CN113171350B - Pharmaceutical dosage forms and uses thereof - Google Patents

Abstract

The present disclosure provides a stable solid pharmaceutical dosage form for oral administration. The pharmaceutical dosage form comprises a matrix forming a compartment internally; and a drug matrix contained in the compartment. The design of the pharmaceutical dosage form can realize the controllable release of the pharmaceutical active ingredient in the pharmaceutical matrix.

Description

Pharmaceutical dosage forms and uses thereof

The present application is a divisional application of chinese patent application entitled "pharmaceutical dosage form and use thereof" filed on application number 201610395483.9, application date 2016, 6 and 3, and filed on application number 2015, 6 and 3, and priority of U.S. provisional patent application number 62/170,645 filed on application number 2016, 3 and 24, and filed on application number 62/313,092, which are incorporated herein by reference in their entirety.

Technical Field

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

Background

The medicine must be prepared into pharmaceutical dosage forms for marketing. Conventional pharmaceutical dosage forms are typically made by mixing pharmaceutically active and inactive ingredients (excipients) and other non-reusable materials such as capsule shells. Drug dosage forms classes include liquid drug dosage forms (e.g., solutions, syrups, elixirs, suspensions, and emulsions), solid drug dosage forms (e.g., tablets, capsules, caplets, and gel caps), and semisolid drug dosage forms (e.g., ointments and suppositories), with solid drug dosage forms being most advantageous for systems for oral administration of drugs.

Tablets are the most commonly used solid pharmaceutical dosage forms, which are more advantageous in terms of manufacture, packaging and transportation, and easier to identify and swallow. After administration to a living organism, the tablet interacts with the body to exert a drug effect. The pharmaceutically active ingredient must be released before the tablet is absorbed into the blood circulation. The pharmaceutical ingredients are then dispersed or dissolved in the body by the body fluids and tissues. During this drug absorption, deposition, metabolism and elimination, the drug dosage form plays a decisive role in determining the drug release profile as well as bioavailability. Accordingly, there is a continuing need to develop a pharmaceutical dosage form that provides a controlled delivery system that can provide desired levels of drug in plasma, reduce side effects, and improve patient compliance with the dosage form.

Disclosure of Invention

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

In some embodiments, the matrix is a thermoplastic material selected from the group consisting of hydrophilic polymers, hydrophobic polymers, swellable polymers, non-swellable 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, polyvinyl pyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60/40, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc) and polyvinyl pyrrolidone (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), polyvinyl acetate (PVAc), polybutylmethacrylate-poly 2-dimethylaminoethyl methacrylate-polymethyl methacrylate copolymer 1:2: polymethyl methacrylate-polymethyl methacrylate copolymer, polyethyl acrylate-polymethyl methacrylate-poly (trimethyl ethyl chloride) copolymer, polymethyl acrylate-polymethyl methacrylate-poly (methyl methacrylate-poly (methacrylic acid) copolymer 7:3:1, polymethyl methacrylate-polymethyl methacrylate copolymer 1:2, a poly (methacrylic acid) -poly (ethyl acrylate) copolymer 1:1, a poly (methacrylic acid) -poly (methyl methacrylate) copolymer 1: polyethylene oxide (PEO), polyethylene glycol (PEG), hyperbranched polyesters, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose or Hydroxypropyl Methylcellulose (HMPC), hydroxypropyl methylcellulose succinate or hydroxypropyl methylcellulose acetate succinate (HPMCAS), polylactide-polylactic acid copolymers (PLGA), carbomers, polyethylene-polyvinyl acetate copolymers, ethylene-vinyl acetate copolymers, polyethylene (PE) and Polycaprolactone (PCL), hydroxypropyl cellulose (HPC), polyoxyethylene 40 hydrogenated castor oil, methylcellulose (MC), ethylcellulose (EC), poloxamers, hydroxypropyl methylcellulose phthalate (HPMCP), poloxamers, hydrogenated castor oil, glyceryl palmitostearate, carnauba wax, polylactic acid (PLA), polyglycolic acid (PGA), cellulose Acetate Butyrate (CAB), colloidal silicon, titanium oxide, sucrose, glucose, polyvinyl acetate phthalate (PVAP) and combinations thereof.

In some embodiments, the compartment shape may be pie, cone, pyramid, cylinder, cube, cuboid, triangular or polygonal prism, tetrahedron, or a combination of these shapes.

In some embodiments, the first drug is present in nanoparticle, microneedle, or mesh form.

In some embodiments, the pharmaceutical matrix comprises a pharmaceutically active ingredient (API). In some embodiments, the API may be a local anesthetic, sleep modulator, antiepileptic, anticonvulsant, anti-alzheimer's disease drug, analgesic, gout treatment drug, antihypertensive drug, antiarrhythmic drug, diuretic, hepatoprotective drug, pancreatic disease treatment drug, central nervous system disease treatment drug, gastrointestinal disease treatment drug, antihistamine drug, antiallergic drug, glucocorticoid drug, hormonal drug, contraceptive, hypoglycemic drug, anti-osteoporosis drug, antibiotic, sulfonamide drug, quinolone drug, and other synthetic antibacterial drug, antitubercular drug, antiviral drug, antineoplastic drug, immunomodulator, cosmetic active agent, or chinese traditional chinese 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/insecticidal agent.

In some embodiments, the pharmaceutical matrix further comprises an excipient. In some embodiments, the excipient is made of a water-soluble material, a non-water-soluble 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, fructooligosaccharides and combinations thereof, gels, celluloses, polyesters, polyethylene oxides, polyethylenes, polyacrylic acids or combinations thereof.

In some embodiments, the compartment has a hole (aperture) that is blocked and/or closed by a plug (plug). In some embodiments, the plug is made of a porous polymer, erodable polymer, pH sensitive polymer, or 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, non-water-soluble polymers, waxes, saccharides, gels, celluloses, polyesters, polyethylene oxides, polyethylenes, polyacrylic acids, or combinations thereof.

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

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 comprises 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 is connected to the second compartment. 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 hole blocked by a first plug and the second compartment has a second hole 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 erodes at a higher 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 corrosive than the second wall.

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

In some embodiments, the two or more substrate 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 ingredient and a second matrix layer comprising a second pharmaceutical ingredient, wherein the second matrix layer is disposed relatively outward relative to the first matrix layer such that the second pharmaceutical ingredient is released prior to the first pharmaceutical ingredient.

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 in the compartment.

In some embodiments, the substrate is integrally formed.

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

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

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

In some embodiments, the compartment is closed.

In some embodiments, the compartments are configured in a pie, pyramid, column, cone, cube, cylinder, cone, triangular prism, polygonal prism, tetrahedron, or a combination of these shapes.

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

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

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

In some embodiments, the compartments are configured in 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 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 have a dissolution time in an aqueous solution that is longer than the shortest dissolution time of the matrix, such that the pharmaceutically active ingredient in the drug matrix is able to be released through the pores after 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.

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

In some embodiments, the plurality of compartments are configured as mutually spaced columnar spaces.

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

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

In some embodiments, the compartment contains a gas generating component therein.

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

In some embodiments, the compartment is hollow.

In some embodiments, the compartment is 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 located therein; and a plurality of drug matrices respectively contained 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 separated 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 boundary.

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

In some embodiments, the matrix 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 compartments are configured to have an area of dissolution boundary that increases inwardly from the opening such that the pharmaceutically active ingredient in the drug matrix corresponding to the opening is released in 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 compartments are configured in a pie, pyramid, column, cone, cube, cylinder, cone, triangular prism, polygonal prism, tetrahedron, or a combination of these shapes.

In some embodiments, the openings have different areas.

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

In some embodiments, the substrate 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 have a dissolution time in an aqueous solution that is longer than the shortest dissolution time of the matrix, such that the pharmaceutically active ingredient in the drug matrix is able to be released through the pores after dissolution of the plug.

In some embodiments, different plugs are configured to have different dissolution times in aqueous solutions such that the pharmaceutically active ingredient in the plurality of drug matrices is 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 dissolution boundary.

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

In some embodiments, the plurality of compartments are separated 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 matrix are configured as a stacked configuration spaced apart from one another.

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

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

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 plurality of drug matrices, wherein each drug matrix is made of at least one thermoformable material, respectively, and the plurality of drug matrices are connected together.

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

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

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

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

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

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

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 plurality of drug matrices is comprised of nanoparticles.

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

Brief description of the drawings

FIG. 1A illustrates 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 concentration after administration.

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

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

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

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

FIG. 4A illustrates an exemplary pharmaceutical dosage form having a matrix and pie-shaped compartments within the matrix;

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

FIG. 4C illustrates an exemplary pharmaceutical dosage form having a matrix and compartments positioned at different angles within the matrix;

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

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

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

FIG. 6 illustrates an exemplary drug 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 drug dosage form having a matrix, a compartment within the matrix, and a microneedle-shaped drug matrix contained within the compartment;

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

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

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

fig. 10A shows an exemplary pharmaceutical dosage form having a matrix and 3 columnar compartments within the matrix. Each compartment contains a drug matrix. Each drug matrix has a columnar 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 laminate; each matrix is a mixture of the same API and different substrates having different solubilities;

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

FIG. 10D shows the 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 medicament for a patient with a 3D printer;

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

FIG. 12B illustrates the release of the drug dosage form of FIG. 12A to two APIs;

fig. 13A shows an exemplary drug 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 plug;

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

FIG. 14A shows an exemplary drug dosage form having a matrix and three compartments within the matrix, each compartment being loaded with a drug 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 an API and a base.

Fig. 14C shows the simultaneous release 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 illustrates the controlled release of two APIs from one pharmaceutical dosage form as shown in FIG. 15A;

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

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

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

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

FIG. 17C shows a continuous release profile of the drug dosage form shown in FIG. 17A for four APIs;

FIG. 18A shows a schematic of a pie-shaped pharmaceutical form;

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

fig. 18C shows the percent release profile of the drug dosage form of fig. 18A for benzoic acid and PEG 8000.

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

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

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

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

Detailed Description

In the foregoing summary and detailed description of the invention, and in the following claims and drawings, references are made to specific features of the invention (including method steps). It is to be understood that the disclosure of the invention in this specification includes all possible combinations of these specific features. For example, when a particular aspect or embodiment of the invention or a particular claim discloses a particular feature, that feature may be used in combination with the remaining features and embodiments of the invention, or the entire invention, to the extent possible.

The use of "including" and its synonyms herein means that other components, ingredients, steps, etc. may also be present. For example, an article that "includes" components A, B and C may consist of (i.e., consist of only) A, B and C, or may contain more components in addition to A, B and C.

When reference is made to a method comprising two or more particular steps, the particular steps may be performed in any order or simultaneously (unless the context clearly excludes the possibility), and the method includes one or more other steps, which may be performed before, during or after any particular step (unless the context clearly excludes the possibility).

When a numerical range is referred to, 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 remaining stated or intervening value in that range, is encompassed within the disclosure and excluding the limits of that range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are still included in the disclosure.

The "at least" following number indicates a range with the number as a lower limit (the range may or may not have an upper limit depending on the variables defined). For example, "at least 1" indicates 1 or greater than 1. The "up to" followed by a number indicates a range with the upper limit of the number (the range may be limited to 1 or 0, or no lower limit, depending on the variables defined). For example, "up to 4" means 4 or less than 4, and "up to 40%" means 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 is indicated that the lower limit of the range is the first number and the upper limit is the second number. For example, 2 to 10 mm indicates that a range has a lower limit of 2 mm and an upper limit of 10 mm.

