agents, diagnostic agents, reagents, cosmetic agents and agricultural/pesticidal agents.

Background

The medicine must be prepared into a medicine dosage form for being sold and used. Conventional pharmaceutical dosage forms are typically made by mixing the pharmaceutically active ingredient with inactive ingredients (excipients) and other non-reusable materials such as capsule shells. Pharmaceutical dosage forms are classified as liquid pharmaceutical dosage forms (e.g., solutions, syrups, elixirs, suspensions and emulsions), solid pharmaceutical dosage forms (e.g., tablets, capsules, caplets and gel caps), and semisolid pharmaceutical dosage forms (e.g., ointments and suppositories), with solid pharmaceutical dosage forms being most advantageous for oral drug systems.

Tablets are the most commonly used solid pharmaceutical dosage form, which is advantageous in terms of manufacturing, packaging and shipping, and is easier to identify and swallow. After being administered to an organism, the tablet interacts with the body to exert a medicinal effect. The pharmaceutically active ingredient must be released before the tablet is absorbed into the blood circulation. The pharmaceutical composition is then dispersed, or dissolved, in the body by body fluids and tissues. In this process of drug absorption, deposition, metabolism and elimination, the pharmaceutical dosage form plays a crucial role in determining the drug release profile and bioavailability. Accordingly, there is a continuing need to develop a drug dosage form that provides a controlled delivery system that provides desirable levels of drug in the plasma, reduces side effects, and improves patient compliance with the drug.

Disclosure of Invention

In one aspect, the present disclosure provides a pharmaceutical dosage form comprising a substrate comprising at least one compartment and a drug matrix contained in the compartment. In some embodiments, the drug is operably immobilized on a substrate. In some embodiments, the drug is separate from the matrix and can move freely in the compartment.

In some embodiments, the matrix is a thermoplastic material selected from hydrophilic polymers, hydrophobic polymers, swellable polymers, non-swelling polymers, porous polymers, non-porous polymers, erodable polymers, and non-erodable polymers. In some embodiments, the thermoformable material is selected from the group consisting of polyvinyl caprolactam polyvinyl acetate-polyethylene glycol graft copolymer 57/30/13, polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP-VA)60/40, polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP) copolymer 80/20, polyethylene glycol-polyvinyl alcohol graft copolymer 25/75, Kollicoat IR-polyvinyl alcohol copolymer 60/40, polyvinyl alcohol (PVA or PV-OH), polybutylmethacrylate-poly 2-dimethylaminoethylmethacrylate-polymethylmethacrylate copolymer 1: 2: 1, a polymethacrylic acid dimethylamino-polymethacrylate copolymer, a polyethylacrylate-polymethylmethacrylate-polytrimethylethylvinylchloride copolymer, a polymethyl acrylate-polymethylmethacrylate-polyacrylic acid copolymer 7: 3: 1, polymethacrylic acid-polymethylmethacrylate copolymer 1: 2, poly (methacrylic acid) -poly (ethyl acrylate) copolymer 1:1, poly (methacrylic acid) -poly (methyl methacrylate) copolymer 1: polyethylene oxide (PEO), polyethylene glycol (PEG), hyperbranched polyesters, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose or Hydroxypropylmethylcellulose (HMPC), hydroxypropylmethylcellulose succinate or hydroxypropylmethylcellulose acetate succinate (HPMCAS), polylactide-polylactic acid copolymer (PLGA), carbomer, polyethylene-polyvinyl acetate copolymer, ethylene-vinyl acetate copolymer, Polyethylene (PE) and Polycaprolactone (PCL), Hydroxypropylcellulose (HPC), polyoxyethylene 40 hydrogenated castor oil, Methylcellulose (MC), Ethylcellulose (EC), poloxamer, hydroxypropylmethylcellulose phthalate (HPMCP), poloxamer, hydrogenated castor oil, glyceryl palmitostearate, carnauba wax, polylactic acid (PLA), polyglycolic acid (PGA), Cellulose Acetate Butyrate (CAB), colloidal silica, titanium oxide, sucrose, glucose, polyvinyl acetate phthalate (PVAP), and combinations thereof.

In some embodiments, the cell shape can be pie-shaped, conical, pyramidal, cylindrical, cubic, rectangular, triangular or polygonal prism-shaped, tetrahedral, or a combination of these shapes.

In some embodiments, the first drug is in the form of nanoparticles, microneedles, or networks.

In some embodiments, the drug matrix comprises a pharmaceutically active ingredient (API). In some embodiments, the API can be a local anesthetic, sleep modulator, antiepileptic, anticonvulsant, anti-alzheimer's disease agent, analgesic, gout therapy agent, antihypertensive agent, antiarrhythmic agent, diuretic agent, liver therapy agent, pancreatic therapy agent, central nervous system therapy agent, gastrointestinal therapy agent, antihistamine, antiallergic agent, glucocorticoid agent, hormonal agent, contraceptive, hypoglycemic agent, anti-osteoporosis agent, antibiotic, sulfonamide, ketone, and other synthetic antibacterial agents, antitubercular agents, antiviral agents, antineoplastic agents, immunomodulators, cosmetic active agents, or chinese traditional medicine. In some embodiments, the API is a bioactive agent, a diagnostic agent, an agent for scientific research, a cosmetic agent, a veterinary drug, or an agricultural/pesticidal agent.

In some embodiments, the drug matrix further comprises an excipient. In some embodiments, the excipient is made of a water-soluble material, a water-insoluble material, and the material is selected from the group consisting of: cocoa butter, polyethylene glycol (PEG), sucrose, glucose, galactose, fructose, xylose, lactose, maltose, trehalose, sorbitol, mannitol, maltodextrin, raffinose, stachyose, fructo-oligosaccharides and their combination saccharides, gels, celluloses, polyesters, polyethylene oxides, polyethylenes, polyacrylic acids or their combination.

In some embodiments, the compartment has an aperture (aperture) that is blocked and/or closed by a plug (plug). In some embodiments, the plug is made of a porous polymer, an erodible polymer, a pH sensitive polymer, or a naturally occurring substance such as shellac. In some embodiments, the plug is made of a material selected from the group consisting of water soluble polymers, water insoluble polymers, waxes, saccharides, gels, celluloses, polyesters, polyethyleneoxide, polyethylenes, polyacrylics, or combinations thereof.

In some embodiments, the pharmaceutical dosage form includes a gas generant composition located in the first compartment. In some embodiments, the gas generant composition is selected from the group consisting of: water soluble carbonates, sulfites, bicarbonates, sodium carbonate, sodium bicarbonate, sodium metabisulfite, calcium carbonate, or combinations thereof, release carbon dioxide or sulfur dioxide gas when contacted with gastric fluid. In some embodiments, the gas generant composition is a combination of sodium bicarbonate and an organic acid (e.g., citric acid, tartaric acid, and the like).

In another aspect, the present disclosure provides a pharmaceutical dosage form comprising a matrix having at least a first compartment and a second compartment therein. The drug dosage form includes a first drug matrix contained in the first compartment and a second drug matrix contained in the second compartment.

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

In some embodiments, the first drug matrix is the same as the second drug matrix. In some embodiments, the first drug matrix is different from the second drug matrix.

In some embodiments, the first compartment has a first aperture blocked by a first plug and the second compartment has a second aperture blocked by a second plug. In some embodiments, the first plug has a higher permeability than the second plug. In some embodiments, the first plug has a higher erosion rate 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 has a higher permeability than the second wall. In some embodiments, the first wall is more erodible than the second wall.

In another aspect, the present disclosure provides a pharmaceutical dosage form comprising: two or more substrate layers stacked together, wherein at least one of the two or more substrate layers contains at least one drug substrate, respectively.

In some embodiments, the two or more substrate layers can be separated from each other.

In some embodiments, the two or more substrate layers are made of at least one thermoplastic material.

In some embodiments, the two or more substrate layers have different thicknesses.

In some embodiments, the two or more matrix layers have different erosion/dissolution rates.

In some embodiments, the two or more matrix layers are configured to release the contained at least one drug matrix in an aqueous solution based on a predetermined release profile.

In some embodiments, the two or more matrix layers include a first matrix layer comprising a first pharmaceutical component and a second matrix layer comprising a second pharmaceutical component, wherein the second matrix layer is disposed more exterior relative to the first matrix layer such that the second pharmaceutical component is released prior to the first pharmaceutical component.

In another aspect, the present disclosure provides a pharmaceutical dosage form comprising: a substrate having a compartment located therein; and a drug matrix contained in the compartment.

In some embodiments, the drug matrix is fixedly loaded in the compartment.

In some embodiments, the drug matrix is configured to have a size smaller than the compartment so as to be movable therein.

In some embodiments, the substrate is integrally formed.

In some embodiments, the drug matrix is encapsulated in a shell having a needle-like structure, and the shell is contained in the compartment.

In some embodiments, the drug matrix is made of a loose material.

In some embodiments, the loose drug matrix is composed of the same material as the matrix, and the density of the loose drug matrix is less than the density of the matrix.

In some embodiments, the compartment is closed.

In some embodiments, the compartment is configured as a pie, pyramid, column, cone, cube, cylinder, cone, triangular prism, polygonal prism, tetrahedron, or a combination of these shapes.

In some embodiments, the substrate has openings corresponding to the compartments, which expose the drug matrix in the compartments.

In some embodiments, the compartment is configured to have an area of dissolution boundary increasing inwardly from the opening such that the pharmaceutically active ingredient in the drug matrix is released with a predetermined release profile when the drug dosage form is dissolved.

In some embodiments, the release rate of the pharmaceutically active ingredient is constant.

In some embodiments, the base has a hole corresponding to the compartment, the hole being blocked by a plug to close the compartment.

In some embodiments, the plug is configured to dissolve in an aqueous solution for a longer time than the minimum dissolution time of the matrix to enable release of the pharmaceutically active ingredient in the drug matrix through the aperture upon dissolution of the plug.

In some embodiments, the compartment contains a plurality of drug matrices, wherein each of the plurality of drug matrices contains a different pharmaceutically active ingredient therein.

In some embodiments, the plurality of drug matrices are configured as adjacent columnar structures.

In some embodiments, the plurality of compartments are configured as columnar spaces spaced apart from each other.

In some embodiments, the plurality of drug matrices are configured as a stacked structure.

In some embodiments, the compartment has a release layer on the inside thereof for isolating the drug matrix from the matrix, such that the release layer is capable of delaying the release of the pharmaceutically active ingredient from the drug matrix when the pharmaceutical dosage form is dissolved.

In some embodiments, the compartment contains a gas generant composition.

In some embodiments, the drug matrix is comprised of nanoparticles.

In some embodiments, the compartment is hollow.

In some embodiments, the compartments are sized such that the average density of the pharmaceutical dosage form is less than the density of water.

In some embodiments, the drug matrix is configured as a porous structure.

In some embodiments, the substrate is made of at least one thermoformable material.

In yet another aspect, the present disclosure provides a pharmaceutical dosage form comprising: a substrate having a plurality of compartments therein; and a plurality of drug matrices respectively accommodated in the plurality of compartments.

In some embodiments, each of the plurality of compartments is configured as a columnar structure, and the different compartments are spaced apart from each other.

In some embodiments, the plurality of drug matrices contain different pharmaceutically active ingredients.

In some embodiments, the plurality of drug matrices have different lengths.

In some embodiments, the plurality of drug matrices have different areas of dissolution boundaries.

In some embodiments, at least a portion of the plurality of compartments are closed.

In some embodiments, the substrate has openings corresponding to at least some of the plurality of compartments, the openings exposing the drug matrix in the corresponding compartment.

In some embodiments, the compartment is configured to have an area of dissolution boundary increasing inwardly from the opening such that the pharmaceutically active ingredient in the drug matrix corresponding to the opening is released with a predetermined release profile when the drug dosage form is dissolved.

In some embodiments, the openings have different areas.

In some embodiments, the different plugs are configured to have different dissolution times in the aqueous solution such that the pharmaceutically active ingredients in the plurality of drug matrices are released at different times.

In some embodiments, different plugs have different lengths.

In some embodiments, different plugs have different dissolution rates.

In some embodiments, different voids have different areas of the dissolution boundary.

In some embodiments, the plurality of compartments are connected to one another.

In some embodiments, the plurality of compartments are spaced apart from each other.

In some embodiments, the plurality of drug matrices are made of the same matrix material.

In some embodiments, the plurality of compartments of the substrate are configured as a stacked structure spaced apart from each other.

In some embodiments, the drug matrix is comprised of nanoparticles and is contained in a plurality of mutually spaced compartments.

In some embodiments, the substrate comprises a plurality of compartment walls respectively enclosing the plurality of compartments, and the plurality of compartment walls have different thicknesses.

In yet another aspect, the present disclosure provides a pharmaceutical dosage form comprising: a plurality of drug matrices, wherein each drug matrix is made of at least one thermoformable material, respectively, and the plurality of drug matrices are joined together.

In some embodiments, the plurality of drug matrices are configured as columnar structures.

In some embodiments, the plurality of drug matrices have a cross-section of a sector.

In some embodiments, the plurality of drug matrices are stacked together.

In some embodiments, adjacent drug matrices of the plurality of drug matrices contain different pharmaceutically active ingredients.

In some embodiments, the plurality of drug matrices have different thicknesses.

In some embodiments, at least a portion of the drug matrices of the plurality of drug matrices are comprised of nanoparticles.

In some embodiments, the one or more drug matrices located on the non-outermost side of the stacked structure are comprised of nanoparticles.

Brief description of the drawingsTo explain

FIG. 1A shows a conventional pharmaceutical dosage form containing a drug matrix;

FIG. 1B shows the release profile of the pharmaceutical dosage form of FIG. 1A after administration;

fig. 1C blood levels after administration.

