JP2021120384A - Dosage forms and use thereof - Google Patents

Abstract

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

Description

Cross-reference to related applications This application is a US patent provisional application No. 62 / 170,645 filed on June 3, 2015, and a US patent provisional application No. 62/313 filed on March 24, 2016. , 092, which claims priority, the entire disclosure of which is incorporated herein by reference.

The present invention relates to pharmaceutical dosage forms as a whole and to control the release of biologically active substances, diagnostic agents, reagents, cosmetics, and pesticides / pesticides.

Pharmaceutical products must be manufactured in dosage form in order to be marketed for use.
Conventional dosage forms typically include a mixture of the active ingredient of the drug and the Inactive Ingredient (Excipient) along with other non-reusable materials such as capsule shells. Dosage forms include liquid dosage forms (eg, liquids, syrups, elixirs, suspensions and emulsions), solid dosage forms (eg tablets, etc.).
Capsules, caplets and gel caps), and semi-solid dosage forms (eg, ointments and suppositories), of which the solid dosage form is more advantageous for administering systemic drugs by oral route. Is.

Tablets are the most commonly used solid dosage form, exhibiting more benefits in terms of manufacturing, packaging and transportation, and are easy to identify and swallow. After the tablet is administered to the living body,
It interacts with the body when exerting a medicinal effect. The active pharmaceutical ingredient must be released from the tablet before it is absorbed into the blood circulation. The pharmaceutical component then disperses, disintegrates, or dissolves throughout body fluids and tissues. In drug absorption, distribution, metabolism, and excretion processes, dosage forms play a key role in determining drug release profiles and bioavailability. Therefore, there is a constant need to develop dosage forms that provide controlled drug delivery systems that can provide the desired plasma drug levels, 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 through the compartment.

In some embodiments, the substrate is selected from the group consisting of hydrophilic polymers, hydrophobic polymers, swellable polymers, non-swellable polymers, porous polymers, non-porous polymers, erosive polymers, non-erosive polymers. It is made from a thermoplastic material that is made of. In some embodiments, the thermoplastic material is polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer 57/30/13, polyvinylpyrrolidone-c.
o-Vinyl Acetate (PVP-VA), Polyvinylpyrrolidone-Polyvinylacetate Copolymer (PVP-VA) 60/40, Polyvinylpyrrolidone (PVP), Polyvinylacetate (PVAC) and Polyvinylpyrrolidone (PVP) 80/20, Polyethylene Glycol-Polyvinyl Alcohol Graft Copolymer 25/75, colilicat
IR-polyvinyl alcohol 60/40, polyvinyl alcohol (PVA or PV-O)
H), polyvinyl acetate (PVAc), poly (butyl methacrylate-co- (2-)
Dimethylaminoethyl) methacrylate-co-methylmethacrylate) 1: 2: 1, poly (dimethylaminoethyl methacrylate-co-methacrylic acid ester), poly (ethylacrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride) , Poly (methyl acrylate-co-methyl methacrylate-co)
-Methacrylic acid) 7: 3: 1, poly (methacrylic acid-co-methylmethacrylate) 1:
2. Poly (methacrylic acid-co-ethyl acrylate) 1: 1, poly (methacrylic acid-c)
o-methylmethacrylate) 1: 1, poly (ethylene oxide) (PEO), poly (ethylene glycol) (PEG), polybranched polyesteramide, hydroxypropylmethylcellulose phthalate, hypromellose phthalate, hydroxypropylmethylcellulose or hypromellose (HMPC) , Hydroxypropyl Methyl Cellulose Acetate Succinate or Hypromellose Acetate Succinate (HPMCAS), Poly (Lactide-co-Glycolide) (PLGA), Carbomer, Poly (Ethethylene-co-Vinyl Acetate), Ethylene-Vinyl Acetate Copolymer, Polyethylene (PE), and Polycaprolactone (PCL), Hydroxylpropyl Cellulose (HPC), Polyoxyl 40 Hardened Himasi Oil, Methyl Cellulose (MC), Ethyl Cellulose (EC), Poroxamer, Hydroxypropyl Methyl Cellulose Phallate (HPMCP), Poroxamer, Hardened Himasi Oil And soybean oil, glyceryl palmitostearate, carnauba wax, polylactic acid (PLA), polyglycolic acid (PGA), cellulose acetate butyrate (CAB)
), Colloidal silicon dioxide, sucrose, glucose, polyvinyl acetate phthalate (PVAP), and combinations thereof.

In some embodiments, the compartments are pie-shaped, conical, pyramidal,
It has a shape selected from the group consisting of a cylinder, a cube or a rectangular parallelepiped, a triangular or polygonal prism, a tetrahedron and combinations thereof.

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

In some embodiments, the drug content comprises a pharmaceutical active ingredient (API). In some embodiments, the API comprises local anesthetics, antiepileptic and anticonvulsants, anti-Alzheimer's disease agents, analgesics, anti-gouts, antihypertensive agents, antiarrhythmic agents, diuretics, hepatic disease treatment agents, Pancreatic disease treatments, antihistamines, antiallergic drugs, glucocorticoids, hormones and contraceptives, hypoglycemic agents, anti-osteoporosis agents, antibiotics, sulfonamides, quinolones, and other synthetic antibacterial agents, antituberculosis agents , Anti-viral drugs, anti-neoplastic drugs, immunomodulators, cosmetic active substances and traditional Chinese medicines. In some embodiments, the API is a biologically active substance, diagnostic agent, reagent for scientific research, cosmetics, or pesticide / insecticide.

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

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

In some embodiments, the dosage form comprises a gas generating component packed in a first compartment. In some embodiments, the gas generating component is selected from the group consisting of water-soluble carbonates, sulfites, hydrogen carbonates, sodium carbonate, sodium hydrogen carbonate, sodium metabisulfate, calcium carbonate, and combinations thereof. It releases carbon dioxide or sulfur dioxide gas when it comes in contact with gastric fluid. In some embodiments, the gas generating component is a combination of sodium bicarbonate and an organic acid (eg, citric acid, tartaric acid, etc.).

In another aspect, the present disclosure provides a dosage form comprising at least a first compartment and a substrate forming a second compartment. Dosage forms include a first drug content packed in a first compartment and a second drug content packed in a second compartment.

In some embodiments, the first compartment and the second compartment are concatenated. In some embodiments, the first compartment and the second compartment are unconnected.

In some embodiments, the first drug content is the same as the second drug content. In some embodiments, the first drug content differs from the second drug content.

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

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

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

It is a figure which shows the conventional dosage form containing a drug content. It is a figure which illustrates the release profile when the dosage form of FIG. 1A is administered to a subject. It is a figure which shows the drug level in plasma when the dosage form of FIG. 1A is administered to a subject. It is a figure which shows the plasma drug level at the time of administration to the subject the release control dosage form which has a zero-order drug release profile. FIG. 5 shows an exemplary dosage form having a substrate forming a compartment and having the drug content packed into the compartment. It is a figure which shows the release of API from the dosage form exemplified in FIG. 2A. FIG. 5 shows an exemplary dosage form having a substrate forming a compartment and another dosage form packed in the compartment. FIG. 5 shows an exemplary dosage form with a substrate forming a pie-shaped compartment. It is a figure which shows an exemplary dosage form which has a substrate forming a plurality of compartments including openings of various sizes. It is a figure which shows an exemplary dosage form which has a substrate which forms a compartment which forms an angle. It is a figure which shows the exemplary dosage form which has the substrate forming a plurality of compartments with different radius sizes. FIG. 5 illustrates an exemplary dosage form having substrates forming multiple compartments with different geometries that can be used to modulate the rate of release of the API. FIG. 5 shows a cross section of an exemplary dosage form with a pie-shaped compartment. It is a figure which shows the exemplary dosage form which has the base material which forms a plurality of layers, and is in the form of nanoparticles in which a drug content is dispersed between layers. FIG. 5 shows an exemplary dosage form having a substrate forming a compartment and having a microneedle-shaped drug content packed into the compartment. FIG. 5 shows an exemplary dosage form having a substrate forming a compartment in which the drug content is packed. The drug contents have a network structure. The substrate is made of a material that dissolves in 1-5 minutes and the drug content dissolves in seconds. It is a figure which shows the rapid release of API from the dosage form exemplified in FIG. 8A. FIG. 5 shows an exemplary dosage form having a substrate forming a group of cylindrical compartments. Each compartment is packed with one drug content. Release of drug content can be controlled by the number and size of compartments. FIG. 5 shows an exemplary dosage form having a substrate forming three cylindrical compartments. Each compartment is packed with one drug content. Each drug content has a stopper that closes the aperture of each compartment. It is a figure which shows the exemplary dosage form which has a multi-layer base material, and the drug content is embedded in each layer. FIG. 5 shows a consistent release of drug content from the dosage forms exemplified in FIG. 10A or 10B. It is a figure which shows the drug level in plasma when the release control dosage form exemplified in FIG. 10A or 10B is administered to a subject. It is a workflow schematic diagram which shows the use of the 3D printer which prepares a patient-specific dosage form. It is a figure which shows the exemplary dosage form which has 3 layers of a base material, and different drug contents are embedded in each layer. It is a figure which illustrates the release of three APIs from the dosage form exemplified in FIG. 12A. FIG. 5 shows an exemplary dosage form having a substrate forming three compartments, each packed with one drug content. The release profile of the drug content can be controlled by the rate of dissolution of the drug content. It is a figure which illustrates the release profile of API from the dosage form exemplified in FIG. 13A. It is a figure which shows an exemplary dosage form which has a base material which has three segments of a pie shape, and the drug content is embedded in each segment. FIG. 5 shows an exemplary dosage form having a substrate in which three pie-shaped segments are wrapped in a shell structure. It is a figure which shows the release profile of API from the dosage form exemplified in FIG. 8A and FIG. 8B. FIG. 5 shows an exemplary dosage form with a base forming a compartment filled with drug content. A second API is embedded in the substrate and released when the substrate dissolves. It is a figure which shows the release control of API from the dosage form exemplified in FIG. 15A. FIG. 5 shows an exemplary dosage form having a substrate forming three cylindrically shaped compartments. Each compartment is packed with one drug content. Each drug content has a plug that closes the opening of each compartment. The release of the drug content in each compartment can be controlled by the permeability, degradability or erosion of the plug. It is a figure which shows the release profile of API from the dosage form exemplified in FIG. 16A. FIG. 5 shows an exemplary dosage form with a substrate forming four compartments. Each compartment is packed with drug contents. FIG. 5 shows the release of API from a dosage form having a substrate consisting of four segments in which the drug content is embedded. It is a figure which shows the release control of API from the dosage form exemplified in FIG. 17A. FIG. 6 is a schematic diagram showing a drug form having a substrate forming a pie-shaped compartment. It is a photograph which shows the drug release process of the drug form exemplified in FIG. 18A. It is a figure which shows the release rate curve of benzoic acid and PEG8000 from the dosage form of FIG. 18A. FIG. 5 is a perspective view of a dosage form containing two compartments. It is sectional drawing of the dosage form of FIG. 19A. FIG. 6 shows an exemplary release profile of the dosage form of FIG. 19A. FIG. 9 shows another exemplary release profile of the dosage form of FIG. 19A.

The outline of the invention, the embodiments for carrying out the invention, and the claims below, as well as the accompanying drawings, describe specific features of the invention (including method steps). It is understood that the disclosure of the present invention herein includes all possible combinations of such particular features. For example, if a particular feature is disclosed in connection with a particular aspect or embodiment of the invention, or a particular claim, that feature may be combined as much as possible with other particular aspects and embodiments of the invention. And / or in connection with them,
It can also be used as a whole in the present invention.

The term "comprises" and its grammatically equivalent terms are used herein to mean that other ingredients, materials, steps, etc. may be present. for example,
"Comprising" (or "which" includes components A, B, and C
) Articles can consist of (ie, contain only) components A, B, and C, or can contain not only components A, B, and C but also one or more other components.

Where a method involving two or more specified steps is described herein, the specified steps are in any order (unless the context excludes that possibility) or at the same time. It can be carried out and the method is before any of the specified steps (unless the context excludes that possibility) and between the two steps of the specified step.
Alternatively, it may include one or more other steps performed after all specified steps.

If a range of values is listed, each value between the upper and lower bounds of the range (up to 1/10 of the lower bound unit unless it is clear from the context) and its. It will be appreciated that any other stated value or any value in between in the stated range is included within the present disclosure, except if there are limits specifically excluded in the stated range. Where the stated scope includes one or both of the upper and lower bounds, the scope of this disclosure also excludes either or both of them.

The term "at least" followed by a number is used herein to indicate the beginning of a range beginning with that number (depending on the variables defined, it can be a range with or without an upper limit). ). For example, "at least 1" means 1 or more. The term "at most" followed by a number is used to describe the end of a range ending in that number (a range with or without a lower bound, depending on the variable being defined). Can be). For example, "maximum 4" means 4 or less than 4, and "maximum 40%" means 40% or less than 40%. In the present disclosure, a range is "(first number) to (second number)" or "(first number) ~.
When described as "(second number)", this means a range in which the lower limit is the first number and the upper limit is the second number. For example, 2 to 10 millimeters means a range in which 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 the illustration, reference numerals are repeated between different drawings to indicate corresponding or similar components as needed. In addition, a number of specific details are provided to fully understand the embodiments described herein. However, the embodiments described herein can be implemented without these specific details. In other cases, so as not to obscure the relevant and meaningful features described.
Methods, procedures and ingredients are not detailed. Also, the description is not considered to limit the scope of the embodiments described herein. It will be appreciated that the description and characterization of the embodiments described in this disclosure are not considered incompatible with each other unless otherwise noted.