For simplicity of description, reference numerals have been repeated among the different figures to indicate corresponding or analogous elements. Furthermore, the description provides numerous specific details to provide a thorough understanding of the embodiments described herein. However, the embodiments described herein may be practiced without these specific details. In the rest of the cases, methods, procedures and components have not been disclosed in detail so as not to obscure the description of the relevant functions. Furthermore, the descriptions herein should not be construed as limiting the scope of the embodiments described herein. It should be understood that the descriptions and characterizations of the embodiments set forth in this disclosure are not mutually exclusive unless otherwise indicated.

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 the pharmaceutically active ingredient in a matrix. Existing conventional solid pharmaceutical dosage forms exhibit a first order drug release profile (fig. 1B), wherein the drug level in the plasma increases rapidly after administration, followed by an exponential decrease (fig. 1C). The disadvantage of this release profile is the reduced therapeutic efficacy resulting from reduced levels of drug, or the toxicity resulting from high concentrations of drug. This drug release is detrimental to the balance of drug levels in plasma. The present invention relates to an adjustable or controllably releasable oral drug delivery system having the advantages of enhanced patient compliance, selective pharmacological action, reduced side effects, and reduced frequency of administration as compared to conventional systems. The controlled release prolongs the administration process and can maintain the blood concentration during the treatment period. For example, an administration system exhibiting a zero order release profile (fig. 1D) allows a constant dose of drug to be released continuously over an extended period, achieving a uniform and constant administration process. Thus, antibiotic delivery, hypertension treatment, pain management, antidepressant delivery, and many other conditions requiring constant plasma drug levels may also require zero order release characteristics.

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 such that the pharmaceutically active ingredient in the pharmaceutical matrix is released in a controlled manner.

A. Matrix body

As used herein, the term "matrix" refers to a structure comprising or having 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 oblong tablet having dimensions of about a mm x b mm, where a has a value of between 5 and 15 and b has a value of between 2 and 10. In some embodiments, the substrate is capsule-shaped.

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

In some embodiments, the pharmaceutical agent has a monolithic matrix. In some embodiments, the substrate is formed of multiple pieces, each made of the same or different materials.

In some embodiments, the matrix is made of a thermoplastic material. "thermoplastic" as used herein refers to a material that can be plastic 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 a hydrophobic material, and the drug matrix is released by diffusion out through the pores in the matrix. Polymers, in particular cellulose ethers, cellulose esters and/or acrylic resins, can be used as hydrophilic thermoplastic materials. Ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, poly (meth) acrylic acid and/or derivatives thereof, such as salts, amides or esters, may also be used as thermoplastic materials. Hydrophobic materials which are physiologically approved and known to the person skilled in the art, such as 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 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, polyvinyl pyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60/40, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc) and polyvinyl pyrrolidone (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), polyvinyl acetate (PVAc), polybutylmethacrylate-poly 2-dimethylaminoethyl methacrylate-polymethyl methacrylate copolymer 1:2: polymethyl methacrylate-polymethyl methacrylate copolymer, polyethyl acrylate-polymethyl methacrylate-poly (trimethyl ethyl chloride) copolymer, polymethyl acrylate-polymethyl methacrylate-poly (methyl methacrylate-poly (methacrylic acid) copolymer 7:3:1, polymethyl methacrylate-polymethyl methacrylate copolymer 1:2, a poly (methacrylic acid) -poly (ethyl acrylate) copolymer 1:1, a poly (methacrylic acid) -poly (methyl methacrylate) copolymer 1: polyethylene oxide (PEO), polyethylene glycol (PEG), hyperbranched polyesters, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose or Hydroxypropyl Methylcellulose (HMPC), hydroxypropyl methylcellulose succinate or hydroxypropyl methylcellulose acetate succinate (HPMCAS), polylactide-polylactic acid copolymers (PLGA), carbomers, polyethylene-polyvinyl acetate copolymers, ethylene-vinyl acetate copolymers, polyethylene (PE) and Polycaprolactone (PCL), hydroxypropyl cellulose (HPC), polyoxyethylene 40 hydrogenated castor oil, methylcellulose (MC), ethylcellulose (EC), poloxamers, hydroxypropyl methylcellulose phthalate (HPMCP), poloxamers, hydrogenated castor oil, glyceryl palmitostearate, carnauba wax, polylactic acid (PLA), polyglycolic acid (PGA), cellulose Acetate Butyrate (CAB), colloidal silicon, 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 processes, such as Fused Deposition Modeling (FDM). In some embodiments, the pharmaceutical dosage form may be manufactured by extruding the thermoformed material through a 3D printer. Typically, the thermoformable material is melted in a 3D printer and then extruded to form a matrix. In some embodiments, suitable extruders include, but are not limited to, single or twin screw extruders, with the extruder temperature being set between 50 ℃ and 180 ℃ and between 80 ℃ and 140 ℃. In general, the extrusion process may be performed between 10 ℃ and 40 ℃ above the glass transition (Tg) temperature of the thermoformable material. Once the 3D printer reaches the proper temperature, the thermoformable material can be deposited onto the three-dimensional printing surface. Control of the shape and size of the matrix and compartments made of thermoformable material can be achieved by programming the printing process of the 3D printer.

In some embodiments, the release profile of the drug matrix may be controlled by selecting the matrix material. For example, a matrix made of a material of a particular solubility, permeability or erodibility may, after 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 dissolvable substance, and the pharmaceutically active ingredient (API) is embedded in 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 may also be controlled by adjusting the thickness of the matrix. For example, the matrix forming the compartment 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 and the later the release of the drug.

B. Compartment with a cover

In certain embodiments, the pharmaceutical dosage forms disclosed herein comprise at least one compartment in a matrix. "compartment" herein refers to a space, portion or room marked or separated by a matrix. One 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, pyramid, column, or cone.

In some embodiments, the specially designed compartment shape allows for release of the drug matrix at a specific rate. In some embodiments, the cell shape may be wedge-shaped, triangular prism-shaped, pie-shaped, pyramid-shaped, column-shaped, cube-shaped, oval-shaped, or cone-shaped.

In certain embodiments, inclusion of compartments 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 therein. Referring to fig. 2A, a pharmaceutical dosage form 100 has a matrix 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 pharmaceutical dosage form 100 to extend its residence time in the stomach or liquid environment or acidic environment. The solubility of the matrix material determines the residence time of the pharmaceutical dosage form and may accordingly achieve sustained release of the API as shown in fig. 2B.

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

In one embodiment, the compartments of the pharmaceutical dosage form have different geometries. Fig. 4A shows an exemplary pharmaceutical dosage form having a pie-shaped compartment within a matrix of the pharmaceutical dosage form, the pie-shaped compartment having a dissolution boundary that increases in area inwardly from proximate an outer side of the pharmaceutical dosage form such that the pie-shaped compartment is generally fan-shaped when viewed from top to bottom in the direction of fig. 4A. Fig. 4B shows an exemplary pharmaceutical dosage form having a plurality of compartments with different opening sizes within a matrix of the pharmaceutical dosage form, the compartments being generally prismatic in shape. Fig. 4C shows an exemplary pharmaceutical dosage form having compartments of different angles within the matrix of the pharmaceutical dosage form. Fig. 4D shows an exemplary pharmaceutical dosage form having pie-shaped compartments with different radii in the matrix of the pharmaceutical dosage form.

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 zero order release profiles as shown in FIG. 5. Fig. 5 shows a cross-sectional view of an application system with pie-shaped compartments. The compartment may communicate with the outside through a small opening. The compartment is loaded with a drug matrix and the drug matrix, after dissolution, releases the API to the outside through a small opening. The dissolution rate of a 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). In another aspect, the dissolution rate of an API in an environment is inversely related to the diffusion path length λ. Thus, as the dissolution of the drug matrix increases, the dissolution rate of the drug matrix increases. On the other hand, the diffusion path length increases as the drug matrix dissolves. The API released in the compartment needs to be transferred a longer distance to diffuse out of the pharmaceutical dosage form. Assuming that the pharmaceutical dosage form can be designed to conform to the analysis of the theoretical behavior of zero order release kinetics (R.A. Lipper and W.I. Higuchi (1977) for zero order drug administration systems, journal of medicine science 66 (2): 163-4; D.Brooke and R.J. Washkuhn (1977) zero order drug administration systems: theoretical and primary testing, journal of medicine science 66 (2) 159-162).