FIG. 1D shows the zero order release profile of a controlled release pharmaceutical dosage form;

FIG. 2A illustrates an exemplary pharmaceutical dosage form having a base and a compartment within the base and a pharmaceutical matrix contained within the compartment;

FIG. 2B illustrates the release process of the API of the pharmaceutical dosage form illustrated in FIG. 2A;

FIG. 3 illustrates an exemplary drug dosage form having a base and a compartment within the base, and another drug dosage form contained within the compartment;

FIG. 4A illustrates an exemplary pharmaceutical dosage form having a base and a pie-shaped compartment located within the base;

FIG. 4B illustrates an exemplary pharmaceutical dosage form having a base and a plurality of compartments with differently sized openings located within the base;

FIG. 4C illustrates an exemplary drug dosage form having a base and compartments at different angles within the base;

FIG. 4D illustrates an exemplary pharmaceutical dosage form having a base and compartments with different radii located within the base;

FIG. 4E illustrates an exemplary pharmaceutical dosage form having a matrix and a plurality of compartments within the matrix, and the compartments having different geometries to adjust the release rate of the API;

FIG. 5 illustrates a cross-sectional view of an exemplary drug dosage form containing pie-shaped compartments;

FIG. 6 illustrates an exemplary pharmaceutical dosage form having a matrix and a layered structure within the matrix with a drug matrix dispersed between the layers in the form of nanoparticles;

FIG. 7 illustrates an exemplary pharmaceutical dosage form having a base, a compartment within the base, and a microneedle-shaped drug matrix contained within the compartment;

fig. 8A illustrates an exemplary pharmaceutical dosage form having a base, a compartment located within the base, and a drug matrix contained within the compartment. The drug matrix is constructed in a network structure. The matrix is made of a material that dissolves in 1-5 minutes, while the drug matrix dissolves in seconds;

FIG. 8B illustrates the rapid release process for the API of the pharmaceutical dosage form illustrated in FIG. 8A;

FIG. 9 illustrates an exemplary pharmaceutical dosage form having a base and a plurality of columnar compartments located within the base; each compartment contains a drug matrix. The release of the drug from the compartments is determined by the number of compartments and the size of the compartments;

fig. 10A shows an exemplary drug dosage form having a base and 3 columnar compartments located within the base. Each compartment contains a drug matrix. Each drug matrix has a cylindrical base to block the opening of each compartment. Each substrate having a different length;

FIG. 10B illustrates an exemplary pharmaceutical dosage form having several drug matrices encapsulated in a stack; each matrix is a mixture of the same API and different substrates with different solubilities;

FIG. 10C illustrates the controlled release of the three APIs of the pharmaceutical dosage form illustrated in FIGS. 10A and 10B;

FIG. 10D shows a zero order release profile of the API of the pharmaceutical dosage form shown in FIG. 10A or 10B;

FIG. 11 shows a workflow diagram for preparing an API medication for a patient with a 3D printer;

FIG. 12A illustrates an exemplary pharmaceutical dosage form containing two drug matrices;

FIG. 12B shows the release of the drug dosage form of FIG. 12A for two APIs;

fig. 13A illustrates an exemplary pharmaceutical dosage form having a matrix and three compartments within the matrix, each compartment being loaded with a drug matrix. The release process of each drug is controlled by the solubility of the stopper;

FIG. 13B illustrates the release profile of the three APIs of the pharmaceutical dosage form illustrated in FIG. 13A;

FIG. 14A illustrates an exemplary pharmaceutical dosage form having a base and three compartments within the base, each compartment being loaded with a pharmaceutical matrix;

fig. 14B shows an exemplary drug dosage form having a matrix and three compartments within the matrix, with the three compartments contained in a large body, each compartment loaded with a drug matrix. Each drug matrix carries a mixture of API and base.

Fig. 14C shows the simultaneous release process of the pharmaceutical dosage form shown in fig. 14A and 14B for 3 different APIs.

FIG. 15A shows a pharmaceutical dosage form containing two APIs;

FIG. 15B shows the controlled release of two APIs by one of the drug dosage forms shown in FIG. 15A;

FIG. 16A illustrates an exemplary pharmaceutical dosage form having a base and three columnar compartments located within the base; each compartment being loaded with a drug matrix; each drug matrix has a cylindrical base to block the opening of each compartment. Each substrate has a different solubility;

FIG. 16B shows the controlled release of three APIs by the pharmaceutical dosage form shown in FIG. 16A;

fig. 17A shows an exemplary drug dosage form having a base and four columnar compartments located within the base. Each compartment being loaded with a drug matrix;

FIG. 17B shows the simultaneous release profile of the pharmaceutical dosage form shown in FIG. 17A for four APIs;

figure 17C shows a continuous release profile of the pharmaceutical dosage form shown in figure 17A for four APIs;

figure 18A shows a schematic of a pie drug form;

FIG. 18B is a photograph of a drug release process for a drug;

figure 18C shows the percent release profile for benzoic acid and PEG8000 for the drug dosage form in figure 18A.

FIG. 19A shows a perspective view of a pharmaceutical dosage form containing two compartments;

FIG. 19B shows a cross-sectional view of the drug dosage form of FIG. 19A;

FIG. 19C shows an exemplary release profile of the drug dosage form of FIG. 19A;

fig. 19D shows another exemplary release profile of the drug dosage form of fig. 19A.

Detailed Description

In the foregoing summary and detailed description of the invention and in the following claims and accompanying drawings, reference has been made to specific features (including method steps) of the invention. It is to be understood that the disclosure of the invention in this specification includes all possible combinations of these specific features. For example, where a particular aspect or embodiment of the invention or a particular claim discloses a particular feature, that feature can, to the extent possible, also be used in combination with other features and embodiments of the invention, or the invention as a whole.

The use of "including" and its equivalents herein means that additional components, ingredients, steps, etc., are optionally present. For example, an article "comprising" components A, B and C can consist of (i.e., consist only of) A, B and C, or contain more components in addition to A, B and C.

When reference is made to a method comprising two or more specific steps, the specific steps may be performed in any order or simultaneously (unless the context clearly excludes this possibility), and the method may comprise one or more further steps, which may be performed before, during or after any of the specific steps (unless the context clearly excludes this possibility).

When a range of values is recited, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range, and any other stated or intervening value in that stated range, is encompassed within the disclosure, excluding the limits expressly stated in that range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

A "at least" followed by a number indicates a range with the number as the lower limit (which range may or may not have an upper limit, depending on the variable being defined). For example, "at least 1" indicates 1 or greater than 1. A number following "at most" indicates a range with the number of the change as the upper limit (depending on the variable being defined, the range may have a lower limit of 1 or 0, or no lower limit). For example, "at most 4" indicates 4 or less than 4, and "at most 40%" indicates 40% or less than 40%. In the present disclosure, when a range is defined as "(first number) to (second number)" or "(first number) - (second number)", it means that the lower limit of the range is the first number and the upper limit is the second number. For example, 2 to 10 millimeters indicates that the lower limit of a range is 2 millimeters and the upper limit is 10 millimeters.

For purposes of simplicity of explanation, the reference numbers are repeated among the different figures to indicate corresponding or analogous elements, where appropriate. In addition, this description provides numerous specific details for a thorough understanding of the embodiments described herein. However, the embodiments described herein may be practiced without these details. In other instances, methods, procedures, and components have not been disclosed in detail so as not to obscure the description of the relevant functionality. Furthermore, the description herein should not be read as limiting the scope of the embodiments described herein. It should be understood that the description and characterization of the embodiments set forth in this disclosure are not mutually exclusive, unless otherwise specified.

Controlled release pharmaceutical dosage form

As shown in FIG. 1A, conventional solid pharmaceutical dosage forms, such as flat tablets, are made by dissolving or embedding a pharmaceutically active ingredient in a matrix. Existing conventional solid pharmaceutical dosage forms exhibit a first order drug release profile (fig. 1B) in which the drug level in plasma increases rapidly after administration and then decreases exponentially (fig. 1C). The disadvantage of this release profile is the reduced therapeutic efficacy due to reduced drug levels or the toxicity associated with high drug concentrations. This drug release is detrimental to the balance of drug levels in the plasma. The present invention relates to an adjustable or controlled release oral delivery system having the advantages of increased patient compliance, selective pharmacological effects, reduced side effects, and reduced frequency of drug delivery as compared to conventional systems. The controlled release prolongs the administration process and can maintain the blood concentration in the treatment period. For example, a delivery system exhibiting a zero order release profile (fig. 1D) allows a constant dose of drug to be released continuously over an extended period, resulting in a uniform and constant delivery process. Thus, zero order release profiles may also be required for antibiotic delivery, hypertension treatment, pain management, antidepressant delivery, and many other situations requiring constant plasma drug levels.

The present disclosure thus provides a stable oral solid pharmaceutical dosage form. In some embodiments, a pharmaceutical dosage form includes a matrix, at least one compartment formed within the matrix, and a drug matrix loaded in the compartment. Pharmaceutical dosage forms are designed to allow the release of the pharmaceutically active ingredient in a controlled manner from a pharmaceutical matrix.

A. Base body

As used herein, "matrix" refers to a structure that contains or has embedded therein a drug matrix. The matrix of the pharmaceutical dosage form may be of any size or shape suitable for oral administration. In some embodiments, the matrix is a flat circular tablet having a diameter of 2mm, 3mm, 4mm, 5mm, 6mm, 7mm, 8mm, 9mm, 10mm, 11mm, or 12 mm. In some embodiments, the matrix is an oval tablet having a size of about a mm x b mm, wherein a is between 5 and 15 and b is between 2 and 10. In some embodiments, the substrate is capsule-shaped.

In some embodiments, the matrix is made of hydrophilic polymers (e.g., Hydroxypropylmethylcellulose (HPMC) and poly (ethylene oxide) (PEO)), hydrophobic polymers (e.g., Ethylcellulose (EC)), swellable polymers, non-swelling polymers, porous polymers, non-porous polymers, erodable polymers, or non-erodable polymers.

In some embodiments, the pharmaceutical agent has a monomer matrix. In some embodiments, the substrate is constructed of multiple components, each component being made of the same or different materials.

In some embodiments, the matrix is made of a thermoplastic material. By "thermoplastic material" is meant herein a material that can be deformed by heat or pressure. In some embodiments, for example, the thermoplastic material may be a hydrophilic gel material that releases the drug matrix by diffusion; or hydrophobic material, and the drug matrix is released by diffusion out through the pores of the matrix. Polymers, in particular 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, can also be used as thermoplastic materials. Hydrophobic materials which are physiologically recognized and known to the person skilled in the art, for example mono-or diglycerides of C12-C30 fatty acids and/or C12-C30 fatty alcohols and/or waxes or mixtures thereof, can be used as thermoplastic materials. The matrix may also be made of hydrophobic materials, such as hydrophobic polymers, waxes, fats, long chain fatty acids, fatty alcohols or the corresponding esters or ethers or mixtures thereof.

In some embodiments, the thermoformable material is selected from the group consisting of polyvinyl caprolactam polyvinyl acetate-polyethylene glycol graft copolymer 57/30/13, polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP-VA)60/40, polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP) copolymer 80/20, polyethylene glycol-polyvinyl alcohol graft copolymer 25/75, Kollicoat IR-polyvinyl alcohol copolymer 60/40, polyvinyl alcohol (PVA or PV-OH), polybutylmethacrylate-poly 2-dimethylaminoethylmethacrylate-polymethylmethacrylate copolymer 1: 2: 1, a polymethacrylic acid dimethylamino-polymethacrylate copolymer, a polyethylacrylate-polymethylmethacrylate-polytrimethylethylvinylchloride copolymer, a polymethyl acrylate-polymethylmethacrylate-polyacrylic acid copolymer 7: 3: 1, polymethacrylic acid-polymethylmethacrylate copolymer 1: 2, poly (methacrylic acid) -poly (ethyl acrylate) copolymer 1:1, poly (methacrylic acid) -poly (methyl methacrylate) copolymer 1: polyethylene oxide (PEO), polyethylene glycol (PEG), hyperbranched polyesters, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose or Hydroxypropylmethylcellulose (HMPC), hydroxypropylmethylcellulose succinate or hydroxypropylmethylcellulose acetate succinate (HPMCAS), polylactide-polylactic acid copolymer (PLGA), carbomer, polyethylene-polyvinyl acetate copolymer, ethylene-vinyl acetate copolymer, Polyethylene (PE) and Polycaprolactone (PCL), Hydroxypropylcellulose (HPC), polyoxyethylene 40 hydrogenated castor oil, Methylcellulose (MC), Ethylcellulose (EC), poloxamer, hydroxypropylmethylcellulose phthalate (HPMCP), poloxamer, hydrogenated castor oil, glyceryl palmitostearate, carnauba wax, polylactic acid (PLA), polyglycolic acid (PGA), Cellulose Acetate Butyrate (CAB), colloidal silica, titanium oxide, sucrose, glucose, polyvinyl acetate phthalate (PVAP), and combinations thereof.

In some embodiments, the thermoformable material allows the pharmaceutical dosage form to be made by additive methods, such as Fused Deposition Modeling (FDM). In some embodiments, the pharmaceutical dosage form may be manufactured by extruding the thermoformable material through a 3D printer. Typically, the thermoformable material is melted in a 3D printer and then extruded to form the matrix. In some embodiments, suitable extruders include, but are not limited to, single or twin screw extruders, with the extruder temperature set between 50 ℃ and 180 ℃ and between 80 ℃ and 140 ℃. In general, the extrusion process can be carried out between 10 ℃ and 40 ℃ above the glass transition (Tg) temperature of the thermoformable material. Once the 3D printer reaches the appropriate temperature, the thermoformable material may be deposited onto the stereographic printing surface. Control of the shape and size of the substrate and compartment made of thermoformable material may be achieved by programming the printing process of the 3D printer.

In some embodiments, the release profile of the drug matrix can be controlled by the selection of the matrix material. For example, a matrix made of a material of a particular solubility, permeability or erodibility can, upon administration, open the compartment in a predetermined manner and release the drug matrix at a desired rate. In some embodiments, the matrix is made of an erodable or soluble substance, and the pharmaceutically active ingredient (API) is embedded or dissolved in the matrix. The active pharmaceutical ingredient is released as the matrix erodes or dissolves.

