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Home , Crofelemer, Pipamperone, Rebamipide, Teprenone, Tolimidone, Topiroxostat

US 20160354315A1 (19) United States (2) Patent Application Publication (10) Pub. No.: US 2016/0354315 A1 Li (43) Pub. Date: Dec. 8, 2016

(54) DOSAGE FORMS AND USE THEREOF Publication Classification (71) Applicant: Triastek, Inc., Nanjing (CN) (51) Int. Cl. A61 K 9/20 (2006.01) (72) Inventor: Xiaoling Li, Dublin, CA (US) A61 K 9/24 (2006.01) A61 K 31/192 (2006.01) (52) U.S. CI. (21) Appl. No.: 15/173,596 CPC ...... A61K 9/2031 (2013.01); A61K 9/2027 (2013.01); A61K 31/192 (2013.01); A61 K 9/209 (2013.01) (22) Filed: Jun. 3, 2016 (57) ABSTRACT The present disclosure provides a stable solid pharmaceuti Related U.S. Application Data cal dosage form for oral administration. The dosage form - - - ... - includes a substrate that forms at least one compartment and (60) Provisional application No. 62/170,645, filed on Jun. a drug content loaded into the compartment. The dosage 3, 2015, provisional application No. 62/313,092, filed form is so designed that the active pharmaceutical ingredient on Mar 24, 2016. of the drug content is released in a controlled manner. Patent Application Publication Dec. 8, 2016 Sheet 1 of 20 US 2016/0354315 A1

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FIG. 3 Patent Application Publication Dec. 8, 2016 Sheet 4 of 20 US 2016/0354315 A1

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FIG. 5 Patent Application Publication Dec. 8, 2016 Sheet 6 of 20 US 2016/0354315 A1

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FIG. 8B Patent Application Publication Dec. 8, 2016 Sheet 8 of 20 US 2016/0354315 A1

FIG. 9 Patent Application Publication Dec. 8, 2016 Sheet 9 of 20 US 2016/0354315 A1

FIG. 10B Patent Application Publication Dec. 8, 2016 Sheet 10 of 20 US 2016/0354315 A1

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FIG. 10D Patent Application Publication Dec. 8, 2016 Sheet 11 of 20 US 2016/0354315 A1

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FIG. 11 Patent Application Publication Dec. 8, 2016 Sheet 12 of 20 US 2016/0354315 A1

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FIG. 13B Patent Application Publication Dec. 8, 2016 Sheet 14 of 20 US 2016/0354315 A1

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FIG. 14C Patent Application Publication Dec. 8, 2016 Sheet 15 of 20 US 2016/0354315 A1

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FIG. 15B Patent Application Publication Dec. 8, 2016 Sheet 16 of 20 US 2016/0354315 A1

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FIG. 19A

FIG. 19B Patent Application Publication Dec. 8, 2016 Sheet 20 of 20 US 2016/0354315 A1