C. Drug matrix

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

The term "pharmaceutically active ingredient (API)" as used herein refers to an ingredient that is biologically active 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, anti-gout drugs, antihypertensives, antiarrhythmics, diuretics, hepatopathy 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, antitubercular drugs, antiviral drugs, antitumor 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) -foliixorin, lidocaine, ethyl 11-di-deuterium linoleate, 16-dehydropregnenolone, 17-beta-estradiol, 2-iminobiotin, 3, 5-diiodothyroic acid, 5-fluoro-2-deoxycytidine, 6-mercaptopurine, eptic, abacavir, bazalin, abiraterone, acamprosate, calcium acamprosate, acarbose, aceclidine, aceclofenac, guanamine hydrochloride, mengmenan, acenew's acid, acetaminophen, acetylcysteine, acetyl-colpitis, acetyl-L-carnitine hydrochloride, acetylsalicylic acid, acyclovir, acixib, azasett, abane, aclidinium, acibenzoglisten, agoraphani, adenosine, afatinib, acil, acitretin Aldenafil citrate, ralin acetate, alatroviruscin methanesulfonate, albendazole, salbutamol sulfate, alcaftadine, alendronate sodium hydrate, alendronate, alfacalcidol, alfaxalone, alfentanil, alfuzosin, aliskiren, allantoin, alisartan ester, acellular dermis, allopregnanolone, allopurinol, almotriptan Algliptin, alogliptin benzoate, alosetron, alpha ketoglutaric acid, lipoic acid, alpha-cyclodextrin stabilized glucoraphanin, alprazolam transdermal patches, alprostadil cream, altretamine, aluminum sulfate, alvimopan, amantadine hydrochloride, ambroxide, ambroxol hydrochloride, amphetamine sulfonated divinylbenzene, the pharmaceutical composition comprises, as active ingredients, at least one of azathioprine, amifostine, amikacin, amiloride, aminoacetyl, aminolevulinic acid, levulinic acid hydrochloride, aminopterin, amiodarone, amisulpride, amitriptyline, amlexanox, amlodipine besylate, amlodipine maleate, amlodipine nicotinate, amlodipine orotate, ammonium lactate, amodiaquine, amorolfine, an Sulong, amoxicillin hydrate, amphetamine, aspartic acid amphetamine, amphetamine sulfate, amphotericin B cholesterol sulfate, ampicillin sodium, ampiroxicam, amantadine, alegliptin, anagrelide, amantadine, aclidinazole, aclidinone, andrographolide, necetamine, anilamide, anilazel Aripinase, an Luoti Nib, antazoline, antiandrogen, antimonous antofloxacin hydrochloride, an Zhuokui Nol, apatinib mesylate, apixaban, apomorphine hydrochloride, apremilast, aprepitant, apremilast, abrudipine, arbekacin, abbezaar sulfate, adequacy heparin sodium, arformoterol, argatroban, aripiprazole lauryl, armodafinil, amiodafinil arsenic trioxide, arsenite, artemether, arteannuin, artesunate, asenapine, azlactone, astragaloside IV, atazanavir sulfate, atenolol, tomoxetine, atorvastatin, atorvastatin calcium, atorvastatin strontium, atorvastatin quinone, atrasentan, atropine, auranofin, atorvastatin, avibactam sodium, aviptadil, axitinib, azacytidine, cytidine, azasetron, azelaic acid, azelastine hydrochloride, azelnidipine, azilsartan sartan potassium, azilsartan trimethylethanolamine, azimilide, azithromycin lactobionate, aztreonam lysine, aztreonam, baclofen, baloflatinib, baicalin, BAK pratazin, balofloxacin, balsalazide sodium, bambuterol, barbiterpine, bazedoxifene, beclomethasone propionate, beclomethasone dipropionate, bedoradrine, belloteprosan, benazepril benzphetamine bromide, bendamustine hydrochloride, benidipine, benserazide, benzalkonium chloride, bennidazole, benzocaine, benzoyl peroxide, benzydamine hydrochloride, bepotastine calcium dihydrate, bepotastine salicylate, bei Lakang, beraprost sodium, besifloxacin, bei Xifu, besipine, beta-elemene, betahistine, anhydrous betaine, betamethasone propionate, betamethasone cream, betamethasone dipropionate, betamethasone valerate, betamethasone, betaxolol hydrochloride, carbomethine, urachol, betuxiban, bevacizumab, bexarotene, bezafibrate, biapenem, bicalutamide, bicyclic alcohol, pefekang, bilastine, bimatoprost, bismuth gallate, ecabet, bisoprolol, bezalol, pharmaceutical compositions containing the same bisoprolol fumarate, bitterspiramycin, bleomycin, blonanserin, boan hydrochloride, boceprevir bortezomib, bosentan hydrate, bosutinib, bufazomib, bripiprazole, brimonidine, bosentan hydrate, bosutinib, brimonidine, and brimonidine, brimoni, paipine, brivaracetam, brivudine, brizepam, bromfenac, sodium bromfenate, bromocriptine, brotizolam, bryostatin-1, bucindolol, bradienone, budesonide, ding Shuangben piperidine, buflomedil, bunazosin, bupivacaine hydrochloride, buprenorphine hydrochloride, bupropion Li Shafu, buserelin acetate, buspirone hydrochloride, busulfan, butenafine, butorphanol tartrate, buprenorphine butylphthalide, cabazitaxel, cabergoline, cabazitaxel malate, caducine, caffeine citrate, calcipotriol, calcitriol, calcium acetate, calcium folinate, calcium levofolinate, polycarbophil, calfastat, calmeldipyrate, calpain, camptothecine, canagliflozin, candesartan cilexetil, cangrelor, cannabis, capecitabine, capsaicin, captopril, carbamazepine, carbo Bei Suguan, carbitolcine, carbidopa, carbinoxamine, carbocisteine, carboplatin, carbidopa, carbophetamine Mi Bu, carboglutamic acid, carboline, carmustine, carbotilol, carbotillol hydrochloride, carboframomonam, carvedilol phosphate, caspofungin, catechin, cetirizine, cefaclor, cefadroxil, cefathiamidine, cefazolin sodium pentahydrate, cefcapene, cefdinir, ceftolenpinate, cefepime hydrochloride, cefetamet pivoxil hydrochloride, cefminox, cefpirome sodium, ceftioxime sodium, cefotiam, cefpiramide, cefpirome, cefpodoxime, cefprozil, ceftaroline, cefalotin, ceftriadime, ceftazidime, ceftibuten, ceftolterote, ceftriaxone sodium, cefuroxime sodium, celecoxib, cigo, celecoxil, cephalosporin, ceritinib, ceric nitrate, cetirizine, cetrimate, cevimeline, chenodeoxycholic acid, chlorhexidine, chlordygestrel, chlorogenic acid, chloroquine, chlorphenamine, chlorpheniramine maleate, and pharmaceutical compositions containing the same chlorpheniramine, chlorthalidone, cholecalciferol, cholic acid, choline alfoscerate, choline fenofibrate, ciclesonide, ciclopirox olamine, cyclosporin, cidofovir, cidozepine, cilastatin, cilazapril, cilnidipine, cilostazol, cimetidine, cinacalcet, cinepazide maleate, cinbipril tartaric acid, ciprofibrate, ciprofloxacin hydrochloride, ciprofloxacin, bescis-A Qu Kuan, cisplatin citalopram, citalopram hydrobromide, citicoline, citrulline, cladribine, clarithromycin, potassium clavulanate, clavulanic acid, clavulanate, clevidipine, clavulandine, clindamycin hydrochloride, clindamycin phosphate, clioquinol, clobazam, clobetasol propionate, clodronic acid, antomine, clofazimine, clomipramine hydrochloride, clonazepam, clonidine clonidine hydrochloride, clopidogrel benzenesulfonic acid, clopidogrel bisulfate, clopidogrel camphor, clopidogrel bisulfate, clopidogrel Lei Nai disulfonate, clopidogrel resinate, clotrimazole, clozapine, cobalamin, cobratite, codeine, colchicine, cholecalciferol, colesevelam, colestolide, colfunew damagedate, colporzil palmitate, colistin sodium, colnetant, colevanescents, conjugated estrogens, copper histidine, 11-deoxyleather alcohol 17 alpha-vinylpropionic acid, crizotinib, cromolyn sodium, cyanocobalamin, cyprohexate, cyclobenzaprine hydrochloride, cyclophosphamide monohydrate, cyclosporine, cyproterone acetate, cytarabine phosphate, dabigatran etexilate, darafanib, dacarbazine, dactyltinib dapagliflozin, dapitracin, aminopyridine, dapiptin, daparinux sodium, dantrolene sodium, dapsone Lu Sheti, aspartame, acesulfame Li Kangbing diol, dapiprazole, dapinoline dapoxetine, dapsone, darifenacin, darunavir, dasatinib, daunorubicin, decitabine, laroset, deferiprone, deferoxamine mesylate, deflazacort, delafloxacin, danamycin, and danamycin Demidodide, lapril, delabril hydrochloride, deravirdine, denillin, deoxyandrographolide, dermatan sulfate, defluoroether, dexipamine hydrochloride, loratadine, desmopressin acetate, desogestrel, deaned, desvenlafaxine, dextromethorphan hydrobromide, verteporfin, deuterated levodopa, deuterated venlafaxine, dexamethasone acetate, de-Methylene dexamethasone Mi Songpei ester, dexamethasone palmitate, dexamethasone sodium phosphate, dextroamphetamine, dexanabinol, iron dextran, dexketoprofen tromethamine, dexlansoprazole, dexmedetomidine, dextromethorphan hydrochloride, dexpropimide, sotalol, dextrorotatory sucrose, dextroamphetamine sulfate, dextromethorphan hydrobromide, dextropropoxyphenyl, diacerein, epoxylactic alcohol, diazepam, diazoxide choline, diclofenac potassium, diclofenac sodium, diclofenac amine, dicycloplatin, didanol, norgestrel, difluprednate, digoxin, linolenic acid, dihydroergotin, dihydroergotamine dihydroergotamine mesylate, diltiazem hydrochloride, dimesna, dimethyl fumarate, dimetiracetam, dienoprost, diphenylcyclopropenone, dipyridamole, sodium pyrophosphate tobramycin, ditetrazine, anthracnose, methadone, docarbazine, docetaxel, glycol, dofenozide, dolasetron, dolutegravir, domperidone, sorafenib besylate, donepezil hydrochloride, dopamine, doripenem, dorzolamide hydrochloride, doesamate, docusate, doxazosin mesylate, doxepin hydrochloride, doxepin, doxcalcitol, doxepin hydrochloride doxifluridine, doxofylline, doxorubicin hydrochloride, doxycycline hydrochloride, doxylamine succinate, dronabinol, dronedarone, drospirenone, droxidopa, D-tagatose, duloxetine hydrochloride, dutasteride, ebastine, bai Kang, ebselen, ecabet, isoconazole nitrate, dacloppam, edaravone, edoxaban, efavirenz, efalconazole, enonisole, efodipine