The release of the drug matrix or the pharmaceutically active ingredient can also be controlled by adjusting the thickness of the matrix. For example, the matrix forming the compartments is made of a soluble substance. The opening of the compartment and thus the release of the drug can be controlled by adjusting the walls of the matrix surrounding the compartment. For example, the thicker the walls of the compartment, the later the opening of the compartment, the later the release of the drug.

B. Compartment

In certain embodiments, the pharmaceutical dosage forms disclosed herein comprise at least one compartment in the matrix. By "compartment" herein is meant a space, portion or room marked or separated by a substrate. A compartment may be either closed or open (i.e. with holes). One compartment may be of any geometry that facilitates loading of the drug matrix. In some embodiments, the compartment shape may be pie-shaped, pyramid-shaped, column-shaped, or cone-shaped.

In some embodiments, the specially designed compartment shape is such that it can release the drug matrix at a specific rate. In some embodiments, the compartment shape can be wedge-like, triangular prism-like, pie-like, pyramid-like, column-like, cube-like, oval-like, or cone-like.

In certain embodiments, the inclusion of a compartment in the pharmaceutical dosage form may increase residence in the gastrointestinal tract. Fig. 2A illustrates an exemplary pharmaceutical dosage form having a matrix forming a compartment containing a drug matrix. Referring to fig. 2A, a pharmaceutical dosage form 100 has a base 101 forming a compartment 102. The drug matrix 103 is contained in the compartment 102 by connecting the inner walls of the compartment 102. The compartment 102 may provide buoyancy to the drug dosage form 100 to extend its residence time in the stomach or in a liquid or acidic environment. The solubility of the matrix material determines the lifetime of the pharmaceutical dosage form and a sustained release of the API as shown in figure 2B can be achieved accordingly.

Figure 3 illustrates exemplary drug dosage forms that increase gastrointestinal residence time. Referring to fig. 3, a compartment 202 of a drug dosage form 200 includes a second drug dosage form 203 (e.g., a tablet) that is freely movable therein. The gastrointestinal residence time of the pharmaceutical dosage form is limited. The floating system allows the system to stay in the stomach and continuously release the drug in the upper gastrointestinal tract to maximize absorption in the small intestine.

In one embodiment, the compartments of the drug dosage form have different geometries. Fig. 4A shows an exemplary pharmaceutical dosage form having a matrix containing pie-shaped compartments within the matrix, the areas of the dissolution boundaries of the pie-shaped compartments increasing inwardly from adjacent the outer side of the pharmaceutical dosage form such that the pie-shaped compartments are generally fan-shaped when viewed from above and downward in the direction of fig. 4A. Fig. 4B illustrates an exemplary pharmaceutical dosage form having a matrix containing a plurality of compartments with different opening sizes therein, the compartments being generally prismoid-shaped. Fig. 4C illustrates an exemplary pharmaceutical dosage form having compartments at different angles within the matrix. Fig. 4D illustrates an exemplary drug dosage form having pie-shaped compartments with different radii contained within a matrix.

The shape of the compartments may be used to control the release profile of the pharmaceutical dosage form. For example, r.a. lipper and w.i. higuichi describe an application system that can achieve a zero order release profile as shown in fig. 5. Figure 5 shows a cross-sectional view of an application system with a pie-shaped compartment. The compartment may communicate with the outside through a small opening. The compartment is loaded with the drug matrix and the drug matrix upon dissolution will release the API to the outside through a small opening. The dissolution rate of the drug matrix is positively correlated with the area of the dissolution boundary of the drug matrix (the interface between the drug matrix and the compartment space). On the other hand, the dissolution rate of the API in the environment is inversely related to the diffusion path length λ. Thus, as the drug matrix dissolves, the area of the dissolution boundary increases, and the rate of dissolution of the drug matrix also increases. On the other hand, the diffusion path length also increases as the drug matrix dissolves. The API released in the compartment needs to be transferred a longer distance to diffuse out of the drug dosage form. It is assumed that the pharmaceutical dosage form may be designed to comply with zero order release kinetics (R.A. Lipper and W.I.Higuchi (1977) analysis of the theoretical behaviour of a pseudo-zero order drug delivery system, J.Pharmaol.Sci.66 (2): 163-4; D.Brooke and R.J.Washkuhn (1977) zero order drug delivery system: theory and preliminary tests, J.Pharmaol.66 (2) 159-.

C.Pharmaceutical matrix

As used herein, a pharmaceutical base refers to a composition containing one or more active ingredients, including pharmaceutically active ingredients (APIs), cosmetic agents, biological agents, diagnostic agents, and scientific laboratory agents.

The term "pharmaceutically active ingredient (API)" as used herein refers to an ingredient having biological activity in a pharmaceutical product. In some embodiments, the API may be selected from the group consisting of: local anesthetics, antiepileptics and anticonvulsants, anti-alzheimer's disease drugs, analgesics, antihypergetics, antihypertensives, antiarrhythmics, diuretics, liver disease drugs, pancreatic disease drugs, antihistamines, antiallergic drugs, glucocorticoid drugs, sex hormone drugs and contraceptive drugs, hypoglycemic drugs, anti-osteoporosis drugs, antibiotics, sulfonamides, quinolones and other synthetic antibacterial drugs, antituberculosis drugs, antiviral drugs, antineoplastic drugs, immunomodulators, cosmetic active agents, chinese traditional medicine (TCM) and chinese traditional medicine extracts.

