Dosage forms and their uses

Abstract

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

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority based on U.S. Provisional Patent Application No. 62 / 170,645, filed on June 3, 2015 , and U.S. Provisional Patent Application No. 62 / 313,092, filed on March 24, 2016, and the entire disclosures of those are incorporated herein by reference. The present invention relates generally to pharmaceutical dosage forms and the controlled release of biologically active substances, diagnostic agents, reagents, cosmetics, and pesticides / insecticides. Incorporated herein by reference.

[0002] The present invention relates generally to pharmaceutical dosage forms and the controlled release of biologically active substances, diagnostic agents, reagents, cosmetics, and pesticides / insecticides. Incorporated herein by reference.

Background Art

[0003] Pharmaceutical products must be manufactured into dosage forms in order to be put on the market for use. Conventional dosage forms typically contain a mixture of a pharmaceutical active ingredient and an inactive ingredient (excipient) with other non - reusable materials such as a capsule shell. Types of dosage forms include liquid dosage forms (e.g., solutions, syrups, elixirs, suspensions, and emulsions), solid dosage forms (e.g., tablets, capsules, caplets, and gel caps), and semi - solid dosage forms (e.g., ointments and suppositories), among which solid dosage forms are more advantageous for orally administering drugs with systemic effects. Tablets are the most commonly used solid dosage forms, showing more benefits from the perspectives of manufacturing, packaging, and transportation, and are easy to identify and swallow. After being administered to a living body, tablets undergo interactions with the body when exerting a pharmaceutical effect. The pharmaceutical active ingredient must be released from the tablet before being absorbed into the blood circulation. Then, the pharmaceutical component is in body fluids and body tissues Tablets are the most commonly used solid dosage forms, showing more benefits from the perspectives of manufacturing, packaging, and transportation, and are easy to identify and swallow. After being administered to a living body, tablets undergo interactions with the body when exerting a pharmaceutical effect. The pharmaceutical active ingredient must be released from the tablet before being absorbed into the blood circulation. Then, the pharmaceutical component is in body fluids and body tissues for the pharmaceutical effect.

[0004] Tablets are the most commonly used solid dosage forms, showing more benefits from the perspectives of manufacturing, packaging, and transportation, and are easy to identify and swallow. After being administered to a living body, tablets undergo interactions with the body when exerting a pharmaceutical effect. The pharmaceutical active ingredient must be released from the tablet before being absorbed into the blood circulation. Then, the pharmaceutical component is in body fluids and body tissues before being absorbed into the blood circulation. Then, the pharmaceutical component is in body fluids and body tissues before being absorbed into the blood circulation. Then, the pharmaceutical component is in body fluids and body tissues Disperse, disintegrate, or dissolve throughout the fabric. In the drug absorption, distribution, metabolism, and excretion processes, the dosage form plays a crucial role in determining the drug release profile and bioavailability. Therefore, there is an ongoing need to develop dosage forms that can achieve a controlled drug delivery system, which can provide the desired plasma drug level, reduce side effects, and improve patient compliance. In the drug absorption, distribution, metabolism, and excretion processes, the dosage form plays a crucial role in determining the drug release profile and bioavailability. Therefore, there is an ongoing need to develop dosage forms that can achieve a controlled drug delivery system, which can provide the desired plasma drug level, reduce side effects, and improve patient compliance. In one aspect, the present disclosure provides a dosage form comprising a substrate forming at least one compartment and a drug content packed in the compartment. In some embodiments, the drug content is operably linked to the substrate. In some embodiments, the drug content is separated from the substrate and can move freely in the compartment. In some embodiments, the substrate is made of a thermoplastic material selected from the group consisting of hydrophilic polymers, hydrophobic polymers, swellable polymers, non-swellable polymers, porous polymers, non-porous polymers, erodible polymers, and non-erodible polymers. In some embodiments, the thermoplastic material is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 57 / 30 / 13, polyvinyl pyrrolidone-co-vinyl acetate (PVP-VA), polyvinyl pyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60 / 40, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc) and polyvinyl pyrrolidone (PVP) 80 / 20, polyethylene glycol SUMMARY OF THE INVENTION

[0005] In one aspect, the present disclosure provides a dosage form comprising a substrate forming at least one compartment and a drug content packed in the compartment. In some embodiments, the drug content is operably linked to the substrate. In some embodiments, the drug content is separated from the substrate and can move freely in the compartment. In some embodiments, the drug content is operably linked to the substrate. In some embodiments, the drug content is separated from the substrate and can move freely in the compartment. In some embodiments, the substrate is made of a thermoplastic material selected from the group consisting of hydrophilic polymers, hydrophobic polymers, swellable polymers, non-swellable polymers, porous polymers, non-porous polymers, erodible polymers, and non-erodible polymers. In some embodiments, the drug content is separated from the substrate and can move freely in the compartment.

[0006] In some embodiments, the substrate is made of a thermoplastic material selected from the group consisting of hydrophilic polymers, hydrophobic polymers, swellable polymers, non-swellable polymers, porous polymers, non-porous polymers, erodible polymers, and non-erodible polymers. In some embodiments, the thermoplastic material is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 57 / 30 / 13, polyvinyl pyrrolidone-co-vinyl acetate (PVP-VA), polyvinyl pyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60 / 40, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc) and polyvinyl pyrrolidone (PVP) 80 / 20, polyethylene glycol In some embodiments, the thermoplastic material is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 57 / 30 / 13, polyvinyl pyrrolidone-co-vinyl acetate (PVP-VA), polyvinyl pyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60 / 40, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc) and polyvinyl pyrrolidone (PVP) 80 / 20, polyethylene glycol In some embodiments, the thermoplastic material is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 57 / 30 / 13, polyvinyl pyrrolidone-co-vinyl acetate (PVP-VA), polyvinyl pyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60 / 40, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc) and polyvinyl pyrrolidone (PVP) 80 / 20, polyethylene glycol In some embodiments, the thermoplastic material is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 57 / 30 / 13, polyvinyl pyrrolidone-co-vinyl acetate (PVP-VA), polyvinyl pyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60 / 40, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc) and polyvinyl pyrrolidone (PVP) 80 / 20, polyethylene glycol In some embodiments, the thermoplastic material is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 57 / 30 / 13, polyvinyl pyrrolidone-co-vinyl acetate (PVP-VA), polyvinyl pyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60 / 40, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc) and polyvinyl pyrrolidone (PVP) 80 / 20, polyethylene glycol In some embodiments, the thermoplastic material is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 57 / 30 / 13, polyvinyl pyrrolidone-co-vinyl acetate (PVP-VA), polyvinyl pyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60 / 40, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc) and polyvinyl pyrrolidone (PVP) 80 / 20, polyethylene glycol In some embodiments, the thermoplastic material is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 57 / 30 / 13, polyvinyl pyrrolidone-co-vinyl acetate (PVP-VA), polyvinyl pyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60 / 40, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc) and polyvinyl pyrrolidone (PVP) 80 / 20, polyethylene glycol Recall - Polyvinyl Alcohol Graft Copolymer 25 / 75, kollicoat IR - Polyvinyl Alcohol 60 / 40, Polyvinyl Alcohol (PVA or PV - O H), Polyvinyl Acetate (PVAc), Poly(butyl methacrylate - co - (2 - dimethylaminoethyl) methacrylate - co - methyl methacrylate) 1:2:1, Poly (dimethylaminoethyl methacrylate - co - methacrylic acid ester), Poly(ethyl acrylate - co - methyl methacrylate - co - trimethylammonioethyl meth acrylate chloride), Poly(methyl acrylate - co - methyl methacrylate - co - methacrylic acid) 7:3:1, Poly(methacrylic acid - co - methyl methacrylate) 1: 2, Poly(methacrylic acid - co - ethyl acrylate) 1:1, Poly(methacrylic acid - c o - methyl methacrylate) 1:1, Poly(ethylene oxide) (PEO), Poly(ethyl ene glycol) (PEG), Multi - branched polyester amide, Hydroxypropyl methyl cellulose phthalate, Hypromellose phthalate, Hydroxypropyl methylcellulo se or Hypromellose (HMPC), Hydroxypropyl methylcellulose acetate succinate or Hypromellose acetate succinate (HPMCAS), Poly(lac tide - co - glycolide) (PLGA), Carbomer, Poly(ethylene - co - vinyl acetate), Ethylene - vinyl acetate copolymer, Polyethylene (PE), and Polycaprolactone (PCL), Hydroxylpropyl cellulose (HPC), Polyox yl 40 hydrogenated castor oil, Methyl cellulose (MC), Ethyl cellulose (EC), Polox amer, Hydroxypropyl methylcellulose phthalate (HPMCP), Poloxamer Selected from the group consisting of hydrogenated castor oil, soybean oil, glyceryl palmitostearate, carnauba wax, poly lactic acid (PLA), polyglycolic acid (PGA), cellulose acetate butyrate (CAB ), colloidal silicon dioxide, sucrose, glucose, polyvinyl acetate phthalate (PVAP), and combinations thereof.

[0007] In some embodiments, the compartment has a shape selected from the group consisting of pie-shaped, conical, pyramidal, cylindrical, cubic or cuboid, triangular or polygonal prism-shaped, tetrahedral and combinations thereof.

[0008] In some embodiments, the first drug content is in the form of nanoparticles, microneedles, or forms a network structure.

[0009] In some embodiments, the drug content contains an active pharmaceutical ingredient (API). In some embodiments, the API is a local anesthetic, an anti-epileptic and anti-convulsant drug, an anti-Alzheimer's drug, an analgesic, an anti-gout drug, an anti-hypertensive drug, an anti-arrhythmic drug, a diuretic, a liver disease treatment drug, a pancreatic disease treatment drug, an antihistamine drug, an anti-allergy drug, a glucocorticoid drug, a hormone drug and a contraceptive drug, an anti-diabetic drug, an anti-osteoporosis drug, an antibiotic, a sulfonamide, a quinolone, and other synthetic antibacterial drugs, anti-tuberculosis drugs, anti-viral drugs, anti-neoplastic drugs, immunomodulators, cosmetic active substances and traditional Chinese medicine drugs. In some embodiments, the API is a biologically active substance, a diagnostic agent, a reagent for scientific research, a cosmetic, or a pesticide / insecticide .

[0010] In some embodiments, the drug content further comprises an excipient. In some embodiments the excipient is made of a material selected from the group consisting of cocoa butter, polyethylene glycol (PEG), sucrose, glucose, galactose, fructose, xylose lactose, maltose, trehalose, sorbitol, mannitol, maltodextrin, raffinose, stachyose, fructooligosaccharide, water-soluble oligomers and polymers, and combinations thereof. In some embodiments, the compartment has an aperture that is plugged and / or sealed. In some embodiments, the plug is made of a porous polymer, an erodible polymer, a pH-sensitive polymer, or a natural material such as shellac. In some embodiments, the plug is made of a material selected from the group consisting of a water-soluble polymer, an erodible or soluble polymer, a wax-like material or sugar, or any of the above materials.

[0011] In some embodiments, the dosage form contains a gas-generating component packed 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, and combinations thereof, and releases 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 some embodiments, the dosage form contains a gas-generating component packed 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, and combinations thereof, and releases 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 some embodiments, the dosage form contains a gas-generating component packed 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, and combinations thereof, and releases 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 some embodiments, the dosage form contains a gas-generating component packed 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, and combinations thereof, and releases 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 some embodiments, the dosage form contains a gas-generating component packed 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, and combinations thereof, and releases 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 some embodiments, the dosage form contains a gas-generating component packed 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, and combinations thereof, and releases 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.).

[0012] In some embodiments, the dosage form contains a gas-generating component packed 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, and combinations thereof, and releases 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 some embodiments, the dosage form contains a gas-generating component packed 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, and combinations thereof, and releases 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 some embodiments, the dosage form contains a gas-generating component packed 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, and combinations thereof, and releases 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 some embodiments, the dosage form contains a gas-generating component packed 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, and combinations thereof, and releases 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 some embodiments, the dosage form contains a gas-generating component packed 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, and combinations thereof, and releases 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 some embodiments, the dosage form contains a gas-generating component packed 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, and combinations thereof, and releases 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 some embodiments, the gas-generating component is a combination of sodium bicarbonate and an organic acid (e.g., citric acid, tartaric acid, etc.).

[0013] In another aspect, the present disclosure provides a dosage form comprising a substrate forming at least a first compartment and a second compartment. The dosage form includes a first drug content packed in the first compartment and a second drug content packed in the second compartment.

[0014] In some embodiments, the first compartment and the second compartment are connected. In some embodiments, the first compartment and the second compartment are not connected.

[0015] In some embodiments, the first drug content is the same as the second drug content. In some embodiments, the first drug content is different from the second drug content.

[0016] In some embodiments, the first compartment has a first aperture covered by a first stopper, and the second compartment has a second aperture covered by a second stopper. In some embodiments, the first stopper is more permeable than the second stopper. In some embodiments, the first stopper is eroded faster than the second stopper.

[0017] In some embodiments, the first compartment is surrounded by a first wall, and the second compartment is surrounded by a second wall.

[0018] In some embodiments, the first wall is thicker than the second wall. In some embodiments, the first wall is more permeable than the second wall. In some embodiments, the first wall is eroded faster than the second wall. BRIEF DESCRIPTION OF THE DRAWINGS ​​​​​​​​​​​​

[0019]

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[0020] The above summary of the invention, the detailed description of the invention, and the following claims, as well as Certain features of the invention (including method steps) are set forth in the accompanying drawings. The disclosure of the invention in this specification encompasses all possible combinations of such particular features. For example, it is understood that certain features are encompassed by certain aspects or aspects of the invention. When disclosed in connection with an embodiment or a particular claim, the features are In combination and / or in conjunction with other particular aspects and embodiments of the invention: It may also be used in its entirety in the present invention.

[0021] The term "comprises" and its grammatical equivalents are used herein to refer to other components. It is used to indicate the occasional presence of a material, step, etc. For example, An article “comprising” (or “which comprises”) components A, B, and C can consist of (i.e., consist only of) components A, B, and C, or can include, in addition to components A, B, and C, one or more other components.

[0022] Where a method is described herein that includes two or more recited steps, the recited steps can be performed in any order (except where the context excludes that possibility) or simultaneously, and the method can include one or more other steps that are performed before any of the recited steps, between two of the recited steps, or after all of the recited steps (except where the context excludes that possibility).

[0023] If a range of values is recited, each value that lies between the upper and lower limits of that range (down to one-tenth of the unit of the lower limit unless the context clearly dictates otherwise) and any other recited value or interposed value in that recited range is included within the disclosure, except where specifically excluded by the disclosure or where there are specifically recited limits. Where the recited range includes one or both of the upper and lower limits, ranges excluding either or both of those limits are also included within the disclosure.

[0024] The term “at least” followed by a number is used herein to denote the beginning of a range that starts with that number (which can be a range having an upper limit or no upper limit, depending on the variable being defined). For example, “at least 1” means 1 or more. The term "at most" followed by a number represents the end of a range that ends with that number (which can be a range with a lower limit of 1 or 0 or no lower limit depending on the defined variable). For example, "at most 4" means 4 or less than 4, and "at most 40%" means 40% or less than 40%. In the present disclosure, when a range is described as "(a first number) to (a second number)" or "(a first number) ~ (a second number)", this means a range where the lower limit is the first number and the upper limit is the second number. For example, 2 to 10 millimeters means a range where the lower limit is 2 millimeters and the upper limit is 10 millimeters. It should be understood that, for the sake of simplicity and clarity of illustration, reference numerals may be repeated between different drawings as necessary to indicate corresponding or similar components. Further, in order to fully understand the embodiments described herein, a number of specific details are set forth. However, the embodiments described herein may be practiced without these specific details. (In other instances, methods, procedures, and components are not detailed so as not to obscure the relevant significant functions described. Also, the description is not to be regarded as limiting the scope of the embodiments described herein. It will be understood that the descriptions and characterizations of the embodiments described in the present disclosure are not to be regarded as mutually exclusive unless otherwise noted.) Release control dosage form Conventional solid dosage forms, such as compressed tablets, have an active drug ingredient dissolved or embedded

[0025] in them. in them. For a more complete understanding of the embodiments described herein, numerous specific details are set forth. However, the embodiments described herein may be practiced without these specific details. In other instances, methods, procedures, and components are not detailed so as not to obscure the relevant significant functions described. Also, the description is not to be regarded as limiting the scope of the embodiments described herein. It will be understood that the descriptions and characterizations of the embodiments described in the present disclosure are not to be regarded as mutually exclusive unless otherwise noted. without these specific details. In other cases, methods, procedures, and components are not detailed so as not to obscure the relevant significant functions described. Also, the description is not to be regarded as limiting the scope of the embodiments described herein. It will be understood that the descriptions and characterizations of the embodiments described in the present disclosure are not to be regarded as mutually exclusive unless otherwise noted. The description is not considered to limit the scope of the embodiments described herein. It should be understood that the descriptions and characterizations of the embodiments described in this disclosure are not considered mutually exclusive unless otherwise noted. The description of the embodiments described in this disclosure and their characterizations are not considered mutually exclusive unless otherwise noted. It should be understood that the descriptions and characterizations of the embodiments described in this disclosure are not considered mutually exclusive unless otherwise noted. It will be understood that the descriptions and characterizations of the embodiments described in the present disclosure are not to be regarded as mutually exclusive unless otherwise noted.