Release control dosage form
Conventional solid dosage forms, such as compressed tablets, consist of a substrate in which the active drug component is dissolved or embedded (FIG. 1A). Currently the usual solid dosage form is the primary drug release profile (
As shown in FIG. 1B), plasma levels of the drug rapidly rise to very high levels after administration and then fall exponentially (see Figure 1C). It has drawbacks such as minimal therapeutic efficacy due to reduced drug levels or drug toxicity that can occur at high concentrations. This type of drug release does not provide an adequate balance of plasma drug concentrations. The present invention relates to a release-regulated or controlled-release oral drug delivery system that provides advantages over conventional systems, including improved patient compliance, selective pharmacological effects, reduced side effects and reduced frequency of administration. Controlled release results in prolonged drug delivery and maintenance of plasma levels within the therapeutic range. For example, a drug delivery system showing a zero-order drug release profile (FIG. 1D)
It enables a certain amount of drug release over a long period of time and realizes uniform and continuous drug delivery. As a result, zero-order release profiles may be desirable in antibiotic delivery, treatment of hypertension, pain management, antidepressant delivery and many other conditions requiring constant plasma drug levels.

Therefore, one aspect of the present disclosure provides a stable solid pharmaceutical dosage form for oral administration with a release control profile. In some embodiments, the dosage form comprises a substrate forming at least one compartment and the drug content packed in the compartment. The dosage form is designed so that the release of the active ingredient of the drug content can be controlled, for example by opening the compartment in a predetermined manner.

A. Base Material As used herein, "base material" refers to a structure in which a drug is enclosed or embedded. The substrate of the dosage form of the present invention may be of any size and shape as long as it is suitable for oral administration. In some embodiments, the substrate is about 2 mm in diameter, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8
Flat, circular tablets of mm, 9 mm, 10 mm, 11 mm, 12 mm. In some embodiments, the substrate is an oval tablet measuring approximately am x b mm, where a.
Is 5 to 15 and b is 2 to 10. In some embodiments, the substrate is in the form of a capsule.

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

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

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

In some embodiments, the thermoplastic material is polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer 57/30/13, polyvinylpyrrolidone-co-vinylacetate (PVP-VA), polyvinylpyrrolidone-polyvinylacetate copolymer (PVP-). VA) 60/40, polyvinylpyrrolidone (PV)
P), polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP) 80/20
, Polyethylene Glycol-Polyvinyl Alcohol Graft Copolymer 25/75, ko
llicoat IR-polyvinyl alcohol 60/40, polyvinyl alcohol (PV
A or PV-OH), poly (vinyl acetate) (PVAc), poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1: 2: 1, poly (dimethylaminoethyl methacrylate-) co-methacrylic acid ester), poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonio ethyl methacrylate chloride), poly (methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7: 3: 1, poly ( Methacrylate-co-methylmethacrylate) 1: 2, poly (methacrylate-co-ethylacrylate) 1: 1, poly (methacrylate-co-methylmethacrylate) 1: 1, poly (ethylene oxide) (
PEO), poly (ethylene glycol) (PEG), polybranched polyesteramide, hydroxypropylmethylcellulose phthalate, hypromellose phthalate, hydroxypropylmethylcellulose or hypromellose (HMPC), hydroxypropylmethylcellulose acetate succinate or hypromellose acetates Cucinate (HP
MCAS), poly (lactide-co-glycolide) (PLGA), carbomer, poly (ethylene-co-vinyl acetate), ethylene-vinyl acetate copolymer, polyethylene (PE), and polycaprolactone (PCL), hydroxylpropyl cellulose (HPC). ), Polyoxyl 40-cured castor oil, methylcellulose (MC), ethylcellulose (EC), poroxamer, hydroxypropylmethylcellulosephthalate (HPM)
CP), poloxamer, hardened castor oil and soybean oil, glyceryl palmitostearate, carnauba wax, polylactic acid (PLA), polyglycolic acid (PGA), cellulose acetate butyrate (CAB), colloidal silicon dioxide, sucrose, glucose, It is selected from the group consisting of polyvinyl acetate phthalate (PVAP) and combinations thereof.

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

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

In some embodiments, the material of the substrate can be selected so that the release profile of the drug is controlled. For example, the substrate is made of a material with the desired erosion / dissolution rate, permeation rate and therefore, when administered, the compartment can be opened in a predetermined manner and the drug content can be removed from the compartment at the desired rate. Be released. In some embodiments, the substrate is erosive or soluble and is embedded with a Pharmaceutical Active Ingredient (API). The API is released when the substrate is eroded or dissolved.

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

B. Compartments In certain embodiments, the dosage forms disclosed herein include at least one compartment within the substrate. As used herein, "compartment" refers to a space, portion or room characterized or divided by a substrate. The compartment can be closed or opened (eg, with an aperture or aisle). The compartment may have any geometry suitable for packing the drug contents. In some embodiments, the compartment has a shape selected from the group consisting of pie, conical, pyramidal, cylindrical, cubic or rectangular parallelepiped, triangular or polygonal prismatic, tetrahedral and combinations thereof. Have.

In some embodiments, inclusion of a compartment in the dosage form can enhance its retention in the gastrointestinal tract. FIG. 2A illustrates an exemplary dosage form with a substrate forming a compartment filled with drug contents. Referring to FIG. 2A, in dosage form 100, the compartment 102 is formed by the substrate 101. The drug content 103 is connected to the inner wall of the compartment 102 so that the compartment 10 is connected.
It is packed in 2. The compartment 102 provides a floating effect on the dosage form, thereby prolonging 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 base material, A as shown in FIG. 2B.
It can result in sustained release of PI.

FIG. 3 illustrates another exemplary dosage form with increased retention in the gastrointestinal tract. Referring to FIG. 3, the dosage form 200 has a configuration in which the compartment 202 includes a second dosage form 203 (eg, a tablet) that freely moves the compartment 202. The dosage form has a limited residence time in the gastrointestinal tract. By using a floating system, it may be possible for the dosage form to stay in the stomach, continuously release the drug in the upper part of the gastrointestinal tract, and maximize absorption in the small intestine.

In some embodiments, the shape of the compartment is uniquely created to allow the drug content to be released at a controlled rate. In some embodiments, the compartment is selected from the group consisting of wedges, pis, cones, pyramids, cylinders, cubes or rectangular parallelepipeds, triangular or polygonal prisms, tetrahedrons and combinations thereof. Has a shape.

In one embodiment, the dosage form compartments have different geometries. FIG. 4A shows an exemplary dosage form with a substrate forming a pie-shaped compartment. FIG. 4B shows an exemplary dosage form with a substrate forming multiple compartments containing openings of various sizes. FIG. 4C shows an exemplary dosage form with a substrate forming an angled compartment. FIG. 4D shows an exemplary dosage form with substrates forming multiple compartments with different radius sizes.

The shape of the compartment can be used to control the release profile of the dosage form. For example, R. A. Lipper and W. I. Higuichi described a delivery system that achieves the zero-order emission profile illustrated in FIG. FIG. 5 shows a cross-sectional view of a delivery system with a pie-shaped compartment. The compartment communicates with the environment through a small opening. The compartment is packed with drug contents that dissolve and release the API. The API is then released into the environment through a small opening. The dissolution rate of the drug content is positively correlated with the dissolution boundary (interface between the drug content and the compartment space) region of the drug content. On the other hand, the diffusion rate of API into the environment negatively correlates 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 pathway length λ increases. Therefore, APIs released in the compartment need to be transported longer lengths to diffuse from the dosage form. It is envisioned that the dosage form will be designed to achieve zero-order emission kinetics (RA Lipper and WI Higuchi (1977)).
, Analysis of theoretical behavior of a p
rosed zero-order drug delivery system.
J. Pharm Sci 66 (2): 163-4; D. Brooke and R.M. J. Washkuhn (1977), Zero-order drug de
live system: theory and preliminary te
sting. J Pharm Sci. 66 (2): 159-162).

C. Drug Contents In the present specification, the term "drug content" includes one or more active ingredients including active pharmaceutical ingredients (APIs), cosmetics, biological substances, diagnostic agents and reagents for scientific experiments. Refers to the composition.

As used herein, API refers to a biologically active ingredient in a pharmaceutical product. In some embodiments, the API is a local anesthetic, an antiepileptic and anticonvulsant, an Alzheimer's disease therapeutic agent, an analgesic, an anti-gout agent, an antihypertensive agent, an anti-arrhythmic agent, a diuretic, a liver disease therapeutic agent, Pancreatic disease treatments, antihistamines, antiallergic drugs, glucocorticoids, sex hormones and contraceptives, hypoglycemic agents, anti-osteoporosis agents, antibiotics, sulfonamides, quinolones, and other synthetic antibacterial agents, antituberculosis It is selected from the group consisting of drugs, antivirals, antineoplastics, immunomodulators, cosmetic active substances, Chinese traditional medicine (TCM) and TCM extracts.