In some embodiments, the API may be selected from the group consisting of: (R) -folitixorin, lidocaine, ethyl 11-di-deuterium linoleate, 16-dehydropregnenolone, 17-beta-estradiol, 2-iminobiotin, 3, 5-diiodothyronic acid, 5-fluoro-2-deoxycytidine, 6-mercaptopurine, eltopridine, abacavir, abalone hemocyanin, abiraterone, acamprosate, calcium acamprosate, acarbose, aceclidine, aceclofenac, guanidosin hydrochloride, mennane, acenivalic acid, acetaminophen, acetylcysteine, acetyl cylindromycin, acetyl carnitine L-hydrochloride, acetyl salicylic acid, acyclovir, acipimox, azailast, abamectin, aclidinium bromide, arbifene, aclatin, acrivastine, acltalaride, adapalene, adefovir pivoxil, adefovir dipivoxil, Ademetionine, afatinib, agomelatine, edenafil citric acid, relinacetic acid, alatrovafloxacin mesylate, albendazole, salbutamol sulfate, alcaftadine, alendronate sodium hydrate, alendronate, alfacalcidol, alfaxalone, alfaxazone, alfentanil, alfuzosin, aliskiren, alitretinoin, allantoin, alisartan ester, decellularized dermis, allopregnanolone, allopurinol, almotriptan, alogliptin benzoate, alosetron, alpha ketonic acid, lipoic acid, alpha-cyclodextrin stabilized sulforaphane, alprazolam transdermal patch, alprostadil cream, hexamethylmelamine, aluminum sulfate, alvimopan, amantadine hydrochloride, ambroxol, amphetamine, sulindac, sultap-b, Amipridine, amipridine phosphate, amifostine, amikacin, amiloride, aminoacetyl, aminolevulinic acid, levulinic acid hydrochloride, aminopterin, amiodarone, amisulpride, amitriptyline, amlexanox, amlodipine besylate, amlodipine camsylate, amlodipine maleate, amlodipine nicotinate, amlodipine orotate, ammonium lactate, amodiaquine, amorolfine, amsulone, amoxicillin hydrate, amphetamine aspartate, amphetamine sulfate, amphotericin B cholesterol sulfate, ampicillin sodium, ampiroxicam, amrinone, amrubicin, guamidomethacin, alagliptin, anagrelide, anammoxine, anastrozole, ancrod, androgens, andrographolide, anecortave, anidulafungin, amifostine, amitriptyline, amclovir, amantadine, androgens, andrographolide, anadrolide, and a, Aniracetam, aninoprasme, aritinib, antazoline, antiandrogen, antineoxolone antofloxacin hydrochloride, android quinuclide, apatinib mesylate, apixaban, apomorphine hydrochloride, apremilast, aprepitant, alitabine, aranidine, arbadipine, arbekacin sulfate, arbekacin sodium, arformoterol, argatroban, aripiprazole laurate, armodafinil, arsenic trioxide, arsenious acid, artemether, artemisinil, artesunate, asenapine, asimadoline, astragaloside, anapirovir, atazanavir sulfate, ativur, atitinit, atomoxetine, atorvastatin calcium, statins, strontium, atovaquone, atoepinastan, atropine, ranol, ranofuranafine, abamectin, avibactam sodium, aviptavatriptan, aviptadine, amitriptolide, atorvastatin sodium, Acitinib, azacitidine, cytidine, azasetron, azelaic acid, azelastine hydrochloride, azelnidipine, azilsartan sartanate potassium, azilsartan trimethylethanolamine, azimilide, azithromycin lactobionic acid, aztreonam lysine, azlovudine, baclofen, baflutinib, baicalein, baicalin, BAK latanoprost, balofloxacin, balsalazide sodium, bambuterol, barrectin, barnidipine, bazedoxifene, beclomethasone propionate, beclomethasone dipropionate, bedoradrine, belotene, benazepril, benzphetamine bromide, bendamustine hydrochloride, benidipine, benserazide, benzalkonium, benznidazole, benzocaine, benzoyl peroxide, benzydamine hydrochloride, bepotamine hydrochloride, betahistine dihydrate, calcium tacrine dihydrate, Betadine salicylate, beractam, beraprost sodium, besifloxacin, beta-elemene, betahistine, betaine anhydrous, betamethasone propionate, betamethasone cream, betamethasone dipropionate, betamethasone mousse, betamethasone valerate, betamipron, betaxolol hydrochloride, carbamoylmethylcholine, uracaine, Betrexaban, bevacizumab, Bexarotene, bezafibrate, biapenem, bicalutamide, bicyclol, pefinavir, bilastine, bimatoprost, bismuth gallate, ecabet, sobiprolol, bisoprolol fumarate, bitridamycin, bleomycin, blonanserin hydrochloride, boceprevir, bortezomib, bosentan hydrate, bosufotatan, brisbufatan, brivaracetam, brimonidine, brivudine, Palimine, brixitane, brivudine, bromazepam, bromfenac sodium, bromocriptine, brotizolam, bryostatin-1, bucindolol, brazalin, budesonide, bufadipiride, buflomedil, bunazosin, bupivacaine hydrochloride, buprenorphine hydrochloride, bupropion hydrochloride, brixafop, buserelin acetate, buspirone hydrochloride, buspirone, busulfan, butenafine, butorphanol tartrate, butorphanol, butylphthalide, cabazitaxel, cabergoline malate, cadofloxacin, caffeine, citric acid, calcipotriol, calcitriol, calcium acetate, calcium folinate, calcium levofolinate, calcium polycarbophilate, calcium polycarbophil, calfava, calcium ferforth, camptothecin, canvasicidin, carvachien, camostatin, candesartan, candelilla, and candelilla, and candelilla, and candelilla, and candelilla, and candelilla, and candelilla, cangrelor, cannabis, capecitabine, capsaicin, captopril, carbamazepine, capecitabine, carbitol, carbidopa, carbinoxamine, carbocisteine, carboplatin, carbidopa, carfavudine, carglumine, carlira, carmustine, carteolol hydrochloride, carruminan, carvedilol phosphate, caspofungin, catechin, cediranib, cefaclor, cefadroxil, cefathiamidine, ceftizoxime sodium pentahydrate, cefcapene, cefdinir, cefditoren pivoxil, cefepime hydrochloride, cefetamet hydrochloride, cefminox, cefoperazone sodium, cefotiam sodium, cefotiam, cefozopran, cefpirome, cefpodoxime, cefprozil, cefalotin, cefprozil, ceftarol, cefprozil, ceftazime, ceftiofur-L, ceftazidime, Cefbupirine, cefditoren pivoxil, ceftriaxone sodium, cefuroxime sodium, celecoxib, cerivavir, celiprolol, cephalosporin, ceritinib, cerous nitrate, cetilistat, cetirizine, cetrorate, cevimeline, chenodeoxycholic acid, chlorhexidine acetate, chlorgenic acid, chloroquine combination, chloroquine, chlorpheniramine maleate, chlorpheniramine, chlorthalidone, cholecalciferol, cholic acid, choline alfibrate, ciclesonide, ciclopirox olamine, ciclosporin, cidofovir, cidosepine, cilastatin, cilazapril, cilnidipine, cilostazol, cimetidine, cinacalcetacacetuxide, cinepazide maleate, cinidide tartrate, ciprofloxacin, cyprosulfamide, citaloperamide, citalophathiazide, citalopram, ciprofloxacin hydrochloride, ciprofloxacin, citalopride, citalopram, ciprofloxacin, clorac, clomipide, clofibrate, and so, or, Citalopram hydrobromide, citicoline, citrulline, cladribine, clarithromycin, clavulanate potassium, clavulanic acid, clavulanate, clevidipine, cladribine, clindamycin hydrochloride, clindamycin phosphate, clioquinol, clobazam, clobetasol propionate, clodronic acid, antamine, clofazimine, clomipramine hydrochloride, clonitrazepam, clonidine hydrochloride, clopidogrel benzenesulfonic acid, clopidogrel sulfate, clopidogrel camphor, clopidogrel hydrogen sulfate, clopidogrel napsylate, clopidogrel, clotrimazole, clozapine, cobalamin, cobicistat, codeine, colchicine, cholecalciferol, colesevelam, colestidol, colesevelam, colesevelandide, colesevela, coleseveladin, valsartan palmitate, fossai palmitate, valsartan sodium, colistin, conjugated estrogens, colesevelam palmitate, valsartan sodium, valsartan, and other, Copper histidine, 11-deoxycortisol 17 alpha-vinylpropionic acid, cridanimod sodium, crizotinib, cromolyn sodium, cyanocobalamin, ciclovir, cyclobenzaprine hydrochloride, cyclophosphamide monohydrate, cyclosporine, cyproterone acetate, cytarabine octadecyl phosphate, dabigatran etexilate, dabrafenib, daclatasvir, dactinomycin, dalbavancin, daceprazole, aminopyridine, dalfopristin, dalteparin sodium, danazol, danatrix sodium, darusseptib, astrazepam propylene glycol, dapiprazole, dapivine, dapoxetine, dapsone, darifenacin, darunavir, dasabuvir, dasatinib, erythromycin, decitabine, larosol, deferiprone, deferoxamine mesylate, troxacin, trovafloxacin, Diemetid, lapril, delapril hydrochloride, delavirdine, delabulin, deoxyandrographolide, dermatan sulfate, desflurane, desipramine hydrochloride, loratadine, desmopressin acetate, desogestrel, desonide, desvenlafaxine, dextromethorphan hydrobromide, verteporfin, deuterated levodopa, deuterated venlafaxine, dexamethasone acetate, dexamethasone pexanolate, dexamethasone palmitate, dexamethasone sodium phosphate, dextroamphetamine, dexanabinol, iron dextran, dexketoprofen tromethamine, dexlansoprazole, dexmedetomidine, dexmethylphenidate hydrochloride, deximipramine, sotalol, dextrosucrose, dextroamphetamine sulfate, dextromethorphan hydrobromide, dexpropoxyphene, diacerein, lactonol epoxide, diazepam, diazoxide, choline, and choline, Diclofenac, diclofenac potassium, diclofenac sodium, diclofenamide, dicycloplatin, didanosine, norgestrel, difluprednate, digoxin, linolenic acid, dihydroergotamine mesylate, diltiazem hydrochloride, dimesna sodium, dimethyl fumarate, diletastane, dinoprostone, diphenylcyclopropenone, dipyridamole, sodium pyrophosphate, tobramycin, desifenaton sodium, disulfiram, anthratriphenol, methadone, polycarbobamide, docetaxel, glycerol, dofetilide, dolasetron, dolutegravir, domperidone, doxofibrutine sulfonate, donepezil hydrochloride, dopamine, doripenemine, dorzolamide hydrochloride, dosomaxilate, docosammonium chloride, doxazosin mesylate, doxazosin hydrochloride, doxepin, doxifluorine, doxifluoride, doxepin hydrochloride, doxifylline hydrochloride, doxepin hydrochloride, doxepin, and, Doxofylline, doxorubicin hydrochloride, doxycycline hydrochloride, doxylamine succinate, dronabinol, dronedarone, drospirenone, droxidopa, D-tagatose, duloxetine hydrochloride, dutasteride, ebastine, eberconazole, ebselen, ecabet, isoconazole nitrate, dacloprazine, edaravone, idaxaban, efavirenz, efaconazole, efonicet, efonidipine hydrochloride, efavirenz sodium, glyceryl icosapent-pentaenoate, oxagolide, eldecalixol, illimomium, eletriptan, eltrombopag, eltamivir, amelogenin, emedasatin, empagliflozin, enlicarin, emtricitabine, enalapril maleate, enrichine, lomicrin, tamoxifen, enoxacin, enoxate sodium, Enprostinil, entacapone, entecavir maleate, entinostat, enzalutamide, epalrestat, eperisone, ephedrine sulfate, epinastine hydrochloride, epinephrine, epirubicin hydrochloride, epitinib, eplerenone, epoprostenol, epristeride, ilodesacet, eprosartan, eptaplatin, erdosteine, eribulin mesylate, erlotinib, ertapenem, erythromycin stearate, erythromycin propionate, escitalopram, esketamine, ketamine hydrochloride, eslicarbazepine acetate, esmolol hydrochloride, esomeprazole magnesium, esomeprazole, estriol, estradiol acetate, estradiol cypionate, valeric acid, estradiol, estriol, ethylamine, esbutanol, eszopiclone, esmolol hydrochloride, Ethanesulfonin, ethioninol, ethinylestradiol, dicalcium phosphate ethylfumarate, magnesium hydroxide ethylfumarate, zinc hydrogen ethylfumarate, ethinylestradiol, etidronic acid, etimicin sulfate, etizolam, etodolac, etonogestrel, etoposide phosphate, etoricoxib, etravirine, isoeupatilin, everolimus, exemestane, exenatide, ezetimibe, favuzole, fatrozole, flucalcitol, famciclovir, famotidine, aminopyridine, faropenem, faxostat, fasudil hydrochloride, fasudil mesylate, faviravir, febuxostat, felbamate, felbinac, felodipine, fenfluramine hydrochloride, fenofibrate, fenbutamol, fenfluramine, fenconazole, citric acid, fentiazamide, fenflurazole, fenfluramine, fenflurazole, fenfluramine, fenflurazole, fenfluramine, flufluramine, ethiprolide, and so, Ferric citrate, ferric maltolate, fexolone fumarate, fexofenadine, fibrin glue, fibrinogen matrix patch, fidaxomicin, fimasartan, finafloxacin hydrochloride, finasteride, fingolide, flecainide, fleroxacin, flibanserin, flomoxef, floxuridine, fludarabine, flumazenil, flunisolide, fluocinonide acetate, fluorouracil, fluoxetine hydrochloride, flupirtine, flurbiprofen ester, flurbiprofen sodium, flutemycin, fluticasone furoate, fluticasone propionate, flutramadol, fluvastatin, fluvoxamine, folic acid, folinic acid, methylpyrazole, fondaparine sodium, formestane, formoterol fumarate, forrestitude, furazavir, saxavir, fexofenadine, flufenadine, flufenamate, flufenamic acid, flufenamate, fludarabine, fludard, Fosaprepitant, fosfluconazole, fosfomycin disodium, fosfomycin trometamol, fosinopril sodium, fosmidomycin, fosphenytoin, fospropofol, fotemustine, frovatriptan, furoquintinib, fudosteine, fulvestrant, furosemide, fusidic acid, gabapentin enacarbil, gabexate mesylate, gadobutrol, gadofoamide, galantamine, gallium nitrate, gambogic acid, ganaxolone, ganciclovir acetate, grifloxacin, gatifloxacin mesylate, gefitinib, gemcitabine hydrochloride, gemfibrozil, genistein, gentamycin, gentisic, gecoside, gepirone, gestodene, timatrienone, timolol maleate, gemmolindolol, ginsenoside, grist, glatiramerib acetate, glibenclamide, gliclazide, Glimepiride, glipizide, glufosfamide, glutamine, glycerobenzene, glycolone, glycopyrrolate mesylate, glycyrrhizic acid, golimod, golagliptin, granisetron hydrochloride, guaifenesin, guaiaretic willow, guanfacine, guanrolimus hydrochloride, haemophilus influenzae, halobetasol propionate, halofantrine, halometasone, sodium hyaluronate, hematoporphyrin, arginine heme, heparin, greedy, hydroxyethyl starch, norcoclaurine hydrochloride, histamine dihydrochloride, huperzine A, sodium hyaluronate, hydralazine, hydrochloric acid, hydrochlorothiazide, hydrocodone, hydrocortisone tartrate, hydrocortisone, hydromorphone hydrochloride, hydromorphone, hydroxycobalamin, hydroxyurea, hydroxychloroquine, hydroxyprogesterone caproate, hydroxysafflorin A, hypericin, ibandronate, eportan, ibandrostaphyl, Ibrutinib, ibudilast, ibuprofen, ibutilide fumarate, epimedium, elaprine, eicosapentaenoic acid, ethyl eicosapentaenoate, icosatetratinib hydrochloride, idebenone, idoxuridine, ifetroban sodium, ilamod, ilaprazole, iloperidone, iloprost, imatinib mesylate, imidafenacin, imidapril, imidazole salicylate, imipenem, imiquimod, ericoxib, incadronic acid, indacaterol maleate, indapamide, indalazinan, indinavir, indisetron, indomethacin, indoramine, inecalcitol, ingenol mebutate, inosine, itraconazole, idegliflozin, ipratropium bromide, etazolirtine hydrochloride, irbesartan, irinotecan, and its salt, Irinotecan hydrochloride, irinotecan sulfate, iloufen, ferric succinate protein, elsonidine maleate, isoflurane, isoniazid, unoprostone isopropyl, isosorbide dinitrate, isostere, isotretinoin, isradipine, istradefylline, itopride hydrochloride, itraconazole, ivabradine hemisulfate sulfate, ivabradine hydrochloride, ivermectin, aflibercept IVT, ixabepilone, kallikrein, ketamine, ketanserin, ketoconazole, ketoprofen, ketorolac tromethamine, ketotifen, kukojic acid B mesylate, lacidipine, lacosamide, lactitol, lafutidine, lamotrigine, landiolol hydrochloride, nanciclovir nano-octanoate, lanoconazole, lansoprazole, lanthanum carbonate, lapatinib, lasofoxifene, lansoprazole, Latanoprost, ledipasvir, leflunomide, lenalidomide, lentinan sulfate, lercanidipine, Leprinine potassium, letrozole, leucine, leuprolide acetate, levalbuterol hydrochloride, levamisole, levamlodipine besylate, levamlodipine maleate, levamlodipine levetiracetam, levobupivacaine, levocabastine hydrochloride, levocarnitine, levocetirizine, levodopa, levofloxacin, levo18-methylnorethindrone, levonorgestrel, levo18-methylnorethindrone butyrate, phencyclamate, levoornidazole, levosimendan, L-glutamine, lidocaine, ligustrazine hydrochloride, limaprost, linagliptin, linezolid, liothyronine, lipoteine, lipoteichol hydrochloride, Levoxamine, Levoglitazobactam, Levoacaine, Levogliptin, Levopirimidyl sulfate, Lepidil potassium, Lepririne, letrozole, leucine, leuprolide, levocabastine, levocabastin acetate, levocabastin hydrochloride, levocabastin hydrochloride, and other, Rilalanaftate, lisinopril, theophylline, lysergil maleate, lithium citrate, lithiosuccinic acid, lobaplatin, ledenafil carbonate, lofexidine, lomefloxacin, lomerizine dihydrochloride, lopinamide, lopinavir, loratadine tablets, lorazepam, L-ornithine L-aspartate, lornoxicam, losartan potassium, loteprednol, lovastatin, loxapine succinate, loxoprofen, levopraziquantel, clomaxib, lysine aspirin, sulfamylon, magnesium carbonate, isoglycyrrhizic acid magnesium, mangafodipir, manidipine dihydrochloride, mannitol, maraviroc, malibacir, mefenadine, mebendazole, mecobalamin, megestrol acetate, meloxicam, memantine, amantadine hydrochloride, memantine, amantadine sulfite, sodium, Menatetrenone, mepacriline, aclacin, p-cresol, cysteamine bitartrate, cysteamine hydrochloride, mercaptopurine, meropenem, mesalazine, metacavir, metadoxine, analgin, metaxalone, benzyl ergot, metformin hydrochloride, methadone hydrochloride, methazolamide acetate, methotrexate, methoxyflurane, methylpentanoic acid hydrochloride, methylnaltrexone bromide, methylnaltrexone, methylphenidate hydrochloride, 6-methylprednisolone, methylprednisolone aceponate, methylene blue, methyltyrosine, metoclopramide, metoprolol succinate, metoprolol, metronidazole, metiprone, mexiletine, mibefradilal, miconazole nitrate, midazolam hydrochloride, midodrine, midostaurin, mivampin, mifeprinol, miglitol, meglitol, Milnacipran, milrinone, miltefosine, milnacipran, minocycline hydrochloride, minodronic acid, minoxidil, milaberon, mibobeuron, miboplatin hydrate, milonafil hydrochloride, mirtazapine, misoprostol, miglitide, mitomycin, mitoxantrone hydrochloride, mefenate, mizolastine, mizoribine, moclobemide, modafinil, doxycycline, madecapafane, moexipril, mufenamic acid, morpholinone hydrochloride, mometasone furoate, momemimi furoate, monoammonium glycyrrhizinate, moxabenzone, minodron, monoterpene perillyl alcohol, montelukast sodium, montmorillonite, morronite, morethazine, tegafol, morpholine nitrate, morphine, pravastatin, morphine sulfate, moxidectin, moxibufenamic acid, moxidectin hydrochloride, moxidectin hydrochloride, moxidehydi, Moxonidine, moxonidine hydrochloride, mozavaptan, mupirocin, mycophenolate, myristyl nicotinate, cannabirone, nabumetone, N-acetylcysteine, nadifloxacin, nadolol, nadroparin calcium, naftifine hydrochloride gel, naftopidil, nalbuphine, naftifine, nalmefene hydrochloride, naloxonol ether, naloxone hydrochloride, naltrexone hydrochloride, nandrolone decanoate, naphazoline, naphthoquine, naproxen sodium, naratriptan, nosaprose, nateglinide, nebivolol, nedaplatin, nedocromil, nelarabine, nelfinavir, nemorubicin, neosaxitoxin, neostigmine mesylate, nepadutant, pratamide, nepinamide, nerepinasil, neritinib hydrochloride, neritinib, napropamide, naproxide, and other, naproxide, netilmicin, netupitant, nevirapine, niacin, nicardipine, nicergoline, nicorandil, nicotiflorine, nicotinic acid, niclosamide, nifedipine, nifekalant, nifedipine, nifolimus, nifuroxazide, nikkomycin, nilotinib, nilutamide, nilvadipine, nimesulide, nimodipine, morpholine ornidazole, nisoldipine, nitazoxan, nitrexinafol, nitrendipine, nitric oxide, nitroglycerin, nizatidine, lorazetidine, nomegestrol, norgestrel, norepinephrine, norethindrone acetate, norethindrone heptonate, norethindrone acetate, norethindrone, octreotide hydrochloride, oxypaelate, olanzapine, ocinolvaglipizide, oxsultam, nifedipine, olmesartan medoxomil, indacaterol, ondansterol hydrochloride, olopatadine hydrochloride, olprinone, olsalazine, oltipraz, homoharringtonine, augustine, omeprazole, ormoconazole, onapristone, ondansetron, opiperazine, methylphenidate, ololetekacin, orlistat, ornithine phenylacetate, oloprost, oseltamivir, ospemifene, oteracil potassium, oxaliplatin, oxaloacetic acid, oxandrolone, oxazepam, oxcarbazepine, oxfendazole, oxidized glutathione sodium, oxiracetam, oxybutynin hydrochloride, oxycodone hydrochloride, oxymetazoline, oxymorphone hydrochloride, oxymorphone, oxytocin, ozagrel sodium, olgrel hydrochloride, ozagrel, oxepagrel, oxeparol, paclitaxel, and paclitaxel Paliperidone palmitate, pamidol, palonosetron, paroxetine, pamidronate disodium, pancreatic lipase, panipenem, panobinostat, pantoprazole, acetaminophen, parecoxib, paricalcitol, palirrier, sodium parnaparin, paloglutagliptin, palogliflozin, paromomycin, paroxetine hydrochloride hemihydrate, paroxetine methanesulfonate, paliperidone, pazopanide, pazufloxacin mesylate, pegylated lipol, pelubiprofen, pemetrexed disodium, pemilast potassium, pemirolast sodium, penciclovir, pentostatin, pentamidine, calcium sodium pentetate, zinc sodium pentetate, pentan sodium sulfate, pentostatin, pentone theobromine, peramivir, piracetam paamphetamine, pirenza, fenpyrazoxanide, perfluoropentane, perfluorooctylammonium bromide, pergolide, coronatine, perhexine, perhexiline, Piperacillin, perindopril arginine, piropiroctone, fenclorone, phenethylisothiocyanate, phenoxybenzamine hydrochloride, phentermine, topiramate, phentermine hydrochloride, phentolamine mesylate, sodium phenylbutyrate, phenylephrine hydrochloride, phenylephrine suppository, phenytoin, phosphatidylcholine and acetylsalicylic acid, sapelin, picrorhizin, podophyllotoxin, pidotimod, pilocarpine hydrochloride, piricarb, pimecroline, pimecrolimus, pimobendan, pinocembrin, pioglitazone hydrochloride, pipradine, pipecolin, piperacillin sodium, piperaquine phosphate, piperidone hydrochloride, piperine, piracetam, pirarubicin, pirfenidone, pimenox, piroxicam, pitavastatin, calcium pivastatin, pitavastatin, and pivoxim, Pistajon, propranonil, proconapril, pranosalol, pradafil, L-carnosine zinc, polifeprosan 20 carmustine, resveratrol glycoside, pomalidomide, pinatinib, porfimer sodium, posaconazole, potassium bicarbonate, potassium citrate, clavulanate, paladefovir, prodefovir, aminopterin, pramipexole, pramipentan, pravastatin hydrate, prasterone testosterone, prasugrel, pravastatin, prazosin, prednimustine, prednisolone acetate, prednisolone sodium phosphate, prednisone, pregabalin, bimetan, prilocaine, procaterol hydrochloride, prochlorperazine maleate, progesterone, progestin, gestagen, dienogest, proguanil, promethazine, propafenone, propaferol, propranolol hydrochloride, sertraline hydrochloride, prasudoxorubin, prasugrel hydrochloride, prasugrel, prasukol, prasukola, prasukol, prasukola, prasukol, and other, potassium bicarbonate, prasukola, prasuko, Pruroca, prulifloxacin, prussian blue, pseudoephedrine hydrochloride, puerarin, priquintinib mesylate, pyrazinamide, pyridoxamine hydrochloride, pyridoxine hydrochloride, pyrimethamine, quinapride, pyronaridine, quazepam, quetiapine fumarate, quetiapine, quinagolide hydrochloride, quinapril hydrochloride, quinidine sulfate, quinupristin, quinapride, rabeprazole sodium, racecadotril, ladtinib, raloxifene, nalocifene, raloxifene, raltitrivir, raltitrexed, ramatroban, ramet, ramipril, ramosetron, ranitidine, bismuth citrate, ranitidine, ranolazine, rasagiline, rebamipide, rebobapide, reboxetine mesylate, ibuprofen, naproxen, glycopyrrolate, diclofenac, glycopyrroside, tolamine, tolazamide, tolazazolirtin, tolmetin, luteinium, aluminum, tolmetin, troglitazone, thion, thiofantrine, fludarone, fludarabine, fludaruss, fludara, fludaruss, fludara, fludarbemisincarbide, fludara, fludarbexapride, fludara, fludarusside, fludara, fludaruss, fludarbexapride, fludara, fludarbefrabenclamide, fludaruss, fludarbefrataxide, fludarbexapride, fludarbefrabenfurbenfurbenclamide, fludarbexapride, fludarbefrabenclamide, fludarbefrazid, fludara, fludarbefrabenfurbenfurbenfurbenfurbenfurbenfurbenfurbenfurbenfurbenfurbenfurbenfurbenfurbenfurbenfurbenfurbenfurbenfurbenfurbenfurbenfurbenfurbenfurbenclamide, and so, fludara, etc Regorafenib, remifentanil hydrochloride, repaglinide, repirast, amlexanox, clorazine hydrochloride, bucilamine, guanabenz, mazindol, naltrexone, nitazone, ondansetron, retigabine, rosiglitazone, sodium phenylbutyrate, resiniferatoxin, ranisimotene, resveratrol, regagliptin, retapalene, retastatin, retigabine, tretinoin, revaprazan, heparine sodium, rhein, rhenium-186 etidronate sodium, ribavirin, rifabutin, rifampin, rifamycin, rifapentine, rifaximin, retapadide, rilpivirine hydrochloride, riluzole, rimantadine, rimexolone, risperidone, riluzat, rilisavugga hydrochloride, risedronate sodium, risperidone, ritonavir, rivastigmine, ritriptan, ritatriptan, rizatriptan, ritatriptan hydrochloride, risperidone hydrochloride, risperidone hydrochloride, risperidone hydrochloride, risperidone hydrochloride, or hydrochloride, risperidone, or acid, or the like, Roflumilast, roticin, rollitant, romotene, ropinirole hydrochloride, ropivacaine, sodium rose oxide, rosiglitazone maleate, rosiglitazone sodium, rosuvastatin calcium, rotigotine, roxithromycin, rubitecan, rufinamide, rufloxacin, rupatadine, ruxolitinib, disodium levonidazole phosphate, shakubitrex, safinamide, albuterol ehydrazide, salbutamol sulfate, salicylic acid, salmeterol xinafoate, salvinine, sambucarb-marix, 3-carboxamide-4-hydroxycyclopropanol oxymorphone, S-amlodipine nicotinate, sapropterin, saproprione dihydrochloride, saquinavirus, secatinib, sargracillin hydrochloride, sargraluride, hyogliptin, scopolamine, scorpiosin, scorpion venom, Seal oil omega-3 polyunsaturated fatty acid, secnidazole, selegiline hydrochloride, Semetinib, seratrodast, ciladax, seliprolol hydrochloride, sertaconazole nitrate, sertindole, sertraline hydrochloride, sesquiterpenes, sevelamer carbonate, sevelamer hydrochloride, sevelamer, sevoflurane, maleic acid sibutramine, sibutramine mesylate, sildenafil citrate, silodosin, sulfadiazine silver salt, cimetivir, simotinib hydrochloride, simvastatin, nonitegam, siponimod, sirolimus, sitafloxacin, sitagliptin phosphate, cevesene, sizofuran, sisofilan, cilorubin, smilacin, S-modafinil, sobuzosin, sodium sevelan, sodium ascorbate, sodium benzoate, sodium bicarbonate, sodium cromolyn, sodium chloride, sertraline, simotinib, simethionine, sodium salicylate, and sodium salicylate, and sodium salicylate, and sodium salicylate, Sodium glycinediazole, sodium guaranate, sodium hyaluronate, ibandronate, sodium nitrate, sodium nitrite, sodium oxybate, sodium phenylacetate, sodium phenylbutyrate, prasterone sodium natsufate, sodium pyruvate, sodium taurocholate, sodium thiosulfate, hypo, sodium hyposulfite, sodium zirconium cyclosilicate, sofosbuvir, solifenacin, soluble ferric pyrophosphate citrate, soluble guanylate cyclase stimulation, sophocarpine, sophoridine hydrochloride, sorafenib, sorbitol, sparfloxacin, spirapril, ambrox, squalamine, stannsoporfin, stavudine, S-tenatoprazole, sethionine, setiprentanol, streptozotocin, strontium malonate, strontium ranelate, succinic acid, aluminum thionate, sucrose gels, sufentanil, zinc sultalam, sugamol, sulbactam sodium, sulcardin sulfate, sulfafurazofamide, sulfasalazine, sulindac, sulbactam sodium, Sofositinib, sulfonylureas, sulforaphane, tanshinone IIA sodium sulfonate, sulindac, sulodexide, sulfamethoxazole, thiothiazide, sumatriptan succinate, sunitinib, petalite, mesolalast, suramin sodium, verapamil hydrochloride, rilpivirine, tacalcitol, tecocol, tacrine, tacrolimus, tadalafil, chlorphenamide, tafenoquine, tafluprost, talaporfin, talikex, taltirelin, tamibaroteran, tamoxifen, tamsulosin hydrochloride, tamsulosin, temospirone, tamiprosin, talutadolastatin, talmetrazone, taquinimod, tazarotene, tazobactam, tazolbactam sodium, tipipenem ester, tevirin, irilone, tedisamide, tedizolid, tedin, tegafur, furazoline phosphate, furazolidone, sultamsultap, sultap, sulpirtine, sulindac, tamsulindac, tamarine, Tilapatinib, telbivudine, telithromycin, telmisartan, temocapril, temoporphine, temoporfin, temozolomide, sirolimus, telocidine, tenofovir alafenamide, tenofovir aspartic acid, tenofovir disoproxil fumarate, tenoxicam, teprenone, terazosin, terbinafine hydrochloride, terguride, teriflunomide, tesofensine, testosterone undecanoate, butylbenzene, tetracaine hydrochloride, tetracycline, tetrathiomolybdate, tetrahydronaphazoline, thalidomide, theophylline, thienylorphine hydrochloride, thiotepa, thrombin microcapsules, thyroxine, tiagabine, nepafen, netipramine, ticalone, ticagrel, ticloprid, ticlopidine, tigecycline, disodium tiludronate, timolol, timidazoie, temozolol, temepholol, temephalol, temephlol, temephalo, temephalol, temephalo, temephlol, temephalo, temephlol, temepho, temephlol, temepho-l, temephlol, temepho-I, temepho-D, temepho-I, temepho-p-D-I, temepho-D-I, temepho, Titazaparin sodium, tioconazole, tiopronin, tiotropium bromide monohydrate, tipepidine hyacinate, tipepidine, tipifarnib, tiravir, tirapazamine, tirapazat, tirapaban hydrochloride, oxcarbazepine, tirapaban hydrochloride, tizanidine, tobramycin, tocoferol, vee formate, vitamin a tocopheryl ester, tofacitinib, tolmetrazine, tolcapone, tolimione, tolperisone, tolterodine tartrate, tolvaptan, tolnaftate, topiramate, tolpirolate, topotecan hydrochloride, tolisamide, tolperistalate, tolterodine, trabectedin, tramadol hydrochloride, tramadol, tranilit, trandol, traniliprolil hydrochloride, traniliprolide hydrochloride, traniliprolide hydrochloride, tolmetin, Trazodone, trehalose, trogliptin succinate, busulfan, treprostinil ethanolamine, tretinoin, triamcinolone acetonide, triazolam, trichlorthiazine, triciribine, triclabendazole, triclocarban, trientine hydrochloride, trifluorothymidine, trifluoracetic acid, triheptanoin, trostan, trimebutine 3-thiocarbamoyl-benzene, trimebutine tosylate, trimegestone, trimethoprim, trimetrexate, trinitrate, tripotassium bicistronic acid bismuth, tropicamide, tropisetron, trospium chloride, trovafloxacin, troxipide, tubuterol, tylosin, ubenidine, ubenix, ubinone, udenafil, ulinastatin, ulistat, uratasol, uracil, urapidil, uridine triacetate, uropoly-peptide, deoxycholic acid, valacil, valacyclovir, trexate, tretinomycin, Valacyclovir hydrochloride, valdecoxib, valganciclovir, valproic acid, valrubicin, valsartan hemipentahydrate trisodium phosphate, vancomycin hydrochloride, vandetanib, vanoxerine, valdenafil hydrochloride, valnemadex, visfatib, venlafaxine hydrochloride, verapamil hydrochloride, phencycl, vinacalan hydrochloride, verteporfin, vesnarinone, vinzolinone, vigabatrin, vilanterol, vilazodone, vildagliptin, vincristine sulfate, vinflunine, vinorelbine, vinpocetine, vismod, vitamin E nicotinate, vitamin E, vobose, vonolazan fumarate, vilapazab, vorapazab, voriconazole, vorinose, vorinoside, valtacrine, valsartan hemin, valsartan, valbutine, valatidine, valdecoxitin, valdecoxib, valtretin, valsartan, valdecoxib, valsartan, valdecoxib, valsartan, valdecoxib, valsartan, valdecoxib, valtretin, valdecoxib, valtretin, valdecoxib, valtretin, valtretinob, valdecoxib, valtretin, valtretinob, valtretino, Timilofiban, milofiban, imipitavir, eucranafil, zafirlukast, zalcitabine, zaleplon, zaltoprofen, zanamivir, zidovudine, zileuton, zinc acetate, cilastatin, ziprasidone, zofenopril calcium, levofenopril, disodium zoledronate, zoledronic acid, zolmitriptan, zolpidem tartrate, zonisamide, zopiclone, zotepine, dacarbazine, and daclothiol.