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DOSAGE FORMS AND USE THEREOF copolymer 57/30/13, -co-vinyl-acetate (PVP-VA), polyvinylpyrrolidone-polyvinyl acetate copoly CROSS-REFERENCE TO RELATED mer (PVP-VA) 60/40, polyvinylpyrrolidone (PVP), polyvi APPLICATIONS nyl acetate (PVAc) and polyvinylpyrrolidone (PVP) 80/20, polyethylene glycol-polyvinyl graft copolymer [0001] This application claims priority to U.S. Provisional 25/75, kollicoat IR-polyvinyl alcohol 60/40, polyvinyl alco Patent Applications Ser. Nos. 62/170,645, filed Jun. 3, 2015, hol (PVA or PV-OH), poly(vinyl acetate) (PVAc), poly(butyl 62/296,087, filed Feb. 17, 2016 and 62/313,092, filed Mar. methacrylate-co-(2-dimethylaminoethyl) methacrylate-co 24, 2016, the entire disclosures of which are incorporated methyl methacrylate) 1:2:1, poly(dimethylaminoethylmeth herein by reference. acrylate-co-methacrylic esters), poly(ethyl acrylate-co FIELD OF THE INVENTION methyl methacrylate-co-trimethylammonioethyl methacrylate ), poly(methyl acrylate-co-methyl [0002] The present invention generally relates to a phar methacrylate-co-methacrylic acid) 7:3:1, poly(methacrylic maceutical dosage form and controlled release of biologi acid-co-methylmethacrylate) 1:2, poly(methacylic acid-co cally active agents, diagnostic agents, reagents, cosmetic ethyl acrylate) 1:1, poly(methacylic acid-co-methyl meth agents, and agricultural/insecticide agents. acrylate) 1:1, poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG), hyperbranched polyesteramide, hydroxypro BACKGROUND pyl methylcellulose phthalate, hypromellose phthalate, [0003) Pharmaceutical drug products must be manufac hydroxypropyl methylcellulose or hypromellose (HMPC), tured into dosage forms in order to be marketed for use. hydroxypropyl methylcellulose acetate succinate or Conventional dosage forms typically involve a mixture of hypromellose acetate succinate (HPMCAS), poly(lactide active pharmaceutical ingredients and inactive components co-glycolide) (PLGA), carbomer, poly(ethylene-co-vinyl (excipients), along with other non-reusable materials such as acetate), ethylene-vinyl acetate copolymer, polyethylene a capsule shell. Categories of dosage forms include liquid (PE), and polycaprolactone (PCL), hydroxyl propyl cellu dosage forms (e.g., solutions, syrups, elixirs, suspensions lose (HPC), Polyoxyl 40 Hydrogenerated Castor Oil, Methyl and emulsions), solid dosage forms (e.g., tablets, capsules, cellulose (MC), Ethyl cellulose (EC), Poloxamer, hydroxy caplets and gel-caps), and semi-solid dosage form (e.g., propyl methylcellulose phthalate (HPMCP), Poloxamer, ointments and suppositories), among which solid dosage Hydrogenated Castor & Soybean Oil, Glyceryl Palmitoste forms are more advantages to administer drugs in systemic arate, Carnauba Wax, polylactic acid (PLA), polyglycolic effect through oral route. acid (PGA), Cellulose acetate butyrate (CAB), Colloidal [0004] Tablets are most commonly used solid dosage Silicon, Dioxide, Sucrose, Glucose, Polyvinyl Acetate forms, which shows more benefits in terms of manufactur Phthalate (PVAP) and a combination thereof. ing, packaging and shipping, and easy to identify and [0007] In certain embodiments, the compartment has a swallow. After being administered into a living organism, a shape selected from the group consisting of a pie shape, a tablet undergoes interplay with the body in exerting phar cone shape, a pyramid shape, a cylindrical shape, a cubic or maceutical effects. The active pharmaceutical ingredient cuboidal shape, a triangular or polygonal prism shape, a must be released from the tablet before being absorbed into tetrahedron and a combination thereof. the blood circulation. The pharmaceutical ingredient then [0008] In certain embodiments, the first drug content is in disperses, disintegrates or dissolves throughout the fluids a form of nanoparticles, microneedles or forms a net. and tissues of the body. During drug absorption, disposition, [0009] In certain embodiments, the drug content com metabolism, and elimination process, dosage forms play a prises an active pharmaceutical ingredient (API). In certain critical role in determining the release profile and bioavail embodiments, the API is selected from the groups consisting ability of the drugs. Therefore, there is a continuing needs of local anesthetics, antiepileptic drugs and anticonvulsants, for developing dosage forms that provides controlled drug anti-Alzheimer’s disease drugs, analgesics, antipodagric, delivery systems, which may offer desired drug plasma anti-hypertensive drugs, antiarrhythmic drugs, diuretic levels, reduced side effects as well as improved patient drugs, drugs for treating liver diseases, drugs for treating compliance. pancreatic diseases, drugs, anti-allergic drugs, glucocorticoid drugs, hormone drugs and contraceptive BRIEF SUMMARY OF THE INVENTION drugs, hypoglycemic drugs, anti-osteoporosis drugs, antibi [0005] In one aspect, the present disclosure provides a otics, sulfonamides, quinolones, and other synthetic antibac dosage form including a substrate forming at least one terial drugs, anti-tuberculosis drugs, antiviral drugs, anti compartment and a drug content loaded into the compart neoplasm drugs, immune-modulators, cosmetically active ment. In certain embodiments, the drug content is operably agents and traditional Chinese medicine. In certain embodi linked to the substrate. In certain embodiments, the drug ments, the API is a biologically active agent, a diagnostic content is detached from the substrate and freely movable in agent, a reagent for scientific research, a cosmetic agent, or the compartment. an agricultural/insecticide agent. [0006] In certain embodiments, the substrate is made from [0010] In certain embodiments, the drug content further a thermoplastic material selected from the group consisting comprises an excipient. In certain embodiments, the excipi of a hydrophilic polymer, a hydrophobic polymer, a ent is made from materials selected from the group consist swellable polymer, a non-swellable polymer, a porous poly ing of cocoa butter, polyethylene glycol (PEG), sucrose, mer, a non-porous polymer, an erodible polymer, a non glucose, galactose, fructose, xyloselactose, maltose, treha erodible polymer. In certain embodiments, the thermoplastic lose, sorbitol, mannitol, maltodextrins, raffinose, stachyose, material is selected from the group consisting of polyvinyl fructo-oligosaccharides, water-soluble oligomers and poly caprolactam-polyvinyl acetate-polyethylene glycol graft mers and a combination thereof. US 2016/0354315 A1 Dec. 8, 2016