In some embodiments, the API is (R) -folithixotropy, lidocaine, 1
1-di-dutero-ethyllinoleate, 16-dehydro-pregnenolone, 17β-
Estradiol, 2-iminobiotin, 3,5-diiodotyropropionic acid, 5-fluoro-2-deoxycitidine, 6-mercaptopurine, edthreothide, abacavir, abalone hemocyanin, abametapill, avegiterol, avemacicrib, abexinostat, avilateron , Acarabrutinib, acamprosate, acamprosate calcium, acarbose, acevirstat, acecrydin, acecrophenac, acehithycin hydrochloride, acemannan, acenoylamic acid, acetaminophen, acetylcysteine, acetylkitasamicin, acetyl-L-carnitine hydrochloride Salt, acetylsalicylic acid, acyclovir, acipimox, acitazanolast, acitretin, acridinium, acridinium bromide, acotiamide, acolafloxacin, acotiamide, acribastin, actarit, adaparene, adaparene, adehovir dipivoxil, admethionine Afimoxyphene, Afresertib, Agomeratin, ailedenafilcitrate, Aradrian, Aralebonadifloxacin mesylate, Aralerin acetate, Alatrofloxacin mesylate, Albendazole, Albuterol sulfate, Albuterpenoid, Alkaphthaldine , Aldoxorbicin, arectinib, alendronate, sodium alendronate, sodium alendronate hydrate, alendronate, alphacalcidol, alphaxalon,
Alfentanil, Alfuzosin, Alicertib, Aliskilen, Alicepolyvir, Aritretinoin, Allantin, Alisartane Isoproxil, Aroprinol, Almotriptan, Arogliptin, Allogliptin benzoate, Alosetron, Alpericib, α-ketoglutarate, αlipoic acid, α1-Anti Trypsin, α-cyclodextrin stabilized sulforaphane, alprazolam, alprostadil, alprostadil alfadex, altiratinib, altretamine, altropan, aluminum sulfate, albimopan, arbosideib, amantazine, amantazine hydrochloride, amlodipine, ambroxol, amlodipine Xol hydrochloride, amlodipine, amphetamine, amlodipinepolystylex, amlodipine, amlodipine phosphate, amlodipine, amlodipine, amylolide, aminolevulinic, aminolevulinic acid, aminolevulinate, amlodipine, amyodalone, amlodipine, amlodipine Amlodipine Hydrochloride, Amitriptyrin, Anlexanox, Amlodipine, Amlodipine, Amlodipine Besilate, Amlodipine Besilate, Amlodipine Cansylate, Amlodipine Maleate, Amlodipine Nicotinate, Amlodipine Orotate,
Ammonium lactate, amodiaquine, amorolfine, amosuralol, amoxicillin,
Amoxicillin Hydrate, Amphetamine, Amphetamine Aspartate, Amphetamine Sulfate, Amphotericin B, Amphotericin B Cholesteryl Sulfate, Amphotericin B Lipid Complex, Ampicillin Sodium, Amphetamine, Amrinone, Amurubicin, Amphotericin Acrylic, Anagliptin, Anagliptin , Anagliptin, Anastrosol, Amphotericin, Androgen, Androglahydride,
Anecortab, Anidurafungin, Anilacetam, Anistreplase, Anrotinib, Antazoline, Antiandrogen, Antineoplaston A-10, Antineoplaston AS2-1, Antofluxacin hydrochloride, Antroquinonol, Apabetaron, Apartamide , Apatinib mesylate, apadicone, apirimodomesylate, apixaban, apomorphine, apomorphine hydrochloride, apremirast, aprepitant, apricitabine, alamcol, aranidipine, arasertaconazole, arasertaconazolenitrate, albacrazole, albacrazole Rubil, Albecacin, Albecacin Sulfate, Aldeparin Sodium, Alformotelol, Argatroban, Alhalophenate, Arimochromine, Aripiprazole, Aripiprazole Lauroxil,
Armodafinil, arsenic trioxide, arsenous acid, artefenomel mesylate, artemether,
Artemotil, Artenimol, Artesunate, Artesunate, Artis [
Artiss], Asapiplant, Asenapine, Asimadrin, Astodrimer, Astragaloside, Asnaprevir, Atashiguato, Atarlen, Atazanavir, Atazanavir Sulfate, Atenolol, Atmoxetine, Atorvastatin, Atorvastatin Calcium, Atorvastatin, Atorvastatin, Atorvastatin, Atorvastatin, Atorvastatin, Atorvastatin, Atorvastatin , Auriclosen, abaccincapta dopegor sodium, abacopane, avanafil, abatrombopag, avibactam, avivactum sodium, avidinox [AvidinOx], aviptadyl, avitinib, avoralstat, axeloplan, axitinib, azacitidine, azacitidine , Azelavir acid, azelastin,
Azelastine hydrochloride, azelnidipine, azelnidipine, azilsartan, azilsartan medoxomil potassium, azilsartan trimethylethanolamine, azithromycin, azithromycin, azithromycin lactobionate, azthromycin, azthreonamricin, azbudin, bacrophen, bafetinib, baicalein, baicalein Contains ratanoprost, barofloxacin, balsalazide, balsalazido sodium, vanbuterol, balacertib, baldoxolonemethyl, valicitinib, balnidipine, basmisanil, batefenterol succinate, bazedoxyphene, beclabvir, beclomethasone dipropionate, beclomethasone dipropionate Verinostat, beloranib, verotecan, bempedonic acid, benapenem,
Benazepril, Bencyclochidium bromide, Bendamustine, Bendamustine hydrochloride,
Benidipine, benzeradide, bentamapimod, benzalconium chloride, benzhydrocodon, benznidazole, benzokine, benzoyl peroxide, benzidamine HCL, bepotastin, bepotastine calcium dihydrate, bepotastin salicylate, veractant, sodium veraprost, besifloxacin Betamethasone, betamethasone butypropionate, betamethasone dipropionate, betamethasone ballerate, betamipron, betaxolol, betaxolol hydrochloride, betanecol, betamethasone, betamethasone, betamethasone, betamethasone, betamethasone, betamethasone, betamethasone, betamethasone, betamethasone, betamethasone, betamethasone, betamethasone. Betaxolol, Bezamethasone, Biafungin, Biapenem, Bicartamide, Bicizar, Victegravir, Bicyclol, Vilastin, Bimatoprost, Vinimetinib, Biotin, Vilabresib Dihydrate, Biscalcitrate Potassium, Biscalcin Hydrate, Bismuthylecaveto , Bimatoprost, Betaxolol Fumarate, Vitespiramycin, Bixalomer, Breomycin, Bronanserin,
Boenmycin hydrochloride, boceprevir, bortezomib, bosentan, bosentan hydrate,
Bosutinib, bovacant, blexiprazole, bricyclib sodium, brigatinib, brimonidine, brimapitide, brimonidine, brinsidephobyl, brinzolamide, bribanibualaninate, bribalacetam, bribzin, brorcizumab, bromazepam, bromocriptine, bromocriptine, bromocriptine, bromocriptine, bromocriptine Broncostat, brotizolam, bryostatin-1, bosuindrol, bucladesin, budesonide,
Bupivacaine, Buflomezil, Brakin, Bunazocin, Bupivacaine, Bupivacaine, Bupivacaine Hydrochloride, Buprenorfin, Buprenorfin Hydrochloride, Bupropion, Bupropion Hydrochloride, Brixafol, Busererin Acetate, Buspyrone, Buspilone Hydrochloride, Busulfane, Busulfex, Butenaphate , Bupivacaine, cabergolin, cabotegravir, cabozanthinib S-malate, cadazolide, cadofloxacine, caffeine, caffeine citrate, cafnea, cafseltib hydrochloride, calcipotriol, calcitriol, calcium acetate, calcium phophosphate, calcium levofophosphate, Polycarbofil Calcium, Calfactorant, Calmangahodipil, Calsurf, Camicinal, Camostat Mecilate, Camptothecin, Canagliflozin, Candesartan, Candesartan cilexetil, Camphosphamide, Cangrelol, Cannavidiol, Capecitabin, Capmatinib, Capsaicin, Captopril Carbamazepine, carvetocin, carbidopa, carbinoxamine, carbocysteine, carboplatin, cardidopa, calfilzomib, carglumate, caliprazine, charisbamate, carmustin, carotegrastomethyl, carteolol, carteolol hydrochloride, carmonum, carvegirol, carvegilol phosphate Catequin, sebranopadol, sedilanib, cefaclor, cefadoroxyl, cefatiamidine, cefazoline sodium pentahydrate, cefcapene, cefzinyl, cefditoren pivoxil, cefepim, cefepim dihydrochloride, cefetamethopivoxil hydrochloride, cefidelocol Cefoperazone, cefoperazone sodium, cefoselis, cefotaxim, cefotaxim sodium, cefotiam, cefosoplan, cefpyrom, cefpodoxime, cefprodil, ceftalolin,
Ceftaroline fosamil, ceftazidime, ceftibuten, theft viprol medcaryl,
Ceftrozan Sulfate,

Ceftriaxone, Ceftriaxone Sodium, Cefuroxime, Cefuroxime Sodium, Celecoxib, Sergosibir, Celiprolol, Celecoxib, Senestin, Senicribiroc, Sensabdin, Centanafazine, Cephalosporins, Celecoxib,
Cerduratinib, seritinib, cerium nitrate, cetirizine, cetirizine, setraxate, cevimerin, chenodeoxycholic acid, chlorsibutamine, chlorhexidine, chlormaginone acetate, chlorogenic acid, chloroquine, chloroxoquinoline, chlorpheniramine, chlorpheniramine maleate, chlorpheniramine maleate, chlorpheniramine. Chlortalidone, chlortalidone, cholecalciferol, cholic acid, cholinealphosserato,
Corindie palrestat, cholinephenofibrate, ciclesonide, cyclopyroxolamine, cyclosporine, cidofovir, cidoxepin, silastatin, cirazapril, cilnidipine, cilostazol, cimetidine, cinacalcet, cinepazidomaleate,
Sodium cinhyaluronate, cinitapridotartrate, cypargamine, ciprofloxacin, ciprofloxacin, ciprofloxacin hydrochloride, cilaparantag, circadine, cisatraculium vesylate, cisplatin, citalopram, citalopram hydrobromide, citicoline , Ciprofloxacin, Cladribin, Clarithromycin, Potassium clavulanate, Clavulanic acid, Clazocentan, Klevidipin, Klebdin, Clindamycin,
Clindamycin hydrochloride, Clindamycin phosphate, clioquinol, clobazam, clobetasol propionate, clobetasol propionate foam, clodronic acid, clomipramine, clomipramine, clomipramine, clomipramine hydrochloride, clonazepam, clonidine, clonidine hydrochloride, clopidogrel, Clobetasol vesylate,
Cropidogrel bisulfate, Cropidogrel camcillate, Cropidogrel hydrochloride, Cropidogrel napadisylate, Cropidogrel reginate, Clotrimazole, Crozapin, Kobamamid, Cobicistat, Cobimethinib, Cobiproston, Codeine, Codeine polysylene, codeine Cholestilan, corhorsindalopert, corphosceryl palmitate, colistin metasodium, conibaptane, copanricib, copper histidine, cortexolone 17α-propionate, cositecan, clenoranib, cridanimodosodium, chrysabolol, chryzotinib, cloferemer, chloride, chloride. Sodium, kutamesin dihydrochloride, cyanocobalamin, cyclidine lactate, cyclobenzaprine hydrochloride, cyclophosphamide, cyclophosphamide monohydrate, cyclosporin, cyproterone,
Ciproteron acetate, cytarabine, cytarabine ocphosphate, dabigatran etexilate, dabrafenib, daclatasvir, dacomitinib, dalvavancin, dalcetrapib, dalfampridin, dalhopristin, dalteparin sodium, danapaloid sodium, danazol, danilixin ,
Danucertib, dapaconazole, dapagliflozin, dapagliflozin propanediol, dapiprazole, dapivirin, dapoxetine, daprodustat, dapson, dalifenasin, darinaparcin, darnavir, dasabvir, dasatinib, dasotralin, daunorubicin, decitamphetamine , Deferroxamine mesylate, defrazacoat, deflexifol, derafoxacin, delamand, delapril, derapril hydrochloride, delavirdin, denibrin, deoxyandroglaholide, dermatansulfate, desflurane, decipramine hydrochloride, desloratadine, desmopresine, desmopresine Desonide, Desben Rafaxin, Dextromethorphan Hydrobromide, Deuteporfin, Dehydrohydrate Levodopa, Diclofenac Benlafaxin, Dutetrabenazine, Diclofenac, Dexametazone Acetate, Dexametazone Cipecilate, Dexametazone Palmitate , Dexamethasone sodium phosphate, dexpanphetamine, dexanabinol, dexferm, dexketoprofentromateol, dextransoprazole, dexmedetomidine, dexmethylphenidate, dextromethorphan, dexrazoxane, dexsotalol, dextroamphetamine saccharate, dextroamphetamine. Sulfate, dextromethorphan, dextromethorphan hydrobromide, dextropropoxyphene, diacerein, diamorphine hydrochloride, dianhydrogalactitol, diazepam, diazoxidocholine, diclofenac, diclofenac potassium, diclofenac sodium, diclofenamide, dicycloplatin , Didanocin, dienogest, diflupredonato, digoxin, dihomo-γ-linolenic acid, dihydroergocristine, dihydroergotamine, dihydroergotamine mesylate, zyrthiazem, zirthiazem hydrochloride, dimesna, dimethyl fumarate, dimiracetam, dinoprostone, diphenylcyclopropenon , Dipyridamol, diquahosoltetrasodium, dilisromycin, dysfenton sodium, dysulfyllam,
Ditranol, d-mesadon, docarpamine, docetaxel, docipulse tat, docosanol, dofetilide, dracetron, dolutegravir, donperidone, donaphenibtosilate, donepezil, donepezil hydrochloride, dopamine, dravilin, dolipenem, dolsolamide, dolsolamide hydrochloride , Doxacrium chloride, doxazosin, doxazocin mesylate, doxepin hydrochloride, doxelcalciferol, doxifrulysin, doxophylline, doxorubicin, doxorbisin hydrochloride, doxicycrine, doxicycrine hydrochloride, doxylamine succinate, dronabinol, dronedarone , D-Tagatos, Duloxetine, Duloxetine Hydrochloride, Dutasteride, Duberisib, Evastin, Eberconazole, Evselen, Ecabet, Econazolenitrate, Ecopipam, Edarabon, Edivoxetine, Edner Pick Maleate, Edoxaban, Efatsutazone Nazole, Eflornitine, Ehonidipine Hydrochloride, Egualen Sodium, Eicosapentaenoic Acid Monoglyceride, Elafibranol, Elagolix, Elamipretide, Elvasvir, Eldecarcitol, Elekladin, Ereschromol Sodium, Eletriptan, Eliglutat Tartrate, Erobixibat, Elthrombopag, Elxadrin Dihydrochloride, Elbitegrabir, Emdgain, Emedastin, Emeramide, Emixstat, Emodepside, Empaglyfrosin, Emricasan, Emtricitabin, Enarapril, Enarapril maleate, Enacidenib, Enaseniceneb Xyphene, Enovosalm, Enoxa Single Conate, Enoxaparin Sodium, Emprostil, Entakapon, Entasobulin, Entecavir, Entecavir Maleate, Enthinostat, Enthospretinib, Entrectinib, Enzartamide, Enzastaurine, Epacadostat, Eparrestat Epetrabolol, Efedrin Sulfate, Epinastine Hydrochloride, Epinephrine, Epirubicin, Epirubicin Hydrochloride, Episalvan, Epitinib, Eprelenone, Epoprostenol, Epristeride, Eprodisate, Eprosartane, E Ptaplatin, Elabacyclin, Eldaphytinib, Eldostain, Eribulin Mesylate, Elrotinib, Eltapenem, Elteberel, Ertugliflozin, Estromycin, Estromycin Assistrate, Estromycin Stinoplate, Escitaloplum, Esketamine, Escitamine Hydrochloride, Estrogen , Esmorol hydrochloride, esomeprazole, esomeprazole magnesium, esomeprazole strontium, esomeprazole, estheticol, estradiol, estradiol acetate, estradiol cypionate, estradiol valerate, estrogen, estrogen, esveraprost sodium, es Zopiclone, etamicastat, etambutol hydrochloride, etaselen, ethynyl estradiol, calcium salt of ethyl hydrogen fumarate, magnesium salt of ethyl hydrogen fumarate, zinc salt of ethyl hydrogen fumarate, ethynyl estradiol, etidronic acid, ethimicin sulfate, Echilinotecampegol, etizolam, etodrac, etonogestrel, etopocid, etopocid phosphate, etricoxyb, etlavylin, etripamil, eupathilin, ebenamide hydrochloride, eberolimus, evophosphamide, evoglycin, exemestane, exemestane, exemestane. Chloride, Ezatiostat, Ezetimib, Estrogen, Fadormidin, Fadrosol, Faldaprevir, Falecalcitriol, Famcyclovir, Famichinib, Famotidin, Fampridin, Faropenem,
Fasitibant Chloride, Fasolacetam, Faszil, Faszil Hydrochloride, Faszil Mesylate, Fabipilavir, Febalbamart, Febuxostat, Fedovapagon, Ferbamart, Ferbinactrometamole, Ferrodipine, Femitra, Fenflulamin Hydrochloride, Phenovam, Phenofib Rate, phenofibric acid, phenoldopam, phenotelol, fenretinide, fentanyl, fentanylcitrate, fexofenadine, fermagato, ferric citrate, ferrous maltol, fermoxidol, fesoterodin fumarate, fevipiplant, fexini Dazole, Fexofenadine, Fibrin Sealant, Fibrinogen, Fibrinogen Sealant, Fidaxomycin, Firanesib, Filgothinib, Philocyclovir, Fimaporfin, Phimasartan, Finafoxacin, Finafoxacin Hydrochloride, Finasteride, Finnerenone, Fingolimod , Fipamesol, fibrtecampegol, frekinide, freroxacin, frivanserin, flomoxef,