[0026] Release control dosage form Conventional solid dosage forms, such as compressed tablets, have an active drug ingredient dissolved or embedded Composed of a substrate (Figure 1A). Current conventional solid dosage forms have a primary drug release profile ( Figure 1B), where the plasma level of the drug rapidly rises to a very high level after administration and then decreases exponentially (see Figure 1C). This has drawbacks such as the loss of therapeutic efficacy due to the decrease in drug level or drug toxicity that can occur at high concentrations. In this type of drug release, an appropriate balance of plasma drug concentration cannot be achieved. The present invention relates to an orally administered drug delivery system with regulated or controlled release, which provides advantages over conventional systems, including improved patient compliance, selective pharmacological action, reduced side effects, and decreased dosing frequency. Controlled release results in an extension of drug delivery and maintenance of plasma levels within the therapeutic range. For example, a drug delivery system that exhibits a zero-order drug release profile (Figure 1D) enables a constant amount of drug release over a long period of time, achieving uniform and sustained drug delivery. As a result, the zero-order release profile may be desirable in antibiotic delivery, treatment of hypertension, pain management, antidepressant delivery, and many other conditions that require a constant plasma drug level. Therefore, one aspect of the present disclosure provides a stable solid pharmaceutical dosage form for oral administration having a controlled release profile. In some embodiments, the dosage form comprises a substrate that forms at least one compartment and a drug content contained within the compartment. The dosage form is designed to be able to control the release of the active pharmaceutical ingredient of the drug content, for example, by opening the compartment in a predetermined manner. .

[0027] Accordingly, one aspect of the present disclosure provides a stable solid pharmaceutical dosage form for oral administration having a controlled release profile. In some embodiments, the dosage form comprises a substrate that forms at least one compartment and a drug content contained within the compartment. The dosage form is designed to be able to control the release of the active pharmaceutical ingredient of the drug content, for example, by opening the compartment in a predetermined manner.

[0028] A. Substrate ​​​As used herein, "substrate" refers to the structure in which the drug is encapsulated or embedded. The dosage form of the substrate may be of any size and shape as long as it is suitable for oral administration. In some embodiments, the substrate is a flat, circular tablet with a diameter of about 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, or 12 mm. In some embodiments, the substrate is an oval tablet with a size of about a mm × b mm, where a is from 5 to 15 and b is from 2 to 10. In some embodiments, the substrate is in the shape of a capsule.

[0029] In some embodiments, the substrate is made of a hydrophilic polymer (e.g., hydroxypropyl methylcellulose (HPMC) and poly(ethylene oxide) (PEO)), a hydrophobic polymer (e.g., ethylcellulose (EC)), a swellable polymer, a non-swellable polymer, a porous polymer, a non-porous polymer, an erodible polymer, or a non-erodible polymer.

[0030] In some embodiments, the dosage form has an integrated substrate. In some embodiments, the substrate consists of several parts, and each part is made of the same or different materials.

[0031] In some embodiments, the substrate is made of a thermoplastic material. As used herein, "thermoplastic material" refers to a material that can be shaped using heat and pressure. In some embodiments, the thermoplastic material can be, for example, a hydrophilic gel-forming material or a hydrophobic material, and the release of the drug content from the hydrophilic gel-forming material mainly proceeds by Release of the drug content from the aqueous material mainly proceeds by diffusion from the pores in the substrate. Poly mers, especially cellulose ethers, cellulose esters and / or acrylic resins, can be used as hydrophilic aqueous thermoplastic materials. Ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, poly (meth)acrylic acid, and / or their salts, amides or esters, such as their derivatives, are suitable for use as thermoplastic materials. Mono- or diglycerides of C12-C30 fatty acids and / or C12-C30 fatty alcohols and / or waxes or their mixtures, etc., physiologically acceptable hydrophobic materials known to those skilled in the art can be used as thermoplastic materials . Hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or corresponding esters or ethers or mixtures thereof, etc., hydrophobic materials can also be considered as substrates prepared therefrom.

[0032] In some embodiments, the thermoplastic material is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 57 / 30 / 13, polyvinyl pyrrolidone-co-vinyl acetate (PVP-VA), polyvinyl pyrrolidone-poly vinyl acetate copolymer (PVP-VA) 60 / 40, polyvinyl pyrrolidone (PV P), polyvinyl acetate (PVAc) and polyvinyl pyrrolidone (PVP) 80 / 20 , polyethylene glycol-polyvinyl alcohol graft copolymer 25 / 75, ko llicoat IR-polyvinyl alcohol 60 / 40, polyvinyl alcohol (PV A or PV-OH), poly(vinyl acetate) (PVAc), poly(butyl methacry Rate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate 1:2:1, poly(dimethylaminoethyl methacrylate-co-methacrylic acid ester) Stell), poly(ethyl acrylate-co-methyl methacrylate-co-trimethyl Ammonioethyl methacrylate chloride), poly(methyl acrylate-co-methyl Methacrylate-co-methacrylic acid) 7:3:1, poly(methacrylic acid-co-methyl Methacrylate) 1:2, poly(methacrylic acid-co-ethyl acrylate) 1:1, poly (Methacrylic acid-co-methyl methacrylate) 1:1, poly(ethylene oxide)( PEO), poly(ethylene glycol)(PEG), multi-branched polyester amide, hyd Roxypropylmethylcellulose phthalate, hypromellose phthalate, hydroxypropyl Methylcellulose or hypromellose (HMPC), hydroxypropylmethyl Cellulose acetate succinate or hypromellose acetate succinate (HP MCAS), poly(lactide-co-glycolide)(PLGA), carbomer, poly(ethylene Co-vinyl acetate), ethylene-vinyl acetate copolymer, polyethylene (PE), and polycaprolactone (PCL), hydroxylpropylcellulose (HPC), polyoxyl 40 hydrogenated castor oil, methylcellulose (MC), ethylcellulose EC), poloxamer, hydroxypropylmethylcellulose phthalate (HPM CP), poloxamer, hydrogenated castor oil and soybean oil, glyceryl palmitostearate, ka Rnauba wax, polylactic acid (PLA), polyglycolic acid (PGA), cellulose acetate Tobutyrate (CAB), colloidal silicon dioxide, sucrose, glucose, polyvinyl selected from the group consisting of acetate phthalate (PVAP) and combinations thereof .

[0033] Table 1 lists the properties and suppliers of various thermoplastic materials.

[0034] In some embodiments, an additive method such as fused deposition modeling (FDM) can be utilized to fabricate dosage forms from thermoplastic materials. In some embodiments, a three-dimensional printer (3D printer) configured to extrude a thermoplastic material can be used to fabricate a substrate. Typically, the thermoplastic material is melted in a 3D printer and then extruded to form the substrate. In one embodiment, suitable extruders include, but are not limited to, single-screw or twin-screw extruders, and the temperature within the extruder is in the range of 50°C to 180°C and 80°C to 140°C. Generally, the extrusion process can be carried out at a temperature 10°C to 40°C above the glass transition (Tg) of the thermoplastic material . When it reaches a temperature suitable for use in a three-dimensional printer, the thermoplastic material can be deposited on the three-dimensional printing surface. The shape and size of the substrate and compartments made of the thermoplastic material can be controlled by programming the three-dimensional printing process. When it reaches a temperature suitable for use in a three-dimensional printer, the thermoplastic material can be deposited on the three-dimensional printing surface. The substrate and compartments made of the thermoplastic material and their shape and size can be controlled by programming the three-dimensional printing process.

[0035] In some embodiments, the material of the substrate can be selected such that the drug release profile is controlled . For example, the substrate is made of a material having a desired erosion / dissolution rate and permeation rate, and thus, when administered, the compartment opens in a predetermined manner .​ It can be formed, and the drug content is released from the compartment at a desired rate. In some embodiments the base material is erodible or soluble, and the active pharmaceutical ingredient (API) is embedded therein. When the base material is eroded or dissolved, the API is released.

[0036] The release of the drug content can also be controlled by adjusting the thickness of the base material. For example, the base material forming the compartment is made of a soluble material. The opening of the compartment, and thus the release of the drug content packed therein, can be controlled by adjusting the thickness of the wall surrounding the compartment. The thicker the wall, the slower the opening of the compartment and the slower the release of the drug content.

[0037] B. Compartment In certain embodiments, the dosage forms disclosed herein include at least one compartment within the base material. As used herein, "compartment" refers to a space, portion or cavity characterized or divided by the base material. The compartment can be closed or open (e.g., having an aperture or passageway). The compartment can have any geometry suitable for containing the drug content. In some embodiments, the compartment is selected from the group consisting of a pie shape, a conical shape, a pyramidal shape, a cylindrical shape, a cubic shape or a rectangular prismatic shape, a triangular or polygonal prism shape, a tetrahedron and combinations thereof.

[0038] In some embodiments, including a compartment in the dosage form can enhance its retention in the gastrointestinal tract. Figure 2A shows a compartment filled with the drug content An exemplary dosage form having a substrate that forms a compartment is illustrated. Referring to Figure 2A, in dosage form 100, compartment 102 is formed by substrate 101. The drug content 103 is packed into compartment 10 2 by connecting to the inner wall of compartment 102. Compartment 102 provides a floating effect to the dosage form, thereby extending its residence time in the stomach or in an aqueous or acidic environment. The residence time is determined by the erosion / dissolution rate of the material of the substrate and, as shown in Figure 2B, can result in the sustained release of API.

[0039] Figure 3 illustrates another exemplary dosage form with increased retention in the gastrointestinal tract. Referring to Figure 3, dosage form 200 has a configuration that includes a second dosage form 203 (e.g., a tablet) that can move freely into compartment 202. The residence time of the dosage form in the gastrointestinal tract is limited. By using a floating system, the dosage form can stay in the stomach and continuously release the drug at the upper part of the gastrointestinal tract, maximizing absorption in the small intestine.

[0040] In some embodiments, the shape of the compartment is uniquely created so that the drug content can be released at a controlled rate. In some embodiments the compartment has a shape selected from the group consisting of wedge-shaped, pie-shaped, conical, pyramid-shaped, cylindrical, cubic, or rectangular parallelepiped-shaped, triangular or polygonal prism-shaped, tetrahedral, and combinations thereof.

[0041] In one embodiment, the compartments of the dosage form have different geometric shapes. Figure 4A shows​​​​​​​​ An exemplary dosage form having a substrate that forms a pie-shaped compartment is shown. Figure 4B shows an exemplary dosage form having a substrate that forms a plurality of compartments including openings of various sizes. Figure 4C shows an exemplary dosage form having a substrate that forms compartments at an angle. Figure 4D shows an exemplary dosage form having a substrate that forms a plurality of compartments with different radius sizes. The shape of the compartment can be utilized to control the release profile of the dosage form. For example, R.A. Lipper and W.I. Higuichi described a delivery system that achieves a zero-order release profile illustrated in Figure 5. Figure 5 shows a cross-sectional view of a delivery system having a pie-shaped compartment. The compartment communicates with the environment through a small opening. The compartment is filled with a drug content that dissolves to release the API. Then, the API is released into the environment through the small opening.

[0042] The dissolution rate of the drug content is positively correlated with the dissolution boundary region (the interface between the drug content and the space of the compartment). On the other hand, the diffusion rate of the API into the environment is negatively correlated with the diffusion path length λ. As a result, as the drug content dissolves, the dissolution boundary region increases, and the dissolution rate of the drug content increases. On the other hand, as the drug content dissolves, the diffusion path length λ increases. Therefore, the API released in the compartment needs to be transported a longer length to diffuse from the dosage form. It is envisioned that the dosage form can be designed to achieve zero-order kinetics (R.A. Lipper and W.I. Higuichi (1977), Analysis of theoretical behavior of a p 、Analysis of theoretical behavior of a p​​ Proposed zero-order drug delivery system. J. Pharm Sci 66(2): 163~4; D. Brooke and R. J. Washkuhn (1977), Zero-order drug de livery system: theory and preliminary te sting. J Pharm Sci. 66(2):159~162).

[0043] C. Drug content As used herein, the term "drug content" refers to a composition containing one or more active ingredients, including pharmaceutical active ingredients (APIs), cosmetics, biological substances, diagnostic agents, and reagents for scientific experiments. That is.

[0044] As used herein, API refers to the biologically active ingredient in a pharmaceutical product. In some embodiments the API is a local anesthetic, an antiepileptic and anticonvulsant drug, an Alzheimer's disease treatment drug, an analgesic, an antigout drug, an antihypertensive drug, an antiarrhythmic drug, a diuretic, a liver disease treatment drug, a pancreatic disease treatment drug, an antihistamine drug, an anti-allergy drug, a glucocorticoid drug, a sex hormone drug and a contraceptive drug, an antidiabetic drug, an osteoporosis drug, an antibiotic, a sulfonamide, a quinolone, and other synthetic antibacterial drugs, antituberculosis drugs, antiviral drugs, antineoplastic drugs, immunomodulators, cosmetic active substances substances, traditional Chinese medicine (TCM) and TCM extracts, selected from the group consisting of.