[0011] In certain embodiments, the compartment has an [0025] FIG. 3 shows an exemplary dosage form having a aperture that is blocked and/or sealed by a plug. In certain substrate that forms a compartment with another dosage embodiments, the plug is made from a porous polymer, an form loaded into the compartment. erodible polymer, a pH sensitive polymer or natural occur [0026] FIG. 4A shows an exemplary dosage form having ring material such as shellac. In certain embodiments, the a substrate forming a compartment of pie shape. plug is made from a material selected from the group [0027] FIG. 4B shows an exemplary dosage form having consisting of water-soluble polymers, erodible or dissolv a substrate forming multiple compartments containing vari able polymers, wax like materials or saccharides or any ous sized openings. materials mentioned above. [0028] FIG. 4C shows an exemplary dosage form having [0012] In certain embodiments, the dosage form com a substrate forming an angled compartment. prises a gas-generating component loaded into the first [0029] FIG. 4D shows an exemplary dosage form having compartment. In certain embodiments, the gas-generating a substrate forming multiple compartments of different sized component is selected from the group consisting of water radius. soluble carbonates, sulphites, bicarbonates, carbon [0030] FIG. 4E shows an exemplary dosage form having ate, sodium bicarbonate, sodium metabisulphite, a substrate forming multiple compartments of different carbonate, and combinations thereof, which on contact with geometric-shape that can be used to modulate release rate of gastric fluid releases carbon dioxide or sulphur dioxide gas. the API. In certain embodiments, the gas-generating component is a [0031] FIG. 5 shows the cross section of an exemplary combination of sodium bicarbonate and organic acid (e.g., dosage form having a pie-shaped compartment. citric acid, tartaric acid etc). [0032] FIG. 6 shows an exemplary dosage form having a [0013] In another aspect, the present disclosure provides a substrate that forms layers with drug content in the form of dosage form including a substrate forming at least a first nanoparticles dispersed between the layers. compartment and a second compartment. The dosage form [0033] FIG. 7 shows an exemplary dosage form having a includes a first drug content loaded into the first compart substrate that forms a compartment with a microneedle ment and a second drug content loaded into the second shaped drug content loaded into the compartment. compartment. [0034] FIG. 8A shows an exemplary dosage form having [0014] In certain embodiments, the first compartment and a substrate forming a compartment loaded with a drug the second compartment are connected. In certain embodi content. The drug content forms a network. The substrate is ments, the first compartment and the second compartment made of a material that dissolves between 1-5 minutes, and are disconnected. the drug content dissolves in seconds. [0015] In certain embodiments, the first drug content is the [0035] FIG. 8B shows the quick release of the API from same as the second drug content. In certain embodiments, the dosage form illustrated in FIG. 8A. the first drug content is different from the second drug [0036] FIG. 9 shows an exemplary dosage form having a COntent. substrate forming a plurality of column-shaped compart [0016] In certain embodiments, the first compartment has ments. Each compartment is loaded with one drug content. a first aperture that is covered by a first plug, and the second The release of the drug content can be controlled by the compartment has a second aperture that is covered by a number and size of the compartments. second plug. In certain embodiments, the first plug is more [0037] FIG. 10A shows an exemplary dosage form having permeable than the second plug. In certain embodiments, the a substrate forming three column-shaped compartments. first plug erodes faster than the second plug. Each compartment is loaded with one drug content. Each [0017] In certain embodiments, the first compartment is drug content has a plug that blocks the aperture of each enclosed by a first wall, and the second compartment is compartment. enclosed by a second wall. [0038] FIG. 10B shows an exemplary dosage form having [0018] In certain embodiments, the first wall is thicker a multiple-layered substrate with drug content embedded than the second wall. In certain embodiments, the first wall into each layer. is more permeable than the second wall. In certain embodi [0039| FIG. 10C shows the consequential release of the ments, the first wall erodes faster than the second wall. drug content from the dosage form illustrated in FIG. 10A or 10B. BRIEF DESCRIPTION OF THE DRAWINGS [0040] FIG. 10D shows the plasma drug level of the controlled release dosage form illustrated in FIG. 10A or [0019] FIG. 1A shows a conventional dosage form com 10B when administered to a subject. prising a drug content. [0041] FIG. 11 is a schematic workflow for using of a [0020) FIG. 1B illustrates the release profile of the dosage three-dimensional printer for preparing patient specific dos form of FIG. 1A when administered to a subject. age form. [0021] FIG. 1C shows the plasma drug level when the [0042] FIG. 12A shows an exemplary dosage form having dosage form of FIG. 1A is administered to a subject. a three-layered substrate with different drug content embed [0022] FIG. 1D shows the plasma drug level of a con ded into each layer. trolled release dosage form having the zero-order drug [0043] FIG. 12B illustrates the release of three APIs from release profile when administered to a subject. the dosage form illustrated in FIG. 12A. [0023] FIG. 2A shows an exemplary dosage form having [0044] FIG. 13A shows an exemplary dosage form having a substrate that forms a compartment with a drug content a substrate forming three compartments, each of which loaded into the compartment. loaded with one drug content. The release profile of the drug [0024] FIG. 2B shows the release of the API from the content can be controlled by the dissolution rate of the drug dosage form illustrated in FIG. 2A. COntent. US 2016/0354315 A1 Dec. 8, 2016