hydrochloride, acetoguanamine sodium, eicosapentaenoic acid glyceride, oxaprozin, idecalcitol, illimesna, irinotecan, eltrombopag, etiquevir, enamel matrix proteins, emedastine, epagliflozin, emtricitabine, enalapril maleate, emclomiphene citrate, tamoxifen, enoxacin gluconate, and, enoxaparin sodium, enprost, entacapone, entecavir maleate, entinostat, enzalutamide, epalrestat, eperisone, ephedrine sulfate, epinastine hydrochloride epinephrine, epirubicin hydrochloride, ibrutinib, eplerenone, epoprostenol, eplerenone, irinotecan, eprosartan, eplatin, erdosteine, eribulin mesylate erlotinib, ertapenem, erythromycin stearate, erythromycin aspropionate, escitalopram, esketamine, ketamine hydrochloride, eslicarbazepine acetate, esmolol hydrochloride, esomeprazole magnesium, esomeprazole strontium, esomeprazole, estetrol, estradiol acetate, estradiol cyclopentapropionate, estradiol valerate, alsatide, estradiol, estrogens eszopiclone, ethambutol hydrochloride, ethane selen, ethinyl estradiol, calcium hydrogen ethyl fumarate, magnesium ethyl fumarate, zinc ethyl hydrogen fumarate, ethinyl estradiol, etidronic acid, etimicin sulfate, etizolam, etodolac, etogestrel, etoposide phosphate, etoricoxib, itravirlin, eupatilin, everolimus, exemestane, exenatide, ezetimibe, fatrozole, fluocinol, famciclovir, famotidine, aminopyridine, faropenem, famoxapol, fasudil hydrochloride, fasudil mesylate, famciclovir, febane, febuxostat, feamate, felbinac acid, tromethamine, felodipine, fenfluramine hydrochloride, fenofibrate, fenoldopal, fenretinide, fenpropitiamide, fentanyl, fentanyl citrate, fenticonazole, ferric citrate, ferric maltol, fexole fumarate, fexofenadine, fibrin glue, fibrinogen matrix patch, fidaxomycin, fimasartan, finafloxacin hydrochloride, finasteride, fingolimod, fluanide, fleroxacin, flibanserin, floxuridine, fluconazole, fludarabine Fluomazinib, flunisolide, fluocinolone acetonide, fluorouracil, fluoxetine hydrochloride, flupirtine, flurbiprofen ester, flurbiprofen sodium, erythromycin, fluticasone furoate, fluticasone propionate, flutramazole, fluvastatin, fluvoxamine, folic acid, folinic acid, methylpyrazole, fondaparinux sodium, formestane, formoterol Fusarium fumarate, forodesine, fusarium, fosaprepitant, fosfoconazole, fosfomycin disodium, fosfomycin trometamol, fosinopril sodium, fosinomycin, fosphenytoin, fospropofol, fotemustine, furotetratan, furalttinib, fodosteine, fulvestrant, furosemide, fusidic acid, gabapentin enrolment, gabexate mesylate, gadobutrol, fosinopril gadoferamide, galanthamine, gallium nitrate, gambogic acid, ganaxolone, ganciclovir, ganirelix acetate, ganaxacin, gatifloxacin mesylate, gefitinib, gemcitabine hydrochloride, gemfibrozil, gemifloxacin, genistein, gentamicin, gentiopicroside, gepirone, gestodene, timolol maleate, gimeracil, ginsenoside, glatiramer acetate, glibenclamide, gliclazide, glimepiride, glipizide, meglumine, glutamine, glycerylbenzene, glycopyrrole mesylate, glyburide, golimod, golidagliptin, granisetron hydrochloride, guaifenesin, guanamine, guanfacine, guansirolimus hydrochloride, haemophilus influenzae, halobetasol propionate, halofant, halometasone, sodium hyaluronate, hematoporphyrin, arginine heme, heparin, he Birong, hydroxyethyl starch, norlinne hydrochloride, histamine dihydrochloride, huperzine A, sodium hyaluronate, hydralazine, hydrochlorothiazide, hydrocodone tartrate, hydrocortisone, hydromorphone hydrochloride, hydromorphone, hydroxycobalaminin, hydroxyurea, hydroxychloroquine, oxygestrel, hydroxysaflupin A, hypericin sodium ibandronate, ibandronic acid, iboditan, ibrutinib, ibudilast, ibuprofen, ibutilide fumarate, epimedium, ilaprine, eicosapentaenoic acid, ethyl eicosapentaenoic acid, eicosapentaenoic acid ethyl ester, icotinib hydrochloride, idebenone, iodoside, ifetroban sodium, iguratimod, ilaprazole, iloperidone, iloprost, imatinib imatinib mesylate, imidafenacin, imidacloprid, imidazole salicylate, imipenem, imiquimod, eremophil, incadronic acid, indacaterol maleate, indapamide, indenofloxacin, indinavir, indisetron, indomethacin, indoramin, inecalcitol, ingenol methyl butenoate, inosine, ideconazole, irinotecan, ipratropium bromide, estarcalin hydrochloride, irbesartan, irinotecan hydrochloride, irinotecan thioester, irinotecan, ferrisuccinic acid, irinotecan maleate, isoflurane, isoniazid, unoprostone isopropyl, isosorbide dinitrate, isosteviol, isotretinoin, isradipine, itraconazole, irinotecan sulfate, irinotecan hydrochloride, ivermectin, albespriv, ixabepilone, laspizosin, clevidone, ketamine, ketochrome, ketoconazole, ketoprofen, ketorolac tromethamine, ketotifen, dicumyl mesylate, lanmide, lactitol, raffinolimus, lafutidine, lamivudine, fluvaldecolonil lamotrigine, landiolol hydrochloride, nannie Wei Xinsuan ester, lanoconazole, lansoprazole, lanthanum carbonate, lapatinib, laquinimod, lasofoxifene, latanoprost, ledipasvir, leflunomide, lenalidomide, lentinan sulfate, lercanidipine, potassium leporide, letrozole, leucine, leuprolide acetate, levalbuterol hydrochloride, levamisole, levamlodipine besylate, maleic acid, levetiracetam, levobupivacaine, levocabastine hydrochloride, levocabastine, levocetirizine, levodopa, levofloxacin, levonorgestrel-18-methyl alkynone, levonorgestrel, L-18-methyl norethindrone butanoic acid, L-phencyclized hydrochloride, L-ornidazole, L-simendan, L-glutamine, lidocaine, ligustrazine hydrochloride, rimexosin, and linagliptin, linezolid, liothyronine, sodium iocelecoxib, lipoteichoic acid, linanaproxen, lisinopril, theophylline, hydrogen ergotoxuridine, lithium citrate, lithium succinate, lobaplatin, rotifer carbonate, lofexidine, lomefloxacin, lomefloxazine dihydrochloride, lonidamine, lopinavir, loratadine, lorazepam, L-ornithine L-aspartic acid, lornoxicam, losartan potassium, loteprednol, lovastatin, lomefloxapine succinate, loxoprofen, levopraziquantel, lomefloxacin, lysine aspirin, sulfamilone, magnesium carbonate, magnesium isoglycyrrhizinate, manganese fodizime, manidipine dihydrochloride, mannitol, maraglibenclamide, ma Liba, mositemide, mefenamide, mecobalamin, megestrol acetate meloxicam, memantine hydrochloride, sodium memantine sulfite, menatetrenone, maphalin, alapine, paracetamol, mercaptoethylamine bitartrate, mercaptoethylamine hydrochloride, mercaptopurine, meropenem, mesalazine, metacavir, metadoxine, analgin, metaxalone, ergobenzyl ester, metformin hydrochloride, methadone hydrochloride, methadone Methanolamine, methotrexate, methoxyflurane, methylpentanoate, methylnaltrexone bromide, methylnaltrexone, methylphenidate hydrochloride, 6-methylprednisolone, methylpredniso Long Cubing, methylene blue, methyltryptamine, metoclopramide succinate, metoprolol, metronidazole, topirane, mexiletine, milbezadil, miconazole nitrate, midazolam, amidazolam hydrochloride, midodrine, midostaurin, mivarilin, mifepristone, miglitol, milnacipran, milrinone, miltefosine, milnacipran, minocycline hydrochloride, minodronic acid, minoxidil, milberon, miplatin hydrate, milnacafil hydrochloride, mirtazapine, misoprost, miglitol, mitomycin, mitoxantrone hydrochloride, mi Fu tiester, mizostatin, mizoribine, mollobine, modafinil, doxycycline, moschus, mofenamic acid, morpholone hydrochloride, mometasone furoate, momil furoate, monoammonium glycyrrhizinate, mo Nuoben relizon, luminol, monoterpene perillol, montelukast sodium, montmorillonite, moxazine, tigecycline, morpholinnidazole, morphine glucuronate, morphine of pitavastatin, morphine sulfate, mosapride, moxidectin, moxifloxacin hydrochloride, moxifloxacin, moxidectin hydrochloride, moxivaptan, mupirocin, mycophenolate, myristate nicotinate, cannabinone, nabumetone, N-acetylcysteine, nadifloxacin, nadolol, nadropanol calcium, naftifine hydrochloride, naftifine gel, naftopidil, nalbuphine, nalbuphine sebacate, nalfurorphine, nalmefene hydrochloride, naloxol ether, naloxone hydrochloride, naltrexone hydrochloride, naloxone decanoate, naphazoline, naphthoquine, naproxen sodium, naratriptan, natepinase, nateglinide, nebivolol, nedaplatin, nedocromil, nelarabine, nelfinavir, nemorubil, nemorubicin, neoandrographolide, neosaxitoxin, neostigmine mesylate, neostigmine, nepatan, nepalamine, nepidostat, nila, latinib, nerisperidonic acid, netilmicin, netupitan, nevirapine, nicotinic acid, nicaidipine, neergoline, nicotidil, fivelin, nicotine, nicotinic acid, nitrosal, nifedipine, nifecalin, nifeverle, nifuralamide, nicotinamide, nirotinib, ni Lu Temi, nivaldipine, nimodipine, mordazole, nitrovazole, nisodipine, nizoniter, nitidronic, nitrodipine, nitric oxide, nitroglycerin, nizatidine, lorat, nomegestrel acetate, norgestrel, norethindrone acetate, norgestrel, norfloxacin, norethindrone acetate, obetaine, obeticholic acid, tinib, octahydroacridine, octreotide hydrochloride Ofloxacin, olanzapine, olmesartan medoxomil, indacaterol, ondacaterol hydrochloride, olopatrol, olopatadine hydrochloride, olratadine hydrochloride, olprinone, olsalazine, oltipraz, homoharringtonine, oxybutynin, omeprazole, omoconazole, onapristone, ondansetron, ospemine, methylphenidate, olmesartan Le Saite, olanzapine, orlistat, ornithine phenylacetate, enoprost, oseltamivir, ospemifene, potassium oxazinate, oxaliplatin, oxaloacetate, oxandron, oxazipam, oxcarbazepine, oxfendazole, oxidized glutathione sodium, oxiracetam, oxybutynin hydrochloride, oxycodone hydrochloride, oxymetazoline hydrochloride, oxymorphone, oxytetrazine, sodium, ozagrel hydrochloride, ozagrel, ozagrel sodium, ozafloxacin, paclitaxel polyglutamic