Floxuridine, fluazorepari, fluconazole, fludarabine, flumatinib, flumazenyl, flunisolide, fluocinolone acetonide, fluocinolone, fluorapacin, fluorouracil, fluoxetine, fluoxetine hydrochloride, flupirtine, flurbiprofen, flurbiprofen Profen sodium, flurisromycin, fluticasone, fluticasone floate, fluticasone propionate,
Frutrimazole, fluvastatin, fluvoxamine, folic acid, holinate, fosravucon, homepizol, fonadelpal, fosda parinux sodium, holetinib, formestan, formoterol, formoterol fumarate, forodesin, fosfomycin, fosravuconto, fosbre Tabulin, phosbretabrin disodium, phosfluconazole, fosfomycin, fosfomycin disodium, phosphomycintromethamole, hosinopril, hosinopril sodium, phosmidomycin, phosphenytoin, phospropofol, fosravuconazole, hostamatinib, hostemsavirtromethamine, Hotagliptin benzoate, hotemstin, flovatriptan, fluvinite nib, hudstein, fluvestrant, funapide, frosemide, fosfomycin,
Gabapentin, Gabapentin enacarbyl, gabexate mesylate, gasicridine, gadobutrol, gadobercetamide, disodium gadoxetate, galantamine, galeteron, galidecivir, gallium nitrate, garnicertib, gamboginic acid, ganaxolone, ganfacine, ganfacine , Gachifloxacin mesylate, gedatricib, gefitinib, gemkaben, gemcitabine, gemcitabine hydrochloride, gemfibrodil, gemifloxacin, gemigliptin, gemigliptin tartrate, genistein, gentamycin, gentiopicrin, gepiron, gemcitidacin, gemcitabine, gemcitabine, gemcitabine , Gimeracil, Ginsenoside CK, Ginsenoside Rg3, Gibinostat, Glasdigib, Gratilamaacetate, Grecaprevir, Gresatinib Glycolate, Glybenclamide, Glyclazide, Glymepyride, Gripidide, Gluphosphamide, Glutamine, Glutathionalsenoxide, Gloxaphenylbutylate , Glycopyrronium, Glycopyrronium bromide, Glycopyrronium tosylate, Glycyrrhizinate, Ganglioside, Gemcitabine, Gosogliptin, Granisetron, Granisetron hydrochloride, Glazoprevir, Guaiphenesin, Guaymesal, Guanfacine, Gusperimus trichloride, Influenza, Halobetazol Propionate, halophantrin, halomethasone, healon, hematoporphyrin, hemearginate, hemocoagulase actus, heparin,
Herbiron, Herbiron, Hextende, Higenamine hydrochloride, Histamine dihydrochloride, HPPH photosensitizer, Human apotransferase, Human plasminogen, Huperzin A, Sodium hyaluronate, Hydralazine hydrochloride, Hydrochlorothiazide, Hydrocodon, Hydrocodon Vitaltrate, Hydrocodonpolistilex, Hydrocortisol, Hydrochloride, Hydromorphone, Hydromorphone Hydrochloride, Hydroxocobalamine, Hydroxycarbamide, Hydrochlorokin, Hydroxyprogesterone Caproate,
Hydroxysaflor Yellow A, Hirastan, Hypericin, Hypericin, Hipestoxide, Ibandronate, Ibandronate, Iberogast N, Ivodutant, Ibulutinib, Ibutilast, Ibuprofen, Ibutilide, Ibutilide fumarate, Icaritine, Iclaprime, Icosapentate ester,
Icotinib hydrochloride, idalopyrdin, idasanutrin, idebenone, ideralisib, idoxuridine, idronoxyl, ifetroban, ifetrovan sodium, igratimodo, iransoprazole, iraprazole, iroperidone, iroprost, iroprostobetadexclaslate, imatinib Imatinib, imidaphenacin, imidazole, imidazole salicylate, imidol hydrochloride, imiglycutin dihydrochloride, imipenem, imimiquimod, imisopasemmanganese, imatinib, incadronic acid, incobotulinum toxin, indapamide, indapamideolmaleate, indapamide. Inderoxazine, indimitecan, indinavir, indicetron, indapamide, indalamine, indotecan, indapamide, inecalcitol, infigratinib, ingabilin, ingenolmebutate, inhaled sodium nitrite, carboxymartose ferric iron, inosin, intepil Din, iodiconazole,
Ipataseltib dihydrochloride, ipragliflozin, ipratropium, ipratropium bromide, iptacarim, ilvesartane, irinotecan, irinotecan hydrochloride, irinotecan scrosophate, irofluben, iron isomaltoside 1000, iron protein succinate, irosstat, ylsogradin maleate Nazonium chloride / sulfate, isodibut, isoflurane, isoniazide, isopropylunoproston, isosorbidodinitrate, isosorbidemononitrate, isosteviol, isothifludin, isotretinoin, isradipine, istaloxime, istradefylin, itraconazole, itraconazole, itraconazole hydrochloride. , Ivabrazine hemisulfate, Ivabrazine hydrochloride, Ibakaftor, Ibermectin, Ivosidenib, Afribercept, Ixavepyrone, Ixazomibcitrate, Caliclein, Kangbeide, Ketamine, Ketanserin, Ketoconazole, Ketoprofen , Ketotiphen, Kebetarin, Cucoamine B Mecillate, L-4-chloroquinurenin, Lasidipine, Lacosamide, Lactitol, Ladarixin, Ladostigil, Laflunimus, Laftidine, Lamibudin, Lamotrigin, Landiolol, Landiolol Hydrochloride, Laninamivir Octaate Lanoconazole, lansoprazole, lanthanum carbonate, lapatinib, lakinimod, laromustin, rasmiditane, lasofoxyphene, ratanoprost, ratanoprostem chloride, lauflumide, regipasvir, refamulin, leflunomide, lenbolexant, renbolexant, lenalid Fate, lentinanviral, lembatinib mesylate,
Lercanidipine, Resinurad, Leteprinim, Letermovir, Letrozole, Leucine,
Leuprorelin Acetate, Levetiracetam, Levetiracetamate, Revavterol Hydrochloride, Revamisol, Revam Logipin, Revam Logipin Vecilate, Revam Logipin Maleate, Levetiracetam, Levobupivacaine, Levetiracetam, Levobupivacaine Hydrochloride, Levocarnitine,
Levocetirizine dihydrochloride, levodopa, levodoxazosin mesylate, levofloxacin,
Levoquetoconazole, Levomilnasiplan, Levonadifloxacin arginine salt, Levonorgestrel, Levonorgestrel butanoate, Levo-fensinone hydrochloride, Levornidazole, Levorfanol, Levosimendan, Levothyroxine sodium, Levotus ], L-glutamine, lidocaine, refiteglast, ligstradine hydrochloride, limaprost, linagliptin, linezolide, liotyronine, liothyronine sodium, lipobean, liposome curcumin, lipotaycoic acid, liranaphthate, lisdexanthhetamine, lysinopril, lysophylline Maleate, Lithium Citrate, Lithium Succinate, Rixibaptane, Robaplatin, Lobeglycazone, Lodenafil Carbonate, Lofexidine, Lomefloxacin, Lomerizine, Lomeridine Dihydrochloride, Lomitapide, Lonafarnib, Lonidamine, Loperamide, Loperamide Oxide, Lopinavir, Loperamide, Loperamide [Lorediplon], lorlatinib, L-ornithin-L-aspartate, lornoxicum, rosaltan, rosaltan potassium, losmapimod, rotepredonol etabonate, lovasstatin, loxapine, loxoprofen, L-prazicantel, rubiproston, lucellastat [lucerastat]
], Lucinactant, Lucitanib hydrochloride, Luriconazole, Lumacaftor, Lumateperone hydrochloride sulfonate, Lumephantrin, Lumiracoxib, Lunacalcipole, Lulacidone, Lulubinectedin, Luceogliflozin hydrate, Lustronbopag, Lysine lysine , Macimorelin, Macitentan, Maphenide, Magnesium Carbonate, Magnesium Isoglycyrrhizinate, Mangahodipil, Manidipine, Manidipine Dihydrochloride, Mannitol, Malabilok, Maribabir, Marizomib,
Masilcast, macitinib, maboglulanto, maxacalcitol, mebendazole, mebiphon, mechamilamine, mechamilamine hydrochloride, mechloretamine, mecobalamine, medroxyprogesterone, medroxyprogesterone acetate, meflokin, megestrol, megestrol acetate, mace oscillus meisuoshuli], melebodopa, meroxycam, melphalan, melphalanflufenamide hydrochloride, memantine, memantine hydrochloride, menadion sodium sulfite, menatetrenone, mepaclin, mequinol, mercaptamine, mercaptamine bitartrate, mercaptamine hydrochloride, mercaptopurine, merestinib , Melopenem, merotocin, mesalamine, mesalazine, metacavir, metadoxine, metamizole sodium, metaxalone, metergoline, metformin, metformin hydrochloride, mesadon, metazolamide, methotrexate, methoxyflurane, aminolevulinate methyl hydrochloride, methylnaltrexone bromide, Methylnaltrexone, Methylphenylate, Methylphenylate hydrochloride, Methylprednisolone, Methylprednisolone aceponate,