[0045] In some embodiments, the API is (R)-folic acid, lidocaine, 1 1-di-deuterio-ethyl linoleate, 16-dehydro-pregnenolone, 17β- estradiol, 2-iminobiotin, 3,5-diiodothyropropionic acid, 5-flu Oro-2-deoxycytidine, 6-mercaptopurine, edotreotide, abacavir, a vian hemocyanin, abametapir, abediterol, abemaciclib, abexinostat , abiraterone, acalabrutinib, acamprosate, acamprosate calcium m, acarbose, aselastat, aceclidine, aceclofenac, acehicitin hydrochloride, acemannan, acenolamic acid, acetaminophen, acetylcysteine , acetyl kitasamycin, acetyl-L-carnitine hydrochloride, acetylsalicylic acid, a cyclovir, acipimox, asitazanolast, acitretin, acridinium, ac ridinium bromide, acolbifene, acolafloxacin, acotiamide, acrivast ine, actarit, adapalene, adapalene, adefovir dipivoxil, ademetion ine, adoair, afatinib, afimoxifene, afuresertib, agomelatine, a ildenafil citrate [aildenafilcitrate], aradrian, aralenobadifloxi sacin mesylate, aralelin acetate, aratrofloxacin mesylate, albend azole, albuterol sulfate, albuterpenoid, alkafutadine, ald oxorubicin, alectinib, alendronate, sodium alendronate, alend ronate sodium hydrate, alendronic acid, alfacalcidol, alfaxalone, alfentanil, alfuzosin, alisertib, aliskiren, alispoviral, ali tretinoin, allantoin, alisartan isoproxil, allopurinol, almot riptan,alogliptin,alogliptin benzoate,alosetron,alpelisib , α-ketoglutarate, α-lipoic acid, α1-antitrypsin, α-cyclodextrin Stabilized sulforaphane, alprazolam, alprostadil, alprostadil alpha Dex, altiratinib, altretamine, atropine, aluminum sulfate, albimo Pan, albosidib, amantadine, amantadine hydrochloride, ambrisentan, ambro Xol, ambroxol hydrochloride, amcasertib, amphetamine, amphetamine Polystyrex, amifampridine, amifampridine phosphate, amifostine , amikacin, amiloride, aminolevulinic, aminolevulinic acid , aminolevulinic acid hydrochloride, aminopterin, amiodarone, amisermod, amisulpride Lid, amitriptyline hydrochloride, amitriptyline, anlexanox, amlodipine, a Mlodipine, amlodipine besylate, amlodipine besylate, amlodipine cancylate -t, amlodipine maleate, amlodipine nicotinate, amlodipine orotate, Ammonium lactate, amodiaquine, amorolfine, amosulalol, amoxicillin, Amoxicillin hydrate, amphetamine, amphetamine aspartate, amphetami n sulfate, amphotericin B, amphotericin B cholesteryl sulfate, am photericin B lipid complex, ampicillin sodium, ampiroxicam, amrinone, a Murubicin, amtotremecin acyl, anacetrapib, anagrelide, anagrelide , anamorelin, anastrozole, ancrod, androgen, andrographolide, Anecortab, anidulafungin, aniracetam, anisoylated plasminogen streptokinase activator complex, anlotinib , antazoline, antiandrogen drug, antineoplaston A-10, antineoplaston Ston AS2-1, Anthofloxacin Hydrochloride, Antroquinonol, Apabetalone, A partamide, Apatinib Mesylate, Apazicon, Apilimod Mesylate, Apixaban , Apomorphine, Apomorphine Hydrochloride, Apremilast, Aprepitant, Apicitab ine, Alamcol, Amlodipine, Alacecloconazole, Alacecloconazole Nitrate , Albaclofene, Albaclofene Pracalbil, Albeckacin, Albeckacin Sulfate, Aldeperine Sodium, Alformoterol, Argatroban, Al halofenate, Alimocromol, Aripiprazole, Aripiprazole Lauroxil, Almodafinil, Arsenic Trioxide, Arsenous Acid, Altefenomel Mesylate, Altebeterol, Altemotil, Altenimol, Alteolol Maleate, Altesunate, Altesis Artiss], Asapiprant, Asenapine, Asimadoline, Astodrimer, Astragalo sid, Asnaprevir, Ataciguat, Ataluren, Atazanavir, Atazanavir Sulfate , Atenolol, Atomoxetine, Atorvastatin, Atorvastatin Calcium , Atorvastatin Strontium, Atovaquone, Atrasentan, Atropine, O lanolafin, Auriclosene, Abacicaptadopegol Sodium, Abacopan, Aba naphil, Abatrombopag, Avibactam, Avibactam Sodium, Avidin Oxide AvidinOx, Aviptadil, Avitinib, Aborlastat, Accelopran, Aki tinib, Azacitidine, Azacitidine, Azaseron, Azelaic Acid, Azelastine, Azelastine Hydrochloride, Azeliragon, Azelnidipine, Azilsartan, Azilsartan Medoksomil potassium, Azilsartan trimethylethanolamine, Azimilide, Azi Sromycin, Azithromycin lactobionate, Aztreonam, Aztreonam li sin, Azubutin, Baclofen, Bafetinib, Baicalein, Baicalin, BAK non containing latanoprost, Balofloxacin, balsalazide, balsalazide sodium, bamb terol, Barasertib, Bardoxolone methyl, Baricitinib, Barnidipine, Basmi sanil, Batefenterol succinate, Bazedoxifene, Bekrabvir, Becrom tazone dipropionate, Becromethasone dipropionate, Bedaquiline, Bedradrine , Belinostat, Biloranib, Belotecan, Benpeidic acid, Benapenem 〔benapenem〕, Benazepril, Benzcycloxydium bromide, Bendamustine, Bendamustine hydrochloride, Benidipine, Benserazide, Bentamipimod, Benzalkonium chloride, Benzhydro codone, Benzidazole, Benzocaine, Benzoyl peroxide, Benzydamine HCL, Be potastin, Bepotastin calcium dihydrate, Bepotastin salicylate, Beractant to, Beraprost sodium, Besifloxacin, Besifovir, Besipiridine, β-Ele men, Betahistine, Betaine anhydrous, Betamethasone, Betamethasone butyrate propione ate, Betamethasone dipropionate, Betamethasone valerate, Betamipron, Betaki solol, Betaxolol hydrochloride, Bethanechol, Betrixaban, Bevacizumab, Beki sagliflozin, Bexarotene, Bezafibrate, Biafungin, Biapenem, Bical tamid, Bicifadine, Bictegravir, Bicyclol, Virastin, Bimatoprost, Bi nimetinib, Biotin, Virabrexin dihydrate, Biscalcitriol potassium, Gallic acid Bismuth acid, bismuthyl ecaverot, bisnorcymserine, bisoprolol, bisoprolol fumarate, bitespiramycin, bixalomer, bleomycin, bronantherine, boanmycin hydrochloride, boceprevir, bortezomib, bosentan, bosentan hydrate, bosutinib, bobactant, brexpiprazole, brisiclib sodium, brigat inib, brilacidin, brimapitide, brimonidine, brincidofovir, brinzolami d, brivanib alaninate, brivaracetam, brivudin, brodalumab, bromaze pam, bromfenac, bromfenac sodium, bromocriptine, broncostat t, brotizolam, bryostatin-1, busindolol, bucladesine, budesonide, buzepin, bufromezil, brakin, bunazosin, buparlisib, bupivacaine, bupi vacaine hydrochloride, buprenorphine, buprenorphine hydrochloride, bupropion, bupropion hydrochloride, brixafol, buserelin acetate, buspirone, buspirone hydrochloride, b sulfan, busulfex, butenafine, butorphanol tartrate, butylph talide, cabazitaxel, cabergoline, cabotegravir, cabozantinib S-malate 、cadazolid, cadorfloxacin, caffeine, caffeine citrate, cafnea, c afuseltyb hydrochloride, calcipotriol, calcitriol, calcium acetate, phosphoric calcium, calcium levophosphate, polycarbophil calcium, calfactant 、carmangafodipyl, calfactant, camisinol, camostat mesilate, camptothe cin, canagliflozin, candesartan, candesartan cilexetil, canfosfa Mid, Congulrol, Cannabidiol, Capecitabine, Capmatinib, Capsaicin , Captopril, Carbamazepine, Carbethocine, Carbidopa, Carbinoxamine, Car bocisteine, Carboplatin, Cardidopa, Calfilzomib, Carbulminic acid, Kali prazine, Calisbamate, Carmustine, Carteololomethyl, Carteolol, Ca rteolol hydrochloride, Carmonaum, Carvedilol, Carvedilol phosphate, Cya stopfungin, Catechin, Cebranopadol, Cediranib, Cefaclor, Cefadro xyl, Cefatiamidine, Cefazolin sodium pentahydrate, Cefcapene, Cefdinir , Cefditoren pivoxil, Cefepime, Cefepime dihydrochloride, Cefetamet pivoxil hydrochloride, Cefiderocol, Cefilavansin, Cefminox, Cefoperazone, Cefope razone sodium, Cefoseris, Cefotaxime, Cefotaxime sodium, Cefo thiam, Cefozopran, Cefpirome, Cefpodoxime, Cefprozil, Cefatolin, Cefatolin fosamil, Cefotaxime, Cefibuten, Ceftobiprole medocaril, Ceftolozane sulfate,

[0046] Ceftriaxone, Ceftriaxone sodium, Cefuroxime, Cefuroxime sodium m, Celecoxib, Selgosib, Seriprool, Seriprotect, Senestin, Sene criviroc, Sensabudin, Centanafazine, Cephalosporin, Seralifimod, Seldualatinib, Seritinib, Cerium nitrate, Cetylistat, Cetylidin, Cetrax ert, Sevimerin, Chenodeoxycholic acid, Crosibutamine, Chlorhexidine, Chro lumazinone acetate, Chlorogenic acid, Chloroquine, Chloroxoquinoline, Chlorpheni Lamin, Chlorpheniramine Maleate, Chlorpheniramine Polystyrex, Chlortha lidone, Chlortalidone, Colecalciferol, Cholic Acid, Choline Alphoscerate, Choline Gemeparstat, Choline Fenofibrate, Ciclesonide, Ciclopirox Olamine, Cyclosporine, Cidofovir, Cidoxepin, Silastatin, Sirazapril , Silnidipine, Sirostazol, Cimetidine, Cinacalcet, Cinepazide Maleate, Sodium Syndet Hydrochloride, Sinaprid Tartrate, Sipagamin, Ciprofib Rate, Ciprofloxacin, Ciprofloxacin Hydrochloride, Silaparantag, Sarcadi n, Sisomicin Besilate, Cisplatin, Citalopram, Citalopram Hydrobromide Salt, Citicoline, Citrulline, Cladribine, Clarithromycin, Potassium Clavulanate um, Clavulanic Acid, Clazocentean, Clevidipine, Clebopride, Clindamycin, Clindamycin Hydrochloride, Clindamycin Phosphate, Clioquinol, Clobazam , Clobetasol Propionate, Clobetasol Propionate Form, Clodronic Acid, Clofarabine, Clofazimine, Clomipramine, Clomipramine Hydrochloride, Clona zepam, Clonidine, Clonidine Hydrochloride, Clopidogrel, Clopidogrel Besilate, Clopidogrel Bisulfate, Clopidogrel Campsilate, Clopidogrel Hydrogen Sulf ate, Clopidogrel Napadisilate, Clopidogrel Resinate, Clotrimazole l, Clozapine, Cobamamide, Cobicistat, Cobimetinib, Cobiprostone, Codei n, Codeine Polystyrex, Colchicine, Colecalciferol, Colesevelam, Cole Styrene, Colforsin Daropate, Colfosceril Palmitate, Colistin Methanesulfonate Lithium, Conivaptan, Copanlisib, Copper Histidine, Cortexolone 17α-Propionate Corticosteroid, Crenolanib, Cridanimod Sodium, Crisaborole, Crisotinib Crofelemer, Chlorambucil, Cromolyn Acid, Cromolyn Sodium, Cutimicin Dihydrochloride Cyanocobalamin, Cyclizine Lactate, Cyclobenzaprine Hydrochloride , Cyclophosphamide, Cyclophosphamide Monohydrate, Cyclosporine, Cyproterone, Cyproterone Acetate, Cytarabine, Cytarabine Octophosphate, Dabigatran Etexilate Dabrafenib, Daclatasvir, Dacomitinib, Dalbavancin, Dalsartan Darapladib, Darbepoetin Alfa, Darbepoetin Zeta, Darbepoetin Omega, Darifenacin Sodium, Danazol, Danirixin, Danoprevir, Dantrolene Sodium Danusertib, Dapaconazole, Dapagliflozin, Dapagliflozin Propanediol , Dapiprazole, Dapivirine, Dapoxetine, Daprodustat, Dapsone, Darifenacin Enasidenib, Darinaparsin, Darunavir, Dasabuvir, Dasatinib, Dasotraline, Dazoxiben Decitabine, Dectercept, Defactinib, Deferasirox, Deferiprone Deferoxamine Mesylate, Deflazacort, Deflazafylline, Delafloxacin Delamanid, Delapril, Delapril Hydrochloride, Delavirdine, Denibulin, Denifanstat Dexandrogranolide, Dermatan Sulfate, Desflurane, Desipramine Hydrochloride Salt, Desloratadine, Desmopressin, Desmopressin Acetate, Desogestrel, Des Dexamethasone, Desvenlafaxine, Dextromethorphan Hydrobromide, Dextro Porphine, deuterated levodopa, deuterated venlafaxine, deutetrabenazine, de xamethasone, dexamethasone acetate, dexamethasone cypionate, dexamethas ne palmitate, dexamethasone sodium phosphate, dexfenamine, dex nabinol, dexfelm, dexketoprofen trometamol, dexlansoprazole, dex medetomidine, dexmethylphenidate, dexpramipexole, de kisrazoxane, dexsotalol, dextroamphetamine saccharate, dextro amphetamine sulfate, dextromethorphan, dextromethorphan hydrobromide salt, dextropropoxyphene, diacerein, diamorphine hydrochloride, dianhyd drogallactitol, diazepam, diazoxide choline, diclofenac, diclofenac potassium, diclofenac sodium, dichlorphenamide, cisplatin, dacino cin, dienogest, difluprednate, digoxin, dihomo-γ-linolenic acid, dihy droergocristine, dihydroergotamine, dihydroergotamine mesylate, dilt iazem, diltiazem hydrochloride, mesna, dimethyl fumarate, dimyracetam, dinopro stone, diphenylcyclopropenone, dipraglurant, dipyridamole, diquafosol tetrasodium, dirithromycin, disfenpton sodium, disulfiram, ditoranol, d-methadone, docarpamine, docetaxel, dosipalustat, docosa nol, dofetilide, dolasetron, dolutegravir, domperidone, donafenib silate, donepezil, donepezil hydrochloride, dopamine, dravirine, doriperem, dol Zolamide, dorzolamide hydrochloride, dosmalfate, doxacurium chloride, doxazo sin, doxazosin mesylate, doxepin hydrochloride, doxercalciferol, dox fluridine, doxophylline, doxorubicin, doxorubicin hydrochloride, doxacycli ne, doxycycline hyclate, doxylamine succinate, dronabinol, dron dalone, drospirenone, levodopa, D-tagatose, duloxetine, duloxe tine hydrochloride, dutasteride, duberisib, ebastine, econazole, ebsele n, ecarbet, econazole nitrate, ecopipam, edarabone, ediboxetine, e donapic maleate, edoxaban, efaproxiral, efavirenz, efina conazole, efloridzin, efonidipine hydrochloride, eguarena sodium, eicosapen taenoic acid monoglyceride, elafibranor, elagolix, elamipretide, el basvir, eldecalcitol, eleclazine, elechromol sodium, eletript tan, eliglustat tartrate, elobixibat, eltrombopag, eluxa doline dihydrochloride, elvitegravir, emdogen, emedastine, emaramide, emic susstat, emodepside, empagliflozin, emricasan, emtricitabine, e nalapril, enalapril maleate, enasidenib, ensitrelvir, enclomiphe ne citrate, encorafenib, endoxifen, enobosarm, enoxacin single coneate, enoxaparin sodium, enprostil, entacapone, entasobrin , entecavir, entecavir maleate, entinostat, entospletinib, e ntrectinib, enzalutamide, enzastaurin, epacadostat, epalrestat Dutasteride, Eperisone, Epetraborole, Ephedrine Sulfate, Epinastine Hydrochloride , Epinephrine, Epirubicin, Epirubicin Hydrochloride, Episalvarsan, Epitinib, Ep renolone, Epoprostenol, Epristeride, Eprodicet, Eprosartan, E ptaplatin, Eravacycline, Erdafitinib, Erdosteine, Eribulin Mesylate Rate, Erlotinib, Ertapenem, Ertugliflozin, Erythromycin Isin, Erythromycin Assistrate, Erythromycin Stinoplate, Escitalopram Ropram, Esketamine, Esketamine Hydrochloride, Eslicarbazepine Acetate, Esmo lol Hydrochloride, Esomeprazole, Esomeprazole Magnesium, Esomeprazole S tronchium, Esomeprazole, Estetrol, Estradiol, Estradio l Acetate, Estradiol Cypionate, Estradiol Valerate, Estro diol, Estrogen, Esberaprost Sodium, Eszopiclone, Etamicast tt, Ethanolol Hydrochloride, Etacelene, Ethinyl Estradiol, Calcium Salt of Hydrogen Fumarate Ethyl , Magnesium Salt of Hydrogen Fumarate Ethyl, Zinc Salt of Hydrogen Fumarate Ethyl , Ethinyl Estradiol, Etidronic Acid, Ethimicin Sulfate, Ethirinotecan Pegol , Etizolam, Etodolac, Ethynogestrel, Etoposide, Etoposide Phosphate ate, Etoricoxib, Etravirine, Etripamil, Oipatilin, Ebenamide Hydrochloride Salt, Everolimus, Evofosfamide, Evogliptin, Exemestane, Exendin(9-39) , Exeporphinium Chloride, Ezatiostat, Ezetimibe, Ez Tromid, Fadomizine, Fadrozole, Faldaprevir, Falecalcitriol L, Famciclovir, Famitinib, Famotidine, Fanpridin, Faropenem, Facitibant Chloride, Fasoracetam, Fasudil, Fasudil Hydrochloride, Fasudil Mesylate, Favipiravir, Febarbamate, Febuxostat, Fedvapegon , Felbamate, Felbinac Trometamol, Felodipine, Femitra, Fenfl Luramine Hydrochloride, Phenobarb, Fenofibrate, Fenofibric Acid, Phenoldopa M, Phenoterol, Fenretinide, Fentanyl, Fentanyl Citrate, Fen Ticonazole, Ferimagert, Ferric Citrate, Ferric Maltolate, Ferumoxytol L, Fesoterodine Fumarate, Febipiprant, Fexinidazole, Fexofen Nazine, Fibrin Sealant, Fibrinogen, Fibrinogen Sealant, Fidax Somycin, Filanesib, Filgotinib, Filocyclovir, Fimaporfin, F imasartan, Finafloxacin, Finafloxacin Hydrochloride, Finasteride, F nerenone, Fingolimod, Fipamezole, Filtecampelgol, Flecainide, Fle roxacin, Flibanserin, Flomoxef,