In some embodiments, the traditional Chinese medicine is selected from the group consisting of sunset abelmoschus flower, abrus cantoniensis hance, heuma, wilsonii radix, acanthopanax root, manyprickle acanthopanax root, lycopus herb, achyranthes root, blackleaf, prepared kusnezoff monkshood root, monkshood, prepared monkshood root, acorus tatarinowii, acorus gramineus soland, adenophora tetraphylla, long-noded pit viper, hairyvein agrimony, bark of clavus, ajuga, akebia stem, akebia fruit, silktree albizzia flower, zerumb, white garlic, tuber onion seed, aloe, dogbane, alpinia spinosa, galangal fruit, alpinia oxyphylla, baikola, fabacearum, amomum villous fruit, white zium herb, andrographolide, common anemarrhena rhizome, rhizoma anemarrhenae, tippy root, angelica dahurica, anise star-bark, dogbane leaf, agalloch, concha arca, butus, ardisia crenata, ardisia japonica, tarragon, arisaema cum bile, jack-tuber, jack-b, manypar tuber, manyprickle, manypar, manyprickle, manypar, manyprickle, manypol, manyprickle, manyprind acanthopanax, manyprickle, manyprind root, manyprind leaf, manyprickle tree bark, manyprickle, manypar, manyprickle, manypol, manyprickle, manyprind-like root, etc, Asarum, Asiatic moonseed rhizome extract, donkey-hide gelatin, asparagus, aspongopus, aster, flatstem milkvetch seed, fried yellow sprout, white atractylodes rhizome, rhizoma atractylodis, costustoot, fructus aurantii immaturus, bamboo, tabasheer, south isatis root, blackberry lily, belladonna extract, belladonna fluid extract, belladonna herb, Chinese waxgourd peel, benzoin, root of Chinese barberry, bergenia, bergenin, bistort, rhizoma bletillae, rhizoma bolbostemmae, muscardine, borneol (synthetic borneol), natural borneol (dextral borneol), artificial bezoar, in vitro cultured bezoar, lamp anthocyanidin, semen cassiae, brucea fruit, buffalo horn, pale butterflybush flower, , bungarter parvus, bupleurum, calamine, guangdong beautyberry, beautyberry leaf, calomel, campsis, Chinese trumpet creeper, green fruit, sword bean, hempseed nut, pepper, south pepper, sesame seed, castor oil, cassia seed, cockscomb, and Chinese pricklyash, Centella asiatica, agrimony, Chinese insect white gambir, meadowrue, cornu cervi degelatinatum, luan, cornu cervi degelatinatum, colla cornus cervi, pawpaw, changium smyrnioides, fructus chebulae, river, celandine, angelica fluid extract, green shit, guanghua, chrysanthemum, wild chrysanthemum flower, szechuan lovage rhizome, rhizoma cibotii, beehive, chrysanthemum tissue, cimicifugae foetidae, cinnabar, cassia twig, cinnamon oil, xiaoli, daoli charcoal, daoli, cistanches, herba cistanches, gristle, exocarpium citri, citron, clematis root, clinopodium polycephalum, pummelo peel, tangerine peel, citrus reticulata seed, finger citron, clematis root, clinopodium polycephalum, cnidium fruit, codonopsis pilosula, coix seed, origanum, conyza japonica, Chinese caterpillar fungus, corium versicolor, dogwood fruit, corydalis tuber, folium vitiligo chinensis, hawthorn, mountain wood, arrowroot, mountain ash, arrowhead, carbonized hair, sanguinea chard, stigma crocus, saffrond, turmeric, zedoary, radix astragali, rhizoma polygonum, cornus, polygonum, cornus, polygonum, cornus, polygonum, cornus, polygonum, cornus, polygonum, cornus, polygonum, Cynanchum atratum, cynanchum paniculatum, cynanchum glaucescens, cynomorium songaricum, rhizoma cyperi, rhododendron dauricum, rosewood heart wood, datura flower, clinopodium malabarium, semen lepidii, desmodium styracifolium, wheat, antifebrile dichroa, cortex dictamni, dioscorea panthainanensis, meadowrue SU, dioscorea nipponica, dioscorea batatas, fritillaria thunbergii, suum, teasel root, dragon's blood, drynaria rhizome, aspidium elata, cyrtomium rhizome, giant reed rhizome, eclipta, vine, gentiana rubra, gentiana lutea, epimedium wushanense, horsetail, asarum, denrod asarum (lantern flower), loquat leaf, pipewort, agrimony, caulis Erycibes, eucalyptus oil, eucommia bark leaf, Wuleiocarpus, eupatorium, lindley eupatorium, Chinese stellera root, euphorbia, hairy euphorbia, humifuse euphorbia, euphorbia pex pekinensis, stephania japonica, spica mularia japonica, spica, oriental waterplantain rhizome, oriental stephania, oriental waterplantain rhizome, oriental wormwood, oriental stephania, fritillary bulb, oriental stephania, fritillary bulb, stephania, fritillaria japonica, stephania, fritillary bulb, stephania japonica, fritillaria thunbergia japonica, fritillaria thun, Thunberg fritillary bulb, red bean, Chinese gall, chicken's gizzard-membrane, lucid ganoderma, oriental wormwood extract, fructus akebiae, fructus xanthil, gastrodia elata, gecko, aleppo avens, genkwa, Qinzheng, gentian, ginger-derived plant, ginkgo leaf extract, ginkgo seed, ginseng leaf, ginseng, glabrous sarcandra herb extract, glechoma longituba, mond's hair, fujiaci, glehnia root, honey-fried licorice root, liquorice, kapok, pomegranate bark, herb, wrought haline, ochre, abalone shell, halite, red sage root, mountain plant leaf extract, moxibustion red seedling, cotton rose hibiscus leaf, sea horse, sea buckthorn, Chinese parsnip, homalomena, malt, setaria japonica, red powder, henbane, peach, Chinese holly leaf, ovateleaf holly bark, ground bark, garden balsam seed, cogongrass rhizome, isatis root, hypericum japonicum, elecampelopsis root, elecampane, costus root, elecampane, isatis root, isatis leaf, blackberry lily root, blackberry lily rhizome, blackberry lily bulb, blackberry lily rhizome, blackberry lily rhizome, tussic leaf, tussilia sinensis, tussic leaf, lily, tussic stem, tussilia leaf, tussilia sinensis, blackberry lily, tussilia leaf, tussilia sinensis, tussilia leaf, rhizome, tussilago-leaf, tussilia leaf, tussilago-leaf, tuchaulmus leaf, tussilago-, Radix et rhizoma Rhei, radix Angelicae sinensis, radix Paeoniae alba, herba Dendrobii, caulis Spatholobi, rhizoma Dioscoreae , calyx kaki, radix kansui, radix Knoxiae, Kochiae fructus, semen lablab album, herba Laggera pterodonta, herba Lagotis, thallus laminariae, radix Lamiophlomidis Rotatae, Lasiosphaera Seu Calvatia, fructus Litseae, herba Leonuri, radix Glycyrrhizae extract, rhizoma Ligustici, fructus Ligustri Lucidi, Bulbus Lilii, Limonitum, radix Linderae, fructus Liquidambaris, resina Toxicodendri, radix Ophiopogonis, ramulus et folium Rapae, semen Cestrum, herba Centellae, herba Lobeliae chinensis, arillus longan, flos Lonicerae, caulis Lonicerae, flos Lonicerae, folium Bambusae, retinervus Luffae fructus, cortex Lycii, fructus Lycii, herba Lycopodii, herba Lygodii, spora Lygodii, herba Lysimachiae Christinae, herba Lysimachiae, herba Lysionoti Papaveris (L.) Gagnetum, Mentholum, Magnetitum, flos Magnoliae officinalis, cortex Magnolia officinalis, caulis Mahoniae, WANGHUMUKUHONGHUGUO, squama Manis, , Margarita, Concha Margaritifera, caulis Margaritifera, Mel, cortex Periploca, cortex Melia, fructus Benia, cortex Melia serpentinatum, fructus Benia, and radix Melia serpentinatum, fructus Benedicellae, fructus Akebiae, fructus Euphorbiae, fructus, Mint, clam shell, lapis chloriti, buchen, watermelon crystal, cochinchina momordica seed, white mulberry root-bark, mulberry leaf, mulberry can, mulberry twig, morinda root, response incense, Chinese mosla herb, tree peony bark, plum blossom, dark plum fruit, murraya paniculata, honey spot, young bean, myrrh, nardostachys root, glauber salt, mirabilite, lotus leaf, lotus plumule, lotus seed, lotus stamen, black seed, black grass seed, notoginseng, notoginsenoside, kaempferide, lilac leaf, clove basil oil, frankincense, omphalia, ophicalcite, ophiopogon root, orostachys fimbriata, oroxylum seed, rice bud, osmunda rhizome, oyster shell, white gourmet powder, red bean, Japanese ginseng, rhizome of pearl, paris rhizome, patchouli, herb, mountain pepper root vegetable oil, peppermint oil, perilla stem, leaf, perilla seed, caraway, peach kernel, purple flower, peucedar seed, yellow sophora root, morning glory seed, yellow-hogfenneI, yellow-wolf root, yellow-tree-leaved Chinese-tree, yellow-tree bark, yellow-tree-leaved kalanchoe, lith-tree-leaved spurge, etc Pokeberry root, Japanese bitter wood, picria felterrae lour, picrorhiza rhizome, rhizoma pinelliae preparata, rhizoma pinelliae praeparata, pinellia ternate, Chinese pinelliae, pine pollen, pepper, kadsura pepper stem, piper longum, plantain herb, plantain seed, biota orientalis, platycladi seed, JI stem, patchouli, polygala tenuifolia fluid extract, Japanese polygala root, polygonatum, polygonum cuspidatum, vine of multiflorum, prepared fleece-flower root, polygonum orientale, polygonum perfoliatum, folium isatidis, pig, poria cocos, pericarpium physalis, portulaca oleracea, potentilla chinensis, potentilla discolor, buffalo horn concentrated powder, kernel, propolis, selfheal, bunge cherry seed, psammosilene, berchemia, pseudolarix pseudostellaria root, drynaria, pteris indica, kudzuvine root, kudzu vine root, Chinese pulsatilla root, hairy deerhorn root, wintergreen root, rhubarb, senna, safflower, rhubarb, safflower, rhubarb, etc Fluid extract of rhubarb, fructus cannabis, flos rosae chinensis, fructus rosae laevigatae, rose, raspberry, juncao, linaria, total uric acid extract of salvia miltiorrhiza, euphorbia, sandalwood, saposhnikovia divaricata, sappan wood, parsnip of the moon, seaweed, sargentgloryvine stem, sauropus rostratus, saururus chinensis, saussurea involucrate, fructus schizandrae, schizonepeta charcoal, schizonepeta, spica schizonepeta chard, schizonepeta spike, bentazone, scorpion, figwort, yellow and other extracts, sculellaria barbata, yellow and other extracts, sedum sarmentosum, selaginella tamariscina, smallflower clubmoss herb, pistachio, cuttlebone, snake ant, sesame oil, black sesame seed, rice sprout, setaria italica, silybum marigold, mustard seed, orienavine, smallflower herb, diverse wormwood herb, momordica grosvenorii, thistle, thistle chinaroot greenbrier, woodrue, black bean jelly, black bean, common selfheal, common sage herb, common clubmoss herb, common burreed rhizome, common sage herb, common clubmoss herb, common aneflower, common sage herb, common sage root, etc, The Chinese medicinal materials include stauntonvine, starwort root, stemona root, tetrandra root, sterculia scaphigera, nux vomica, storax, pig gall powder, sulfur, swertia japonica, swertia mileensis, sea otter, sea dragon, amur lilac bark, talcum powder, talc, cacumen tamaricis, tanshinone extract, dandelion, parasitic loranthus, -tea oil, Terminalia chebula, tortoise-shell glue, tortoise shell, ricepaperplant pith, salamander deserted, Zhebei river extract, golden fruit envelope, ginseng stem and leaf total saponin, szechwan chinaberry fruit, vertebra, ginseng total fukunoside, resina Toxicodendri, Chinese starjasmine stem, palm, caili, snakegourd fruit, trichosanthes root, fried fructus trichosanthis, semen trichosanthis, fenugreek, pangolin, tsaoko amomum tsaoko cardamon, turpentine oil, turpinia leaf, cattail pollen, giant typhonium rhizome, uncaria, cowherb seed, vaccaria, spider, herb, indian, herb, Chinese violet, turmeric, Chinese violet, etc, Radix Zanthoxyli, Zaocys, oleum Atractylodis Macrocephalae, rhizoma Zingiberis Preparata, rhizoma Zingiberis recens, and sour semen.