Methylthioninium chloride, methyrosine, methoclopramide, methoprolol, methoprolol succinate, methylhonate, metronidazole, methirapon, mexiretin, mibefradil, myconazole, myconazole nitrate, midazolam, midazolam hydrochloride, middrine, midstaurine Migitol, Miglutat, Mirnashiplan, Mirlinone, Mirtehocin, Minaprin, Minocycline, Minocycline Hydrochloride, Minodronic Acid, Minoxidil, Mirabeglon, Milliplatin Hydrate, Mirodenafil, Mirodenafil Hydrochloride, Mirogavarin, Mirtazapine, Misoprostol, Mitiglinide , Mitoxanthron, Mitoxanthron hydrochloride, mibotylate, misorastine, misolibin, mosetinostat hydrobromide, moclobemid, modafinyl, doxicycline, modipafant, moexipril, mofezolac, molidustat, molindon hydrochloride, momerotinib Moxifloxacin, Monepantel, Monoammonium glycyrrhizinate, Monobenzone, Monosodium α-luminol, Monoterpenperyl alcohol, Montercast, Montercast sodium, Montmorillonite, Moracidin, Morinidazole, Morphine, Morphine glucuronide, Morphinepitabastatin, Morphine sulphet, Morphine sulphetin Rate, mosupride, motrimod, moxifloxacin, moxifloxacin, moxifloxacin hydrochloride, moxifloxacin, moxonidin hydrochloride, mozabaptane, mupafostat sodium, mupyrosine, mycobactovir, mycobactovir, mycophenolate mofetyl, myristylnicotinate. , Navilon, Naviximorus, Nabmeton, N-
Acetylcysteine, nacysteline, nadifloxacin, nadolol, nadroparin calcium, naftifine hydrochloride, naftifine, nalbuphine, nalbuphine sebacate,
Naldemedine, Nalfurafine, Nalmefene, Naloxoneol, Naloxone, Naloxone hydrochloride, Naltrexone, Naltrexone hydrochloride, Nalzotan, Nandrolone decanoate, Napabucasin, Nafazoline, Naftkin, Naproxene, Naproxene sodium, Nacotinib mesylate, Naratriptan nasapaque]
, Nasalplase, nastorazepide calcium, nateglinide, navamepent, nazartinib, nebivolol, necupa
ranib], nedaplatin, nedocromil, nelarabine, nelfinavir, nerotanserin, nemonapride, nemonoxacin, neoandroguraholide, neosaxitoxin, neostigmine methylsulfate, nepaztanto, nepafenac, nepicastat, neporong [nepolong], neratinib. netarsud
il], netylmycin, netupitant, nevirapine, niacin, nicardipine, nicergoline, nicorandil, nicotiflorin, nicotine, nicotinic acid, nixamide, nifedipine, nifecalant, nifeviroc, nifurtimox, nifurzide,
Nikkomycin, nilotinib, nilutamide, nilvadipine, nimesulide, nimodipine, nimorazole, ningetinib, nintedanib, niraparib, nisoldipine,
Nitazoxanide, niticinone, nitrangepin, nitrogen monoxide, nitroglycerin, nitroglycerin, nizatidine, nokxaban, noratrexed, nomegestrol acetate, norugestromine, norepinephrine, noruetindron, noruetindron acetate, noruetindronenantate Norethisterone, norethisterone acetate, norfloxacin, norgestimate, noryvogine, norursodeoxycholic acid, oveticolic acid, octenidin, octreohydroaminoacrine succinate, octreotide, octreotide hydrochloride, oderasvir, odalasvir , Oresoxime, olmesartan, olmesartan, olmesartan cilexetil, olmesartan medoxomil, olodaterol, orodaterol hydrochloride, olopatazine, olopatadine hydrochloride, olprinone, olsalazine, ortiprazu, omacetaxin omepecusinate , Ombitasvir, omecamtive mecarvir, ω-3 carboxylic acid, omeprazole, omigapill, omoconazole, onalespib, onapriston, ondansetron, onderoplan, opicapon, opipramol, methylphenidet, orcinoside, oricinoside, olmesartan, olmesartan , Ornitine phenylacetate, ornoprostil, olmesartan, olmesartan, orthobisc, olmesartan, oseltamivir, osilodrostat, osimeltinib, osiris phleu
m pretense], ospretense, oteracil potassium, otececonazole, oxaliplatin, oxaloacetate, oxandrolone, oxazepam, oxycarbazepine, oxfendazole, sodium oxide glutathione, oxyracetam, oxybutinine, oxybutinine hydrochloride, oxycodone, oxycodone hydrochloride Salt, Oxymethazoline, Oxymethazoline Hydrochloride, Oxymorphone, Oxytocin, Ozagrel, Ozagrel Hydrochloride, Ozagrel Sodium, Ozanimod, Ozenoxacin, Paclitaxel, Palbociclib Polygourcox, Pacritinib, Palbociclib, Paliperidone, Paliperidone Palmitate,
Palmidorol, palonosetron, parovarotene, disodium pamidronate, pancrelipase, panipenem, panobinostat, pantoprazole, paracetamol, parecoxib, paricalcitol, paritaprevir, parnaparin sodium, parogrelyl,
Paroxetine, paroxetine, paroxetine hydrochloride 0.5 hydrate, paroxetine mesylate, pachiromer calcium, patupilone, pazopanib, pazfloxacin, pazopanib, pefcalcitol, peficitinib, pegated apo-filgrastim, perbiprofen Sodium, pemirolast,
Pemilolast Potassium, Pemilolast Sodium, Penciclovir, Penehicrine Hydrochloride, Pentamidine, Calcium Trisodium Pentate, Trisodium Zinc Pentate,
Pentetrazole, pentosan sodium hydrochloride, pentostatin, pentoxyphylline, peramivir, peranpanel, percrozone, peretinoin, perfrenapent, perflubron emulsion, perfluorooctylbromid, pergoride, perhexylin maleate, perihocin, perindopril, perindopril arginine, Perospyrone, pebonezstat, pexidartinib, fagobioderm [PhagoBioDerm], phenchlobenpyrrone, phenoxybenzamine hydrochloride, fentermine, fentermine hydrochloride, fenthramine mesylate, phenylbutyrate, phenylephrine, phenylephrine. Hydrochloride, phenylephrine, phosphazide, pibrentasvir, pisibanil, picrorib, picropodophylline, pidotimodo, pirocarpine, pirocarpine hydrochloride, pyrsicainide, pimacertibu hydrochloride, pimavanserin, pimechlorimus, pimobendan, pinosembrin, pinomethazone , Pipecronium, piperacilin, piperacillin sodium, piperakin, piperakin phosphate, piperidone hydrochloride, piperin, piperphentonamine, pyracetam, pyrarubicin, pyrphenidone, pyrmenol, pyromeratine , Pitabastatin Calcium, Pitrisanto, Pixantron, Prazomycin, Preconalyl, Prelixafo, Phenylephrine, Pocapavir [po]
capavir], hydromorphone, podophilox, porapresinc, pormacoxyb, polydatine, polyoxidenium, pomagourmet tadmethionyl, pomalidomide, ponatinib, ponatinib, porphymer sodium, posaconazole, posaconazole, posiphen,
Potassium hydrogen carbonate, potassium citrate, potassium clavrate, positiotinib, prasinostat, pradehovir, plaratlexate, pramipexole, pramipexole, pranlukast, pranlukast hydrate, plasterone, prasugrel, prabastatin,
Prazosin, prednisolone, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisone, pregavalin, prenpro, presatovir, pretomanid, previdersin, previdersin, previdersin, prexasertib, prexasertib, prexasertib, prexasertib, prexasertib, prexasertib , Prochlorperazine maleate, profezyme
, Progesterone, Progestogen, Progestogen dienogest, Proguanil, Promethazine, Promitil, Propafenone, Propagermanium, Propofol, Propranolol, Propranolol hydrochloride, Prostat, Proxodolol,
Pulcaropride, Plurifloxacin, Plurisol, Insoluble Prusian Blue, Pseudoephedrine, Pseudoephedrine Hydrochloride, Puerarin, Pucitinib Mecilate, Pyrazinamide, Pyridoxamine Dihydrochloride, Pyridoxine Hydrochloride, Pyrimethamine,
Pyronalysin, pyrroltinib maleate, quazepam, quetiapine fumarate, quetiapine, quinagolide hydrochloride, quinapril hydrochloride, quinidine sulfate, quinine sulfate, quinupristin, xinostat, quizartinib dihydrochloride, labeprazole,
Rabeprazole sodium, labeximod, racecadtolyl, radezolide, radtinib,
Ralfinamide, larimetinib, larinepag, raloxifene, raltegravir, raltitrexed, ramatroban, ramelteon, ramipril, ramosetron,

Lanitidin, lanitidin bismascitrate, ondansetron, rasagirin, ravidasvir hydrochloride, laxatrigine, levamipid, levastinib, levoxetin, levoxetine mesylate, resilicib sodium, recoflavone, recoflavone, recoflavone Niumbromid, refamethinib, regorafenib, relevactum, relenopride, relenopride, relenopride, remeglurant, remifentanil, remifentanil hydrochloride, remimazolam, remimazolamtosylate, remogliflozin etabonate, lepaglycinide Lysine Hydrochloride, Bushiramine, Guanabens, Magindole, Naproxone, Niticinone, Ondansetron, Phasetoperan, Retigabin,
Rostafuroxin, sodium phenylbutyrate, leciniferatoxin, reshikimod, resminostat, risveratrol, retagliptin, letapamulin, retigabin, retinoic acid, retociban, levaplazan, lebephenacin, leviparin sodium, rain, renium 186 etidronate Ribabylin, ribocyclib, ricolinostate, ridinirazole, lidostin, rifabutin, rifampicin, rifampycin, rifapentin, rifampicin, rigoseltib sodium, lyrapradib, lylpibirin, lylpybylin hydrochloride, lylzole, limantadine, lymepolydo, lymexolone hydrate Thing, lysedronate sodium, risperidone, ritonavir, riverloxaban, rivastigmin, rivipansel sodium, lysatryptane, lysaptropan benzoate, rmululation, rosiretinib, roflumirast, rokitamycin, lorapitant, romlucide, ronatarelet roneparstat], ronopterin, ropinirol, ropinirol hydrochloride, ropivakine, rosebengal sodium, rosiglitazone, rosiglitazone maleate, rosiglitazone sodium, rostafuroxin, rosvasstatin, rosvasstatin calcium, rotigotin, lobatirelin, losadustat Thromycin,
Rubitecan, Lucaparibu phosphate, rufinamide, rufloxacin, rupatadine, ruxolitinib, S- (-)-ornidazole phosphate disodium, sabalbisin,
Sakubitril, saffinamide, salbutamol, salbutamol sulfate, salicylic acid, salmeterol, salmeterol xinahoeate, salbrinal, salbisin, samarium (153Sm) lexidronum, samarium, S-amodipine nicotinate, sapacitabine, sapropterin, sapropiterin salt. Saracatinib, Salecyclin, Salogritazal, Salmeterolate Hydrochloride, Savoli
tinib], saxagliptin, scopolamine, scorpion toxin, ω-3 polyunsaturated fatty acid, secnidazole, segesterone acetate, selegiline, selegiline hydrochloride, selepressin, selegiline, selegiline, serinexol, sevelamer, selmethinib, serlan panel, serlanolone [Sepranolone], ceratrodust, cellulopitant, sertaconazole, sertaconazole nitrate, sertraline, sertraline, sertraline hydrochloride, cetipiplant, sevelamer carbonate, sevelamer hydrochloride, sevite
ronel], sevoflurane, sebuparin sodium [sevuparin sodium], sibutramine maleate, sibutramine mesylate, sildenafil, sildenafil citrate, silibinin dihydrogen succinate, silybinin dihydrogen succinate [si]
lmitasertib], silodosin, silver sulfadiazine, simeprevir, simitecan hydrochloride,
Simotinib hydrochloride, simvastatin, sinotecean, siponimod, sirolimus, citafloxacin, citagliptin, citagliptin phosphate, cibelestat, sizophyllan, smiragenin, S-modafinyl, sodium sobzoxane, sodium escorbate, sodium hydrogen carbonate, sodium ascorbate , Sodium cromoglycate, sodium ferric gluconate complex, sodium glycidazole,
Sodium guarenate, sodium hyaluronate, sodium ibandronate, sodium nitrate, sodium nitrite, oxybate sodium, sodium phenylacetate, sodium phenylbutyrate, sodium polysulfionate, sodium plasteronsulfate, sodium pyruvate, sodium taurocholate , Sodium thiosulfate, sodium zirconium cyclic silicate, sophosbuvir, sofpyrronium bromide, sorabegron, solifenasin, sorislomycin, sonidigib, sonolisib, sohocarpine, sophoridine hydrochloride, sorafenib, sorbitol, sotagriflozin, sochilimodo, sotras Taurine, sotylize, buckwheat previr, spulfloxacin, sparcentan, spebrutinib, spirapril, spironolactone, squalamine, stansoporfin, stubzin, S-tenatoprazole, stepronin, stillipentol, streptozocin, strontium malonate, strontium lanate. , Succinic acid, sucralfate, scrooxyhydroxide, sphentanyl, sphthalane zinc, sugamadex, sulbactam, sulbactam sodium, sulcardine sulfate, sulfamethoxypyrazine, sulfasalazine, sulfatinib, sulfonylurea, sulforaphane,
Sodium sulfotancinone, sulindac, throdexide, sulfamethoxazole, sultium, sumatriptan, sumatriptan succinate, snitinib, photonic acid, suplasyn, splatastotosylate, sodium suramin, verapamil hydrochloride,
Lilpivirin, stezolide, suvorexant, tacalcitol, taclin, tachlorimus, tadalafil, tafamidis, taphenokin, tafluprost, tafoxiparin sodium, taradigib, taraporphin, tarazoparib, tazobactam, talpexol, tamsulosin , Tandospiron, tanesulosin, tapentador, talafenacin, tarenflurubir, talloxotinib bromide, tacericib, tasimertheon, tasquinimod, tababorol, tavilermide, tazarotene, tazemetostat, tazobactam, tazobactam, tazobactam, tazobactam, tazobactam, tazobactam Tecotrigenin sodium sulfonate, tedisamil, tedizolid phosphate, tefinostat, tegafur, tegacerodo, teicoplanin, telaprevir, terapristone acetate, teratinib, terbibdin, telithromycin, thermisartan, telotristate tiprate, Temanogrel, Temocapril, Temoporfin, Temozoromid, Temsilolimus, Tenalisib [tenalisib]
, Tenofovir, teneriglycin, tenofovir, tenofovir arafenamide, tenofovir dipivoxil fumarate, tenofovir disoproxil aspartate, tenofovir disoproxil fumarate, tenoxycam, tenofovir, teprenone, terameprocol, terazocin, terbinafine Terbinafine, teriflunomide, tesevatinib, tesofensine, testosterone, testosterone undecanoate, tetrabenazine, tetracaine, tetracaine hydrochloride, tetrahydrocannavidiol, tetrathiomolybdate, tetrizoline, tezacaftor [tezacaftor], salidomide, ceriatib. , Theophylline, therapeutic
], Thiazid, Thienolfine Hydrochloride, Thiotepa, Trombin, Thromboredactin, Tyroxine, Thiagabin, Thianeptin, Tivoron, Ticagrelor, Ticlopidine, Tigecycline, Disodium Thildronate, Timorol, Timorol Maleate, Tinidazole, Chinzaparin sodium, thioconazole, thiopronin, thiotropium bromide, thiotropium bromide monohydrate, tipelcast, tipepidine hibenzate, tipifarnib, tipiracil hydrochloride, tipranavir, tyrapazamin, tiracemtib, chilirazado, tyrofiban, tyrofiban hydrochloride
Tivozanib, tizanidine, tobramycin, tocophersolan, tocoretinate, tofacitinib, tohogliflozin, tolucapon, trimidone, tolvaptan, tolterodin, tolterodin tartrate, tolvaptan, tonabelsat, topiramate, topyropisostat, topotecan, topotecan Tosedostat, tosfloxacin, topotecan pug, tozadenant, trabectedin, trabodenoson, tradipitant, tramadol, tramadol hydrochloride, tramethinib, trandrapril, tranexamic acid, tranilast, transcrocetinate sodium, transepithelial riboflavine, trabotinterol hydrochloride Trazodon, trehalose, tolvaptan succinate, treosulfan, treprostinyl, treprostinyl diolamin, tretinoin, triamsinolone acetonide, triapin,
Triazolam, tribendimidine, trichlormethiazide, tricilibend, triclabendazole, triclocarban, trientine hydrochloride, trifarotene,
Trifluridine, trifluridine, triheptanoin, trilostane, trimebutine 3-
Thiocarbamoyl-benzenesulfonate, trimebint silate, trimegestone,
Trimethoprim, trimetrexate, trinitrate, tripotassium disitratobismuthate, trofinetide, tropicamide, tropisetron, tropium chloride, trovafloxacin, troxipide, tulobuterol, tylerdipine hydrochloride , Ubenimex, Ubidecarenone, Ubrogepant, Udenafil, Urinastatin, Uripristal, Urexertinib, Urobetasol, Umeclidinium, Umeclidinium bromide, Upamostat
, Uprocertib, uracil, urapidil, uridine triacetate, uroacidide [ur
oacitides], ursodeoxycholic acid, ursoleic acid, bavolbactam, badadastat, valacyclovir, valacyclovir hydrochloride, valbenazine, valdecoxyb, valganciclovir, valomacyclovir stearate, valproicin, valrubicin, valsartan, valsartan trisodium 2.5 hydrate Stuff,