[0045] FIG. 13B illustrates the release profile of the APIs ingredients, steps, etc. are optionally present. For example, from the dosage form illustrated in FIG. 13A. an article “comprising” (or “which comprises”) components [0046] FIG. 14A shows an exemplary dosage form having A, B, and C can consist of (i.e., contain only) components a substrate having three pie-shaped segments, with drug A, B, and C, or can contain not only components A, B, and content embedded into each segment. C but also one or more other components. [0047] FIG. 14B shows an exemplary dosage form having [0065] Where reference is made herein to a method com a substrate having three pie-shaped segments wrapped with prising two or more defined steps, the defined steps can be a shell structure. carried out in any order or simultaneously (except where the [0048] FIG. 14C shows the release profile of the APIs context excludes that possibility), and the method can from the dosage forms illustrated in FIG. 8A and FIG. 8B. include one or more other steps which are carried out before [0049] FIG. 15A shows an exemplary dosage form having any of the defined steps, between two of the defined steps, a substrate forming a compartment filled with a drug con or after all the defined steps (except where the context tent. A second API is embedded in the substrate and is excludes that possibility). released when the substrate dissolves. [0066] Where a range of value is provided, it is understood [0050] FIG. 15B shows the controlled release of the APIs that each intervening value, to the tenth of the unit of the from the dosage form illustrated in FIG. 15A. lower limit unless the context clearly dictate otherwise, [0051] FIG. 16A shows an exemplary dosage form having between the upper and lower limit of that range and any a substrate forming three column-shaped compartments. other stated or intervening value in that stated range, is Each compartment is loaded with one drug content. Each encompassed within the disclosure, subject to any specifi drug content has a plug that blocks the opening of each cally excluded limit in the stated range. Where the stated compartment. The release of the drug content in each range includes one or both of the limits, ranges excluding compartment can be controlled by the permeability, degrad either or both of those included limits are also included in ability or erodibility of the plug. the disclosure. [0052] FIG. 16B shows the release profiles of the APIs [0067] The term “at least” followed by a number is used from the dosage form illustrated in FIG. 16A. herein to denote the start of a range beginning with that [0053] FIG. 17A shows an exemplary dosage form having number (which may be a range having an upper limit or no a substrate forming four compartments. Each compartment upper limit, depending on the variable being defined). For is loaded with a drug content. example, “at least 1” means 1 or more than 1. The term “at [0054] FIG. 17B shows the release of the APIs from a most” followed by a number is used herein to denote the end dosage form having a substrate consisted of four drug of a range ending with that number (which may be a range content embedded segments. having 1 or 0 as its lower limit, or a range having no lower [0055] FIG. 17C shows the controlled release of the APIs limit, depending upon the variable being defined). For from the dosage form illustrated in FIG. 17A. example, “at most 4” means 4 or less than 4, and “at most [0056] FIG. 18A is a schematic diagram of the drug form 40%" means 40% or less than 40%. In this disclosure, when having a substrate forming a pie-shaped compartment. a range is given as “(a first number) to (a second number)” [0057] FIG. 18B is a photograph of a drug release pro or “(a first number)-(a second number),” this means a range cesses of the drug form illustrated in FIG. 18A. whose lower limit is the first number and whose upper limit [0058] FIG. 18C shows release percentage curve of ben is the second number. For example, 2 to 10 millimeters zoic acid and PEG8000 from the dosage form of FIG. 18A. means a range whose lower limit is 2 millimeters, and whose [0059 FIG. 19A shows the perspective view of a dosage upper limit is 10 millimeters. form that contains two compartments. [0068] It will be appreciated that for simplicity and clarity [0060] FIG. 19B shows the cross-sectional view of the of illustration, where appropriate, reference numerals have dosage form of FIG. 19A. been repeated among the different figures to indicate corre [0061] FIG. 19C shows an exemplary release profile of the sponding or analogous elements. In addition, numerous dosage form of FIG. 19A. specific details are set forth in order to provide a thorough [0062] FIG. 19L) shows another exemplary release profile understanding of the embodiments described herein. How of the dosage form of FIG. 19A. ever, the embodiments described herein can be practiced without these specific details. In other instances, methods, DETAILED DESCRIPTION OF THE procedures and components have not been described in INVENTION detail so as not to obscure the related relevant function being [0063] In the Summary of the Invention above and in the described. Also, the description is not to be considered as Detailed Description of the Invention, and the claims below, limiting the scope of the implementations described herein. and in the accompanying drawings, reference is made to It will be understood that descriptions and characterizations particular features (including method steps) of the invention. of the embodiments set forth in this disclosure are not to be It is to be understood that the disclosure of the invention in considered as mutually exclusive, unless otherwise noted. this specification includes all possible combinations of such particular features. For example, where a particular feature Controlled Release Dosage Form is disclosed in the context of a particular aspect or embodi [0069] Conventional solid dosage forms, e.g., compressed ment of the invention, or particular claim, that feature can tablets, are composed of a substrate where active drug also be used, to the extent possible, in combination with ingredient is dissolved or embedded (FIG. 1A). Currently and/or in the context of other particular aspects and embodi conventional solid dosage forms exhibit first-order drug ments of the invention, and in the invention generally. release profile (FIG. 1B) where the plasma level of the drug [0064] The term “comprises” and grammatical equivalents increases rapidly to an extremely high level after adminis thereof are used herein to mean that other components, tration and then decreases exponentially (see FIG. 1C). This