In some embodiments, the drug matrix further comprises a medium. The medium may be associated with an API, for example, the substrate may be in physical contact with the API. In some embodiments, the API may be embedded in the substrate. In some embodiments, the API may be dispersed in the substrate.

In some embodiments, the medium includes a water-soluble excipient. The water soluble excipient is selected from the group consisting of: cocoa butter, polyethylene glycol (PEG), sucrose, glucose, galactose, fructose, xyloselactose, maltose, trehalose, sorbitol, mannitol, maltodextrin, raffinose, stachyose, fructooligosaccharides or combinations thereof. In some embodiments, the substrate further comprises a plasticizer.

In certain embodiments, the media has a higher erosion/dissolution rate than the API.

The drug matrix may be loaded into the compartment in any suitable shape or size.

In some embodiments, the drug matrix is operably linked to the compartment by a covalent bond, a non-covalent bond, or a linker. Thus, the drug matrix and the matrix may be separately prepared and then linked by covalent or non-covalent bonds. In some embodiments, the pharmaceutical dosage form produces the drug matrix and the matrix at one time by a method of 3D printing.

In some embodiments, the drug matrix is shaped into a tablet, an oval tablet, a pill, or a capsule. In some embodiments, the drug matrix shape and the compartment shape are identical. For example, when the compartment is shaped as a cake, the drug matrix is also shaped as a cake to fill the compartment.

In some embodiments, as shown in fig. 6, the drug matrix is in the form of nanoparticles. The drug matrix is mixed with a solution in which the API is dissolved or dispersed. During subsequent 3D printing of the pharmaceutical dosage form, the solution is atomized/sprayed onto the printed layer. Once the solution containing the drug matrix is air dried, the drug matrix is dispersed within the pharmaceutical dosage form. The nanoparticles have a larger surface area and thus a higher dissolution rate.