Vancomycin, vancomycin hydrochloride, vandetanib, vaniprevir, vanoxerin,
Vapendavir, vardenafil hydrochloride, varenicline, varith
ena], valritinib, vatiquinone, vavelta, veliparib, velipatasvir, bersetrag, vemurafenib, venetoclax, venlafaxine, venlafaxine hydrochloride, beporoxamer, verapamil, verapamil hydrochloride, verdinex
or], beregen, verisiguat, verinurad, vernacarant, vernacarant hydrochloride, beroszil, verteporfin, velvecestat, velbrin, besatrimod, vesnarinone, vibeglon, bicagrelu, bigabatrin, vilanterol, vilanterol Tate, vilaprisan, vilazodone, bildaglycin, vincristine sulfate, vincristine, vinorelbine, binposetin, bintaholide, viralim-C, bismodegib, bistucertibu, vitamin E nicotinicate, vitamin E nicotinicate, vitamin E nicotinicate, vortioxetine Xybat potassium ethanolate hydrate, vonorelbine fumarate, volapaxal, boriconazole, borinostat, vortioxetine, vortioxetine hydrobromide, bossaloxin, boxylaprevir, warfarin, xemilobifan, imitasvir, yonkenafil, yonkenafil Zafillucast, Zarcitabine, Zarepron, Zartprofen, Zamicastat [zamicastat]
, Zanamivir, zemistatin, Z-endoxyphen hydrochloride, dibotentan, didebactam, didobudin, dileutone, zinc acetate, diostatin stimalamer, dipracidone, zophenopril, zogenix, zoledronic acid D, L-lysine monohydrate, zoledronic acid di It is selected from the group consisting of sodium, zoledronic acid, zoliflodacin, zolpidem, zolpidem, zolpidem tartrate, zonisamide, zopiclone, zotepine, zucapsaicin, zuclopentixol, and zretinol acetate.

In some embodiments, traditional Chinese medicines are Abelmoschi Corolla, Abri Herba,
Abutili Semen, Acanthopanacis Cortex Acanthopanacis Senticosi Radix Et Rhizoma S
eu Caulis, Acanthopanax Extract, Achilleae Herba, Achyranthis Bidentatae Radix,
Aconiti Kusnezoffii Folium, Aconiti Kusnezoffii Radix Cocta, Aconiti Kusnezoffii
Radix, Aconiti Lateralis Radix Praeparata, Aconiti Radix Cocta, Aconiti Radix,
Acori Calami Rhizoma, Acori Tatarinowii Rhizoma, Adenophorae Radix, Aesculi Seme
n, Agkistrodon, Agrimoniae Herba, Agrimonia Cortex, Ajugae Herba, Akebiae Caulis
, Akebiae Fructus, Albiziae Cortex, Albiziae Flos, Alismatis Rhizoma, Allii Macr
ostemonis Bulbus, Allii Sativi Bulbus, Allii Tuberosi Semen, Aloe, Alpiniae Kats
umadai Semen, Alpiniae Officinarum Rhizoma, Alpiniae Oxyphyllae Fructus, Alumen
, Amomi Fructus Rotundus, Amomi Fructus, Ampelopsis Radix, Andrographis Herba, A
ndrographolides, Anemarrhenae Rhizoma, Anemones Raddeanae Rhizoma, Angelicae Dah
uricae Radix, Angelicae Pubescentis Radix, Angelicae Sinensis Radix, Anisi Stell
ati Fructus, Apocyni Veneti Folium, Aquilariae Lignum Resinatum, Arcae Concha, A
rctii Fructus, Ardisiae Crenatae Radix, Ardisiae Japonicae Herba, Arecae Pericar
pium, Arecae Semen Tostum, Arecae Semen, Arisaema Cum Bil, Arisaematis Rhizoma P
reparatum, Arisaematis Rhizoma, Aristolochiae Fructus, Aristolochiae Herba, Arme
niacae Semen Amarum, Arnebiae Radix, Artemisiae Annuae Herba, Artemisiae Argyi F
olium, Artemisiae Scopariae Herba, Asari Radix Et Rhizoma, Asiatic Moonseed Root
Extract, Asini Corii Colla, Asparagi Radix, Aspongopus, Asteris Radix Et Rhizom
a, Astragali Complanati Semen, Astragali Radix Praeparata Cum Melle, Astragali R
adix, Atractylodis Macrocephalae Rhizoma, Atractylodis Rhizoma, Aucklandiae Radi
x, Aurantii Fructus Immaturus, Aurantii Fructus, Bambusae Caulis In Taenias, Bam
busae Concretio Silicea, Baphicacanthis Cusiae Rhizoma Et Radix, Belamcandae Rhi
zoma, Belladonna Extract, Belladonna Liquid Extract, Belladonnae Herba, Benincas
ae Exocarpium, Bentoinum, Berberidis Radix, Bergeniae Rhizoma, Bergenin, Bistrot
ae Rhizoma, Bletillae Rhizoma, Bolbostemmatis Rhizoma, Bombyx Batryticatus, Born
eolum Syntheticum, Borneolum, Bovis Calculus Artifactus, Bovis Calculus Sativus
, Bovis Calculus, Breviscapine, Brossonetiae 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, Chinese
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, Cistanche Japonici Herba, Cisampelotis Herba, Cistanches Herba,
Citri Exocarpium Rubrum, Citri Fructus, Citri Grandis Exocarpium, Citri Reticula
tae Pericarpium Viride, Citrix Reticulatae Pericarpium, Citrix Reticulatae Semen,
Citri Sarcodactylis Fructus, Clematidis Armandii Caulis, Clematidis Radix Et Rhi
zoma, Clinopodii Herba, Cnidii Fructus, Codonopsis Radix, Coicis Semen, Commelin
ae Herba, Conyzae Herba, Coptidis Rhizoma, Cordyceps, Corni Fructus, Corydalis B
ungeanae Herba, Corydalis Decumbentis Rhizoma, Corydalis Rhizoma, Crataegi Foliu
m, Crataegi Fructus, Cremastrae Pseudobulbus, Pleiones Pseudobulbus, Crinis Carbo
nisatus, Croci Stigma, Crotonis Fructus, Crotonis Semen Pulveratum, Curculiginis
Rhizoma, Curcumae Longae Rhizoma, Curcumae Radix, Curcumae Rhizoma, Cuscutae Se
men, Cyathulae Radix, Cyclovirobuxine, Cynanchi Atrati Radix Et Rhizoma, Cynanch
i Paniculati Radix Et Rhizoma, Cynanchi Stauntonii Rhizoma Et Radix, Cynomorii H
erba, Cyperi Rhizoma, Dahurian Rhododendron Leaf Oil, Dalbergiae Odoriferae Lign
um, Daturae Flos, Dendrobii Caulis, Dendrobii Officinalis Caulis, Descurainiae S
emenlepidii Semen, Desmodii Styracifolii Herba, Dianthi Herba, Dichroae Radix, D
ictamni Cortex, Dioscorea Panthaicae Rhizoma, Dioscoreae Hypoglaucae Rhizoma, Di
oscoreae Nipponicae Rhizoma, Dioscoreae Rhizoma, Dioscoreae Spongiosae Rhizoma,
Dipsaci Radix, Draconis Sanguis, Drynariae Rhizoma, Dryopteridis Crassirhizomati
s Rhizoma Carbonisatum, Dryopteridis Crassirhizomatis Rhizoma, Echinopsis Radix
, Ecliptae Herba, Entadae Semen, Entianae Rhodanthae Herba, Ephedrae Herba, Ephe
drae Radix Et Rhizoma, Epimedii Folium, Epimedii Wushanensis Folium, Equiseti Hi
emalis Herba, Erigerontis Herba, Eriobotryae Folium, Eriocauli Flos, Erodii Herb
a Geranii Herba, Erycibes Caulis, Eucalyptus Oil, Eucommiae Cortex, Eucommiae Fo
lium, Euodiae Fructus, Eupatii Herba, Eupatii Lindleyani Herba, Euphorbiae E
bracteolatae Radix, Euphorbiae Hirtae Herba, Euphorbiae Humifusae Herba, Euphorb
iae Pekinensis Radix, Euphorbiae Semen Pulveratum, Euphorbiae Semen, Eupolyphaga
Steleophaga, Euryales Semen, Fagopyri Dibotryis Rhizoma, Farfarae Flos, Ferulae
Resina, Fibraureae Caulis, Fibriuretinin, Fluoritum, Foeniculi Fructus, Forsyth
iae Fructus, Fraxini Cortex, Fritillariae Cirrhosae Bulbus, Fritillariae Hupehen
sis Bulbus, Fritillariae Pallidiflorae Bulbus, Fritillariae Thunbergii Bulbus, F
ritillariae Ussuriensis Bulbus, Galangae Fructus, Galla Chinensis, Galli Gigerii
Endothelium Corneum, Ganoderma, Capillary Wormwood Extract, Gardeniae Fructus Pr
aeparatus, Gardeniae Fructus, Gastrodiae Rhizoma, Gecko, Gei Herba, Gendarussae
Herba, Genkwa Flos, Gentianae Macrophyllae Radix, Gentianae Radix Et Rhizoma, Gi
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, Hippocampae Fructus, Hirudo
, Homalomenae Rhizoma, Hordei Fructus Germinatus, Houttuyniae Herba, Hydrargyri
Oxydum Rubrum, Hyoscyami Semen,

Hyperici Perforati Herba, Ilicis Chinensis Folium, Ilicis Cornutae Folium, Ilici
s Rotundae Cortex, Ulichii 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, Mereticis 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, Occimum 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, Phenylidis Semen, Phenylodendri 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, Princepiae 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, Spalga
nii Rhizoma, Spatholobi Caulis, Spiceleaf Kernel Oil, Spirodelae Herba, Stachyur
i Medulla Helwingiae Medulla, Staractitum, Star Anise Oil, Stauntoniae Caulis Et
Folium, Stellariae Radix, Stemonae Radix, Stephaniae Tetrandrae Radix, Sterculi
ae Lychnophorae Semen, Strychni Semen Pulveratum, Strychni Semen, Styrax, Suis F
ellis Pulvis, Sulfur, Swertiae Herba, Swertiae Mileensis Herba, Syngnathus, Syri
ngae Cortex, Talci Pulvis, Talcum, Tamaricis Cacumen, Tanshinones, Taraxaci Herb
a, Taxilli Herba, Tea-Seed Oil, Terminaliae Belliricae Fructus, Testudinis Carap
acis Et Plastri Colla, Testudinis Carapax Et Plastrum, Tetrapanacis Medulla, Thl
aspi Herba, Thunberg Fritillary Liquid Extract, Tinosporae Radix, 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
Selected from the group consisting of a, Ziziphi Spinosae Semen.

In some embodiments, the drug content further comprises a vehicle. The medium can be combined with the API, i.e. 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 made of a thermoplastic material disclosed herein.

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

The drug content can have any shape and size suitable for packing in the compartment.

In some embodiments, the drug content is operably linked to the compartment by covalent, non-covalent interactions or via a linker. Thus, the drug content and substrate can be made separately and can be bound by covalent or non-covalent interactions. In some embodiments, the dosage form is made by producing the drug content and substrate in a single step using a 3D printing method.

In some embodiments, the drug content is formed in the form of compressed tablets, oval tablets, pills, or capsules. 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, as it occupies the compartment.

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

The size of the nanoparticles ranges from 1 nm to 900 nm (preferably a size of 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,
4nm, 5nm, 6nm, 7nm, 8nm, 9nm, 10nm, 11nm, 12nm, 1
3nm, 14nm, 15nm, 16nm, 17nm, 18nm, 19nm, 20nm, 1
00nm, 200nm, 300nm, 400nm, 500nm, 600nm, 700nm
, 800 nm, 900 nm). The size of the nanoparticles can be controlled by choosing the appropriate synthesis method and / or system. In order to obtain nanoparticles within the desired size range, for example, synthetic conditions can be appropriately controlled or modified to achieve the desired solution concentration or desired cavity range (detailed review, eg Vincenzo Liveri).
, Controlled synthesis of nanoparticles
in microheterogeneous systems, Publicshed
By Springer, as seen in 2006).