US 2016/0354315 A1 Dec. 8, 2016

[0079] In certain embodiments, the material of the sub exemplary dosage form having a substrate forming a com strate can be so selected to control the release profile of a partment of pie shape. FIG. 4B shows an exemplary dosage drug. For example, the substrate is made of a material having form having a substrate forming multiple compartments desired erosion/dissolution rate, permeation rate so that containing various sized openings. FIG. 4C shows an exem when administered the compartment can be opened in a plary dosage form having a substrate forming an angled predetermined manner, and the drug content is release from compartment. FIG. 4D shows an exemplary dosage form the compartment at desired rate. In certain embodiments, the having a substrate forming multiple compartments of dif substrate is erodible or dissolvable and is embedded with an ferent sized radius. active pharmaceutical ingredient (API). The API is released [0087] The shape of the compartment can be used to when the substrate is eroded or dissolved control the release profile of the dosage form. For example, [0080] The release of the drug content can also be con R. A. Lipper and W. I. Higuichi described a delivery system trolled by adjusting the thickness of the substrate. For that provides zero-order release profile, which is illustrated example, the substrate forming a compartment is made of a in FIG. 5. FIG. 5 shows a cross-sectional view of the soluble material. The opening of the compartment, thus the delivery system having a pie-shaped compartment. The release of the drug content loaded within can be controlled compartment communicates with the environment through a by adjusting the thickness of the walls that enclose the small opening. The compartment is loaded with a drug compartment. The thicker the wall, the slower the compart content that dissolves to release an API. The API is then ment is open, and the later the drug content is released. released to the environment through the small opening. The [0081] B. Compartment dissolution rate of the drug content positively correlates to [0082] In certain embodiment, the dosage form disclosed the area of the dissolution boundary of the drug content (the herein contains at least one compartment within the sub interface between the drug content and the space of the strate. As used herein, “compartment” refers to a space, part compartment). On the other hand, the diffusion rate of the or room marked or partitioned off by the substrate. A API into the environment is negatively correlates to the compartment can be closed or be open (e.g., having an diffusion path length A. As a result, as the drug content aperture or a passageway). A compartment can be of any dissolves, the area of the dissolution boundary increases, and geometry suitable for loading drug contents. In certain the dissolution rate of the drug content increases. On the embodiments, the compartment has a shape selected from other hand, the diffusion path length A increases as the drug the group consisting of a pie shape, a cone shape, a pyramid content dissolves. So the API released in the compartment shape, a cylindrical shape, a cubic or cuboidal shape, a needs to be transported a longer length to diffuse out of the triangular or polygonal prism shape, a tetrahedron and a dosage form. It is assumed that the dosage form can be so combination thereof. designed to provide a zero-order release kinetics (R. A. [0083] In certain embodiments, containing a compartment Lipper and W. I. Higuchi (1977) Analysis of theoretical in the dosage form can increase its retention in the gastro behavior of a proposed zero-order drug delivery system. J. intestinal tract. FIG. 2A illustrates an exemplary dosage Pharm Sci 66(2): 163-4; D. Brooke and R. J. Washkuhn form having a substrate forming a compartment where drug (1977) Zero-order drug delivery system: theory and prelimi content is loaded. Referring to FIG. 2A, a dosage form 100 nary testing. J Pharm Sci. 66(2):159-162). has a compartment 102 formed by a substrate 101. A drug [0088 C. Drug Content content 103 is loaded in the compartment 102 by linking to [0089] As used herein, the term “drug content” refers to a the internal wall of the compartment 102. The compartment composition comprising one or more active ingredient, 102 can provide a floating effect to the dosage form and including active pharmaceutical ingredient (API), cosmetic thereby extend its residence time in the stomach or in an agent, biological agent, diagnostic agent and reagent for aqueous or acidic environment. The residency time can be a