acid, paliperidone palmitate, pamil, palonosetron, pamidronate disodium, pancrelipase, panipenem, panobinostat, pantoprazole, acetaminophen, parecoxib, paricalcitol, palirivir, sodium parparin, paroglibencycline, paroxetine hydrochloride hemihydrate Paroxetine mesylate, pamil, pazopanil, pazufloxacin mesylate, pegolated lipo, pebeprofen, pemetrexed disodium, pemetrexed potassium, pemetrexed sodium, penciclovir, long tolterone, pentamidine, calcium sodium pentetate, zinc sodium pentetate, pentazane, sodium pentosan sulfate, pravastatin, pentoxifylline, peramivir, pirenzenepane amine thiourea, perfluoropentane, perfluorooctyl ammonium bromide, pergolide, perhexiline, pirifacine, perindopril arginine, pirocin, phencycline, phenethyl isothiocyanate, phenoxybenzamine hydrochloride, phentermine, topiramate, benzamine hydrochloride, phentolamine mesylate, sodium phenylbutyrate, phenylephrine hydrochloride, phenylephrine suppository, phenytoin, phosphatidylcholine and acetylsalicylic acid, sarpein, picrorhiza, podophyllotoxin, pidotimod, pilocarpine hydrochloride, piracinmide, pimecrolimus, pimobendan, pinacolone, pioglitazone hydrochloride, amidopiperidone, perkuromine, piperacillin sodium, piperaquine phosphate, piperaquine hydrochloride, piperacillin, piracetam, pirarubicin, piroxicillin, pirfenidone, pirminox, pirotinib, piroxicam, pitavastatin calcium, pitaxetron and pla Le Kangni, prasugrel, pralafafool, prasufofilol, L-carnosine zinc, polifeprosan 20 carmustine, resveratrol glycoside, pomalidomide, panatinib, sodium porphin, posaconazole, potassium bicarbonate, potassium citrate, potassium clavulanate, pradefufo Weipu d fovir, aminopterin, pramipexole, prasuxiracetam, pulullide, pramipexole hydrate, prasugrel, pravastatin, prazosin, melphalan, prednisolone acetate, prednisolone sodium phosphate, prednisone, pregabalin, betamethamine, procaterol hydrochloride, prochlorperazine maleate, prochlorperazine, progesterone, progestin, pregnandrogen, pregnangin, proguanil, promalarenone, propigermanium, isoprenol, propranolol, pranolol hydrochloride, pranolol Sernitan, propranolol, prueca, prulifloxacin, prussian blue, pseudoephedrine hydrochloride, puerarin, praziquantel mesylate, pyrazinamide, pyridoxamine hydrochloride, pyridoxine hydrochloride, ethylpyrimidine, biquinop, flunaridine, quazepam, quetiapine fumarate, quetiapine, que Gao Lai hydrochloride, quinapril hydrochloride, quinidine sulfate, quinine sulfate quinioprene, quinidine, rabeprazole, sodium rabeprazole, racecadotril, radtinib, raloxifene, naloxofene, raltevir, raltitrexed, ramatroban, ramelteon, ramipril, ramosetron, ranitidine, bismuth citrate ranitidine, ranolazine, rasagiline, rebamipide, reboxetine mesylate, raloxine, raloxifene, and combinations thereof, ibuprofen, naproxen, glycopyrrolate, diclofenac, mebendazole, progesterone, sucralfate, zoledronic acid, regorafenib, remifentanil hydrochloride, repaglinide, aminopyramid, chlorocyzine hydrochloride, busyramine, guanabenz, chlorphenidol, mazindole, naltrexone, nitenpyram, ondansetron, retigabine, rosiglitazone, sodium benzoate, resinol, ramote, resveratrol, regagliptin, ritapline, rituximab, retigabine, retinoic acid, revaprazan, sodium raparin, rhein, rhenium-186 sodium etidronate, ribavirin, rifabutin, rifampin, rifapentine, rifaximin, rilapatide, rilpivirin, rilpivirine hydrochloride, riluzole, rimantadine, risperidin Reichthyophthiride, riociquo hydrochloride, risedronate sodium, risperidone, ritonavir, rivaroxaban, rismin, rizatriptan benzoate, roflumilast, rotamycin, zolpidem, romidepide, ropinirole hydrochloride, ropivacaine, rose bengal sodium, rosiglitazone maleate, rosiglitazone sodium, rosuvastatin calcium, and rotigotine, roxithromycin, lu Biti kang, lu Fei amide, rufloxacin, rupatadine, ruxolitinib, zuo Aoxiao disodium oxazole phosphate, sabobiqu, sha Fei amide, salbutamol alisha breath, salbutamol sulfate, salicylic acid, salmeterol xinafoate, salvaping, lemin samarium, 3-carboxamide-4-hydroxycyclopropane-meflomorphone, S-amlodipine nicotinate, salbutamol sulfate, salmeterol, sarnpterin, sapropterin dihydrochloride, saquinavir, celecoxib, sarpogrelate hydrochloride, saxagliptin, scopolamine, scorpion venom, seal oil omega-3 polyunsaturated fatty acid, secnidazole, selegiline hydrochloride, selegiline, seletrazine, cilazasetron, celecoxib hydrochloride, sertaconazole, sertacol nitrate, sertindole, sertraline hydrochloride, sesquiterpene, sevelamer carbonate, sevelamer hydrochloride, sevoflurane, sibutramine maleate, sibutramine mesylate, sildenafil, silver sulfadiazine, zipravir, cetirin hydrochloride, simvastatin, cinnolamine, simonamide, sirolimus, sitagliptin phosphate, cervelamer, sirolimus, sugar, sirolimus, and the like smilagenin, S-modafinil, sobuzosin, sodium aescinate, sodium ascorbate, sodium benzoate, sodium bicarbonate, sodium cromoglycate, sodium glycidic, sodium galenicate, sodium hyaluronate, sodium ibandronate, sodium nitrate, sodium nitrite, sodium hydroxybutyrate, sodium phenylacetate, sodium phenylbutyrate, sodium prasterone sulfate, sodium pyruvate, sodium taurocholate, sodium thiosulfate, sea wave, sodium sulfite sodium zirconium cyclosilicate, sofosbuvir, solifenacin, soluble ferric pyrophosphate citric acid, soluble guanylate cyclase stimulation, sophocarpine, sophoridine hydrochloride, sorafenib, sorbitol, sparfloxacin spiropril, pull-in, squalamine, stannsoporfin, stavudine, S-tenatoprazole, stavonin, stave, streptozotocin, strontium malonate, strontium ranelate, succinic acid, sucralfate, aluminum sulfate, sodium sulfate, potassium sulfate, sodium sulfate, and sodium sulfate, sucrose gel, sufentanil, sultam zinc, sulmore glucose, sulbactam sodium, sulbactam sulfate, sulfamethoxypyrazine, sulfasalazine, sovantinib, sulfonylureas, sulforaphane, sodium tanshinone IIA sulfonate, sulindac, sulodide, sulfamethoxazole, thiothiazine, sumatriptan succinate, sunitinib, daily feldspar, methylsulfustam, sodium sulbactam hydrochloride, verapamil hydrochloride rilpivirine, tacalcitol, tecacol, tacrine, tacrolimus, tadalafil, clofenamic acid, tafenoquin, tafluprost, talaporfin, tacrine, taltirelirelin, tamibarotene, tamoxifen, tamsulosin hydrochloride, tandospirone, tamspiramycin, tapentaretortol, talenaxin, tasimelteon, taquinimod, tazarotene, tazobactam sodium, tazobactam tebipenem ester, tecoviril, tectorigenin sodium sulfonate, tedisamide, tenatozolamide phosphate, tegafur, tegaserod, teicoplanin, telaprevir, tiratinib, tebipudine, telithromycin, telmisartan, temoproli, temoporphine, temopofen, temozolomide, sirolimus, terliptin, tenofovir alafenamide, tenofovir aspartate, tenofovir fumarate, tenofovir disoproxil fumarate, temoprost, temoporfen, temozolomide, and the like tenoxicam, teprenone, terazosin, terbinafine hydrochloride, tertekurea, teriflunomide, terxofenadine, testosterone undecanoate, butylbenzene, tetracaine hydrochloride, tetrathiomolybdate, tetrahydrozoline, tetrahydronaphazoline, thalidomide, theophylline, tenorphine hydrochloride, thiotepa, thrombin microcapsules, thyroxine, tiagabine, neoprene, tibolone, ticagrelor, ticlopidine, tigecycline, disodium tiludronate, timolol maleate, tinidazole, sulfenamizole, tinzaparin sodium, tioconazole, tiopronin, tiotropium bromide monohydrate, tipidine, tipadine, tipifacil, tipinib, tipranavir, tirapazamine, tirapazate, tirofiban, timofiban tirofiban hydrochloride, oxcarbazepine hydrochloride, tirofiban hydrochloride, tizanidine, tobramycin, tolcorosolen, vitamin E-retinoate, vitamin A tocopheryl, tofacitinib, tolgliflozin, tolcapone, tol Li Mi ketone, tolperisone, tolterodine tartrate, tolvaptan, tolnaboxa, topiramate, tolpirstat, topotecan hydrochloride, tolacom, toremifene, tosertdote, tolterone Tusulfloxacin, tolterodine, tramadol hydrochloride, trametin, trandolapril, tranexamic acid, tranilast, chuantetrol hydrochloride, travoprost, trazodone, trehalose, trelagliptin succinate, busulfan, treprostinil ethanolamine, retinoic acid, triamcinolone acetonide, triazolam, triclosazine, triclopyr, triclocarban, triclopyr trientine hydrochloride, trifluothymidine, trifluoracetic acid, triheptanoic acid glyceride, trilostane, trimebutine 3-thiocarbamoyl-benzene, trimebutine tosylate, trimegestone, trimethoprim, trimetrafos, trinitrate, tripotassium bismuth dimitrate, tolfenamide, tropisetron, trospium chloride, trovafloxacin, troxipide, tobuterol, tylosin, ubenimex, ubidecarenone, triamcinolone, udenafil, ulinastatin, ulipristal, udbetaxol, uracil, urapidil, uridine triacetate, uropoly-acid peptide, ursodeoxycholic acid, ursolic acid, valacyclovir hydrochloride, valdecoxib, valganciclovir, valproic acid, valrubicin, valsartan hemi-pentahydrate trisodium phosphate, vancomycin hydrochloride, vandetanib Vanuosline, vardenafil hydrochloride, valnism, vitamin Qu Ge, vemurafenib, venlafaxine hydrochloride, verapamil hydrochloride, feverine, venacalan velacalan hydrochloride, velipofen, velarinone, velagramine, vigabatrin, velamerol, velazone, vildagliptin vincristine sulfate, vinflunine, vinorelbine, vinpocetine, vitamin E nicotinate, vitamin E, voglibose, voronoi fumarate, verapamil, voriconazole, vorinostat, vortioxetine hydrobromide, warfarin, zhimerofiban, milofiban, irinotevir, uvanafil, zafirlukast, zaleplon, zatolofibrine, zanamivir, zidovudine, azidothymidine, zileuton, zinc acetate, clobetadine Ding Sizhi, ziprasidone, zofenopril calcium, levofenopril, disodium zoledronate, zoledronic acid, zolmitriptan, zolpidem, zopican, zopiclone, tiepin, zuelane, zuelacin, and zuclothial.