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

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 forming a network structure. The framework structure of the tablet is 1-1
Made of a material that dissolves in 0 minutes, the substrate is 2-60 seconds, preferably 2, 5, 10, 1
Dissolves in 5, 20, 25, 30, 35, 40, 45, 50, 55, 60 seconds. As shown in FIG. 8B, the dosage form can release the API in seconds after administration.

The drug content can be prepared using an additive method such as Fused Deposition Modeling (FDM). In some embodiments, the drug content can be made by using a three-dimensional printer (3D printer) that is configured to extrude a mixture of API and excipient. The API can be melted prior to extrusion and mixed homogeneously with the melted substrate. Alternatively, a solid API (eg, powder) can be mixed and dispersed in the molten substrate prior to extrusion. Generally, the extrusion process involves a glass transition (Tg) of the substrate.
) And a temperature close to the melting point of the API.
At temperatures suitable for use in 3D printers, the substrate can be adhered to the 3D printing surface. The shape and size of the drug content can be controlled by programming the 3D printing process. In some embodiments, the drug content is made in the same process of substrate. In some embodiments, the drug content is made prior to the preparation of the substrate and is packed into the compartment during or after the substrate is made.

In some embodiments, when the drug content is packed into a compartment, it binds to the substrate, eg, is embedded in or secured to the substrate. In some embodiments, the drug content is separable from the substrate once packed in the compartment.

D. Release Control The dosage forms disclosed herein can provide a variety of 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 realizes zero-order release kinetics.

Appropriate release profiles can benefit several medication regimens. For example, a pulsed release profile controls absorption, resulting in a reduced peak trough ratio, targeted drug release into specific areas within the gastrointestinal tract, and absorption independent of feeding status and thus tolerance. It can be used to prevent, reduce side effects, improve patient compliance and is desirable for treating diseases such as ADHD. In another example, a release profile followed by an initial dose and a maintenance dose may be good for treating chronic conditions such as hypertension and diabetes.

Some of the mechanisms for controlling the release profile using the dosage forms disclosed herein have been described above. For example, by manipulating the exposed area of a substrate that is slowly and constantly eroded, the drug content embedded in the substrate can deliver a constant amount of drug slowly over time. In addition, the emission profile can be controlled by the size of the compartment opening and / or the geometry of the compartment.

In some embodiments, the release profile can be controlled by the design of a compartment with an aperture that is sealed or closed with a stopper. The stopper is made of a water-soluble, porous, or erosive material or a pH-sensitive material or a hydrophobic material that is subject to friction as the dosage form passes through the gastrointestinal tract. When the dosage form is administered to the subject, the plug dissolves, permeates or erodes, thus releasing the drug content from the compartment. The release profile of the drug content can be controlled by selecting an appropriate erosion / dissolution rate or permeation rate plug. Alternatively, the release profile of the drug content can be controlled by utilizing the shape and / or size of the stopper (eg, rod shape of appropriate length). The emission profile can also be controlled by the number of compartments. FIG. 9 shows an exemplary dosage form having a substrate forming a group of cylindrical compartments present on either side of the dosage form. Each compartment is packed with drug contents. Each compartment has an aperture that is closed with a rod-shaped stopper. The stoppers have different dissolution rates. Depending on the size, shape and dissolution rate of the plug, the API persistence,
Continuous, simultaneous, sequential or pulsed emission can be performed.

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

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

In some embodiments, the dosage form comprises a gas generating component packed in a first compartment. In some embodiments, the gas generating components are organic acids and carbonates, sulfites, hydrogen carbonates, sodium carbonate, sodium hydrogen carbonate, sodium metabisulfite,
It is selected from the group consisting of calcium carbonate and combinations thereof, and releases carbon dioxide or sulfur dioxide gas when it comes into contact with gastric juice. When the substrate dissolves, permeates or erodes in the stomach, the gas-producing components are exposed to an acidic environment, or water penetrates the compartment and induces a reaction between the acid and sodium hydrogen carbonate, thus releasing the gas. It develops and releases the drug content while foaming.

Dosage forms disclosed herein may include, at least in part, one or more drug contents in the form of timed release. Timed release is with the help of conventional materials and methods known to those of skill in the art.
This is achieved, for example, by embedding the API in a timed release substrate / substrate or applying one or more timed release coatings. By timed release, API release can be controlled such that administration of the dosage form twice or once daily is sufficient. This is especially advantageous when, for example, a sustained level of effective compound is required to deal with pain.

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

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

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

As used herein, 3D printing refers to a method of manufacturing a 3D object from a digital design in an even more layered manner. The basic 3D printing method is U.S. Pat. No. 5,204,055;
Nos. 5,260,009; Nos. 5,340,656; Nos. 5,387,380; Nos. 5,5
03,785; and 5,633,021. Another U.S. patent and application related to 3D printing is U.S. Pat. No. 5,490,962; No. 5,
518,690; 5,869,170; 6,530,958; 6,280,
771; 6,514,518; 6,471,992; 8,828,411; US Patent Application Publication No. 2002/0015728; 002/0106412; No. 2
No. 003/0143268; No. 2003/0198677; No. 2004/000536
No. 0 can be mentioned. For a detailed description of 3D printing, the patents and applications listed above can be referred to.

Various 3D printing methods have been developed for dosage form production in terms of raw materials, equipment and coagulation. These 3D printing methods include binder attachment (L Gibson et al.,
2015) Adaptive Manufacturing Technologies:
3D Printing, Rapid Prototyping, and Dir
ect Digital Manufacturing. 2 ed. Spring
er, New York; W. E. Katstra et al., (2000) Oral
dose forms fabricated by three dimensions
online printing, J. et al. Control Release 66: 1-
9; W. E. Katstra et al. (2001) Fabrication of c
open oral delivery forms by three dim
Thesis printing, Dissertation in Materi
als Science and Engineering, Massachuse
tts Institute of Technology; Lipson et al.
(2013) Fabricated: The New World of 3D p
lighting, John Wiley & Sons, Inc. G. Jon
athan, A. Karim (2016) 3D printing in pha
RMaceutics: a new tool for designing cus
Tomized drug delivery systems, Int. J. P
harm. 499: 376-394), Material Injection (G. Jones)
an, A. Karim (2016) 3D printing in pharmaceutical
ceutics: a new tool for designing custom
Ized drug delivery systems, Int. J. Phar
m. 499: 376-394), Extrusion (L Gibson et al., (201)
5) Adaptive Manufacturing Technologies: 3D
Printing, Rapid Prototyping, and Direct
Digital Manufacturing. 2 ed. Springer,
See New York), and photopolymerization (FP Melchels et al.), (
2010) A review on star stereolithography and
it application in biomedical engineerin
g. Biomaterials 31: 6121-30).

In some embodiments, the dosage forms disclosed herein are manufactured using extrusion methods. In the extrusion process, the material is driven by the robot and therefore the nozzle is extruded. Binder attachment requires a powder bed, but unlike that, the extrusion method can be printed on any substrate. A variety of 3D printing materials can be extruded, including thermoplastic materials, paste and colloidal suspensions, silicones and other semi-solids disclosed herein. One common type of extrusion printing is Fused Deposition Modeling, which uses solid polymer filaments for printing. In Fused Deposition Modeling, a gearing device pushes the filament into a heated nozzle assembly for extrusion (L Gibson et al., (2015) Adaptive Manfac.
Turing Technologies: 3D Printing, Rapid
Prototyping, and Direct Digital Manufact
uring. 2 ed. See Springer, New York).

Manufacturing instructions for print jobs can be generated in a variety of ways, including direct coding specific to 3D printing machine computer interfaces and application software, derivation from solid CAD models, or other means. These instructions include information about the number and spatial arrangement of droplets, and each length dimension (X).
, Y, Z) can include information about common print parameters such as droplet spacing and volume or mass of fluid per droplet. Given a set of materials, these parameters can be adjusted to improve the quality of the resulting structure. The overall decomposition of the resulting structure is powder particle size, fluid droplet size, print parameters,
And depending on the material properties.

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

Personalized medicine is also promoted by producing dosage forms using the 3D printing method. Personalized medicine refers to the stratification of a biomarker-based patient population to assist in treatment decisions and personalized dosage form design. Modifying a digital design is easier than modifying a physical device. Also, small scale automatic 3D printing can have negligible operating costs. Therefore, 3D printing can make multiple personalized small batches economically feasible, and the designed personalizing agent form can enable improved compliance.

The personalizing agent form can adjust the amount of drug delivered based on the patient's mass and metabolism. The 3D printed dosage form ensures accurate dosing in growing children and allows for personalized administration of extremely potent drugs. In the personalizing form,
All of the patient's medications can be combined into a single daily dose, thus improving patient compliance with the medication.

FIG. 11 illustrates a method of producing an individualizing agent form using 3D printing. For each patient, various clinical trial results can be obtained, including body weight, age, metabolic indicators and genomic biomarkers. Enter clinical trial results into computer software. Combine the information with a physician's prescribing and pharmacokinetic model to design specific doses and dosage forms of the combination. Instructions are then sent to the 3D printer to produce the designed dosage form and administer it to the patient.

Control of release of multiple drugs
To optimize the combination 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 result in an immediate release of atorvastatin calcium and a long-term release of nicotinic acid. In another example, pain-relieving non-steroidal anti-inflammatory drugs (NSAIDs) ensure sustained release of NSAIDs and rapid release of H2 receptor antagonists to prevent NSAID-induced mucosal damage. Can be designed.

In some embodiments, the substrate forms multiple compartments, each packed with drug content. In some embodiments, the plurality of compartments are concatenated. In some embodiments, the plurality of compartments are not concatenated. 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. Dosage forms can be designed to achieve synergistic therapeutic effects by achieving simultaneous or sequential release of multiple drug contents.

FIG. 12A is a diagram showing an exemplary dosage form capable of simultaneously releasing the API. Figure 1
With reference to 2A, dosage form 800 contains stacked three layers 801 to 803, each of which has a different drug content embedded therein. As illustrated in FIG. 12B, when dosage form 800 is administered, the drug content is released simultaneously as the layer dissolves, but at different rates.

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

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

FIG. 15A shows an exemplary dosage form with sequential release profiles of two APIs. With reference to FIG. 15A, dosage form 1200 comprises substrate 1201 forming a compartment filled with drug content 1202. Base material 1201 contains a first API and 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 is dissolved and the drug content is exposed, resulting in a sequential release profile of the API.

FIG. 16A shows another exemplary dosage form with a sequential release profile. FIG. 16
With reference to A, dosage form 1300 has a substrate 1301 forming three cylindrical compartments 1302-1304 packed with three drug contents. The compartments 1302-1304 have apertures that are closed by rod-shaped stoppers of different lengths and / or dissolution rates. As illustrated in FIG. 16B, the API is sequentially released as the plug dissolves sequentially and opens the compartment.

FIG. 17A shows an exemplary dosage form having a simultaneous release profile or a sequential release profile. With reference to FIG. 17A, dosage form 1400 has a substrate containing four segments 1701-1704 with different dissolution rates. In some embodiments, as illustrated in FIG. 17B, the drug content is embedded in segments 1701-1704 and co-released upon dissolution of the substrate. In some embodiments, each segment comprises a compartment packed with drug contents. As illustrated in FIG. 17C, the drug content is sequentially released as the substrate dissolves.

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

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

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

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

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

The release of PEG8000 is measured using the following method. To prepare a calibration curve for PEG8000, 0.1275 g of PEG8000 standard sample was dissolved in water in a 25 mL volumetric flask. Transfer 1 mL, 2 mL, 5 mL and 10 mL to a 10 mL volumetric flask, respectively, and dilute with water to prepare a control solution. Inject 50 μl of control solution into liquid chromatography (3 Waters Ultrahydrogel ™ 120 /
250/500 connected in series, flow velocity 0.5 ml / min, temperature 40 ° C., measured by differential refractometer). The volume site was measured and used as the y-axis. The log number of the control solution concentration was used as the x-axis. A calibration curve of PEG8000 was prepared by the formula y = 1.024x + 8.918. The percentage of released PEG800 was calculated using the following equation.

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

In the formula, C _n means the measured concentration, V _t means the solution volume, V _s means the sample volume, and Q _{PEG 8000} means the amount of PEG 8000 in the dosage form.

Results: As illustrated in FIG. 18C, the release profile of benzoic acid was described in D.I. Broo
ke and R. J. Model profile by Washkuhn (Zero-Ord)
erDrug Delivery System: Theory and Prel
iminary Testing, J Pharm Sci. , 1977, 66:
It is consistent with 159-162) and is controlled by the interface. Therefore, according to the dosage forms disclosed herein, release control profiles can be designed.

[Example 2]
This example demonstrates the design of a dosage form that controls the release of drug content from different compartments.

Administration design: Two dosage forms were produced using Fused Deposition Modeling. The base material of the dosage form is copovidone (Kollidon® VA64) 72%, PEG1500 18% and S.
Made with 10% oluplus®. The drug content consisted of 30% moxifloxacin hydrochloride and 70% PEG1000. The outline of the dosage form is shown in FIGS. 19A and 19B. With reference to FIGS. 19A and 19B, dosage form 1600 contained substrate 1601 forming two compartments 1602 and 1603. The compartments were surrounded by walls 1604 and 1605, respectively. In the first dosage form, the two compartments were surrounded by walls 0.75 mm and 1.5 mm thick, respectively. Second
In the dosage form of, the two compartments are 0.75 mm and 2.25 mm thick, respectively.
Was surrounded by a wall.