scientific experiments. function of the erosion/dissolution rate of the materials of [0090] As used herein, an API refers to an ingredient in a the substrate and result in a sustained release of API as pharmaceutical drug that is biologically active. In certain shown in FIG. 2B. embodiments, the API is selected from the groups consisting [0084] FIG. 3 illustrates another exemplary dosage form of local anesthetics, antiepileptic drugs and anticonvulsants, with increased residence in the gastro intestinal tract. Refer anti-Alzheimer’s disease drugs, analgesics, antipodagric, ring to FIG. 3, a dosage form 200 has a configuration that the anti-hypertensive drugs, antiarrhythmic drugs, diuretic compartment 202 contains a second dosage form 203 (e.g., drugs, drugs for treating liver diseases, drugs for treating a tablet) freely moving within the compartment 202. The pancreatic diseases, antihistamine drugs, anti-allergic drugs, gastro intestinal residence time of a dosage form is limited. glucocorticoid drugs, sex hormone drugs and contraceptive Using floating systems can allow the dosage form to stay in drugs, hypoglycemic drugs, anti-osteoporosis drugs, antibi stomach and continuously release the drug at the upper part otics, sulfonamides, quinolones, and other synthetic antibac of GI tract and maximize the absorption in small intestine. terial drugs, anti-tuberculous drugs, antiviral drugs, anti [0085] In certain embodiments, the shape of the compart neoplasm drugs, immune-modulators, cosmetically active ment is uniquely created so that the drug content can be agents, traditional Chinese medicine (TCM) and TCM released at a controlled rate. In certain embodiments, the eXtracts. compartment has a shape selected from the group consisting [0091] In certain embodiments, the API is selected from of a wedge shape, a pie shape, a cone shape, a pyramid the groups consisting of (R)-folitix.orin, , 11-di shape, a cylindrical shape, a cubic or cuboidal shape, a deutero-ethyllinoleate, 16-dehydro-pregnenolone, 17-beta triangular or polygonal prism shape, a tetrahedron and a , 2-iminobiotin, 3,5-diiodothyropropionicacid, combination thereof. 5-fluoro-2-deoxycytidine, 6-mercaptopurine, edotreotide, [0086) In one embodiment, the compartment of the dosage abacavir, abalone haemocyanin, abametapir, , abe form has different geometric shape. FIG. 4A shows an maciclib, abexinostat, abiraterone, acalabrutinib, acampro US 2016/0354315 A1 Dec. 8, 2016 sate, acamprosatecalcium, acarbose, acebilustat, aceclidine, bardoxolone methyl, baricitinib, , basmisanil, aceclofenac, acehytisine hydrochloride, acemannan, ace batefenterol succinate, bazedoxifene, beclabuvir, beclometa neuramic acid, acetaminophen, acetylcysteine, acetylki some dipropionate, beclomethasone dipropionate, bedaqui tasamycin, acetyl-L-carnitinehydrochloride, acetylsalicyli line, bedoradrine, belinostat, beloranib, belotecan, bempe cacid, aciclovir, acipimox, acitazanolast, acitretin, doic acid, benapenem, benazepril, bencycloquidium aclidinium, aclidinium bromide, acolbifene, acorafloxacin, bromide, bendamustine, bendamustine hydrochloride, beni acotiamide, acrivastine, actarit, adapalene, adapalene, dipine, benserazide, bentamapimod, benzalkonium chloride, adefovirdipivoxil, ademetionine, adoair, afatinib, afimox benzhydrocodone, benznidazole, , benzoylper ifene, afuresertib, , aildenafilcitrate, aladorian, oxide, benzydamineFICL, bepotastine, bepotastine calcium alalevonadifloxacin mesylate, alarelin acetate, alatrofloxacin dihydrate, bepotastine salicylate, beractant, beraprost mesylate, albendazole, albuterol sulfate, albuterpenoids, sodium, besifloxacin, besifovir, besipirdine, beta-elemene, alcaftadine, aldoxorubicin, alectinib, alendronate, alendro betahistine, betaine anhydrous, , betametha nate sodium, alendronate sodiumhydrate, alendronic acid, some butyrate propionate, betamethasonedipropionate, alfacalcidol, alfaxalone, alfentanil, , alisertib, betamethasone valerate, betamipron, , betaxolol aliskiren, alisporivir, alitretinoin, allantoin, allisartaniso hydrochloride, bethanechol, betrixaban, bevacizumab, bexa proxil, , , alogliptin, alogliptin benzo gliflozin, bexarotene, bezafibrate, biafungin, biapenem, ate, , alpelisib, alphaketoglutarate, alphalipoic acid, bicalutamide, bicizar, bictegravir, bicyclol, bilastine, alpha-1 antitrypsin, alpha-cyclodextrin-stabilized sul bimatoprost, binimetinib, biotin, birabresibdihydrate, biska foraphane, alprazolam, alprostadil, alprostadil alfadex, alti lcitrate potassium, bismuth subgallate, bismuthyl ecabet, ratinib, altretamine, altropane, aluminum sulfate, alvimo