In some embodiments of the present invention, in some embodiments, the traditional Chinese medicine is selected from flos Abelmoschi Manihot, herba abri, fructus Cannabis, cortex Acanthopancis, radix Acanthopanacis Senticosi, herba Lycopi, achyranthis radix, radix Aconiti Kusnezoffii Preparata, radix Aconiti lateralis Preparata, radix Aconiti, rhizoma Acori Graminei, radix Adenophorae, semen Cannabis, agkistrodon, herba et Gemma Agrimoniae, cortex Lycii, herba Ajugae, caulis Akebiae, semen Strychni, cortex Albiziae, flos Albiziae, rhizoma Alismatis, herba Lespedezae Cuneatae, bulbus Allii, semen Allii Tuberosi, aloe the Chinese herbal medicines comprise grass bean stripe, high-yield galangal, alpinia oxyphylla, white-colored, bean stripe, fructus amomi, bai Ci, common andrographis herb, andrographolide, rhizoma anemarrhenae, radix anemones raddeanae, radix angelicae pubescentis, angelica sinensis, star anise, dogbane leaf, agilawood, concha arcae, niu Dizi, cinnabar root, japanese ardisia herb, pericarpium arecae, jiao Mo, fraxinus mandshurica, arisaema cum bile, prepared arisaema tuber, ma Jiuling, aristolochia debilis, bitter apricot seed, lithospermum, green fleabane, folium artemisiae argyi, herba artemisiae scopariae, herba artemisiae capillaris, and the like asarum, asiatic moonseed rhizome extract, acro, asparagus, aspongopus, aster, semen astragali complanati, fried yellow shoot, bighead atractylodes rhizome, rhizoma atractylodis, costustoot, fructus kochiae, front bamboo, tabasheer, radix isatidis, blackberry lily, front joss-stick, front-flow soaked asian, front belladonna, white gourd peel, benzoin, radix berberidis, bergenia, bergenin, bistort, bletilla, bolbostemma, stiff, borneol (synthetic borneol), natural borneol (right-handed borneol), artificial bezoar, in-vitro cultured bezoar, lamp , fructus zizanthoxyli, brucea javanica, cornu bubali, buddleja, , bunga, bupleurum, calamine, guangdong beautyberry, folium callicarpi, folium phyllae, calomenii, calomel, campsis, fructus Cannabis, semen cannabis, capsicum, ceris, agrimony, crane, safflower, clove, semen cassii, cassia seed, castor oil, cockscomb, green box, centella asiatica, crane-inedible herb, white worm-grass, bee-method, cornu Cervi Degelatinatum, deer-horn, deer-horn gum, papaya, changium root, fructus chebulae, celandine, angelica sinensis fluid extract, green rock, wild chrysanthemum flower, szechuan lovage rhizome, rhizoma cibotii, bee-taking off, chrysanthemum, cimicifuga foetida, cinnabar, cinnamon, cassia twig, cinnamon oil, li, dali charcoal, dali, nubia (tin raw rattan), cistanche, exocarpium Citri rubrum, bergamot, pummelo peel, green tangerine peel, orange core, fingered citron, clematis root, clinopodium polycephalum, campanumaea pilosula, coix seed, alpine-bird-foot herb, gentian, coptis root, corium versicolor corium, corium versicolor, chinese glossy ganoderma, mountain shiveri, corydalis tuber, hawthorn leaves, chinese hawthorn, chinese magnoliavine, dried orange peel, pseudobulbus Cremastrae seu pleiones, crinis Carbonisatus, stigma croci Sativi, fructus crotonis, semen crotonis Pulveratum, rhizoma Curculiginis, curcuma rhizome, radix Curcumae, curcumae rhizoma, semen Solani Tuber osi, radix Cyathulae, cyclovirobuxine, radix Cynanchi Paniculati, rhizoma Cynanchi Stauntonii, herba Cynomorii, rhizoma Cyperi, oleum Rhododendri Dahurici, lignum Dalbergiae Odoriferae, rhizoma Curcumae, semen Trigonellae, radix Cynanchi Paniculati, and semen Strychni flos Daturae Metelis, herba Lepidii, herba Desmodii Styracifolii, fructus Tritici Levis, radix Dictamni, rhizoma Dioscoreae, cortex Dictamni Radicis, cortex Fraxini, radix Chaenomelis Radicis, rhizoma Dioscoreae, semen Trigonellae, radix Dipsaci, sanguis Draxonis, rhizoma Drynariae, rhizoma Dryopteris Crassirhizomatis charcoal, rhizoma Dryopteris Crassirhizomatis, rhizoma Dioscoreae, and rhizoma Cyrtomii Falcati rhizoma Dryopteris Crassirhizomatis, radix Rhapontici, ecliptae herba, fructus Litseae, radix Gentianae, herba Ephedrae, radix Ephedrae, herba Epimedii, herba Equiseti hiemalis, lamp herba asari (lamp flower), folium Isatidis, flos Eriocauli, herba Erodii seu Geranii, caulis Erycibes, oleum Eucalypti, eucommiae cortex, folium Eucommiae, wu Lai, herba Eupatorii, herba Euphorbiae Fischerianae, radix Euphorbiae Equiseti hiemalis, herba Euphorbiae Humifusae, radix Euphorbiae Pekinensis, semen Euphorbiae Humifusae, semen Euphorbiae, eupolyphaga Seu Steleophaga ( worm), fructus Tsaoko, rhizoma Fagopyri Dibotryis, flos Farfarae, resina Ferulae, radix Angelicae sinensis, caulis Fibraureae, fibrauretine, fluoritum, herba Centipedae, fructus forsythiae, cortex Fraxini, bulbus Fritillariae Cirrhosae, bulbus Fritillariae Hupehensis, bulbus Fritillariae Ussuriensis, bulbus Fritillariae Thunbergii, bulbus Fritillariae Ussuriensis, semen Ormosiae Hosiei, galla chinensis, endothelium corneum Gigeriae Galli, ganoderma, herba Artemisiae Scopariae extract, jiao Ezi, fructus Gardeniae, rhizoma Gastrodiae, radix Mactrae, radix Cynanchi Paniculati, herba Genkwa, qin Chong, radix Gentianae, rhizoma Zingiberis recens fluid extract, folium Ginkgo extract, semen Ginkgo, folium Ginseng, ginseng radix Rubri, ginseng radix, herba Pileae Scriptae extract Glechoma hederacea, mons hygicini, mons verrucosa, radix Glehniae, radix Glycyrrhizae Preparata, radix Glycyrrhizae, flos kapok, pericarpium Granati, dan Yi, forge Dan Yi, haematitum, concha Haliotidis, radix et rhizoma Erycibe Dan Yue, folium Phyllostachydis Henonis extract moxibustion red seedling, folium Hibisci Mutabilis, hippocampus, fructus Hippophae, radix Ipomoeae, rhizoma homalomenae, fructus Hordei Germinatus, fish grass, red powder, semen hyoscyami, herba Hyperici perforati, herba Siraitiae Grosvenorii, folium Ilicis Cornutae, cortex Ilicis Rotundae , and radix Angelicae sinensis semen Impatientis, lalang grass rhizome, indigo naturalis, inulae flos, herba Cichorii, radix Inulae, rhizoma Belamcandae, folium Isatidis, radix Isatidis, semen Juglandis, fructus Anisi Stellati, medulla Junci, caulis Spatholobi, fructus kaki, radix kansui, radix Knoxiae, kochiae fructus, semen lablab album, herba Clerodendri Japonici, herba Hongyi, thallus laminariae, radix Lamiophlomidis Rotatae, lasiosphaera Seu Calvatia, fructus Leonuri, herba Leonuri fluid extract, glycyrrhrizae radix fluid extract, rhizoma Ligustici, fructus Ligustri Lucidi, bulbus Lilii limonite, lindera root, flaxseed, fructus liquidambaris, balsam, liriope spicata, branch and core, lobelia, arillus longan, flos lonicerae, caulis lonicerae, honeysuckle, lophatherum gracile, luffa, cortex lycii radicis, radix polygoni multiflori, semen cassiae, flos lonicerae, herba polygoni multiflori, flos carthami, flos persicae, flos carthami, flos persicae, flos fructus Ponciri, herba Lycopi, herba Lycopodii, spora Lygodii, herba Lysimachiae, folium Artemisiae Argyi (L-borneol), mentholum, magnetitum, flos Magnoliae, cortex Magnoliae officinalis, flos Magnoliae officinalis, caulis Mahoniae, fructus Abutili, herba Pogostemonis, fructus Glehniae, herba Pogostemonis, fructus Gleditsiae Abnormalis, herba Pogostemonis, fructus Momordicae, fructus Pogostemonis, fructus Mollissimae, fructus Pogostem, squama Manis, ramulus Mori , margarita, concha Margaritifera, caulis Marsdeniae Tenacissimae, mel, fu Ussula (green sail), cortex Meliae, semen Benincasae, rhizoma Mentha Makinsoniana, herba Menthae, clam shell, lapis Micae aureus, butcher's broom leaf, watermelon frost, semen Momordicae, cortex Mori, folium Mori, mulberries, ramulus Mori, radix Morindae officinalis, should be added with a herb, herba Moslae, cortex moutan, flos Pruni mume, herba Murrayae, mel, semen Myristicae, myrrha, rhizoma Nardostachyos, natrii sulfas, folium Nelumbinis, plumula Nelumbinis, herba Lobeliae, semen Nelumbinis, stamen Nelumbinis, semen Sojae Atricolor, notoginseng radix total glycosides, panax notoginseng triol, rhizoma Kaempferiae, oleum Ocimi Gratissimi, olibanum, omphalia, ophicalcitum, radix Ophiopogonis, oroxyli, fructus oryzae, rhizoma Osmundae, concha Ostreae, white peony root, radix Paeoniae Rubra, rhizoma Panacis Japonici, radix Panacis Quinquefolii, pericarpium Papaveris, rhizoma paridis, herba Pogostemonis, jowar oil, perilla stem, folium Perillae, fructus Perillae, cortex Periplocae, semen Persicae, radix Peucedani, semen Phragmitis, cortex Phellodendri, radix Angelicae sinensis cortex Phellodendri, lumbricus, rhizoma Phragmitis, fructus Phyllanthi, calyx seu fructus physalis, radix Cynanchi Paniculati, radix Phytolaccae, ramulus Et folium Picrasmae, rhizoma Pinelliae Preparatum, rhizoma Pinelliae Preparata, lignum Pini nodi, pollen Pini, fructus Piperis, caulis Piperis Kadsurae, fructus Piperis Longi, herba plantaginis, folium Platycladi, semen Platycladi, caulis Spatholobi, herba Agastaches, cortex et radix Polygalae fluid extract, herba Polygalae, rhizoma Polygonati Odorati, rhizoma Polygonati, herba Polygoni Cuspidati, caulis Polygoni Multiflori, rhizoma Polygoni Multiflori, herba plantaginis, radix Polygalae, rhizoma Polygoni Avicularis, radix Polygalae, rhizoma Polygonati Odorati, rhizoma picrorhizae, radix Polygalae, radix Polygalae, rhizoma Polygonati radix Polygoni Multiflori Preparata, polygoni Multiflori radix, fructus Polygoni orientalis, herba Polygoni Perfoliati, folium Isatidis, pig etc., poria, pericarpium Camelliae sinensis, herba Sargassum, herba Potentillae chinensis, herba Potentillae Discoloris, cornu Bubali concentrated powder, kernel, propolis, prunellae Spica, semen Prunellae, radix seu folium Psoraleae, cortex pseudolaricis, radix Pseudostellariae, rhizoma Polygoni Cuspidati, herba pterygii Wilfordii, radix Puerariae, radix Pulsatillae, copper, herba Pyrolae, folium Pyrrosiae, fructus quisqualis, herba Polygoni Avicularis, radix Angelicae sinensis, herba Potentillae Discoloris, fructus Lycii, radix Angelicae sinensis, herba Potentillae Discoloris, and radix Angelicae sinensis, oridon, haliro oil, radix Ranunculi Ternati, semen Trigonellae, realgar, radix rehmanniae Preparata, rehmanniae radix, radix Rhapontici, radix et rhizoma Rhei, radix Rhodiolae, flos Rhododendri Dahurici, flos Rhododendri mollis, da Huang Jin parts, radix et rhizoma Rhei fluid extract, semen Juglandis, flos Rosae chinensis, jin Louzi, flos Rosae Rugosae, rubi fructus, herba Juglandis Immaturus, cornu Naemorhedi, total salvianolic acid extract, saviae Miltiorrhizae radix, di Ji, lignum Santali albi, radix Saposhnikoviae, lignum sappan, radix seu ramulus Sambuci Williamsii, sargassum, caulis Sargentodoxae, folium Solani Tuber osi, saururi herba Saussureae Involueratae, extracts of fructus Schisandrae, fructus Schisandrae Sphenantherae, charred herba Schizonepetae, rhizoma Pini, scorpio, radix scrophulariae, and rhizoma Dioscoreae Bulbiferae, herba Scutellariae Barbatae, rhizoma Dioscoreae Bulbiferae, herba Sedi, herba Selaginellae, semen Sojae Atricolor, herba Senecionis Scandentis, folium Pistaciae, os Sepiae, serpentis, oleum Sesami, semen Sesami Niger, fructus Setariae Germinatus, herba Cynanchi Paniculati, herba Emiliae, semen Sinapis Albae, caulis Sinomenii, herba Begoniae Yunnanensis, fructus Siraitiae Grosvenorii, rhizoma Smilacis chinensis, rhizoma Smilacis Bockii, etc., soybean roll, semen Sojae Atricolor semen Sojae Preparatum, herba Solidaginis, radix Sophorae Flavescentis, flos Sophorae Immaturus, fructus Sophorae, radix Sophorae Tonkinensis, rhizoma Sparganii, caulis Spatholobi, fructus Tsaoko, herba Spirodelae, medulla Tetrapanacis, stalactitum, oleum Anisi Stellati, fructus Chaenomelis, radix bupleuri, radix Stemonae, radix Stephaniae Tetrandrae, semen Scaphii Lychnophori, semen Strychni, styrax, pulvis Fellis suis, sulfur, swertia herb, herba Swertiae Mileensis, syngnathus, cortex Syringae, pulvis Talci, salvia Nitri, tanshinone extract, herba Taraxaci, herba Taxilli, semen Strychni Pulveratum, styrax, pulvis Fellii, sulfur, herba Pogostemonis, herba Taxilli, and herba Taxilli-tea oil, fructus Terminaliae Billericae, colla Plastri Testudinis, carapax et Plastrum Testudinis, medulla Tetrapanacis, semen Akebiae lonely, bulbus Fritillariae Thunbergii, caulis et folium Ginseng total saponins, fructus Toosendan, fructus Cannabis, radix Ginseng total Fu glycoside, resina Toxicodendri, caulis Trachelospermi, palm, cai Li, herba Polygoni Avicularis, herba Veronici, herba Pogostemonis, and radix Angelicae sinensis fructus Trichosanthis, pericarpium Trichosanthis, radix Trichosanthis, parched semen Trichosanthis, semen Trigonellae, squama Manis, fructus Tsaoko, oleum Terebinthinae, folium Turpiniae, pollen Typhae, rhizoma Typhonii, ramulus Uncariae cum Uncis, semen Vaccariae, radix Sanguiniae Latifoliae, herba Verbenae, and radix Angelicae sinensis, hive, red bean, herba Violae, herba Taxilli, oleum Viticis negundo, fructus Viticis, folium Viticis negundo, radix aucklandiae, fructus forsythiae extract, rhizoma Wenyujin Concisa, fructus Xanthii, fructus Zanthoxyli, radix Zanthoxyli, zaocys, cultivated oil, rhizoma Zingiberis Preparata, rhizoma Zingiberis recens, rhizoma Zingiberis, and fructus Zizaniae Caduciflorae.