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

The results of the release assay are shown in Figures 19C and 19D. As shown in FIG. 19C, addition of the first dosage form to buffer for 20 minutes opened the first compartment and released the drug contents in the first compartment. 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 wall surrounding the compartment.

Although the principles of the invention have been described in the context of specific embodiments, it is clearly understood that these descriptions are merely examples and are not intended to limit the scope of the invention. Should be. The contents disclosed herein are provided for illustration and explanation.
It is not intended to be comprehensive or to limit the disclosure to the exact form described. Many modified and modified forms will be obvious to those skilled in the art. Various embodiments and modifications that best describe the principles and practical applications of the disclosed embodiments described in the art described, thereby making it suitable for the particular use considered by those of ordinary skill in the art. The disclosure content was selected and explained so that it could be understood. The scope of disclosure is intended to be defined by the claims and their equivalents set forth below.

Claims (52)

The substrate that forms the compartment and
Dosage form containing the drug content packed in the compartment. The dosage form of claim 1, wherein the drug content is operably linked to a substrate. The dosage form of claim 1, wherein the drug content is separated from the substrate. The dosage form of claim 1, wherein the substrate is made from at least one thermoplastic material. 4. The thermoplastic material is selected from the group consisting of hydrophilic polymers, hydrophobic polymers, swellable polymers, non-swellable polymers, porous polymers, non-porous polymers, erosive polymers, non-erosive polymers. The dosage form described in. Thermoplastic material,
Polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer 57/30/13, polyvinylpyrrolidone-co-vinyl acetate (PVP-
VA), polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60
/ 40, polyvinylpyrrolidone (PVP), polyvinylacetate (PVAc) and polyvinylpyrrolidone (PVP) 80/20, polyethylene glycol-polyvinyl alcohol graft copolymer 25/75, kollicaat IR-polyvinyl alcohol 60
/ 40, polyvinyl alcohol (PVA or PV-OH), poly (vinyl acetate)
(PVAc), poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1: 2: 1, poly (dimethylaminoethyl methacrylate-co-methacrylic ester), poly (ethyl acrylate- co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride), poly (methylacrylate-co-methylmethacrylate-co-methacrylate) 7: 3: 1
, Poly (methacrylic acid-co-methylmethacrylate) 1: 2, poly (methacrylic acid-c)
o-ethyl acrylate) 1: 1, poly (methacrylic acid-co-methyl methacrylate)
1: 1, poly (ethylene oxide) (PEO), poly (ethylene glycol) (PEG)
, Polybranched polyester amide, hydroxypropyl methylcellulose phthalate, hypromellose phthalate, hydroxypropylmethylcellulose or hypromellose (H)
MPC), hydroxypropyl methylcellulose acetate succinate or hypromellose acetate succinate (HPMCAS), poly (lactide-co-glycolide)
(PLGA), Carbomer, Poly (Ethylene-co-Vinyl Acetate), Ethylene-Vinyl Acetate Copolymer, Polyethylene (PE), and Polycaprolactone (PCL)
), Hydroxypropyl Cellulose (HPC), Polyoxyl 40 Hardened Castor Oil, Methyl Cellulose (MC), Ethyl Cellulose (EC), Poroxamer, Hydroxypropyl Methyl Cellulosphylphthalate (HPMCP), Poroxamer, Hardened Castor Oil and Soybean Oil,
From glyceryl palmitostearate, carnauba wax, polylactic acid (PLA), polyglycolic acid (PGA), cellulose acetate butyrate (CAB), colloidal silicon dioxide, sucrose, glucose, polyvinyl acetate phthalate (PVAP), and combinations thereof The dosage form according to claim 4, which is selected from the group consisting of. The first aspect of claim 1, wherein the compartment has a shape selected from the group consisting of a pie, a cone, a pyramid, a cylinder, a cube or a rectangular parallelepiped, a triangular or polygonal prism, a tetrahedron and combinations thereof. Dosage form. The dosage form of claim 1, wherein the drug content is in the form of nanoparticles. The dosage form of claim 1, wherein the drug content is in the form of microneedles. The dosage form according to claim 1, wherein the drug content forms a network structure or a porous structure. The dosage form of claim 1, wherein the drug content comprises a pharmaceutical active ingredient (API). API is a local anesthetic, pain management drug, sleep disorder drug, antiepileptic drug and anticonvulsant drug, Alzheimer's disease therapeutic drug, analgesic drug, anti-gout drug, antihypertensive drug, anti-arrhythmic drug, diuretic drug, liver disease therapeutic drug , Pancreatic disease treatment, GI disease treatment, CNS disease treatment, antihistamine, antiallergic drug, glucocorticoid drug, hormone drug and contraceptive drug, hypoglycemic drug, anti-osteoporosis drug, antibiotic, sulfonamide, quinolone, And other synthetic antibacterial agents, anticonvulsants, antiviral agents,
The dosage form according to claim 11, which is selected from the group consisting of an anti-neoplastic drug, an immunomodulator, a veterinary drug, a cosmetic active substance, a traditional Chinese medicine drug and an extract of the traditional Chinese medicine drug. The dosage form of claim 11, wherein the drug content comprises a medium having a faster erosion / dissolution rate than the API. The dosage form of claim 11, wherein the drug content further comprises at least one excipient. The excipients are cocoa butter, polyethylene glycol (PEG), sucrose, glucose, galactose, fructose, xylose lactose, maltose, trehalose,
The dosage form according to claim 14, which is made from a water-soluble material selected from the group consisting of sorbitol, mannitol, maltodextrin, raffinose, stachyose, fructooligosaccharides, and combinations thereof. The dosage form of claim 1, wherein the compartment has an aperture that is blocked by a stopper. 16. The dosage form of claim 16, wherein the stopper is made from a material selected from the group consisting of water-soluble polymers, erosive or soluble polymers, wax-like materials, sugars, or combinations thereof. The dosage form of claim 1, further comprising a gas generating component packed in a compartment. The gas-generating component is selected from the group consisting of water-soluble carbonates, sulfites, hydrogencarbonates, sodium carbonates, sodium hydrogencarbonates, sodium metabisulfites, calcium carbonates, and combinations thereof, and gastrointestinal fluid. The dosage form according to claim 17, which releases carbon dioxide or sulfur dioxide gas when in contact with. With the substrate forming at least the first and second compartments,
A dosage form comprising a first drug content packed in a first compartment and a second drug content packed in a second compartment. 20. The first compartment and the second compartment are connected.
Dosage form described in. 2. Claim 2 in which the first compartment and the second compartment are not connected.
Dosage form according to 0. The dosage form of claim 20, wherein the first drug content is the same as the second drug content. The dosage form according to claim 20, wherein the first drug content is different from the second drug content. The first compartment has a first aperture covered with a first stopper and a second
2. The compartment of has a second aperture covered with a second stopper, claim 2.
Dosage form according to 0. 25. The dosage form of claim 25, wherein the first stopper is longer than the second stopper. 25. The first plug has a first permeation rate and the second plug has a second permeation rate.
Dosage form described in. 27. The dosage form of claim 27, wherein the first permeation rate is the same as the second permeation rate. 27. The dosage form of claim 27, wherein the first permeation rate is higher than the second permeation rate. The first plug has a first erosion / dissolution rate and the second plug has a second erosion / dissolution rate.
The dosage form according to claim 25. 30. The dosage form of claim 30, wherein the first erosion / dissolution rate is the same as the second erosion / dissolution rate. 30. The dosage form of claim 30, wherein the first erosion / dissolution rate is higher than the second erosion / dissolution rate. The first compartment is surrounded by the first wall and the second compartment is the second
20. The dosage form according to claim 20, which is surrounded by a wall of. 33. The dosage form of claim 33, wherein the first wall is thicker than the second wall. 33. The dosage form of claim 33, wherein the first wall is more permeable than the second wall. 33. The dosage form of claim 33, wherein the first wall erodes / dissolves faster than the second wall. Dosage form containing two or more stacked matrix layers
A dosage form in which at least one of two or more matrix layers is each packed with at least one drug content. 37. The dosage form of claim 37, wherein the two or more matrix layers are separable from each other. 37. The dosage form of claim 37, wherein the two or more matrix layers are made from at least one thermoplastic material. At least one thermoplastic material is selected from the group consisting of hydrophilic polymers, hydrophobic polymers, swellable polymers, non-swellable polymers, porous polymers, non-porous polymers, erosive polymers, non-erosive polymers. The dosage form according to claim 39. At least one thermoplastic material is polyvinylcaprolactam-polyvinylacetate-polyvinyl glycol graft copolymer 57/30/13, polyvinylpyrrolidone-co-vinylacetate (PVP-VA), polyvinylpyrrolidone-polyvinylacetate copolymer (PVP-VA) 60 / 40, Polyvinylpyrrolidone (PVP), Polyvinylacetate (PVAC) and Polyvinylpyrrolidone (PVP) 80/20, Polyvinyl Glycol-Polyvinyl Alcohol Graft Copolymer 25/75, kollicoa
t IR-polyvinyl alcohol 60/40, polyvinyl alcohol (PVA or PV
-OH), poly (vinyl acetate) (PVAc), poly (butyl methacrylate-co)
-(2-Dimethylaminoethyl) methacrylate-co-methylmethacrylate) 1: 2
: 1, Poly (dimethylaminoethyl methacrylate-co-methacrylic acid ester), Poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride), Poly (methyl acrylate-co-methyl methacrylate-co-methacryl) Acid) 7: 3: 1, poly (methacrylic acid-co-methylmethacrylate) 1: 2, poly (methacrylic acid-co-ethylacrylate) 1: 1, poly (methacrylic acid-co-methylmethacrylate) 1: 1, Poly (ethylene oxide) (PEO), poly (ethylene glycol) (PEG), polybranched polyesteramide, hydroxypropylmethylcellulose phthalate, hypromellose phthalate, hydroxypropylmethylcellulose or hypromellose (HMPC), hydroxypropylmethylcellulose acetate succinate or Hypromerose acetate succinate (HPMCAS),
Poly (lactide-co-glycolide) (PLGA), carbomer, poly (ethylene-co)
-Vinyl Acetate), Ethylene-Vinyl Acetate Copolymer, Polyethylene (PE)
, And polycaprolactone (PCL), hydroxylpropyl cellulose (HPC),
Polyoxyl 40 hardened castor oil, methyl cellulose (MC), ethyl cellulose (EC)
, Poroxamer, hydroxypropylmethylcellulose phthalate (HPMCP), poroxamer, hardened castor oil and soybean oil, glyceryl palmitostearate, carnauba wax, polylactic acid (PLA), polyglycolic acid (PGA), cellulose acetate butyrate (CAB), colloid The dosage form according to claim 39, which is selected from the group consisting of silicon dioxide, sucrose, glucose, polyvinyl acetate phthalate (PVAP), and combinations thereof, but is not limited to the group consisting of these. 37. The dosage form of claim 37, wherein the drug content is in the form of nanoparticles. 37. The dosage form of claim 37, wherein the drug content is in the form of microneedles. 37. The dosage form of claim 37, wherein the drug content forms a network or porous structure. The dosage form of claim 37, wherein the drug content comprises a pharmaceutical active ingredient (API). API is a local anesthetic, pain management drug, sleep disorder drug, antiepileptic drug and anticonvulsant drug, Alzheimer's disease therapeutic drug, analgesic drug, anti-gout drug, antihypertensive drug, anti-arrhythmic drug, diuretic drug, liver disease therapeutic drug , Pancreatic disease treatment, GI disease treatment, CNS disease treatment, antihistamine, antiallergic drug, glucocorticoid drug, hormone drug and contraceptive drug, hypoglycemic drug, anti-osteoporosis drug, antibiotic, sulfonamide, quinolone, And other synthetic antibacterial agents, anticonvulsants, antiviral agents,
The dosage form of claim 45, selected from the group consisting of anti-neoplastic agents, immunomodulators, veterinary agents, cosmetically active substances, traditional Chinese medicine and extracts of traditional Chinese medicine. 37. The dosage form of claim 37, wherein each matrix layer further comprises at least one excipient. The excipients are cocoa butter, polyethylene glycol (PEG), sucrose, glucose, galactose, fructose, xylose lactose, maltose, trehalose,
47. The dosage form of claim 47, made from a water-soluble material selected from the group consisting of sorbitol, mannitol, maltodextrin, raffinose, stachyose, fructooligosaccharides, and combinations thereof. 37. The dosage form of claim 37, wherein the two or more matrix layers have different thicknesses. 37. The dosage form of claim 37, wherein the two or more matrix layers have different erosion / dissolution rates. 37. The dosage form of claim 37, wherein the two or more matrix layers are configured such that at least one drug content packed therein is released in aqueous solution, respectively, based on a predetermined release profile. Two or more matrix layers are arranged outside the first matrix layer, which is packed with the first drug content and the first matrix layer, which is packed with the second drug content, and thus the second. 37. The dosage form of claim 37, wherein the drug content is comprising a second matrix layer in which the drug content is released prior to the first drug content.

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