The size of the nano-particles is between 1nm and 900nm (preferably 100-800nm, 100-700nm, 100-600nm, 100-500nm, 100-400nm, 100-300nm, 100-200nm, 1nm, 2nm, 3nm, 4nm, 5nm, 6nm, 7nm, 8nm, 9nm, 10nm, 11nm, 12nm, 13nm, 14nm, 15nm, 16nm, 17nm, 18nm, 19nm, 20nm, 100nm, 200nm, 300nm, 400nm, 500nm, 600nm, 700nm, 800nm, 900 nm). The size of the nanoparticles can be controlled by selecting an appropriate synthesis method and/or system. In order to obtain nanoparticles within the desired size range, the synthesis conditions may be suitably controlled or varied to provide, for example, a desired solution concentration or a desired cavity range (for a detailed review, see: Vincenzo Liveri, controlled synthesis of nanoparticles in a micro-heterogeneous system, Springer, 2006).

As shown in fig. 7, in some embodiments, the drug matrix may be in the form of microneedles. The drug matrix in the form of microneedles is typically encapsulated in a housing having a needle-like structure. The microneedles may also be printed with the drug dosage forms or embedded into the drug dosage forms during 3D printing of the drug dosage forms. Microneedles may be composed of saccharides, PLGA polymers, APIs, or combinations thereof. Upon parenteral or enteral administration, the microneedles may help the API enter the circulatory system of the patient.

In some embodiments, the drug matrix may be configured as a network. As shown in FIG. 8A, a drug matrix of a pharmaceutical dosage form is loaded into a compartment within the base. The base of the drug matrix is constructed as a network, for example made of a loose material, the density of which is usually less than the density of the matrix. The frame structure of the tablet is made of a material that dissolves in 1-10 minutes and the base dissolves in 2-60 seconds, preferably in 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 seconds. As shown in fig. 8B, the API may be released within a few seconds after the drug dosage form is applied.

The drug matrix content can be made by using additive methods, such as Fused Deposition Modeling (FDM) methods. In some embodiments, the drug matrix may be made by extruding a mixture of the API and excipient by 3D printing. The API is melted and mixed uniformly with the melted substrate prior to extrusion. Alternatively, the API in solid form (e.g., powder) may also be mixed with or dispersed in the melted substrate prior to extrusion. Typically, the extrusion process is carried out at a temperature between 10 and 40 ℃ above the glass transition temperature of the substrate and close to the melting point of the API. Once the 3D printer reaches the appropriate temperature, the substrate is deposited onto the stereographic printing surface. The shape and size of the drug matrix can be controlled by programming the 3D printing process. In some embodiments, both the drug matrix and the matrix may be manufactured in the same process. In some embodiments, the matrix is manufactured after the drug matrix is manufactured, and the drug matrix is loaded into the compartment during or after the manufacturing process of the matrix.

In some embodiments, the drug matrix is associated with the matrix when the drug matrix is loaded into the compartment, e.g., the drug matrix is embedded or otherwise immobilized in the matrix. In some embodiments, the drug matrix may be separate from the substrate when the drug matrix is loaded into the compartment.

D.Controlled release

The pharmaceutical dosage forms of the present disclosure have different release profiles after oral administration. In some embodiments, the pharmaceutical dosage form has a constant release, pulsed release, delayed release, or nonlinear release profile. In some embodiments, the pharmaceutical dosage form has zero order release kinetics.

In the present disclosure, the release of the drug is measured in an aqueous solution. The aqueous solution includes gastric juice, intestinal juice, body fluid, and aqueous solution containing inorganic or organic compounds. The aqueous solution also includes water.

For a particular field of drug therapy, a suitable release profile would provide a number of benefits. For example, the pulsatile release profile allows for controlled absorption to reduce the peak level/trough level ratio, and for targeted release of the drug matrix to specific regions in the gastrointestinal tract and absorption processes independent of feeding conditions, and thus the profile can be used to improve bias, reduce side effects and improve patient compliance, which are essential for the treatment of ADHD disease. As another example, a loading dose followed by a maintenance dose may be advantageous for treating chronic diseases such as hypertension and diabetes.

Several mechanisms for controlling the release profile using the pharmaceutical dosage forms of the present disclosure have been discussed above. For example, a drug matrix embedded in a matrix can provide a constant amount of drug over a long period of time by adjusting the exposed area of the matrix that is continuously eroded. In addition, the release profile rate of the API 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 designing a compartment with an aperture that is closed or blocked by a plug. The plug is made of water-soluble, porous or erodible material or pH sensitive material or hydrophobic material and the like which can be dissolved, degraded and structurally changed when the medicament dosage form passes through the gastrointestinal tract. When the dosage form is applied to a subject, the stopper is melted, penetrated or eroded and the drug substance in the compartment is released. The rate of release profile of the drug matrix can be controlled by selecting a plug water-soluble material with appropriate solubility, permeability, and erodibility. Alternatively, for plugs used to block holes on a compartment, the release profile rate of the drug matrix API may be controlled by using a plug of suitable shape and/or size (e.g., a cylinder of suitable length). The release profile can also be controlled by a different number of compartments. Fig. 9 illustrates an exemplary dosage form having a matrix containing a plurality of columnar compartments distributed on either side of the drug dosage form. Each compartment contains a drug matrix. Each compartment has a hole blocked by a cylindrical plug. These plugs have different solubilities. Depending on the size, shape and solubility of the plug, the release of the API may be sustained, continuous, simultaneous, sequential or pulsatile.

Fig. 10A illustrates an exemplary pharmaceutical dosage form having a sequential release profile. Referring to FIG. 10A, the drug dosage form 700 includes three columnar compartments 702-704 within a base 701. Each compartment is loaded with a drug matrix containing the same API. Each compartment has a hole that is blocked by rod-like plug 705-707. These plugs are made of the same material but are of different lengths from each other and therefore the time required to dissolve the plugs to open the compartments to release the drug matrix is also different. As shown in fig. 10C, the shortest plug dissolves first and releases the API from the first compartment. After the API in the first compartment is completely released, the medium length plug dissolves and releases the API from the second compartment. After the API in the second compartment is completely released, the third plug dissolves to release the API from the third compartment. Thus, after the drug matrix in the first compartment is released, the plasma drug level reaches a first peak. When the API released from the first compartment begins to be consumed, the plasma drug level begins to drop (see fig. 10D). The API in the second compartment is released before the plasma drug level falls to a critical level (a parallel line below which the drug is ineffective) and the plasma drug level increases again. When the released API in the second compartment reaches a second peak and begins to be consumed, the plug of the third compartment dissolves to open the compartment. Thus, plasma API levels can be maintained above critical levels for extended periods of time, which is beneficial for the treatment of specific diseases.

Sequential release profiles may be achieved by another exemplary pharmaceutical dosage form. The pharmaceutical dosage form contains several drug matrices encapsulated in a stack as shown in figure 10B. Simultaneous dissolution of the layers may achieve a sustained release of the API to provide a continuous, sustained release of the API as shown in fig. 10C. In some embodiments, the outer layer of the pharmaceutical dosage form dissolves and releases the embedded drug matrix immediately after the pharmaceutical dosage form is applied. But the outer layer blocks the sandwiched layer from communicating with the environment, causing the intermediate layer to be insoluble or dissolve at a very slow rate. In other words, the outer layer generally dissolves prior to the intermediate layer, and thus the pharmaceutically active ingredient contained in the outer layer is generally released prior to the pharmaceutically active ingredient in the intermediate layer. The dissolution of the outer layers exposes the sandwiched layers to accelerate their dissolution, thus achieving a sequential release profile as shown in fig. 10C. In some embodiments, the drug dosage form includes a gas generant composition loaded within the first compartment. In some embodiments, the gas generant composition is selected from the group consisting of: organic acids and carbonates, sulfites, bicarbonates, sodium carbonate, sodium bicarbonate, sodium metabisulfite, calcium carbonate and combinations thereof. The gas generating component releases carbon dioxide or sulfur dioxide gas upon contact with gastric fluids. When the matrix is dissolved, permeated or eroded in the stomach, the gas-generating component will effervesce to generate gas to release the drug matrix as the gas-generating component is exposed to an acidic environment or water permeates into the compartment to initiate the reaction of the acid with the sodium bicarbonate. It should be noted that, the dissolution time of the different layers may be set according to the adjustment of the thickness, dissolution rate, permeability, erosion rate, etc. of each layer of the pharmaceutical dosage form, so that the different layers can be dissolved in a preset time or dissolution profile, thereby enabling the active pharmaceutical ingredient therein to be released in a preset release profile.

The pharmaceutical dosage forms of the present disclosure comprise one or more drug matrices in at least partially delayed release form, wherein the delayed release may be controlled by conventional materials or in a manner well known to those skilled in the art, e.g., by embedding an API in a delayed release matrix/substrate or by using one or more delayed release coatings. By delayed release, the API release can be controlled to be satisfactory for administration twice or once a day, which has advantages for treatments requiring sustained doses of the active ingredient to combat pain.

In some embodiments, the pharmaceutical dosage form may release the active ingredient immediately in the oral cavity. For example, in the oral cavity or sublingual area.

In some embodiments, the pharmaceutical dosage form further comprises conventional auxiliary substances well known to those skilled in the art, preferably glyceryl monostearate, semisynthetic triglyceride derivatives, semisynthetic glycerides, hydrogenated castor oil, glyceryl palmitate, glyceryl behenate, polyvinylpyrrolidone, gelatin, magnesium stearate, stearic acid, sodium stearate, talc, sodium benzoate, boric acid, and colloidal silicon dioxide, fatty acids, substituted triglycerides, glycerides, polyoxyalkylene glycols and derivatives thereof.

Preparation of pharmaceutical dosage forms

The controlled release pharmaceutical dosage forms disclosed herein may be produced by any suitable process. In some embodiments, the pharmaceutical dosage form is produced by three-dimensional printing (3D printing).

3D printing as used herein refers to the process of producing 3D articles layer by layer according to a digital design. In U.S. Pat. nos.5,204, 055; 5,260,009, respectively; 5,340,656, respectively; 5,387,380, respectively; 5,503,785; and 5,633,0213D, the basic process of 3D printing. The remaining U.S. patents and applications related to 3D printing include: nos.5,490,962, U.S. Pat. No. 5; 5,518,690, respectively; 5,869,170, respectively; 6,530,958, respectively; 6,280,771, respectively; 6,514,518, respectively; 6,471,992, respectively; 8,828,411, respectively; 2002/0015728, U.S. PG pub.Nos; 002/0106412, respectively; 2003/0143268, respectively; 2003/0198677, respectively; 2004/0005360. For a detailed description of 3D printing, reference may be made to the above-mentioned patents and applications.

Different 3D printing methods involving different raw materials, equipment and curing conditions have been developed for the production of pharmaceutical dosage forms. These 3D printing methods include adhesive deposition (see L Gibson et al (2015) additive production technology: 3D printing, rapid prototyping and direct digital production, version 2, Springer, New York; W.E.Katstra et al (2000) three-dimensional printing of manufactured oral drug dosage forms, controlled release magazines 66: 1-9; W.E.Katstra et al (2001) manufacturing complex oral dosage forms by three-dimensional printing, materials science and engineering institute graduate treatise, Massachusetts institute of technology; H.Lipson et al (2013) assembly: New world for 3D printing, John Willi father, G.Jonathan, A.Karim (2016), 3D printing of pharmaceuticals: New tools for designing custom drug delivery systems, International medicine magazines 499: 376: 394), material jetting (see G.Jonathan, A.Karim (2016), 3D printing of pharmaceuticals: New tools for designing custom drug delivery systems, International medicine magazines 499: 499), extrusion (see LGibson et al (2015) additive production technology: 3D printing, rapid prototyping and direct digital production, version 2, Springer, new york) and photopolymerization (see f.p. melchels et al (2010) for stereolithography and its use in biomedical engineering, biomaterials 31: 6121-30).

In some embodiments, the pharmaceutical dosage forms disclosed herein are manufactured by an extrusion process. During the extrusion process, material is extruded from a robot-actuated nozzle. Unlike adhesive deposition which requires a powder bed, the extrusion process can be printed on any substrate. A variety of materials can be extruded to achieve 3D printing, including the thermoplastic materials disclosed herein, pastes and colloidal suspensions, silicones, and other semi-solids. One common type of extrusion printing is fused deposition modeling, which uses solid polymer filaments for printing. In fused deposition modeling, a gear system introduces a filament into a heated nozzle assembly for extrusion (see L Gibson et al (2015) additive manufacturing technique: 3D printing, rapid prototyping and direct digital production, version 2, Springer, N.Y.).

The production instructions for the print job may be generated in a variety of forms, including direct encoding, derivation from a solid CAD model, or other computer interfaces and applications to the 3D printer. These instructions include information on the number and spatial arrangement of drops, general printing parameters such as drop spacing in each linear dimension (X, Y, Z), and the volume or mass of liquid in each drop. For a given set of materials, the parameters can be adjusted to improve the quality of the structure created. The overall resolution of the created structure is the size of the powder particles, the fluid drop size, the printing parameters and the size of the material properties.

Since 3D printing can handle a range of drug materials and can locally control composition and structure, 3D printing is well suited for manufacturing drug dosage forms of the present invention having complex geometries and compositions.

Manufacturing pharmaceutical dosage forms that also facilitate personalization using 3D printing methods. Personalized medicine refers to a dosage form design based on biomarkers to aid in stratification of a patient population to produce treatment decisions and personalization. It is easier to modify a digital design than to modify a physical device. Furthermore, the operating costs of automated, small-scale 3D printing may be negligible. Thus, 3D printing may make multiple small, personalized mass productions economically feasible, enabling the production of dosage forms that are personalized for increased compliance.

The personalized dosage form allows for customized delivery of drug amounts based on the patient's body weight and metabolic level. The 3D printed dosage form can ensure that growing children and highly effective drugs have accurate personalized doses. The personalized dosage form may also combine all patients' medications into a single daily dose, thereby improving patient adherence to medication.