[0047] Flucytosine, Fluarazole Pari, Fluconazole, Fludarabine, Flumatinib, F lumazenil, Flunisolide, Fluocinonide Acetonide, Fluocinonide, Fluorapacin N, Fluorouracil, Fluoxetine, Fluoxetine Hydrochloride, Flupirtine, Flurl buprofen, Flurbiprofen Axetil, Flurbiprofen Sodium, Flurl ithromycin, Fluticasone, Fluticasone Furoate, Fluticasone Propionate, Flutrimazole, Fluvastatin, Fluvoxamine, Folic Acid, Folinate, Folium Ginseng Niconazole, Homopiperizole, Fondaparinux Sodium, Foretinib, Hormesis Flumesartan, Formoterol, Formoterol Fumarate, Fludarabine, Hosaprenavir Prenavil, Hosaprepitant, Fosbretabulin, Fosbretabulin Disodium Fosfoconazole, Fosfomycin, Fosfomycin Disodium, Fosfomycin Trometamol Fosinopril, Fosinopril Sodium, Fosmidomycin, Fosphenytoin Fospropofol, Fosrabucoconazole, Hostamatinib, Fostemsavir Fostroxamine, Hotaglipitin Benzoate, Hostemicin, Frovatriptan, Fluquinintinib Fudosteine, Flubestrant, Funapide, Furosemide, Fusidic Acid Gabapentin, Gabapentin Enacarbil, Gabexate Mesilate, Gasiclidine, Gadobutrol Gadobenate, Gadoxetic Acid Disodium, Galantamine, Garetelin Galidesivir, Gallium Nitrate, Galunisertib, Gambogic Acid, Ganaxolone, Ganciclovir Ganetespib, Ganirelix Acetate, Galenoxasin, Gatifloxacin Gatifloxacin Mesilate, Gedatolisib, Gefitinib, Gemcabene, Gemcitabine Gemcitabine Hydrochloride, Gemfibrozil, Gemifloxacin, Gemigliptin Gemigliptin Tartrate, Genistein, Gentamicin, Genthiopicrin, Gepirone, Diethyl Eportidepsin Gestoden, Gestrinone, Timolol Maleate, Gilotrifitinib, Gemcitabine Gimeracil, Ginsenoside C-K, Ginsenoside Rg3, Gibinosat, Glasdegib Bu, Glatiramer Acetate, Grecaprevir, Glesatinib Glycolate, Glyburide Ramide, Glucradide, Glimepiride, Glypidide, Glufosfamide, Glutamine, G lutathione Selenoxide, Glycerol Phenylbutyrate, Glycopyrronium, Glyco pyrronium Bromide, Glycopyrronium Tosylate, Glycyrrhizic Acid, Ganglioside , Gorotimod, Gosogliptin, Granisetron, Granisetron Hydrochloride, Grazoprevir , Guaiaphenesin, Guaimesal, Guanfacine, Gusperimus Trihydrochloride, In fluenza Bacteria, Halobetasol Propionate, Halofantrine, Halometasone, He lon, Hematoporphyrin, Hemalginic Acid, Hemocoagulase Actus, Heparin, Herbiron, Hetrombopag, Hextend, Hygromine Hydrochloride, Histami ne Dihydrochloride, HPPH Photosensitizer, Human Apolotransferrin, Human Plasminogen, F erudin A, Sodium Hyaluronate, Hydralazine Hydrochloride, Hydrochlorothiazide, Hi drodone, Hydrocodone Bitartrate, Hydrocodone Polistirex, Hydrocorti sone, Hydrogen Peroxide, Hydromorphone, Hydromorphone Hydrochloride, Hydroxocobalamin, Hi droxylcarbamide, Hydroxychloroquine, Hydroxyprogesterone Caproate, Hydroxysafflor Yellow A, Hirastan, Hypericin, Hypestoxide, Ibandro nate, Ibandronic Acid, Iberogast N, Ibudutant, Ibrutinib, Ibudilast , Ibuprofen, Ibutilide, Ibutilide Fumarate, Ikaritin, Iclaprim , Icosapentate, Icosapent, Icosapent Ethyl, Icosapent Ethyl Ester, Icotinib Hydrochloride, Idalopirdine, Idasanutlin, Idebenone, Idelalisib, Ido Cusuridine, Idronoxil, Ifetroban, Ifetroban Sodium, Iguratimod Mod, Lansoprazole, Ilaprazole, Iloperidone, Iloprost, Iloprost Tobetasol Clobetasol, Imatinib, Imatinib Mesylate, Imeglimin, Imi Daphenethide, Imidapril, Imidazole Salicylate, Imidol Hydrochloride, Imigly ptin Dihydrochloride, Imipenem, Imiquimod, Imisopasem Manganese, Imrecoxib , Incadronic Acid, Inotuzumab Toxin, Indacaterol, Indacaterol Ma rate, Indapamide, Indeloxazine, Indimitecan, Indinavir, Indisep tron, Indomethacin, Indramine, Indotecan, Indoximod, Inercalcitol , Infigratinib, Ingabirin, Ingenol Mebutate, Inhaled Sodium Nitrite um, Carboxymaltose Ferric, Inosine, Inteplide, Iodiconaazole, Ipatasertib Dihydrochloride, Iplagliflozin, Ipratropium, Ipratropium Br omide, Iptakalim, Irbesartan, Irinotecan, Irinotecan Hydrochloride, Irinote can Succinate, Irofubone, Iron Isomaltoside 1000, Ferric Succinate Protein , Irosustat, Ilsogladine Maleate, Isavuconazonium Chloride / Sulfate , Isodibut, Isoflurane, Isoniazid, Isopropyl Unoprostone, Isoso rubid Dinitrate, Isosorbide Mononitrate, Isosteviol, Isothiafuldi n, Isotretinoin, Isradipine, Istarloxime, Istradefylline, Itacit nib, Itopride Hydrochloride, Itraconazole, Ivabradine Hemisulfate, Ivabra Jin hydrochloride, ibacaftor, ivermectin, ivosidenib, aflibercept, iksa Bepirone, ixazomib citrate, kallikrein, kangbeide, keta Min, ketanserin, ketoconazole, ketoprofen, ketorolac, ketorolactrom Tammin, ketotifen, kevetrine, cocoamine B mesylate, L-4-chloroquinurenine Raxipin, lacosamide, lactitol, ladarixin, ladostigil Rafalimus, rafthidine, lamivudine, lamotrigine, landiolol, landiolol hydrochloride Laninamivir octanoate, lanoconazole, lansoprazole, lanthanum carbonate Lapatinib, lakinimod, laromustine, lasmiditan, lasofoxifene Latanoprost, latanoprostene bunod, lauflumide, resipasvir Refamulin, leflunomide, renborexant, lenalidomide, lentinan, lentinan sulfate Lentinan viral, lenvatinib mesylate Relcainidipine, resinarad, reteplimum, retelmovir, letrozole, leucine Leuprorelin acetate, levalbuterol, levalbuterol hydrochloride, levamisole Levamlodipine, levamlodipine besylate, levamlodipine maleate, levothyroxine Levobupivacaine, levocabastine, levocabastine hydrochloride, levocarnitine Levocetirizine dihydrochloride, levodopa, levodioxazosin mesylate, levofloxacin Levoconazole, levomilnacipran, levonadifloxacin arginine salt, levonorgestrel Levonorgestrel butanoate, levo-fenethylline hydrochloride, levo Runitazole, Levorphanol, Levosimendan, Levothyroxine Sodium, Levotuss 〔levotuss〕, L-Glutamine, Lidocaine, Roflumilast, Ligustrazine Hydrochloride Salt, Remaprost, Linagliptin, Linezolid, Liothyronine, Liothyronine Sodium M, Lipobin, Liposome Curcumin, Lipoteichoic Acid, Liranaftate, Lisdexamfetamine , Lisinopril, Lysophosphatidylcholine, Lisuride Hydrogen Maleate, Lithium Citrate , Lithium Succinate, Rixubaptan, Lobaplatin, Lobeglitazone, Rodenafill Carbonate , Rofexidine, Rometloxacin, Rameridine, Rameridine Dihydrochloride, Romidepsin , Ronalfarnib, Ronidamine, Loperamide, Loperamide Oxide, Ritonavir, Rolartazine , Lorazepam, Lorcaserin, Lorediplon, Lorlatinib, L-Ornithine-L-Aspartate , Lornoxicam, Losartan, Losartan Potassium, Roxapimod , Roteprednol Etabonate, Rosuvastatin, Loxapine, Loxoprofen , L-Pradicantel, Rubiprostone, Lucanthone, Lucerastat 〔lucerastat〕, Lucinactant, Lucitanib Hydrochloride, Luliconazole, Lumacaftor, Lumateperone Toluene Sulfonate〔lumateperone toluene sulfonate〕, Lumefantrine, Lumiracoxib , Lunar Calcipotriol, Lurasidone, Lurbinectedin, Luseogliflozin Hydrate Substance, Ruxolitinib, Lysine Acetylsalicylate, Macimorelin, Macitentan, Mafentanide , Magnesium Carbonate, Magnesium Isoglycyrrhizinate, Magnesium Dihydropyridine, Manidipine , Manidipine Dihydrochloride, Mannitol, Maraviroc, Maribavir, Marizomib Masilcast, Macitinib, Maboglutant, Maxacalcitol, Mebendazole, Me Biphon〔mebiphon〕, Mecamylamine, Mecamylamine Hydrochloride, Mechlorethamine, Mecobam ramine, Medroxyprogesterone, Medroxyprogesterone Acetate, Mefloquine , Megestrol, Megestrol Acetate, Meisuoshuli〔meisuoshuli〕, Mele bodopa, Meloxicam, Melphalan, Melphalan Flufenamide Hydrochloride, Memantine , Memantine Hydrochloride, Menadione Sodium Bisulfite, Menatetrenone, Mepacrine, Meki nol, Mercaptamine, Mercaptamine Bitartrate, Mercaptamine Hydrochloride, Merc aptopril, Melesitinib, Meropenem, Merotocin〔merotocin〕, Mesalamine, Me salazine, Metacabil, Metadoxine, Metamizole Sodium, Metaxalone, Mete rgoline, Metformin, Metformin Hydrochloride, Mesadone, Metazolamide, Methotrex ate, Methoxyflurane, Methyl Aminolevulinate Hydrochloride, Methylnaltrexone Bromide , Methylnaltrexone, Methylphenidate, Methylphenidate Hydrochloride, Methylpred nisolone, Methylprednisolone Aceponate,

[0048] Methylthioninium Chloride, Methylosin, Metoclopramide, Metoprolol, Metop rolol Succinate, Metrifonate, Metronidazole, Metyrapone, Mexiletine , Mibefradil, Miconazole, Miconazole Nitrate, Midazolam, Midazolam Hydrochloric Acid Salt, Midodrine, Midostaurin, Mifamurtide, Mifepristone, Migalastat , Miglitol, Miglustat, Milnacipran, Milrinone, Miltefosine, Minap Phosphorus, minocycline, minocycline hydrochloride, minodronic acid, minoxidil, mirabegron lon, milpratin hydrate, milodenafil, milodenafil hydrochloride, milogabalin, mi lutazapine, misoprostol, mitiglinide, mitomycin, mitoxantrone, mi toxantrone hydrochloride, mibotilate, mizolastine, mizoribine, mosecinostat di hydrobromide, moclobemide, modafinil, doxycycline, modipafant, moe xipril, mofezolac, molidustat, molindone hydrochloride, mom lotinib, mometasone, monepantel, glycyrrhizinate monoammonium, monobenzo ne, monosodium α-luminol, monoterpene perillyl alcohol, montelukast montelukast sodium, montmorillonite, moracin, molnidazole, morphi ne, morphine glucuronide, morphine pivalastatin, morphine sulfate, morphoti azine mesylate, mosapride, motrimod, moxidectin, moxifloxacin, mo xifloxacin hydrochloride, moxonidine, moxonidine hydrochloride, mozavaptan, mupafo stat sodium, mupirocin, mycobactovir, mycophenolate tomfetil, myristyl nicotinate, nabivon, naviximols, nabumetone, N- acetylcysteine, n-acetylcysteine, nadifloxacin, nadolol, nadropalin cal cium, naftifine hydrochloride, naphthopyridyl, nalbuphine, nalbuphine sebacate, naldemedine, nalflafine, nalmeffene, naloxegol, naloxone, naloxone hydrochloride, naltrexone, naltrexone hydrochloride, naltazone, nandrolone decanoate Tolnaftate, Naphazoline, Naphthoquinone, Naproxen, Sodium Naproxen , Nacotinib Mesylate, Naratriptan, Nalatrepivir, Nasapaque , Nasalplase, Nastorazepide Calcium, Natiglinide , Navamepent, Nazartinib, Nebivolol, Necuparanib , Nedaplatin, Nedocromil, Nelarabine, Nelfinavir, Nerotanserin , Nemonapride, Nemonoxacin, Neoandrographolide, Neosaxitoxin, Neostigmine Methylsulfate, Nepazitant, Nepafenac, Nepicastat, Nepolong , Neralexan, Neratinib, Neridronic Acid, Netarsudil , Netilmicin, Netupitant, Nevirapine, Niacin, Nicardipine, Nicergoline , Nicorandil, Nicotiflorin, Nicotine, Nicotinic Acid, Nikethamide, Nifedipine , Nifekalant, Nifeviroc, Nifurtimox, Nifuride, Nikkomycin , Nilotinib, Nilutamide, Nilvadipine, Nimesulide, Nimodipine, Nimorazole , Ningetinib, Nintedanib, Niraparib, Nisoldipine , Nitazoxanide, Nitric Oxide, Nitroglycerin, Nitroglycerin, Nizatidine, Nokxaban , Noratrexed, Nomegestrol Acetate, Norergestromin, Norepinephrine , Norethindrone, Norethindrone Acetate, Norethindrone Enanthate, Norethisterone , Norethisterone Acetate, Norfloxacin, Norgestimate, Noribogaine, Norursodeoxycholic Acid Chenodeoxycholic acid, obeticholic acid, octenidine, octahydroaminoacridine succinate -, octreotide, octreotide hydrochloride, odalasvir, odanacatib -, oziparsil, ofloxacin, olanzapine, olaparib, olesoxime, oliceridine -, olmesartan, olmesartan cilexetil, olmesartan medoxomil, olodaterol -, olodaterol hydrochloride, olopatadine, olopatadine hydrochloride -, orprinone, olsalazine, ortipraz, omacetaxine mepesuccinate -, omadacycline, omarigliptin, omaveloxolone, ombitasvir, omecamtiv mecarbil -, ω-3 carboxylic acid, omeprazole, omigapil, omoconazole -, onarespib, onapristone, ondansetron, ondroplan, opicapone, opipramol -, methylphenidate, orcinoside, orilotimod, oritavancin -, orlistat, ornithine phenylacetate, ornoprostil, ortataxel -, ortelone, orthobisque, orbeptant, oseltamivir, osilodrostat -, osimertinib, Osiris Phleum pretense, ospemifene, oteracil potassium -, otesconazole, oxaliplatin, oxaloacetic acid, oxandrolone -, oxazepam, oxcarbazepine, oxfendazole, oxidized glutathione sodium -, oxilacetam, oxybutynin, oxybutynin hydrochloride -, oxycodone, oxycodone hydrochloride, oxymetazoline, oxymetazoline hydrochloride -, oxymorphone, oxytocin, ozagrel, ozagrel hydrochloride, ozagrel Lenaclotide, ozanimod, ozenoxacin, paclitaxel, paclitaxel polyglycol Rumex, pacritinib, palbociclib, perphenazine, perphenazine palmitate, Palmidrol, palonosetron, parvalbumin, disodium pamidronate, pancre Lipase, panipenem, panobinostat, pantoprazole, paracetamol, pareco Xib, paricalcitol, paritaprevir, sodium pamaparin, parogrelil, Paromomycin, paroxetine, paroxetine hydrochloride 0.5 hydrate, paroxetine mesylate -ate, pithomercalcium, patupiroone, pazopanib, pazufloxacin, pazuflo Xacin mesylate, peficalcitol, peficitinib, pegylated apo-filgrastim , perviprofene, pemafibrate, pemetrexed disodium, pemirolast, Pemirolast potassium, pemirolast sodium, penciclovir, penhiclidine hydrochloride Salt, pentamidine, calcium trisodium pentetate, zinc trisodium pentetate, Pentetrazole, sodium pentosan polysulfate, pentostatin, pentoxifylline , peramivir, perampanel, perclozone, peretinoin, perflenapent, per Rubron emulsion, perfluorooctyl bromide, pergolide, perhexiline maleate , periphosin, perindopril, perindopril arginine, perospirone, pebonezi Stat, pexidartinib, PhagoBioDerm, phenchlobenpyrrone , phenethyl isothiocyanate, phenoxybenzamine hydrochloride Salt, phentermine, phentermine hydrochloride, phentermine mesylate, phenylb Chelate, phenylephrine, phenylephrine hydrochloride, phenytoin, phosphazide, pibu Rentasvir, pishivanil, picroliv, picropodophyllin, pidotimod, pyrocar Pin, pilocarpine hydrochloride, pilsicainide, pimasertib hydrochloride, pimavanserin, pi Mecrolimus, pimobendan, pinobanksin, pinometostat, pioglitazone, pi Ogltazone hydrochloride, pipanperone, pipecuronium, piperacillin, piperacillin sodium Lium, piperazine, piperazine phosphate, piperidone hydrochloride, piperine, piperph Entonamine [piperphentonamine], piracetam, pirarubicin, pifenedidone, pi Luminal, piromelatine, pyrotinib, piroxicam, piroxicam Beta dex, pitavastatin, pitavastatin calcium, pitolisant, pixant Ron, plazomycin, preconnail, prelifaxol, prinabulin, pocapavir [po capavir], hydromorphone, podophyllotox, polaprezinc, pormacoxib, po Ridatin, polyoxidonium, pomaglumetad methionyl, pomalidomide, ponatinib B, ponesimod, porfimer sodium, posaconazole, posiphen Potassium bicarbonate, potassium citrate, potassium clavulanate, pozotinib, plasinostat Stat, pradofibril, pralatrexate, pramipexole, pramiracetam, pr Ranolast, ranolast hydrate, plastolone, plasgruel, pravastatin, Prazosin, prednimustine, prednisolone, prednisolone acetate, predni Zolone sodium phosphate, prednisone, pregabalin, prenpro, presatobi Ruprintivir, Pretomanid, Previdersin, Prexasertib Prexasertib, Pridopidine, Prilocaine, Pritelivir, Procaterol Hydrochloride , Prochlorperazine, Prochlorperazine Maleate, Profezyme , Progesterone, Progestogen, Progestogen Dienogest, Proguanil, Pro methazine, Promitil, Propafenone, Propargermanium, Propofol ol, Propranolol, Propranolol Hydrochloride, Prostastat, Proxodrol, Prucalopride, Prulifloxacin, Prurisol, Insoluble Prussian Blue -, Pseudoephedrine, Pseudoephedrine Hydrochloride, Puerarin, Pexidartinib Mesylate , Pyrazinamide, Pyridoxamine Dihydrochloride, Pyridoxine Hydrochloride, Pyrimethamine, Pironalidine, Pyrrolotinib Maleate, Quazepam, Quetiapine Fumarate, Que tiapine, Kinagolide Hydrochloride, Kinalpril Hydrochloride, Quinidine Sulfate, Quinine Sulfate , Quinupristin, Xynosat, Xalkori Dihydrochloride, Rabeprazole, Rabeprazole Sodium, Labeximod, Rasilecadotril, Radenzolide, Radotinib, Ralfidamide, Larimetinib, Larinopag, Raloxifene, Raltegravir, Raltitrexed , Ramatroban, Ramelteon, Ramipril, Serotonin