In some embodiments, the drug matrix further comprises a medium. The medium may be associated with an API, e.g., the substrate may have physical contact with the API. In some implementations, the APIs may be embedded in the substrate. In some implementations, the APIs 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, xylosoctose, maltose, trehalose, sorbitol, mannitol, maltodextrin, raffinose, stachyose, fructooligosaccharides or a combination thereof. In some embodiments, the substrate further comprises a plasticizer.

In certain embodiments, the medium 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 joined by covalent or non-covalent bonds. In some embodiments, the pharmaceutical dosage form produces the drug matrix and matrix at once by a 3D printing process.

In some embodiments, the drug matrix is molded into a compressed tablet, oval tablet, pill, or capsule. In some embodiments, the drug matrix shape and the compartment shape are identical. For example, when the compartment shape is a pie shape, the drug matrix shape is also a pie shape to fill the compartment.

In some embodiments, as shown in fig. 6, the drug matrix is present 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 drug dosage form, the solution is atomized/sprayed over the printed layer. Once the solution containing the drug matrix is dried, the drug matrix is dispersed within the drug dosage form. Nanoparticles have a larger surface area and thus higher dissolution rates.

The nanoparticle size is between 1nm and 900nm (preferably, sizes of 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 in the desired size range, the synthesis conditions may be suitably controlled or varied to provide, for example, the desired solution concentration or the desired cavity range (details can be seen: vincnzo Liveri, controlled synthesis of nanoparticles in microscopic heterogeneous systems, springer, 2006).

As shown in fig. 7, in some embodiments, the drug matrix may be in the form of microneedles. Drug matrices in the form of microneedles are typically encapsulated in a housing having a needle-like structure. In 3D printing of pharmaceutical dosage forms, microneedles may also be printed with the pharmaceutical dosage form or embedded in the pharmaceutical dosage form. The microneedles may be composed of saccharides, PLGA polymers, API, or a combination thereof. When administered parenterally or enterally, the microneedles may assist the API in entering 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 drug dosage form is loaded into a compartment inside the matrix. The base of the drug matrix is configured as a network, for example, made of a loose material, the density of the loose drug matrix typically being less than the density of the matrix. The frame structure of the tablet is made of a material that dissolves in 1-10 minutes, the base being soluble 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.

Drug matrix content can be made by using additive methods, such as Fused Deposition Modeling (FDM) methods. In some embodiments, the mixture of API and excipient may be extruded into a drug matrix by 3D printing. The API was melted and mixed homogeneously 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 performed at a temperature between 10 and 40 ℃ above the glass transition temperature of the substrate and near the melting point of the API. Once the 3D printer reaches the proper temperature, the substrate is deposited onto the three-dimensional 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 drug matrix is manufactured first and then the 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 attached to the matrix when loaded into the compartment, e.g., the drug matrix is embedded or immobilized in the matrix. In some embodiments, the drug matrix may be separated from the matrix when the drug matrix is loaded into the compartment.

D. Controlled release

The pharmaceutical dosage forms of the present disclosure have different release processes after oral administration. In some embodiments, the pharmaceutical dosage form has a constant release, pulsed release, delayed release, or non-linear 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 solutions 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, a pulsatile release profile that achieves controlled absorption to reduce peak/trough ratio and targeted release of drug matrix to specific areas within the gastrointestinal tract and absorption processes independent of feed status may be used to improve deviation, reduce side effects and improve patient compliance is necessary for the treatment of ADHD disease. For another example, loading a 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, by adjusting the exposed area of a substrate that is continuously eroded, the drug matrix embedded in the substrate can provide a constant amount of drug over a long period of time. In addition, the release profile rate of the API may be controlled by the size of the compartment opening and/or the geometry of the compartment.

In some embodiments, the release profile may be controlled by designing a compartment with a hole that is closed or blocked by a plug. The plug is made of water-soluble, porous or erodable material, pH sensitive material or hydrophobic material, which can be dissolved, degraded or structurally mutated when the pharmaceutical dosage form passes through the gastrointestinal tract. When the pharmaceutical dosage form is applied to a subject, the plug will melt, infiltrate or erode and the drug matrix in the compartment will be released. The release profile rate of the drug matrix can be controlled by selecting a plug water-soluble material with the appropriate solubility, permeability, and corrodibility. Alternatively, for plugs used to block holes on compartments, the release profile rate of the drug matrix API may be controlled by using plugs of suitable shape and/or size (e.g., pillars of suitable length). The release profile can also be controlled by a different number of compartments. Fig. 9 shows an exemplary dosage form having a matrix with a plurality of columnar compartments disposed 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 continuous, simultaneous, sequential or pulsed.

Fig. 10A illustrates an exemplary pharmaceutical dosage form having sequential release profiles. Referring to fig. 10A, the matrix 701 of the pharmaceutical dosage form 700 contains three columnar compartments 702-704. Each compartment is loaded with a drug matrix containing the same API. Each compartment has a hole blocked by a stick plug 705-707. These plugs are made of the same material but are of different lengths from each other, so that the time required to dissolve the plug to open the compartment 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). Before the plasma drug level falls to a critical level (a parallel line below which the drug is ineffective), the API in the second compartment is released 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 of great benefit for the treatment of specific diseases.

Sequential release characteristics may be achieved by another exemplary pharmaceutical dosage form. The pharmaceutical dosage form contains several drug matrices encapsulated in a stack as shown in fig. 10B. While dissolving the layers may achieve a sustained release of the API to provide a continuous and persistent release of the API as shown in fig. 10C. In some embodiments, the outer layer of the pharmaceutical dosage form will dissolve and release the embedded drug matrix immediately after the pharmaceutical dosage form is applied. However, the intermediate layer is insoluble or very slow in dissolution rate because the outer layer blocks the communication between the sandwiched layer and the environment. In other words, the dissolution of the outer layer usually precedes the dissolution of the intermediate layer, and thus the pharmaceutically active ingredient contained in the outer layer is usually released prior to the pharmaceutically active ingredient of the intermediate layer. 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 pharmaceutical dosage form includes a gas generant composition loaded in the first compartment. In some embodiments, the gas generating component 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 may release carbon dioxide or sulfur dioxide gas upon contact with gastric juice. When the matrix is dissolved, permeated or eroded in the stomach, the gas generating component will produce gas in an effervescent manner to release the drug matrix as a result of the gas generating component being exposed to an acidic environment or water permeating into the compartment to initiate reaction of the acid with sodium bicarbonate. It should be noted that, the dissolution time of the different layers may be set according to the thickness, dissolution rate, permeability, dissolution rate, etc. of each layer of the pharmaceutical dosage form, so that the different layers may be dissolved in a preset time or dissolution profile, so that the pharmaceutical active ingredient therein may 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 by means well known to those skilled in the art, for example, by embedding an API in a delayed release matrix/substrate or by using one or more delayed release coatings. By delayed release, API release can be controlled to be satisfactory for administration twice or once a day, which has advantages for treatments requiring sustained doses of 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 mouth or in the sublingual area.

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

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).

As used herein, 3D printing refers to a process of producing 3D articles layer by layer according to a digital design. U.S. Pat. nos.5,204,055;5,260,009;5,340,656;5,387,380;5,503,785; and 5,633,0213D describes the basic process of 3D printing. Other U.S. patents and applications relating to 3D printing include: U.S. Pat. nos.5,490,962;5,518,690;5,869,170;6,530,958;6,280,771;6,514,518;6,471,992;8,828,411; U.S. PG pub. Nos. 2002/0015728;002/0106412;2003/0143268;2003/0198677;2004/0005360. For a detailed description of 3D printing, see 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 manufacturing technology: 3D printing, rapid prototyping and direct digital production, 2 edition, springer, N.Y., W.E. Katstra et al (2000) three-dimensional printing manufacturing 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 college graduation paper, massa institute; H.Lipson et al (2013) Assembly: 3D printed new world, john's Willi father company; G.Jonathan, A.Karim (2016), 3D printing of medicaments: new tools for designing customized drug delivery systems, international journal of medicine, 499:376-394), material jetting (see G.Jonathan, A.Karim (2016), 3D printing of medicaments: new tools for designing customized drug delivery systems, international journal of medicine, 499:376-394), extrusion (see ibson et al (2013D additive manufacturing technology: 3D, rapid prototyping and LG, 4.H.Willi father, and direct digital printing in U.S. 21:31, and direct digital printing of stereoscopic printing, etc.).

In some embodiments, the pharmaceutical dosage forms disclosed herein are manufactured by an extrusion process. During extrusion, material is extruded from a robotically 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 thermoplastic materials, pastes and colloidal suspensions, silicones and other semi-solids as disclosed herein. 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 filaments into a heated nozzle assembly for extrusion (see L Gibson et al (2015) additive manufacturing techniques: 3D printing, rapid prototyping and direct digital production, 2 nd edition, springer, N.Y.).

The production indications of 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 application software for the 3D printer. These instructions include information on the number and spatial arrangement of the 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. Parameters may be adjusted for a given set of materials to improve the quality of the created structure. The overall resolution of the created structure is the size of the powder particles, the size of the fluid droplets, the printing parameters and the size of the material properties.