Fig. 11 illustrates a method of manufacturing a personalized dosage form using three-dimensional printing. For each patient, results from various clinical trials can be obtained, including body weight, age, metabolic indicators, genomic biomarkers, and the like. The results of the clinical trial are input into the computer software and combined with the physician's prescription and pharmacokinetic model to design a dosage form for a particular dose and drug combination. The instructions are then sent to a three-dimensional printer to manufacture the dosage form. The resulting dosage form is administered to a patient.

Controlled release of multiple drug matrices

The pharmaceutical dosage forms and methods of the present disclosure may be used to control the release of two or more drug matrices, thereby enabling optimization of drug combinations for a particular medical field. For example, tablets for treating hypercholesterolemia can be designed to release atorvastatin calcium immediately but niacin for extended release. In another example, a non-steroidal anti-inflammatory drug (NSAID) for pain relief is designed to release the NSAID on a sustained basis, but release the H2 receptor antagonist rapidly to prevent NSAID-induced mucosal damage.

In some embodiments, a plurality of compartments are contained within the matrix, each compartment being loaded with a drug matrix. In some embodiments, a plurality of compartments are connected to one another. In some embodiments, the plurality of compartments are not connected to each other. In some embodiments, the drug matrices loaded in different compartments are the same. In some embodiments, the drug matrices loaded in different compartments are different. The pharmaceutical dosage form may be designed to provide simultaneous or sequential release of multiple drug matrices to achieve a synergistic therapeutic effect.

In some embodiments, the release of multiple drug matrices may be simultaneous, sequential, pulsatile, or a combination thereof. Fig. 12A illustrates an exemplary pharmaceutical dosage form that can release multiple APIs simultaneously. Referring to FIG. 12A, the drug dosage form 800 includes three layers of laminate 801-803, each embedded in a different drug matrix. As shown in fig. 12B, when drug dosage form 800 is applied, the drug matrices are released simultaneously but the release rates vary as the layers dissolve.

FIG. 13A depicts another exemplary pharmaceutical dosage form having a simultaneous release profile. Referring to FIG. 13A, the drug dosage form 900 includes three cylindrical compartments 901-903 and these compartments are loaded with three drug matrices. The base of each drug matrix has different solubility and the API is embedded in the base. As shown in fig. 13B, the three APIs are released simultaneously after pharmaceutical dosage form 900 is applied, but at different release rates as the base of the drug matrix dissolves. The release rate of the API can be controlled by the shape of the compartment or the size of the compartment opening.

Fig. 14A and 14B depict another exemplary drug dosage form that can release three APIs simultaneously, and with reference to fig. 14A, the drug dosage form 1000 comprises three pie-shaped segments 1001 with drug matrix embedded therein 1003. As shown in fig. 14C, as the segment dissolves, multiple drug matrices are released simultaneously and the release rate of the drug matrices can be controlled by the solubility of the segment. Referring to fig. 14B, the drug dosage form 1100 includes three pie-shaped segments 1101-1103 surrounded by a shell 1104, the shell 1104 dissolving more slowly than the segments. The release rate of the drug matrix in the potential segment is slowed by the shell 1104 blocking the interface of the segment 1101-1103 with the environment.

Fig. 15A shows an exemplary pharmaceutical dosage form that can sequentially release two APIs. Referring to fig. 15A, the pharmaceutical dosage form 1200 includes a base 1202 having compartments filled with a drug matrix 1202. The matrix 1201 comprises a first API and the drug matrix 1202 comprises a second API. As shown in fig. 15B, following application of the pharmaceutical dosage form, the first API is released as the collective dissolves. The second API is not released until the matrix dissolves and the drug matrix is exposed, thereby achieving a sequential release profile of the various APIs.

Figure 16A illustrates another exemplary pharmaceutical dosage form having a sequential release profile. Referring to FIG. 16A, a drug dosage form 1300 has three cylindrical compartments 1302-1304 loaded with three drug matrices contained within a matrix 1301. The

compartments

1302 and 1304 all have holes that are blocked by a cylindrical plug. Each plug has a different length and/or solubility. As shown in fig. 16B, the various APIs are released sequentially as the plugs sequentially dissolve to open the compartments.

Fig. 17A illustrates an exemplary pharmaceutical dosage form having a simultaneous release or sequential release profile. Referring to FIG. 17A, the drug dosage form 1400 contains within its matrix four segments 1701-1704 having different solubilities. In some embodiments, as shown in FIG. 17B, the drug matrix is embedded in section 1701 and 1704. When the matrix is dissolved, the drug matrix is released simultaneously. In some embodiments, each segment comprises a compartment for holding a drug matrix. As shown in fig. 17C, the drug matrices are sequentially released as the matrix dissolves.

Example one

This example illustrates the design of a controlled release pharmaceutical dosage form.

As shown in FIG. 18A, the pharmaceutical dosage form comprises a flat tablet matrix having pie-shaped compartments therein. The matrix is composed of PEG 8000. Benzoic acid was used as a drug matrix model.

The release profile of benzoic acid in a pharmaceutical dosage form can be measured in the following manner. First, Na with pH 8 is prepared₂HPO₄The aqueous solution was used as a benzoic acid solution to prepare a benzoic acid mother liquor having a concentration of 120. mu.g/mL, and the benzoic acid mother liquor was diluted in this order to give dilutions having concentrations of 30. mu.g/mL, 15. mu.g/mL, 7.5. mu.g/mL, 3.75. mu.g/mL, and 1.875. mu.g/mL, and the dilutions were subjected to UV-visible spectrophotometry at an absorption wavelength of 226 nm. Linear regression of the measured data gave the benzoic acid standard curve y ═ 0.0599x + 0.0347. To measure the amount of benzoic acid released, the pharmaceutical dosage forms were dissolved in Na at pH 8₂HPO₄The aqueous solution was degassed, the temperature was controlled at 37 ℃. + -. 0.5 ℃ and the basket speed was 100rpm, 5mL samples were taken at different time points for measuring the benzoic acid concentration, and 5mL of medium was added to the solution. Filtering the sample solution with a 0.45-micrometer microporous filter membrane, precisely transferring a certain volume of subsequent filtrate, measuring the light absorption value A at the wavelength of 226nm by using an ultraviolet-visible light spectrophotometer, calculating the concentration of benzoic acid according to a standard curve, and calculating the release percentage of benzoic acid according to the following formula:

1.

2. wherein c is_nRepresenting the measured concentration, v_tRepresents the volume of the medium, v_sRepresents the sample volume, Q_benzoic _acidRepresenting the amount of benzoic acid in the pharmaceutical dosage form.

Measurement of the degree of release of PEG 8000: firstly, drawing a standard curve of PEG8000, weighing 0.1275g of PEG8000 standard sample, putting the standard sample into a 25ml volumetric flask, dissolving the standard sample with water and diluting the standard sample to a scale; the above solutions were transferred in 1ml, 2ml, 5ml and 10ml in 10ml volumetric flasks, diluted to the mark with water, to serve as control solutions. A50. mu.l portion of the extract was precisely measured and injected into a liquid chromatograph (Waters Ultrahydrogel)^TM120/250/500 three are connected in series, the flow rate is 0.5ml/min, the column temperature is 40 ℃, and the detector is a refractive index detector). Recording the chromatogram, taking the logarithm value of the concentration of the reference substance as an abscissa, taking the logarithm value of the peak area of the corresponding concentration as an ordinate, and calculating a regression equation as follows: y is 1.024x + 8.918. Wherein the chromatographic conditions are as follows: the chromatographic column is Waters Ultrahydrogel ^TM120/250/500 three are connected in series, the flow rate is 0.5ml/min, the column temperature is 40 ℃, and the detector is a refractive index detector. The volumetric area is measured and labeled as the y-axis. The logarithm of the control solution was used as the x-axis. A standard curve for PEG8000 was generated with y ═ 1.024x + 8.918. The percent release of PEG8000 can be calculated using the following formula:

3. wherein c is_nIndicating the measured concentration, v_tIndicating the volume of the solution, v_sIndicates the sample volume, Q_PEG8000Indicating the amount of PEG8000 in the drug formulation.

As a result: as shown in fig. 18C, the release profile of benzoic acid was consistent with the model in d.brooke and r.j.washkuhn (zero order administration system: theory and initial test results, journal of medical science, 1977), and was influenced by the interface. Thus, a controlled release profile can be designed based on the pharmaceutical dosage forms of the present disclosure.

Example two

This example describes the design of a pharmaceutical dosage form that can achieve controlled release of drug matrices of different compartments.

Designing a medicine: two drug formulations were prepared using a fused deposition modeling method. The matrix of the pharmaceutical dosage form is composed of copovidone

VA64), 72%, PEG 150018% and

19% of the total composition. The drug matrix consists of 30 percent of moxifloxacin hydrochloride and PEG150070 percent. Fig. 19A and 19B are schematic illustrations of these pharmaceutical dosage forms. Referring to fig. 19A and 19B, a drug dosage form 1600 comprises a substrate 1601 and two

compartments

1602 and 1603 within the substrate. Each compartment is surrounded by

walls

1604 and 1605, respectively. For the first drug dosage form, the two compartments are surrounded by walls having a thickness of 0.75mm and 1.5mm, respectively. For the second pharmaceutical dosage form, the two compartments are surrounded by walls having a thickness of 0.75mm and 2.25mm, respectively.

To detect the release of the drug matrix, the drug dosage form was added to 900mL of pH6.8 phosphate buffer at 100 rpm. The uv absorption of the buffer was measured to determine the release of the drug matrix.

The results of the release assay are shown in fig. 19C and 19D. As shown in FIG. 19C, 20 minutes after the first pharmaceutical dosage form is added to the buffer, the first compartment is opened and the drug matrix in the first compartment is released. After 40 minutes of adding the drug formulation to the buffer, the second compartment was opened. The result is shown in fig. 19D for the second drug dosage form, which was added to the buffer for 60 minutes before the second compartment was opened. Thus, the release profile of the drug dosage form may be controlled by the thickness of the walls enclosing the compartment.

While the principles of the invention have been described in connection with embodiments, it is to be understood that this description is made only by way of example and not as a limitation on the scope of the invention. The disclosure has been presented for purposes of illustration and description, and is not intended to be exhaustive or limited to the disclosure in the form disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art. The present disclosure was chosen and described in order to best explain the principles of the embodiments and the practical application, and to thereby enable others skilled in the art to understand the embodiments for various embodiments and with the various modifications as are suited to the particular use contemplated. The scope of the disclosure is defined by the following claims or their equivalents.

Claims

1. A pharmaceutical dosage form comprising:

a substrate forming a compartment therein

The matrix comprises a non-erodible polymer and is made of at least one thermoformable material,

the compartment having an aperture having a predetermined shape,

a drug matrix contained in the compartment; and

a plug that blocks the hole, wherein the plug is water soluble or erodable,

the compartments are configured as pie-shaped, cone-shaped, pyramid-shaped, polygonal prisms or a combination of these shapes,

the drug matrix is made of a loose material, the loose drug matrix being composed of the same material as the matrix and having a density less than the density of the matrix, wherein the pharmaceutical dosage form is manufactured by a 3D printing method.

2. The pharmaceutical dosage form of claim 1, wherein the thermoformable material is selected from the group consisting of polyvinyl caprolactam polyvinyl acetate-polyethylene glycol graft copolymer 57/30/13, polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP-VA)60/40, polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP) copolymer 80/20, polyethylene glycol-polyvinyl alcohol graft copolymer 25/75, Kollicoat IR-polyvinyl alcohol copolymer 60/40, polyvinyl alcohol (PVA or PV-OH), polybutylmethacrylate-poly 2-dimethylaminoethylmethacrylate-polymethylmethacrylate copolymer 1: 2: 1, a polymethacrylic acid dimethylamino-polymethacrylate copolymer, a polyethylacrylate-polymethylmethacrylate-polytrimethylethylvinylchloride copolymer, a polymethyl acrylate-polymethylmethacrylate-polyacrylic acid copolymer 7: 3: 1, polymethacrylic acid-polymethylmethacrylate copolymer 1: 2, poly (methacrylic acid) -poly (ethyl acrylate) copolymer 1:1, poly (methacrylic acid) -poly (methyl methacrylate) copolymer 1: polyethylene oxide (PEO), polyethylene glycol (PEG), hyperbranched polyesters, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose or Hypromellose (HMPC), hydroxypropylmethylcellulose succinate or hydroxypropylmethylcellulose acetate succinate (HPMCAS), polylactide-polylactic acid copolymer (PLGA), carbomer, polyethylene-polyvinyl acetate copolymer, ethylene-vinyl acetate copolymer, Polyethylene (PE) and Polycaprolactone (PCL), Hydroxypropylcellulose (HPC), polyoxyethylene 40 hydrogenated castor oil, Methylcellulose (MC), Ethylcellulose (EC), hydroxypropylmethylcellulose phthalate (HPMCP), poloxamer, hydrogenated castor oil, glyceryl palmitostearate, carnauba wax, polylactic acid (PLA), polyglycolic acid (PGA), cellulose Acetate Butyrate (CAB), colloidal silica, titanium oxide, sucrose, glucose, polyvinyl acetate phthalate (PVAP), and combinations thereof.

3. The drug dosage form of any of claims 1-2, wherein the drug matrix is in the form of nanoparticles.

4. The drug dosage form of any of claims 1-2, wherein the drug matrix is in the form of microneedles.

5. The drug dosage form of any of claims 1-2, wherein the drug matrix forms a network or a porous structure.

6. A pharmaceutical dosage form as defined in claim 1 wherein said drug matrix comprises a pharmaceutically active ingredient exhibiting zero order release characteristics such that a constant dose of the pharmaceutical product is released continuously over an extended period of time.

7. The drug dosage form of claim 1 wherein the base comprises a plurality of compartment walls respectively enclosing a plurality of compartments, and wherein the plurality of compartment walls have different thicknesses.

8. The drug dosage form of claim 1 wherein the drug matrix is covalently attached to the compartment.