[0049] Ranitidine, Ranitidine Bismuth Citrate, Ranolazine, Rasagiline, Rabidasvir Hydrochloride , Raxatrigine, Levamipide, Levastinib, Levoxetin, Levoxetin Mesylate, Recilisib Sodium, Recoflavone, Redapo ​ Rufin, Ibuprofen, Naproxen, Glycopyrronium Bromide, Lefametinib , Regorafenib, Relbactam, Relenopride, Relgorelix, Rem Gulrant, Remifentanil, Remifentanil Hydrochloride, Remimazolam, Remimazolam Tosylate, Remogliflozin Etabonate, Repaglinide, Repalixine, Repirinast To, Anrexinox, Chlorcyclizine Hydrochloride, Busilamine, Guanabenz, Madind -ol, Naltrexone, Nitisinone, Ondansetron, Fasceptilan, Retigabine, Rosiglitazone, Sodium Phenylbutyrate, Reciniferatoxin, Resiquimod, Resmi Nostat, Resveratrol, Retagliptin, Retapamulin, Reti Gabine, Retinoic Acid, Retosiban, Levaprazan, Levophenacine, Levipanatinatri um, Rain, Rhenium 186 Etidronate, Ribavirin, Ribocyclib, Ricolinostat Tat, Lysinirazole, Lidostin, Rifabutin, Rifampicin, Rifamycin , Rifapentine, Rifaximin, Rigosertib Sodium, Rilapladib, Rilpivi rin, Rilpivirine Hydrochloride, Riluzole, Rimantadine, Rimeporide, Rimexolone, Ri osiguate, Lipasudil Hydrochloride Hydrate, Risedronate Sodium, Risperidone, Rito navir, Rivaroxaban, Rivastigmine, Rivipansel Sodium, Rizatriptan , Rizatriptan Benzoate, r Mulation, Roxiletinib, Rof lumilast, Roxithromycin, Rolapitant, Romurtide, Ronacaleret, Ronepars tat, Ronopterin, Ropinirole, Ropinirole Salt Acid salts, ropivacaine, sodium rose bengal, rosiglitazone, rosiglitazone maleate ate, rosiglitazone sodium, roxithromycin, rosuvastatin, rosuvastatin calcium rotigotine, robaxin, roxadustat, roxithromycin, rubitecan, rucaparib phosphate, rufinamide, rifaximin, rupatadine, ruxolitinib, S-(-)-ornidazole phosphate disodium, sabvicine, sacubitril, safinamide, salbutamol, salbutamol sulfate, salicylic acid, salmeterol, salmeterol xinafoate, salbutamol, salvicine, samarium (153Sm) lexidronam, samidorphan, S-amlodipine nicotinate, sapacitabine, sapropterin, sapropterin dihydrochloride, saquinavir, saracatinib, sarecycline, saroglitazar, sarpogrelate hydrochloride, sabotinib [savolitinib], saxagliptin, scopolamine, scorpion venom, ω-3 polyunsaturated fatty acids, secnidazole, segesterone acetate, selegiline, selegiline hydrochloride, selexipag, sericyclib, serinexol, sericistat, selumetinib, selampanel, sepranolone [sepranolone], seratrodast, serlopitant, sertaconazole, sertaconazole nitrate, sertindole, sertraline, sertraline hydrochloride, cetipiprant, sevelamer carbonate, sevelamer hydrochloride, seviteronel [seviteronel], sevoflurane, sevuparin sodium, sibutramine maleate, sibutramine mesylate, sildenafil, sildenafil citrate, silibinin, cetirizine hydrochloride, cetipiprant, sevelamer carbonate, sevelamer hydrochloride, seviteronel [seviteronel], sevoflurane, sevuparin sodium, sibutramine maleate, sibutramine mesylate, sildenafil, sildenafil citrate, silibinin, Silibinin dihydrogen succinate, silmitasertib, silodosin, silver sulfadiazine,simeprevir, simitecan hydrochloride, simotinib hydrochloride, simvastatin, sinotecean, siponimod, silomustine, sitafloxacin, sitagliptin, sitagliptin phosphate, sibelestat, sizofiran, sumiriagenin, S-modafinil, sobuzoxan, sodium esilate, sodium ascorbate, sodium benzoate, sodium bicarbonate, cromogly sodium succinate, sodium ferric gluconate complex, sodium glycidazoxide, sodium guanarate, sodium hyaluronate, sodium ibandronate, sodium nitrate, sodium nitrite, sodium oxybate, sodium phenylacetate, sodium phenylbutyrate, sodium polysulfonate, sodium plastron sulfate, sodium pyruvate, sodium taurocholate, sodium thiosulfate, sodium zirconium cyclic silicate, sofosbuvir, sopirone bromide, solabegron, solifenacin, solithromycin, sonidegib, sonolisib, sophocaripin, sophoridine hydrochloride, sorafenib, sorbitol, sotagliflozin, sotirimod, sotrastaurin, sotylize, soba previr, sparfloxacin, sparcentan, spebrutinib, spirapril, spironolactone, squalamine, stannoporphyrin, stubidium, S-tenatoprazole, streptomycin, strychnopentol, streptozocin, strontium malonate, strontium ranelate, succinic acid, strontium sulfate, ​​Clalfort, Scloxy Iron Hydroxide, Sufentanil, Sphtalane Zinc, Sugamadex S, Sulbactam, Sodium Sulbactam, Sulcaldin Sulfate, Sulfamethox y Pyrazine, Sulfasalazine, Sulfatinib, Sulfonylurea, Sulforaphane, Sulhotansinone Sodium, Sulindac, Surodexide, Sulfamethoxazole, S ulthiam, Sumatriptan, Sumatriptan Succinate, Sunitinib, Sunstone, Spra sin〔suplasyn〕, Spalatast Tosylate, Slamine Sodium, Verapamil Hydrochloride, Rilpivirine, Stesolid, Suborexant, Tacalcitol, Tacrine, Tacrolimus , Tadalafil, Tafamidis, Tafenoquine, Tafuprost, Tafoxiparin Nat rium〔tafoxiparin sodium〕, Taradezib, Talaporfin, Talazoparib, Talipeki sol, Taltyrlerin, Tamibaroten, Tamoxifen, Tamsulosin, Tamsulosin Hydroch loride, Tandospirone, Tanespimycin, Tapentadol, Tarfenacin, Tarenf lurubir, Talroxotininib Bromide, Tascilib, Tasimelteon, Tosedekinimod, T avaborol, Tavilermide〔tavilermide〕, Tazarotene, Tazemetostat, Tazobac tam, Tazobactam Sodium, Tebipenem Pivoxil, Tecalfarin, Tecovirimat to, Tectrogenin Sodium Sulfonate, Tedisamil, Tedizolid Phosphate, Te finostat〔tefinostat〕, Tegafur, Tegaserod, Teicoplanin, Teraprevir le, Terapristone Acetate, Teratinib, Telbivudine, Telithromycin, Telmi sartan, Telotristatetiprate〔telotristatetiprate〕, Temanogrel, Tem Capril, temoporfin, temozolomide, temsirolimus, tenalisib , tenapanor, teneligliptin, tenofovir, tenofovir alafenamide, tenofovir dipivoxil fumarate, tenofovir disoproxil aspartate, tenofovir disopro loxil fumarate, tenoxicam, tepotinib, teprenone, terameprocol, tera zosin, terbinafine, terbinafine hydrochloride, terguride, terflunomide, tese tinib, tesofensine, testosterone, testosterone undecano ate, tetrabenazine, tetracaine, tetracaine hydrochloride, tetrahydrocannabi ol, tetrathiomolybdate, tetrizoline, tezacaftor, thalid omide, theliatinib, theophylline, therapeutic , thiazide, tienorfin hydrochloride, thiotepa, thrombin, thromboredoxin, th roxine, tiagabine, tianeptine, tibolone, ticagrelor, ticlopidine, tiges iclin, tiludronic acid disodium, timolol, timolol maleate, tindama x (tindamax), tinidazole, tinzaparin sodium, tioconazole, thiopro nin, tiotropium bromide, tiotropium bromide monohydrate, tipelcast, tipi din hibenzate, tipifarnib, tipirasyl hydrochloride, tipranavir, tipranazami n, tirastemcib, tirilazad, tirofiban, tirofiban hydrochloride, tibantinib, tivozanib, tizanidine, tobramycin, tocopherol solan, tocoretinate, tof acitinib, tofogliflozin, tolcapone, trimidone, tolperizone, toltrazodine , tortelodine tartrate, tolvaptan, tonabersat, topiramate, topiroxicam sosat, topotecan, topotecan hydrochloride, trapidil, trehalosent, tamoxifen , tosedostat, tosufloxacin, thrombopoietin, tozadant, trabectedin , trabodenoson, trazipitant, tramadol, tramadol hydrochloride, trametinib ,trandolapril, tranexamic acid, tranilast, transclocetinate sodium m, trans-epithelial riboflavin, trandolterol hydrochloride, travoprost, trazodone, trehalose , treagliptin succinate, treosulfan, treprostinil, treprostinil diolamine , tretinoin, triamcinolone acetonide, triapine, triazolam , tribenzimidazole, trichlormethiazide, triciribine, triclabendazole , triclocarban, trientine hydrochloride, trifarotene, trifluridine , triflusal, triheptanoin, trilostane, trimebutine 3-thiocarbamoyl-benzenesulfonate , trimebutine tosylate, trimegestone, trimethoprim, trimethrexate , trinitrate, dicitratobismuthate tripotassium, trofinetide, tropicamide , tropisetron, trospium chloride, trovafloxacin, troxipide, tucatinib , terbutaline, tylerdipine hydrochloride, ubenimex, ubiquinone , ubrogepant, udenafil, ulinastatin, ulipristal, ulixertinib , urobetaine, umeclidinium, umeclidinium bromide, upamostat , yuproselchib, uracil, urapidil, uridine triacetate, uroacitides, ursodeoxycholic acid, ursolic acid, baborbactam, badadast , baracyclovir, baracyclovir hydrochloride, valbenazine, valdecoxib, barganciclovir , valganciclovir stearate, valproic acid, valrubicin, valsartan , valsartan trisodium 2.5 hydrate,

[0050] , vancomycin, vancomycin hydrochloride, vandetanib, vaniprevir, vanoxerine, , vapendavir, vardenafil hydrochloride, varenicline, varithena , baricitinib, batiquinone, vavelta, belinostat, belpatasvir , bersetrag, bemrafenib, venetoclax, venlafaxine, venlafaxine hydrochloride , beporoxamer, verapamil, verapamil hydrochloride, verdinexor , veregen, vericiguat, verinurad, verenacrant , verenacrant hydrochloride, verosild, verteporfin, verbessostat, verbruin , besatrimod, besnarinone, vibegron, vicagrel, vigabatrin, vilanterol , vilanterol trifenate, vilaprisan, vilazodone, viludagliptin, vincristine sulfate , vinflunine, vinorelbine, vinpocetine, vintafolide, viralym-C, bistramidegib, bisucelchib, , vitamin E nicotinate, bizomycin, voglibose, bolarcelchib, bolicxibat potassium ethanolate hydrate, bonoprazan fumarate, bolar celchib, bolicxibat potassium ethanolate hydrate, bonoprazan fumarate, bolar​​ Pacital, voriconazole, vorinostat, volitinib, volitinib bromide Hydrochloride, boscaloxine, boxilaprevir, warfarin, ximelofiban, imita Svir [yimitasvir], yonkenafil, zabofloxacin, zafilur Cast, zalcitabine, zarepron, zaltoprofen, zamicastat [[zamicastat]] , zanamivir, zymistatin, Z-endoxifen hydrochloride, dibotentan, didebacter M, didobuzin, dileuton, zinc acetate, dinostatin stimalamer, diprasidone, zo Fenopril, zogenix, zoledronate D,L-lysine monohydrate, zoledronate two Sodium, zoledronic acid, zoliflodacin, sumatriptan, zolpidem, zolpide Maltolate, zonisamide, zopiclone, zotepine, zucapsaicin, zucropentiki Selected from the group consisting of sol, and zoretinol acetate.