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

The manufacture of pharmaceutical dosage forms using 3D printing methods also facilitates personalization. Personalized medicine refers to a dosage form design based on biomarkers to aid stratification of patient populations to produce therapeutic decisions and individualization. Modifying a digital design is easier than modifying a physical device. Furthermore, the operating costs of automated, small-scale 3D printing may be negligible. Thus, 3D printing can make a number of small, personalized mass productions economically viable, making possible the production of personalized dosage forms aimed at improving compliance.

The personalized dosage form allows for custom delivery of the amount of drug according to the patient's weight and metabolic level. The 3D printed dosage form may ensure that the growing child and the highly effective drug have accurate personalized doses. The personalized dosage form may also combine all of the patient's medications into a single daily dose, thereby improving the patient's adherence to the medication.

Fig. 11 illustrates a method of manufacturing a personalized dosage form using three-dimensional printing. For each patient, the results of various clinical trials, including body weight, age, metabolic index, and genomic biomarkers, etc., are available. The results of the clinical trial are entered into computer software and the formulation of the particular dose and drug combination is designed in conjunction with the physician's prescription and pharmacokinetic model. The instructions are then sent to a three-dimensional printer for manufacturing 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 to achieve optimization of drug combinations for a particular medical field. For example, tablets for the treatment of hypercholesterolemia may be designed to release atorvastatin calcium on-the-fly but to release niacin on an extended basis. In another example, pain-relieving nonsteroidal anti-inflammatory drugs (NSAIDs) are designed to release NSAIDs continuously, but release H2 receptor antagonists rapidly to prevent NSAID-induced mucosal damage.

In some embodiments, the matrix contains a plurality of compartments, each of which is loaded with a drug matrix. In some embodiments, the 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 the different compartments are the same. In some embodiments, the drug matrix loaded in different compartments is 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, pulsed, or a combination of these. Fig. 12A illustrates an exemplary pharmaceutical dosage form that can simultaneously release multiple APIs. Referring to fig. 12A, the pharmaceutical dosage form 800 includes three stacks 801-803, each of which is embedded in a different drug matrix. As shown in fig. 12B, when the drug dosage form 800 is applied, the drug matrix is released simultaneously but the release rate varies with the dissolution of the layers.

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

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

Fig. 15A illustrates an exemplary pharmaceutical dosage form that may sequentially release two APIs. Referring to fig. 15A, the pharmaceutical dosage form 1200 includes a matrix 1202 containing compartments filled with a drug matrix 1202. The matrix 1201 includes a first API and the drug matrix 1202 includes a second API. As shown in fig. 15B, after administration of the pharmaceutical dosage form, the first API is released as the collective dissolution proceeds. The second API is not released until the matrix dissolves and exposes the drug matrix, thereby achieving a sequential release profile of the multiple APIs.

Fig. 16A illustrates another exemplary pharmaceutical dosage form having a sequential release profile. Referring to fig. 16A, a matrix 1301 of a pharmaceutical dosage form 1300 contains three columnar compartments 1302-1304 loaded with three drug matrices. Compartments 1302-1304 all have holes that are blocked by cylindrical plugs. Each plug has a different length and/or solubility. As shown in fig. 16B, as the plugs sequentially dissolve to open the compartments, the various APIs are sequentially released.

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

Example 1

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

As shown in fig. 18A, the pharmaceutical dosage form comprises a flat tablet matrix with pie-shaped compartments contained 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 as follows. Na with ph=8 was first formulated ₂ HPO ₄ The aqueous solution was used as a solution of benzoic acid to prepare benzoic acid having a concentration of 120. Mu.g/mLThe mother liquor was diluted in sequence to a concentration of 30. Mu.g/mL, 15. Mu.g/mL, 7.5. Mu.g/mL, 3.75. Mu.g/mL, 1.875. Mu.g/mL, and the absorption wavelength was 226nm with an ultraviolet-visible spectrophotometer. Linear regression was performed on the measured data to give the benzoic acid standard curve y=0.0599x+0.0347. To measure the release of benzoic acid, the pharmaceutical dosage form was dissolved in Na at ph=8 ₂ HPO ₄ The aqueous solution was degassed at 37.+ -. 0.5 ℃ and the spin basket speed was 100rpm, and 5mL were sampled at different time points for benzoic acid concentration measurement, and 5mL medium was added to the solution. Filtering the sample liquid by a 0.45 mu m microporous filter membrane, precisely removing a certain volume of subsequent filtrate, measuring a light absorption value A at a wavelength of 226nm by an ultraviolet-visible wind-light photometer, calculating the concentration of benzoic acid according to a standard curve, and calculating the release percentage of the benzoic acid according to the following formula:

1.

2. Wherein c _n Representing the measured concentration, v _t Representing the volume of the medium, v _s Represents the sampling volume, Q _{benzoic acid} Representing the amount of benzoic acid in the pharmaceutical dosage form.

Determination of the degree of release of PEG 8000: firstly, drawing a standard curve of PEG8000, weighing 0.1275g PEG8000 standard sample, putting the standard sample into a 25ml volumetric flask, dissolving the standard sample in water and diluting the standard sample to a scale; 1ml, 2ml, 5ml and 10ml of the above solutions were respectively removed in 10ml volumetric flasks and diluted to scale with water as control solutions. 50 μl of the solution was precisely measured and injected into the liquid chromatograph (Waters Ultrahydrogel) ^TM 120/250/500 three were connected in series at a flow rate of 0.5ml/min and a column temperature of 40℃and the detector was a differential refractive index detector). Recording a chromatogram, taking the logarithmic value of the concentration of the reference substance as an abscissa and the logarithmic value of the peak area of the corresponding concentration as an ordinate, and calculating a regression equation as follows: y=1.02lx+8.918. Wherein the chromatographic conditions are: the chromatographic column is Waters Ultrahydrogel ^TM 120/250/500 three are connected in series, the flow rate is 0.5ml/min, and the column is provided with a plurality of columnsThe temperature was 40℃and the detector was a differential refractive detector. The volumetric area is measured and indicated as y-axis. The logarithm of the control solution was used as x-axis. Standard curves for PEG8000 were generated with y=1.02lx+8.918. The percent release of PEG8000 can be calculated using the following formula:

3. Wherein c _n Indicating the measured concentration, v _t Indicating the volume of the solution, v _s Indicating the sampling volume, Q _PEG8000 Indicating that in the pharmaceutical dosage form

Amount of PEG 8000.

Results: as shown in fig. 18C, the release profile of benzoic acid and the model in d.brooke and r.j. Washkuhn (zero order delivery system: theory and initial test results, journal of medical science, 1977) agree and are affected by the interface.

Thus, a controlled release profile can be designed based on the pharmaceutical dosage form of the present disclosure.

Example two

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

Drug design: two pharmaceutical dosage forms were prepared using a fused deposition modeling approach. The matrix of the medicine dosage form is prepared from copovidone

) 72%, PEG150018% and +.>

19%. The medicine matrix consists of moxifloxacin hydrochloride 30% and PEG 150070%. Fig. 19A and 19B are schematic diagrams of these drug dosage forms. Referring to fig. 19A and 19B, a pharmaceutical dosage form 1600 includes a matrix 1601 and two compartments 1602 and 1603 within the matrix. Each compartment is surrounded by walls 1604 and 1605, respectively. For the first pharmaceutical dosage form, the two compartments are surrounded by walls having a thickness of 0.75mm and 1.5mm, respectively. For the second medicine The dosage form, the two compartments being surrounded by walls of thickness 0.75mm and 2.25mm, respectively.

To detect release of the drug matrix, the drug dosage form was added to 900mL of phosphate buffer pH6.8 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, after 20 minutes of addition of the first drug dosage form to the buffer, the first compartment is opened and the drug matrix in the first compartment is released. After 40 minutes of the drug dosage form being added to the buffer solution, the second compartment is opened. For the second drug dosage form, the result is shown in fig. 19D, which shows that the second compartment is opened 60 minutes after the drug dosage form is added to the buffer. Thus, the release profile of the pharmaceutical 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 is for purposes of illustration and description only and is not intended to be exhaustive or to limit the scope of the disclosure to the precise form. Many modifications and variations will be apparent to those skilled in the art. The basis for the disclosure was chosen in order to best explain the principles of the embodiments and the practical application, so that those skilled in the art can understand the various embodiments and modifications for specific applications. The scope of the disclosure is defined by the following claims or equivalents thereof.

Claims (12)

1. A pharmaceutical dosage form, comprising:

a matrix forming at least a first compartment and a second compartment inside, said matrix being made of at least one thermoplastic material; and

a first drug matrix received in the first compartment, and a second drug matrix received in the second compartment;

the release of the drug matrix or the pharmaceutically active ingredient is controlled by adjusting the thickness of the matrix, wherein the drug matrix and matrix are produced at once by a 3D printing method, which is achieved by fused deposition.

2. The pharmaceutical dosage form of claim 1, wherein the first and second compartments have different heights from one another.

3. The pharmaceutical dosage form of claim 1, wherein the first compartment and the second compartment have the same height as each other.

4. The pharmaceutical dosage form of claim 1, wherein the first and second compartments have cross-sectional dimensions that are different from one another.

5. The pharmaceutical dosage form of claim 1, wherein the first and second compartments have the same cross-sectional dimensions as each other.

6. The pharmaceutical dosage form according to claim 1, wherein the thermoplastic material is selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 57/30/13, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyvinylpyrrolidone, polyethylene glycol-polyvinyl alcohol graft copolymer 25/75, kollicoat IR-polyvinyl alcohol copolymer 60/40, polyvinyl alcohol, polyvinyl acetate, polybutylmethacrylate-poly 2-dimethylaminoethyl methacrylate-polymethyl methacrylate copolymer 1:2:1, a polymethyl methacrylate-polymethyl methacrylate copolymer, a polyethyl acrylate-polymethyl methacrylate-poly (trimethylethyl vinyl chloride) copolymer, a polymethyl methacrylate-polymethyl methacrylate copolymer 1:2, a poly (methacrylic acid) -poly (ethyl acrylate) copolymer 1:1, a poly (methacrylic acid) -poly (methyl methacrylate) copolymer 1: polyethylene oxide, polyethylene glycol, hyperbranched polyesters, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate, polylactide-polylactic acid copolymers, carbomers, polyethylene-polyvinyl acetate copolymers, ethylene-vinyl acetate copolymers, polyethylene, polycaprolactone, hydroxypropyl cellulose, polyoxyethylene 40 hydrogenated castor oil, methylcellulose, ethylcellulose, poloxamers, hydrogenated castor oil, glyceryl palmitostearate, carnauba wax, polylactic acid, polyglycolic acid, cellulose acetate butyrate, colloidal silicon, titanium oxide, sucrose, glucose, polyvinyl acetate phthalate.

7. The pharmaceutical dosage form of claim 1, wherein the first compartment and the second compartment are connected.

8. The pharmaceutical dosage form of claim 1, wherein the first compartment and the second compartment carry the same drug.

9. The pharmaceutical dosage form of claim 1, wherein the first drug matrix and the second drug matrix are made of the same matrix material.

10. The pharmaceutical dosage form of claim 1, wherein at least a portion of the compartments are closed.

11. The pharmaceutical dosage form of claim 1, wherein the release rates of the first drug matrix and the second drug matrix are different.

12. A method of preparing the pharmaceutical dosage form of any one of claims 1-11, wherein the pharmaceutical dosage form produces the drug matrix and the matrix at once by a 3D printing process.

Images