bismorcymserine, , bisoprolol fumarate, bitespi pan, alvocidib, , amantadine hydrochloride, ramycin, bixalomer, bleomycin, , boanmycin ambrisentan, ambroxol, ambroxol hydrochloride, amcaser hydrochloride, boceprevir, bortezomib, bosentan, bosentan tib, amfetamine, amfetamine polistirex, , ami hydrate, bosutinib, bovactant, , briciclib fampridine phosphate, amifostine, amikacin, , ami sodium, brigatinib, brilacidin, brimapitide, , molevulinic, aminolevulinic acid, aminolevulinic acid brincidofovir, brinzolamide, brivanibalaninate, brivarac hydrochloride, , , amiselimod, etam, brivudine, brolucizumab, bromazepam, bromfenac, , amitifadine hydrochloride, , aml bromfenac sodium, , bronchostat, brotizolam, exanox, amlodipine, amlodipinebesilate, amlo bryostatin-1, , bucladesine, , budipine, dipine besylate, amlodipine camsylate, amlodipine maleate, , bulaquin, , buparlisib, bupivacaine, amlodipine nicotinate, amlodipine orotate, ammonium lac bupivacaine hydrochloride, , buprenorphine tate, amodiaquine, amorolfine, , amoxicillin, hydrochloride, , bupropion hydrochloride, burixa amoxicillin hydrate, , amphetamine aspartate, for, buserelin acetate, , buspirone hydrochloride, amphetamine sulfate, amphotericinb, amphotericinb cho busulfan, busulfex, butenafine, butorphanol tartrate, butyl lesterylsulfate, amphotericinb lipid complex, ampicillin phthalide, cabazitaxel, , cabotegravir, cabozan sodium, ampiroxicam, amrinone, amrubicin, amtolmet tinib S-malate, cadazolid, cadrofloxacin, , caffeine inguacil, anacetrapib, anagliptin, anagrelide, anamorelin, citrate, cafnea, cafusertib hydrochloride, calcipotriol, calcit anastrozole, ancrod, androgen, andrographolide, anecortave, riol, calcium acetate, calcium folinate, calcium levofolinate, anidulafungin, aniracetam, anistreplase, anlotinib, antazo calcium polycarbophil, calfactant, calmangafodipir, calsurf. line, antiandrogens, antineoplaston A-10, antineoplaston camicinal, camostat mesylate, camptothecin, canagliflozin, AS2-1, antofloxacin hydrochloride, antroduinonol, apabeta candesartan, candesartan cilexetil, canfosfamide, , lone, apalutamide, apatinib mesylate, apaziquone, apilimod , capecitabine, capmatinib, capsaicin, captopril, mesylate, apixaban, , apomorphine hydrochlo , carbetocin, carbidopa, carbinoxamine, car ride, apremilast, aprepitant, apricitabine, aramchol, arani bocysteine, carboplatin, cardidopa, carfilzomib, carglumi dipine, arasertaconazole, arasertaconazol enitrate, arba cacid, , carisbamate, carmustine, carotegastm clofen, , arbekacin, arbekacin sulfate, ethyl, , carteolol hydrochloride, carumonam, ardeparin sodium, , argatroban, arhalofenate, , carvedilolphosphate, caspofungin, , arimoclomol, , , cebranopadol, cediranib, cefaclor, cefadroxil, cefathia , arsenictrioxide, arsenious acid, artefenomel midine, cefazolin sodium pentahydrate, cefcapene, cefdinir, mesylate, artemether, artemotil, artenimol, arterolane cefditorenpivoxil, cefepime, cefepime dihydrochloride, maleate, artesunate, Artiss, asapiprant, , asimado cefetametpivoxil hydrochloride, cefiderocol, cefilavancin, line, astodrimer, astragaloside, asunaprevir, ataciguat, ata cefnminox, cefoperazone, cefoperazone sodium, cefoselis, luren, atazanavir, atazanavir sulfate, , , cefotaxime, cefotaxime sodium, cefotiam, cefozopran, cef , atorvastatin calcium, atorvastatin strontium, pirome, cefpodoxime, cefprozil, ceftaroline, ceftaroline fos atovaquone, atrasentan, atropine, auranofin, auriclosene, amil, ceftazidime, ceftibuten, ceftobiprole medocaril, avacincaptadpegol sodium, avacopan, avanafil, avatrom ceftolozane sulfate, ceftriaxone, ceftriaxone sodium, cefu bopag, avibactam, avibactam sodium, Avidinox, aviptadil, roxime, cefuroxime sodium, celecoxib, celgosivir, celip avitinib, avoralstat, axelopran, axitinib, azacitidine, azacy rolol, cellprotect, cenestin, cenicriviroc, censavudine, cen tidine, , azelaicacid, azelastine, azelastine hydro tanafadine, cephalosporin, ceralifimod, cerdulatinib, chloride, azeliragon, , azilsartan, azilsartan ceritinib, ceriumnitrate, cetilistat, cetirizine, , cevi medoxomil potassium, azilsartan trimethylethanolamine, meline, chenodeoxycholic acid, chlocibutamine, chlorhexi azimilide, azithromycin, azithromycin lactobionate, aztreo dine chlormadinone acetate, chlorogenicacid, chloroquine, nam, aztreonam , azvudine, , bafetinib, Baica chloroxoquinoline, chlorpheniramine, chlorpheniramine lein, baicalin, BAK-freelatanoprost, balofloxacin, balsalaz maleate, chlorpheniramine polistirex, chlortalidone, chlo ide, sodium, , barasertib, rthalidone, cholecalciferol, cholic acid, choline alfoscerate, US 2016/0354315 A1 Dec. 8, 2016