[0051] In some embodiments, traditional Chinese medicine is Abelmoschi Corolla, Abri Herba, Abutili Semen, Acanthopanacis Cortex Acanthopanacis Senticosi Radix Et Rhizoma S eu Caulis, Acanthopanax Extract, Achilleae Herba, Achyranthis Bidentatae Radix, Aconiti Kusnezoffii Folium, Aconiti Kusnezoffii Radix Cocta, Aconiti Kusnezoffii Radix, Aconiti Lateralis Radix Praeparata, Aconiti Radix Cocta, Aconiti Radix, Rhizoma Acori Calami, Rhizoma Acori Tatarinowii, Radix Adenophorae, Semen Aesculi n, Agkistrodon, Herba Agrimoniae, Cortex Ailanthi, Herba Ajugae, Caulis Akebiae , Fructus Akebiae, Cortex Albiziae, Flos Albiziae, Rhizoma Alismatis, Allii Macr ostemonis Bulbus, Bulbus Allii Sativi, Semen Allii Tuberosi, Aloe, Alpiniae Kats umadai Semen, Rhizoma Alpiniae Officinarum, Fructus Alpiniae Oxyphyllae, Alumen , Fructus Amomi Rotundus, Fructus Amomi, Radix Ampelopsis, Herba Andrographis, A ndrographolides, Rhizoma Anemarrhenae, Rhizoma Anemones Raddeanae, Radix Angelicae Dah uricae, Radix Angelicae Pubescentis, Radix Angelicae Sinensis, Anisi Stell ati Fructus, Folium Apocyni Veneti, Lignum Resinatum Aquilariae, Concha Arcae, A rctii Fructus, Radix Ardisiae Crenatae, Herba Ardisiae Japonicae, Arecae Pericar pium, Semen Tostum Arecae, Semen Arecae, Arisaema Cum Bil, Rhizoma Arisaematis P reparatum, Rhizoma Arisaematis, Fructus Aristolochiae, Herba Aristolochiae, Armeni Semen Armeniacae Amarum, Radix Arnebiae, Herba Artemisiae Annuae, Folium Artemisiae Argyi F olium, Herba Artemisiae Scopariae, Radix Et Rhizoma Asari, Radix Menispermi Extract, Colla Corii Asini, Radix Asparagi, Aspongopus, Radix Et Rhizoma Asteris a, Semen Astragali Complanati, Radix Astragali Praeparata Cum Melle, Radix Astragali R adix, Rhizoma Atractylodis Macrocephalae, Rhizoma Atractylodis, Radix Aucklandiae Radi x, Fructus Aurantii Immaturus, Fructus Aurantii, Caulis Bambusae In Taenias, Bam busae Concretio Silicea, Rhizoma Et Radix Baphicacanthis Cusiae, Rhizoma Belamcandae Rhi zoma, Extractum Belladonnae, Belladonnae Extractum Liquidum, Herba Belladonnae, Benincas ae Exocarpium, Benzoinum, Radix Berberidis, Rhizoma Bergeniae, Bergenin, Bistort ae Rhizoma, Rhizoma Bletillae, Rhizoma Bolbostemmatis, Bombyx Batryticatus, Born Eolum Syntheticum, Borneolum, Bovis Calculus Artifactus, Bovis Calculus Sativus , Bovis Calculus, Breviscapine, Broussonetiae Fructus, Bruceae Fructus, Bubali C ornu, Buddlejae Flos, Bufonis Venenum, Bungarus Parvus, Bupleuri Radix, Calamina , Callicarpae Caulis Et Folium, Callicarpae Formosanae Folium, Callicarpae Macro phyllae Folium, Calomelas, Campsis Flos, Canarii Fructus, Canavaliae Semen, Cann abis Fructus, Capsici Fructus, Carotae Fructus, Carpesii Fructus, Carthami Flos , Caryophylli Flos, Caryophylli Fructus, Cassiae Semen, Castor Oil, Catechu, Cel osiae Cristatae Flos, Celosiae Semen, Centella Total Glucosides, Centellae Herba , Centipedae Herba, Cera Chinensis, Cera Flava, Cervi Cornu Degelatinatum, Cervi Cornu Pantotrichum, Cervi Cornu, Cervi Cornus Colla, Chaenomelis Fructus, Chang ii Radix, Chebulae Fructus Immaturus, Chebulae Fructus, Chelidonii Herba, Chines e Angelica Liquid Extract, Chloriti Lapis, Choerospondiatis Fructus, Chrysanthem i Flos, Chrysanthemi Indici Flos, Chuanxiong Rhizoma, Cibotii Rhizoma, Cicadae P eriostracum, Cichorii Herba, Cichorii Radix, Cimicifugae Rhizoma, Cinnabaris, Ci nnamomi Cortex, Cinnamomi Ramulus, Cinnamon Oil, Cirsii Herba, Cirsii Japonici H erba Carbonisata, Cirsii Japonici Herba, Cissampelotis Herba, Cistanches Herba, Citri Exocarpium Rubrum, Citri Fructus, Citri Grandis Exocarpium, Citri Reticula tae Pericarpium Viride, Citri Reticulatae Pericarpium, Citri Reticulatae Semen, Citri Sarcodactylis Fructus, Clematidis Armandii Caulis, Clematidis Radix Et Rhi zoma, Clinopodii Herba, Cnidii Fructus, Codonopsis Radix, Coicis Semen, Commelin ae Herba, Conyzae Herba, Coptidis Rhizoma, Cordyceps, Corni Fructus, Corydalis B ungeanae Herba, Corydalis Decumbentis Rhizoma, Corydalis Rhizoma, Crataegi Foliu m, Hawthorn Fruit, Pseudobulb of Cremastra appendiculata, Pseudobulb of Pleione bulbocodioides, Carbonized Human Hair Nidus Vespae, Stigma of Crocus sativus, Fruit of Croton tiglium, Powdered Seed of Croton tiglium, Rhizome of Curculigo orchioides Rhizome of Curcuma longa, Root of Curcuma aromatica, Rhizome of Curcuma zedoaria, Seed of Cuscuta chinensis Root of Cyathula officinalis, Cyclovirobuxine D, Root and Rhizome of Cynanchum atratum, Root and Rhizome of Cynanchum paniculatum Rhizome and Root of Cynanchum stauntonii, Herba Cynomorii Rhizome of Cyperus rotundus, Leaf Oil of Rhododendron dahuricum, Wood of Dalbergia odorifera Flower of Datura stramonium, Stem of Dendrobium nobile, Stem of Dendrobium officinale Seed of Lepidium apetalum, Herba Desmodii styracifolii, Herba Dianthi, Root of Dichroa febrifuga Bark of Dictamnus dasycarpus, Rhizome of Dioscorea panthaica, Rhizome of Dioscorea hypoglauca Rhizome of Dioscorea nipponica, Rhizome of Dioscorea opposita, Rhizome of Dioscorea spongiosa Root of Dipsacus asperoides, Dragon's Blood, Rhizome of Drynaria fortunei, Rhizome of Dryopteris crassirhizoma Carbonized Rhizome of Dryopteris crassirhizoma Nakai, Rhizome of Dryopteris crassirhizoma Nakai, Radix of Echinopsis tubiflora (Pfeiff.) Zucc. ex A. Dietr. 、Herba Ecliptae, Semen Entadae, Herba Entianae Rhodanthae, Herba Ephedrae, Ephe drae Radix Et Rhizoma, Folium Epimedii, Folium Epimedii Wushanensis, Herba Equiseti Hi emalis, Herba Erigerontis, Folium Eriobotryae, Flos Eriocauli, Herba Erodii Herb a Geranii, Caulis Erycibes, Eucalyptus Oil, Cortex Eucommiae, Eucommiae Fo lium, Fructus Euodiae, Herba Eupatorii, Herba Eupatorii Lindleyani, Euphorbiae E bracteolatae Radix, Herba Euphorbiae Hirtae, Herba Euphorbiae Humifusae, Euphorb iae Pekinensis Radix, Pulveratum Semen Euphorbiae, Semen Euphorbiae, Eupolyphaga Steleophaga, Semen Euryales, Rhizoma Fagopyri dibotryis, Flos Farfarae, Ferulae Resina, Caulis Fibraureae, Fibriuretinin, Fluoritum, Fructus Foeniculi, Forsyth iae Fructus, Cortex Fraxini, Bulbus Fritillariae cirrhosae, Fritillariae Hupehen sis Bulbus, Fritillariae Pallidiflorae Bulbus, Fritillariae Thunbergii Bulbus, F ritillariae Ussuriensis Bulbus, Galangae Fructus, Galla Chinensis, Galli Gigerii Endothelium Corneum, Ganoderma, Capillary Wormwood Extract, GardeniaeFructus Pr aeparatus, Gardeniae Fructus, Gastrodiae Rhizoma, Gecko, Gei Herba, Gendarussae Herba, Genkwa Flos, Gentianae Macrophyllae Radix, Gentianae Radix Et Rhizoma, Gi nger Liquid Extract, Ginkgo Folium, Ginkgo Leaves Extract, Ginkgo Semen, Ginseng Folium, Ginseng Radix Et Rhizoma Rubra, Ginseng Radix Et Rhizoma, Glabrous Sarc andra Extract, Glechomae Herba, Gleditsiae Fructus Abnormalis, Gleditsiae Sinens is Fructus, Gleditsiae Spina, Glehniae Radix, Glycyrrhizae Radix Et Rhizoma Prae parata Cum Melle, Glycyrrhizae Radix Et Rhizoma, Gossampini Flos, Granati Perica rpium, Gypsum Fibrosum, Gypsum Ustum, Haematitum, Haliotidis Concha, Halitum, Ha lloysitum Rubrum, Hawthorn Leave Extract, Hedysari Radix Praeparata Cum Melle, H edysari Radix, Hibisci Mutabilis Folium, Hippocampus, Hippophae Fructus, Hirudo , Homalomenae Rhizoma, Hordei Fructus Germinatus, Houttuyniae Herba, Hydrargyri Oxydum Rubrum, Hyoscyami Semen,

[0052] Hyperici Perforati Herba, Ilicis Chinensis Folium, Ilicis Cornutae Folium, Ilici s Rotundae Cortex, Ulicii Cortex, Impatientis Semen, Imperatae Rhizoma, Indigo N aturalis, Inulae Flos, Inulae Herba, Inulae Radix, Iridis Tectori Rhizoma, Isati dis Folium, Isatidis Radix, Juglandis Semen, Jujubae Fructus, Junci Medulla, Kad surae Caulis, Kaempferiae Rhizoma, Kaki Calyx, Kansui Radix, Knoxiae Radix, Koch iae Fructus, Lablab Semen Album, Laggerae Herba, Lagotidis Herba, Laminariae Tha llus Eckloniae Thallus, Lamiophlomis Herba, Lasiosphaera Calvatia, Leonuri Fruct us, Leonuri Herba, Leonurus Liquid Extract, Licorice Extract, Licorice Liquid Ex tract, Ligustici Rhizoma Et Radix, Ligustri Lucidi Fructus, Lilii Bulbus, Limoni tum, Linderae Radix, Lini Semen, Liquidambaris Fructus, Liquidambaris Resina, Li riopes Radix, Litchi Semen, Litseae Fructus, Lobeliae Chinensis Herba, Longan Ar illus, Lonicerae Flos, Lonicerae Japonicae Caulis, Lonicerae Japonicae Flos, Lop hatheri Herba, Luffae Fructus Retinervus, Lycii Cortex, Lycii Fructus, Lycopi He rba, Lycopodii Herba, Lygodii Spora, Lysimachiae Herba, Lysionoti Herba, / -Borne olum, / -Menthol, Magnetitum, Magnoliae Flos, Magnoliae Officinalis Cortex, Magno liae Officinalis Flos, Mahoniae Caulis, Malvae Fructus, Manis Squama, Mantidis O OTheca, Margarita, Margaritifera Concha, Marsdeniae Tenacissimae Caulis, Mel, Me lanteritum, Meliae Cortex, Melo Semen, Menispermi Rhizoma, Menthae Haplocalycis Herba, Meretricis Concha, Cyclinae Concha, Micae Lapis Aureus, Microctis Folium, Mirabilitum Praeparatum, Momordicae Semen, Mori Cortex, Mori Folium, Mori Fructu s, Mori Ramulus, Morindae Officinalis Radix, Moschus, Moslae Herba, Moutan Corte x, Mume Flos, Mume Fructus, Murrayae Folium Et Cacumen, Mylabris, Myristicae Sem en, Myrrha, Nardostachyos Radix Et Rhizoma, Natrii Sulfas Exsiccatus, Natrii Sul fas, Nelumbinis Folium, Nelumbinis Plumula, Nelumbinis Receptaculum, Nelumbinis Rhizomatis Nodus, Nelumbinis Semen, Nelumbinis Stamen, Nigellae Semen, Notoginse ng Radix Et Rhizoma, Notoginseng Total Saponins, Notoginseng Triol Saponins, Not opterygii Rhizoma Et Radix, Ocimum Gratissimum Oil, Olibanum, Omphalia, Ophicalc itum, Ophiopogonis Radix, Orostachyis Fimbriatae Herba, Oroxyli Semen, Oryzae Fr uctus Germinatus, Osmundae Rhizoma, Ostreae Concha, Paeoniae Radix Alba, Paeonia e Radix Rubra, Panacis Japonici Rhizoma, Panacis Majoris Rhizoma, Panacis Quinqu efolii Radix, Papaveris Pericarpium SI, Paridis Rhizoma, Patchouli Oil, Pegaeoph yti Radix Et Rhizoma, Peppermint Oil, Perillae Caulis, Perillae Folium, Perillae Fructus, Periplocae Cortex, Persicae Ramulus, Persicae Semen, Peucedani Decursi vi Radix, Peucedani Radix, Pharbitidis Semen, Phellodendri Amurensis Cortex, Phe llodendri Chinensis Cortex, Pheretima, Phragmitis Rhizoma, Phyllanthi Fructus, P hysalis Calyx Seu Fructus, Physochlainae Radix, Phytolaccae Radix, Picrasmae Ram ulus Et Folium, Picriae Herba, Picrorhizae Rhizoma, Pinelliae Rhizoma Praeparatu m Cum Alumine, Pinelliae Rhizoma Praeparatum Cum Zingibere Et Alumine, Pinelliae Rhizoma Praeparatum, Pinelliae Rhizoma, Pini Lignum Nodi, Pini Pollen, Piperis Fructus, Piperis Kadsurae Caulis, Piperis Longi Fructus, Plantaginis Herba, Plan taginis Semen, Platycladi Cacumen, Platycladi Semen, Platycodonis Radix, Pogoste monis Herba, Polygala Liquid Extract, Polygalae Japonicae Herba, Polygalae Radix , Polygonati Odorati Rhizoma, Polygonati Rhizoma, Polygoni Avicularis Herba, Pol ygoni Cuspidati Rhizoma Et Radix, Polygoni Multiflori Caulis, Polygoni Multiflor i Radix Praeparata, Polygoni Multiflori Radix, Polygoni Orientalis Fructus, Poly goni Perfoliati Herba, Polygoni Tinctorii Folium, Polyporus, Poria, Poriae Cutis , Portulacae Herba, Potentillae Chinensis Herba, Potentillae Discoloris Herba, P owerdered Buffalo Horn Extract, Prinsepiae Nux, Propolis, Prunellae Spica, Pruni Semen, Psammosilenes Radix, Pseudolaricis Cortex, Pseudostellariae Radix, Psora leae Fructus, Pterocephali Herba, Puerariae Lobatae Radix, Puerariae Thomsonii Radix, Pulsatillae Radix, Pyritum, Pyrolae Herba, Pyrrosiae Folium, Quisqualis F ructus, Rabdosiae Rubescentis Herba, Ranae Oviductus, Ranunculi Ternati Radix, R aphani Semen, Realgar, Rehmanniae Radix Praeparata, Rehmanniae Radix, Rhapontici Radix, Rhei Radix Et Rhizoma, Rhodiolae Crenulatae Radix Et Rhizoma, Rhododendr i Daurici Folium, Rhododendri Mollis Flos, Rhubarb Extract, Rhubarb Liquid Extra ct, Ricini Semen, Rosae Chinensis Flos, Rosae Laevigatae Fructus, Rosae Rugosae Flos, Rubi Fructus, Rubiae Radix Et Rhizoma, Saigae Tataricae Cornu, Salvia Tota l Phenolic Acids, Salviae Miltiorrhizae Radix Et Rhizoma, Sanguisorbae Radix, Sa ntali Albi Lignum, Saposhnikoviae Radix, Sappan Lignum, Sarcandrae Herba, Sargas sum, Sargentodoxae Caulis, Sauropi Folium, Saururi Herba, Saussureae Involucrata e Herba, Schisandrae Chinensis Fructus, Schisandrae Sphenantherae Fructus, Schiz onepetae Herba Carbonisata, Schizonepetae Herba, Schizonepetae Spica Carbonisata , Schizonepetae Spica, Scolopendra, Scorpio, Scrophulariae Radix, Scutellaria Ex tract, Scutellariae Barbatae Herba, Scutellariae Radix, Sedi Herba, Selaginellae Herba, Semiaquilegiae Radix, Senecionis Scandentis Hebra, Sennae Folium, Sepiae Endoconcha, Serpentis Periostracum, Sesame Oil, Sesami Semen Nigrum, Setariae F ructus Germinatus, Siegesbeckiae Herba, Silybi Fructus, Sinapis Semen, Sinomenii Caulis, Sinopodophylli Fructus, Siphonostegiae Herba, Siraitiae Fructus, Smilac is Chinae Rhizoma, Smilacis Glabrae Rhizoma, Sojae Semen Germinatum, Sojae Semen Nigrum, Sojae Semen Praeparatum, Solidaginis Herba, Sophorae Flavescentis Radix , Sophorae Flos, Sophorae Fructus, Sophorae Tonkinensis Radix Et Rhizoma, Sparga nii Rhizoma, Spatholobi Caulis, Spiceleaf Kernel Oil, Spirodelae Herba, Stachyur i Medulla Helwingiae Medulla, Stalactitum, Star Anise Oil, Stauntoniae Caulis Et Folium、Stellariae Radix、Stemonae Radix、Stephaniae Tetrandrae Radix、Sterculi ae Lychnophorae Semen、Strychni Semen Pulveratum、Strychni Semen、Styrax、Suis F ellis Pulvis、Sulfur、Swertiae Herba、Swertiae Mileensis Herba、Syngnathus、Syri ngae Cortex、Talci Pulvis、Talcum、Tamaricis Cacumen、Tanshinones、Taraxaci Herba a、Taxilli Herba、Tea-Seed Oil、Terminaliae Belliricae Fructus、Testudinis Carap acis Et Plastri Colla、Testudinis Carapax Et Plastrum、Tetrapanacis Medulla、Thl aspi Herba、Thunberg Fritillary Liquid Extract、Tinosporae Radix、Toatal Ginseno side Of Ginseng Stems And Leaves、Toosendan Fructus、Torreyae Semen、Total Ginse noside Ginseng Root、Toxicodendri Resina、Trachelospermi Caulis Et Folium、Trach ycarpi Petiolus、Tribuli Fructus、Trichosanthis Fructus、Trichosanthis Pericarpi um、Trichosanthis Radix、Trichosanthis Semen Tostum、Trichosanthis Semen、Trigon ellae Semen, Trionycis Carapax, Tsaoko Fructus, Turpentine Oil, Turpiniae Folium , Typhae Pollen, Typhonii Rhizoma, Uncariae Ramulus Cum Uncis, Vaccariae Semen, Valerianae Jatamansi Rhizoma Et Radix, Verbenae Herba, Vespae Nidus, Vignae Seme n, Violae Herba, Visci Herba, Vitex Oil, Viticis Fructus, Viticis Negundo Folium , Vladimiriae Radix, Weeping Forsythia Extract, Wenyujin Rhizoma Concisum, Xanth ii Fructus, Zanthoxyli Pericarpium, Zanthoxyli Radix, Zaocys, Zedoary Turmeric O il, Zingiberis Rhizoma Praeparatum, Zingiberis Rhizoma Recens, Zingiberis Rhizom a, Ziziphi Spinosae Semen and is selected from the group consisting of.

[0053] In some embodiments, the drug content further includes a medium. The medium can bind to the API, that is, the medium is in physical contact with the API. In some embodiments, the API is embedded in the medium. In some embodiments, the API is dispersed within the medium. In some embodiments, the medium is a thermoplastic material disclosed herein.

[0054] In some embodiments, the medium is cocoa butter, polyethylene glycol (PE G), sucrose, glucose, galactose, fructose, xylose, lactose, maltose, trehalose, sorbitol, mannitol, maltodextrin, raffi nose, stachyose, fructooligosaccharide, and combinations thereof. In some embodiments, the substrate further comprises a plasticizer.

[0055] The drug content can have any shape and size suitable for being packed into the compartment.

[0056] In some embodiments, the drug content is operably linked to the compartment by covalent bonds, non-covalent interactions or via a linker. Thus, the drug content and the substrate are made separately and can be bonded by covalent bonds or non-covalent interactions. In some embodiments, the dosage form is produced by manufacturing the drug content and the substrate in a single step using a 3D printing method.

[0057] In some embodiments, the drug content is formed in the shape of a compressed tablet, an oval tablet, a pill, or a capsule. In some embodiments, the shape of the drug content matches the shape of the compartment. For example, when the compartment is pie-shaped, the drug content is also pie-shaped, for example, so as to occupy the compartment.

[0058] In some embodiments, the drug content takes the form of the nanoparticles illustrated in FIG. 6. The drug content can be mixed with a solution in which the API is dissolved or suspended. Then, the solution is atomized / sprayed onto the printing layer during the three-dimensional printing of the dosage form.​​​ Once a solution containing the drug content dries, the drug content is dispersed in the dosage form. The nanoparticles have a large surface area and a high dissolution rate.

[0059] The size of the nanoparticles ranges from 1 nm to 900 nm (preferred sizes are 10 0 - 800 nm, 100 - 700 nm, 100 - 600 nm, 100 - 500 nm, 10 0 - 400 nm, 100 - 300 nm, 100 - 200 nm, 1 nm, 2 nm, 3 nm, 4 nm, 5 nm, 6 nm, 7 nm, 8 nm, 9 nm, 10 nm, 11 nm, 12 nm, 1 3 nm, 14 nm, 15 nm, 16 nm, 17 nm, 18 nm, 19 nm, 20 nm, 1 00 nm, 200 nm, 300 nm, 400 nm, 500 nm, 600 nm, 700 nm , 800 nm, 900 nm). The size of the nanoparticles can be controlled by selecting an appropriate synthesis method and / or the system. To obtain nanoparticles within the desired size range, for example, the synthesis conditions can be appropriately controlled or changed to achieve the desired solution concentration or the desired cavity range (a detailed review can be found, for example, in Vincenzo Liveri , Controlled synthesis of nanoparticles , Published by Springer, 2006). in microheterogeneous systems, Published by Springer, 2006).

[0060] In some embodiments, the drug content is in the form of microneedles illustrated in Figure 7. The microneedles are printed with the dosage form during three - dimensional printing of the dosage form or inserted into the dosage form. The microneedles are made from sugar, PLGA polymer, API, or a combination thereof or combinations thereof. It can be configured. The microneedles can assist the API to penetrate into the patient's circulatory system when administered parenterally or enterally.

[0061] In some embodiments, the drug content forms a network structure. As shown in FIG. 8A, the dosage form has a substrate that forms a compartment filled with the drug content. The drug content has a substrate that forms a network structure. The frame structure of the tablet is made of a material that dissolves within 1 to 10 minutes, and the substrate dissolves in 2 to 60 seconds, preferably 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 seconds. As shown in FIG. 8B, the dosage form can release the API within a few seconds after administration.

[0062] The drug content can be produced using an additive method such as the fused deposition modeling (FDM) method. In some embodiments, the drug content can be produced by using a three-dimensional printer (3D printer) configured to extrude a mixture of the API and the excipient. The API can be melted before extrusion and can be homogeneously mixed with the melted substrate. Alternatively, a solid API (e.g., powder) can be mixed and dispersed in the melted substrate before extrusion. Generally, the extrusion process can be carried out at a temperature 10°C to 40°C above the glass transition (Tg) of the substrate and at a temperature close to the melting point of the API. When it reaches a temperature suitable for use in a three-dimensional printer, the substrate can be deposited on the three-dimensional printing surface. The shape and size of the drug content can be controlled by programming the three-dimensional printing process. In some embodiments ​​​​​​​​​​​​In this case, the drug content is produced in the same process as the base material. In some embodiments, the drug content is produced before the production of the base material and is packed into the compartment during or after the production of the base material.

[0063] In some embodiments, when the drug content is packed into the compartment, it binds to the base material, for example, is embedded or fixed in the base material. In some embodiments, the drug content is separable from the base material when packed into the compartment.

[0064] D. Release control The dosage forms disclosed herein can provide various release profiles after oral administration. In some embodiments, the dosage form achieves a constant release profile, pulsed or delayed delivery, or non-linear drug release. In some embodiments, the dosage form achieves zero-order release kinetics.

[0065] An appropriate release profile can benefit several drug therapy regimens. For example, in a pulsed release profile, absorption is controlled, a reduction in the peak-trough ratio, targeted drug release to specific regions in the gastrointestinal tract, and absorption independent of the feeding state are obtained, thus preventing resistance, reducing side effects, and improving patient compliance, and is desirable for treating diseases such as ADHD. In another example, a release profile with an initial dose followed by a maintenance dose may be good for treating chronic conditions such as hypertension and diabetes.

[0066] as described above. For example, by manipulating the exposed surface area of the substrate that is eroded steadily over time, the drug contents embedded in the substrate can deliver a certain amount of drug steadily over time. Furthermore, the release profile can be controlled by the size of the compartment opening and / or the geometry of the compartment.

[0067] In some embodiments, the release profile can be controlled by the design of a compartment that is sealed or plugged with a septum. The septum is made of a water-soluble, porous, or erodible material or a pH-sensitive material or a hydrophobic material that undergoes friction as the dosage form passes through the gastrointestinal tract. When the dosage form is administered to a subject, the septum dissolves, permeates, or erodes, and thus the drug contents are released from the compartment. The release profile of the drug contents can be controlled by selecting a septum with an appropriate erosion / dissolution rate or permeation rate. Alternatively, the release profile of the drug contents can be controlled by utilizing the shape and / or size of the septum (e.g., a rod shape of an appropriate length). The release profile can also be controlled by the number of compartments. FIG. 9 shows an exemplary dosage form having a substrate that forms a group of cylindrical compartments on both sides of the dosage form. Each compartment is filled with drug contents. Each compartment has an aperture that is plugged with a rod-shaped septum. The septa have different dissolution rates. Depending on the size, shape, and dissolution rate of the septum, sustained, continuous, simultaneous, sequential, or pulsed release of the API can be achieved.

[0068] ​​​Figure 10A is a diagram showing an exemplary dosage form that realizes a sequential release profile. Figure 10 Referring to A, the dosage form 700 has a substrate 701 that forms three cylindrical compartments 702-704. Each compartment is filled with a drug content of the same API . Each compartment has an aperture that is closed by rod-shaped plugs 705-707. The plugs are made of the same material but have different lengths. Therefore, the amount of time it takes for the plugs to dissolve and open the compartments to release the drug content is different. As illustrated in Figure 10 C, the shortest plug dissolves first, and the API is released from the first compartment. When the API in the first compartment is completely released, the plug of intermediate length dissolves, and the API is released from the second compartment. When the API in the second compartment is completely released, the third plug dissolves, and the API is released from the third compartment. As a result, when the drug content of the first compartment is released, the plasma drug level reaches the first peak. When the API released from the first compartment begins to be excreted, the plasma drug level begins to decline (see Figure 10D). Before the plasma drug level falls below the critical level (the horizontal line, below which the drug becomes ineffective), the API is released from the second compartment, and the plasma drug level rises again . When the API released from the second compartment reaches the second peak and begins to be excreted, the plug of the third compartment dissolves to open the compartment. As a result, the plasma API level above the critical level is maintained for a long time, which benefits several diseases.

[0069] ​​​​​​​​​​​​​A sequential release pattern can also be achieved by another exemplary dosage form in which several drug contents are bundled in the form of layers as illustrated in Figure 10B. By the synchronous dissolution of each layer, the API can be released in a sustained manner, and a continuous and sustained release of the API is achieved as shown in Figure 10C. In some embodiments, when the dosage form is administered, the outer layer of the dosage form dissolves immediately and the embedded drug contents are released. However, the layer sandwiched in the middle does not dissolve or dissolves much more slowly because the outer layer blocks the interface with the environment. When the outer layer dissolves, the layers sandwiched in the middle are exposed, and their dissolution is promoted, thus realizing the sequential release profile illustrated in Figure 10C. In some embodiments, the dosage form may contain a gas generating component packed in a first compartment. In some embodiments, the gas generating component is selected from the group consisting of organic acids and carbonates, bisulfites, bicarbonates, sodium carbonate, sodium bicarbonate, sodium metabisulfite, calcium carbonate, and combinations thereof, and releases carbon dioxide or sulfur dioxide gas when contacted with gastric juice. When the substrate dissolves, permeates or erodes in the stomach, the gas generating component is exposed to an acidic environment, or water penetrates into the compartment, inducing a reaction between the acid and sodium bicarbonate to generate gas and release the drug contents while foaming. The dosage forms disclosed herein may contain one or more drug contents in a time-release form at least in part. Time-release can be achieved with the aid of conventional materials and methods known to those skilled in the art. The sequential release pattern can also be achieved by another exemplary dosage form in which several drug contents are bundled in the form of layers as illustrated in Figure 10B. By the synchronous dissolution of each layer, the API can be released in a sustained manner, and a continuous and sustained release of the API is achieved as shown in Figure 10C. In some embodiments, when the dosage form is administered, the outer layer of the dosage form dissolves immediately and the embedded drug contents are released. However, the layer sandwiched in the middle does not dissolve or dissolves much more slowly because the outer layer blocks the interface with the environment. When the outer layer dissolves, the layers sandwiched in the middle are exposed, and their dissolution is promoted, thus realizing the sequential release profile illustrated in Figure 10C. In some embodiments, the dosage form may contain a gas generating component packed in a first compartment. In some embodiments, the gas generating component is selected from the group consisting of organic acids and carbonates, bisulfites, bicarbonates, sodium carbonate, sodium bicarbonate, sodium metabisulfite, calcium carbonate, and combinations thereof, and releases carbon dioxide or sulfur dioxide gas when contacted with gastric juice.

[0070] When the substrate dissolves, permeates or erodes in the stomach, the gas generating component is exposed to an acidic environment, or water penetrates into the compartment, inducing a reaction between the acid and sodium bicarbonate to generate gas and release the drug contents while foaming. The dosage forms disclosed herein may contain one or more drug contents in a time-release form at least in part. Time-release can be achieved with the aid of conventional materials and methods known to those skilled in the art. The sequential release pattern can also be achieved by another exemplary dosage form in which several drug contents are bundled in the form of layers as illustrated in Figure 10B. By the synchronous dissolution of each layer, the API can be released in a sustained manner, and a continuous and sustained release of the API is achieved as shown in Figure 10C. In some embodiments, when the dosage form is administered, the outer layer of the dosage form dissolves immediately and the embedded drug contents are released. However, the layer sandwiched in the middle does not dissolve or dissolves much more slowly because the outer layer blocks the interface with the environment. When the outer layer dissolves, the layers sandwiched in the middle are exposed, and their dissolution is promoted, thus realizing the sequential release profile illustrated in Figure 10C.

[0071] The sequential release pattern can also be achieved by another exemplary dosage form in which several drug contents are bundled in the form of layers as illustrated in Figure 10B. By the synchronous dissolution of each layer, the API can be released in a sustained manner, and a continuous and sustained release of the API is achieved as shown in Figure 10C. In some embodiments, when the dosage form is administered, the outer layer of the dosage form dissolves immediately and the embedded drug contents are released. However, the layer sandwiched in the middle does not dissolve or dissolves much more slowly because the outer layer blocks the interface with the environment. For example, it can be achieved by embedding the API in a time-release matrix or applying one or more time-release coatings. By means of time-release, the API release can be controlled so that the dosage form can be administered twice or once a day. This is particularly advantageous when, for example, a constant level of the active compound is required to address pain.

[0072] In some embodiments, the dosage form is intended to immediately release the active ingredient in the mouth. As an example, the mouth can be mentioned, or the sublingual area can be selected.

[0073] In some embodiments, the pharmaceutical form preferably further comprises conventional adjuvants known to those skilled in the art, selected from the group consisting of glycerol monostearate, semi-synthetic triglyceride derivatives, semi-synthetic glycerides, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyvinylpyrrolidone, gelatin, magnesium stearate, stearic acid, sodium stearate, talcum, sodium benzoate, boric acid and colloidal silica, fatty acids, substituted triglycerides, glycerides, polyoxyalkylene glycols, and derivatives thereof.

[0074] Manufacture of Dosage Forms The release-controlled dosage forms disclosed herein can be manufactured using any suitable method. In some embodiments, the dosage form is manufactured using three-dimensional printing (3D printing).

[0075] As used herein, 3D printing means manufacturing a 3D object by stacking layer by layer from a digital refers to the method. Basic 3D printing methods are described in U.S. Patent No. 5,204,055; No. 5,260,009; No. 5,340,656; No. 5,387,380; No. 5,5 03,785; and No. 5,633,021. Other U.S. patents and applications related to 3D printing include U.S. Patent No. 5,490,962; No. 5, 518,690; No. 5,869,170; No. 6,530,958; No. 6,280, 771; No. 6,514,518; No. 6,471,992; No. 8,828,411 ; U.S. Patent Application Publication No. 2002 / 0015728; No. 002 / 0106412; No. 2 003 / 0143268; No. 2003 / 0198677; No. 2004 / 000536 0. For a detailed description of 3D printing, reference can be made to the patents and applications listed above.

[0076] From the perspectives of raw materials, equipment, and solidification, various 3D printing methods have been developed for dosage form manufacturing. These 3D printing methods include binder attachment (L Gibson et al., ([[]] (2015) Additive Manufacring Technologies: 3D Printing, Rapid Prototyping, and Dir ect Digital Manufacturing. 2 ed. Spring er, New York; W.E. Katstra et al., (2000) Oral dosage forms fabricated by three dimensi onal printing, J. Control Release 66: 1- 9; W.E. Katstra et al., (2001) Fabrication of c ​​ Complex oral delivery forms by three dime nsional printing, Dissertation in Materi als Science and Engineering, Massachusse tts Institute of Technology; H. Lipson et al., (2013) Fabricated: The New World of 3D p rinting, John Wiley & Sons, Inc.; G. Jon athan, A. Karim(2016) 3D printing in pha rmaceutics: a new tool for designing cus tomized drug delivery systems, Int. J. P harm. 499: 376-394 (see also); material jetting (G. Jonath an, A. Karim(2016) 3D printing in pharma ceutics: a new tool for designing custom ized drug delivery systems, Int. J. Phar m. 499: 376-394 (see also); extrusion (L Gibson et al., (201 5) Additive Manufacring Technologies: 3D Printing, Rapid Prototyping, and Direct Digital Manufacturing. 2 ed. Springer, New York (see also); and photopolymerization (F.P. Melchels et al.,( (2010) A review on stereolithography and its application in biomedical engineerin (see, e.g., Biomaterials 31: 6121-30). .

[0077] In some embodiments, the dosage forms disclosed herein are manufactured using an extrusion method. In the extrusion process, the material is extruded through a nozzle driven by a robot. While binder attachment requires a powder bed, in contrast, the extrusion method can print on any substrate. A variety of 3D printing materials can be extruded, including the thermoplastic materials, pastes and colloidal suspensions, silicones, and other semi-solids disclosed herein. One commonly seen type of extrusion printing is fused deposition modeling, which uses a solid polymer filament for printing. In fused deposition modeling, a gear mechanism pushes the filament into a nozzle assembly heated for extrusion (see L Gibson et al., (2015) Additive Manufacturing Technologies: 3D Printing, Rapid Prototyping, and Direct Digital Manufacturing. 2 ed. Springer, New York).

[0078]

[0078] Manufacturing instructions for a print job can be generated in a variety of ways, including direct coding specific to the computer interface and application software of a 3D printing machine, derivation from a solid CAD model, or other means. ​​These instructions can include information regarding the number and spatial arrangement of droplets, and general printing parameters such as the spacing between droplets and the volume or mass of fluid per droplet in each of the length dimensions (X , Y, Z). When a set of materials is given, these parameters can be adjusted to improve the quality of the resulting structure. The overall resolution of the resulting structure depends on the powder particle size, droplet size of the fluid, printing parameters, and material properties. Since 3D printing can handle various pharmaceutical materials and locally control the composition and structure, it is well-suited for fabricating dosage forms with complex geometries and compositions according to the present invention. By using the 3D printing method to manufacture dosage forms, personalized medicine can also be promoted. Personalized medicine refers to the stratification of a patient population based on biomarkers to assist in treatment decisions and personalized dosage form design. Modifying digital designs is easier than modifying physical devices. Also, small-scale automated 3D printing can have negligible operating costs. Therefore, 3D printing can economically enable multiple individualized small batches, and the designed individualized dosage forms can improve compliance.

[0079]

[0080]

[0081] Personalized dosage forms can adjust the amount of drug delivered based on the patient's mass and metabolism. According to 3D printed dosage forms, accurate dosing in growing children can be achieved, enabling personalized administration of extremely potent drugs. In personalized dosage forms, Combine all of the patient's medications into a single daily dose, thus improving patient compliance with their medications. This can also be improved.

[0082] Figure 11 illustrates a method of manufacturing individualized dosage forms using 3D printing. For each patient, various clinical trial results can be obtained, including weight, age, metabolic indicators, and genomic biomarkers. Input the clinical trial results into the computer software. Combine the information with the physician's prescription and pharmacokinetic model to design specific dosages and compound dosage forms. Then, the instructions are sent to a 3D printer to manufacture the designed dosage forms and administer them to the patient.

[0083] Controlled release of multiple drugs In order to optimize the compound in some treatment regimens, the dosage forms and methods disclosed herein can be used to control the release of two or more drugs. For example, tablets for treating hypercholesterolemia can be designed to provide immediate release of atorvastatin calcium and long-term release of niacin. In another example, non-steroidal anti-inflammatory drugs (NSAIDs) for pain relief can be designed to achieve sustained release of the NSAID and immediate release of an H2 receptor antagonist to prevent NSAID-induced mucosal damage. This can be designed.

[0084] In some embodiments, the substrate forms a plurality of compartments, each filled with a drug content. In some embodiments, the plurality of compartments are connected. In some embodiments, the plurality of compartments are not connected. In some embodiments, the plurality of compartments are connected. Yes. In some embodiments, the drug contents packed in different compartments are the same. In some embodiments, the drug contents packed in different compartments are different. The dosage form can be designed to achieve simultaneous or sequential release of multiple drug contents to exert a synergistic therapeutic effect.

[0085] FIG. 12A is a diagram showing an exemplary dosage form capable of simultaneously releasing APIs. Referring to FIG. 12A, the dosage form 800 includes three stacked layers 801-803, and different drug contents are embedded in each of them. As illustrated in FIG. 12B, when the dosage form 800 is administered, the drug contents are simultaneously released as the layers dissolve, but at different rates.

[0086] FIG. 13A shows another exemplary dosage form having a simultaneous release profile. Referring to FIG. 13A, the dosage form 900 includes three cylindrical compartments 901-903, and three drug contents are packed therein. Each drug content includes an API embedded in a base material with a different dissolution rate. As illustrated in FIG. 13B, when the dosage form 900 is administered, the three APIs are simultaneously released as the base materials of the drug contents dissolve, but at different rates. The release rate of the API can also be controlled by the shape of the compartment or the size of the compartment opening.

[0087] FIGS. 14A and 14B show another exemplary dosage form having a simultaneous release profile of three APIs. Referring to FIG. 14A, the dosage form 1000 is in the shape of a pie and includes three segments 10 It contains 01 to 1003, in which a drug content is embedded. As illustrated in FIG. 14C, the drug content is released simultaneously as the segment dissolves, and the release rate of the drug content can be controlled by the dissolution rate of the segment. Referring to FIG. 14B, the dosage form 1100 includes three pie-shaped segments 1101 to 1103, which are enclosed by a shell 1104 that dissolves more slowly than the segments. The release rate of the drug content embedded in the segment decreases as the shell 1104 closes the interface with the environment of the segments 1101 to 1103.

[0088] FIG. 15A is a diagram showing an exemplary dosage form having a sequential release profile of two APIs. Referring to FIG. 15A, the dosage form 1200 includes a substrate 1201 that forms a compartment filled with a drug content 1202. The substrate 1201 contains a first API, and the drug content 1202 contains a second API. As illustrated in FIG. 15B, the first API is released as the substrate dissolves when the dosage form is administered. The second API is not released until the substrate dissolves and exposes the drug content, and a sequential release profile of the API is realized.

[0089] FIG. 16A is a diagram showing another exemplary dosage form having a sequential release profile. Referring to FIG. 16 A, the dosage form 1300 has a substrate 1301 that forms three cylindrical compartments 1302 to 1304 filled with three drug contents. The compartments 1302 to 1304 have apertures that are blocked by rod-shaped plugs having different lengths and / or dissolution rates. As illustrated in FIG. 16B, the API is the plug dissolves sequentially and is released sequentially as the compartment opens.

[0090] Figure 17A shows an exemplary dosage form having a simultaneous release profile or a sequential release profile is a diagram showing. Referring to Figure 17A, the dosage form 1400 has a substrate including four segments 1701-1704 having different dissolution rates. In some embodiments, as illustrated in Figure 17B, the drug content is embedded in segments 1701-1704 and is released simultaneously as the substrate dissolves. In some embodiments, each segment contains a compartment filled with the drug content. As illustrated in Figure 17C the drug content is released sequentially as the substrate dissolves.

Example

[0091] [Example 1] This example shows the design of a dosage form having a release control profile.

[0092] As shown in Figure 18A, the dosage form included a flat tablet substrate forming a pie-shaped compartment. The substrate was made of PEG8000. Benzoic acid was used as the modular drug content.

[0093] The release profile of benzoic acid from the dosage form was measured as follows. A Na2HPO4 solution at pH 8 was prepared as a solvent for dissolving benzoic acid. A 120 μg / mL benzoic acid solution was serially diluted to solutions of 30 μg / mL, 15 μg / m, 7.5 μg / m, 3.75 μg / mL, and 1.875 μg / mL, and their absorbances at 226 nm were measured using a UV spectrophotometer. The obtained numerical values were processed by linear regression to obtain the benzoic acid concentration A calibration curve of degrees was prepared with the equation y = 0.0599x + 0.0347. The amount of benzoic acid released To measure, the dosage form was dissolved in a degassed Na2HPO4 solution at pH 8 at 37°C ± 0.5°C and centrifuged at 100 rpm. From the solution, 5 mL of the solution was sampled at each time point to measure the concentration of benzoic acid, and 5 mL of the solvent was added back to the solution. The sampled solution was filtered through a 0.45 μm membrane filter and then transferred to a UV spectrophotometer to measure the absorbance at 226 nm . The percentage of benzoic acid released was calculated using the following equation.

[0094]

Equation

[0095] The release of PEG8000 was measured using the following method. To prepare a calibration curve of PEG8000, 0.1275 g of a PEG8000 standard sample was dissolved in water in a 25 mL volumetric flask . 1 mL, 2 mL, 5 mL and 10 mL were each transferred to a 10 mL volumetric flask and diluted with water to prepare a control solution. 50 μl of the control solution was injected into a liquid chromatograph (Three Waters Ultrahydrogel (trademark) 120 / 250 / 500 were connected in series, flow rate 0.5 ml / min, temperature 40°C, measured by a differential refractive index detector ). The volume part was measured and used as the y-axis. The logarithm of the control solution concentration was used as the x-axis . A calibration curve of PEG8000 was prepared with the equation y = 1.024x + 8.918. The percentage of PEG800 released was calculated using the following equation. ​​​​

[0096]

Number

[0097] Result: As illustrated in Figure 18C, the release profile of benzoic acid is the model profile (Zero-Ord er Drug Delivery System: Theory and Prel iminary Testing, J Pharm Sci., 1977, 66: 159-162) by D. Broo ke and R. J. Washkuhn and is controlled by the interface. Therefore, according to the dosage form disclosed in the present specification, a release control profile can be designed.

[0098] [Example 2] This example shows the design of a dosage form for controlling the release of drug contents from different compartments.

[0099] Administration design: Two dosage forms were manufactured using the hot melt lamination method. The base material of the dosage form was made of 72% Kollidon (registered trademark) VA64, 18% PEG1500, and 10% S oluplus (registered trademark). The drug content was composed of 30% moxifloxacin hydrochloride and 70% PEG1000. The schematic of the dosage form is shown in Figures 19A and 19B. Referring to Figures 19A and 19B, the dosage form 1600 has two compartments artments, as shown in Figures 19A and 19B. Referring to Figures 19A and 19B, the dosage form 1600 has two compartments It included a substrate 1601 that formed compartments 1602 and 1603. The compartments were each surrounded by walls 1604 and 1605. In the first dosage form, the two compartments were each surrounded by walls with thicknesses of 0.75 mm and 1.5 mm. In the second dosage form, the two compartments were each surrounded by walls with thicknesses of 0.75 mm and 2.25 mm respectively.

[0100] To detect the release of the drug content, the dosage form was added to 900 ml of phosphate buffer at pH 6.8 at 1 00 rpm. The UV absorption of the buffer was assayed to determine the release of the drug content.

[0101] The results of the release assay are shown in FIGS. 19C and 19D. As shown in FIG. 19C, when the first dosage form was added to the buffer for 20 minutes, the first compartment opened and the drug content in the first compartment was released. The second compartment did not open until 40 minutes after the dosage form was added to the buffer. The results of the second dosage form are shown in FIG. 19D. In the second dosage form, the second compartment did not open until 60 minutes after the dosage form was added to the buffer. Therefore, the release profile of the dosage form can be controlled by the thickness of the walls surrounding the compartments.

[0102] Although the principles of the present invention have been described in connection with specific embodiments, it should be clearly understood that these descriptions are for illustrative purposes only and are not intended to limit the scope of the present invention. The content disclosed herein is described for purposes of illustration and explanation. It is not intended to be exhaustive or to limit the disclosure to the precise form described. It is not. Many modified forms and variant forms will be obvious to those skilled in the art. The disclosed embodiments in the described technical field The principles and actual applications of the disclosed embodiments are best explained, thereby enabling other Those skilled in the art to understand various embodiments and various modified forms suitable for specific uses considered by them To be able to do so, the disclosure content has been selected and explained. The scope of the disclosure content is intended to be defined by the following Claims and their equivalents.

[0103]

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Claims

1. A substrate forming a first compartment and a second compartment, and a first drug content contained in the first compartment and a second drug content contained in the second compartment A three-dimensional (3D) printing method for an oral dosage form comprising: The first compartment is surrounded by a first wall, the second compartment is surrounded by a second wall, the first wall and the second wall are connected, and the first wall is thinner than the second wall, (a) Producing the first compartment and the second compartment by extruding and depositing the molten substrate onto a planar surface; (b) Producing the first drug content and the second drug content by extruding and depositing a molten mixture of the first drug content and a molten mixture of the second drug content onto a planar surface; Thereby obtaining a 3D printed oral dosage form A method comprising.

2. The method according to claim 1, wherein the first wall is more permeable than the second wall.

3. The method according to claim 1, wherein the first wall is eroded faster than the second wall.

4. The method according to claim 1, wherein the first drug content is different from the second drug content.

5. The method according to claim 1, wherein the substrate is made of a soluble material.

6. The method according to claim 1, wherein the dosage form is in the shape of a capsule and the first compartment and the second compartment are not connected.

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