choline diepalrestat, choline , ciclesonide, doripenem, dorzolamide, dorzolamide hydrochloride, dos ciclopiroxolamine, ciclosporin, cidofovir, , cilas malfate, doxacurium chloride, , doxazosin mesy tatin, cilazapril, cilnidipine, , , cinacal late, hydrochloride, doxercalciferol, doxifluridine, cet, cinepazide maleate, cinhyaluronate sodium, doxofylline, doxorubicin, doxorubicin hydrochloride, doxy tartrate, cipargamin, ciprofibrate, ciprofloxacin, ciprofloxa cycline, doxycycline hyclate, doxylamine succinate, dron cin hydrochloride, ciraparantag, circadin, cisatracurium abinol, dronedarone, drospirenone, droxidopa, D-tagatose, besilate, cisplatin, , citalopram hydrobromide, duloxetine, duloxetine hydrochloride, dutasteride, duvelisib, citicoline, citrulline, cladribine, clarithromycin, clavulanate ebastine, eberconazole, ebselen, ecabet, econazolenitrate, potassium, clavulanic acid, clazosentan, , clevu , edaravone, edivoxetine, edonerpic maleate, dine, clindamycin, clindamycin hydrochloride, clindamycin edoxaban, efatutazone, , efinaconazole, efornith phosphate, clioquinol, clobazam, clobetasolpropionate, clo ine, efonidipin hydrochloride, egualen sodium, eicosapen betasolpropionatefoam, clodronic acid, clofarabine, clofaz taenoic acid monoglycerides, elafibranor, elagolix, imine, , clomipramine hydrochloride, clonaze elamipretide, elbasvir, eldecalcitol, eleclazine, elesclomol pam, , clonidine hydrochloride, , sodium, , eliglustattartrate, elobixibat, eltrom clopidogrel besylate, clopidogrel bisulfate, clopidogrel cam bopag, dihydrochloride, elvitegravir, emdogain, sylate, clopidogrel hydrogensulfate, clopidogrel napadisi emedastine, emeramide, emixustat, emodepside, empagli late, clopidogrel resinate, clotrimazole, , cobama flozin, emricasan, emtricitabine, enalapril, enalaprilmaleate, mide, cobicistat, cobimetinib, cobiprostone, , enasidenib, encenicline, enclomifene citrate, encorafenib, codeine polistirex, , colecalciferol, colesevelam, endoxifen, enobosarm, enoxacin gluconate, enoxaparin colestilan, colforsin daropate, colfosceril palmitate, colis sodium, emprostil, entacapone, entasobulin, entecavir, ente timethate sodium, conivaptan, copanlisib, copperhistidine, cavir maleate, entinostat, entospletinib, entrectinib, enzalu cortexolone 17alpha-propionate, cositecan, crenolanib, cri tamide, enzastaurin, epacadostat, epalrestat, eperisone, epe danimod sodium, crisaborole, crizotinib, crofelemer, traborole, sulfate, epinastine hydrochloride, crolibulin, , cromolyn sodium, cutamesine epinephrine, epirubicin, epirubicin hydrochloride, episal dihydrochloride, cyanocobalamin, cyclizine lactate, van, epitinib, eplerenone, epoprostenol, epristeride, eprodi hydrochloride, cyclophosphamide, cyclo sate, eprosartan, eptaplatin, eravacycline, erdafitinib, phosphamide monohydrate, cyclosporin, cyproterone, erdosteine, eribulin mesylate, erlotinib, ertapenem, erte cyproterone acetate, cytarabine, cytarabine ocfosfate, dab berel, ertugliflozin, erythromycin, erythromycin acistrate, igatran etexilate, dabrafenib, daclatasvir, dacomitinib, dal erythromycin stinoprate, escitalopram, , esket bavancin, dalcetrapib, dalfampridine, dalfopristin, amine hydrochloride, , esmolol dalteparin sodium, danaparoid sodium, danazol, danirixin, hydrochloride, , esomeprazole , danoprevir, dantrolene sodium, danusertib, dapaconazole, esomeprazole strontium, esomeprazole, estetrol, estradiol, dapagliflozin, dapagliflozin propanediol, , dapi estradiol acetate, estradiol cypionate, estradiol valerate, virine, dapoxetine, daprodustat, dapsone, darifenacin, dari estrodiol, estrogen, esuberaprost sodium, eszopiclone, naparsin, darunavir, dasabuvir, dasatinib, dasotraline, etamicastat, ethambutol hydrochloride, ethaselen, ethi daunorubicin, decitabine, decuprate, defactinib, deferasirox, nylestradiol, ethylhydrogenfumarate calcium, ethylhydro deferiprone, deferoxamine mesylate, deflazacort, deflexifol, genfumarate magnesium, ethylhydrogenfumara tezinc, ethy delafloxacin, delamanid, delapril, delapril hydrochloride, nylestradiol, etidronicacid, etimicin sulfate, delavirdine, denibulin, deoxyandrographolide, dermatansul etirinotecampegol, etizolam, etodolac, etonogestrel, etopo fate, desflurane, hydrochloride, desloratadine, side, etoposide phosphate, etoricoxib, etravirine, etripamil, desmopressin, desmopressin acetate, desogestrel, desonide, eupatilin, hydrochloride, everolimus, evofosf desvenlafaxine, deudextromethorphan hydrobromide, deu amide, evogliptin, exemestane, exendin(9-39), exepor?inium tepor?in, deuterated levodopa, deuteratedvenlafaxine, deu chloride, ezatiostat, ezetimibe, ezutromid, fadolmidine, , dexamethasone, dexamethasone acetate, dex fadrozole, faldaprevir, falecalcitriol, famciclovir, famitinib, amethasone cipecilate, dexamethasone palmitate, , fampridine, faropenem, fasitibant chloride, faso dexamethasone sodiumphosphate, dexamfetamine, dex racetam, fasudil, fasudil hydrochloride, fasudil mesylate, anabinol, dexferrum, dexketoprofen trometamol, dexlanso favipiravir, febarbamate, , fedovapagon, felbam prazole, , dexmethylphenidate, dex ate, felbinac trometamol, , femitra, , dexrazoxane, dexsotalol, dextroamphetamine hydrochloride, fenobam, fenofibrate, fenofibric acid, saccharate, dextroamphetamine sulfate, dextromethorphan, , , fenretinide, fentanyl, fentanyl cit dextromethorphan hydrobromide, , rate, fenticonazole, fermagate, ferriccitrate, ferricmaltol, diacerein, diamorphine hydrochloride, dianhydrogalactitol, ferumoxytol, fesoterodine fumarate, fevipiprant, fexinida diazepam, diazoxidecholine, diclofenac, diclofenac potas zole, fexofenadine, fibrinsealant, fibrinogen, fibrinogenseal sium, diclofenac sodium, diclofenamide, dicycloplatin, ant, , filanesib, filgotinib, filociclovir, didanosine, dienogest, difluprednate, digoxin, dihomog fimapor?in, fimasartan, finafloxacin, finafloxacin hydrochlo amma-linolenic acid, dihydroergocristine, dihydroergot ride, finasteride, finerenone, fingolimod, fipamezole, firte amine, mesylate, , diltiazem campegol, , fleroxacin, , flomoxef. hydrochloride, dimesna, dimethyl fumarate, dimiracetam, floxuridine, fluazolepali, fluconazole, fludarabine, fluma dinoprostone, diphenylcyclopropenone, dipraglurant, tinib, flumazenil, flunisolide, fluocinolone acetonide, fluo , diduafosoltetra sodium, dirithromycin, dis cinomide, fluorapacin, fluorouracil, , fluoxetine ufenton sodium, disulfiram, dithranol, d-methadone, docar hydrochloride, , flurbiprofen, flurbiprofenaxetil, pamine, docetaxel, dociparstat, docosanol, , dola flurbiprofen sodium, flurithromycin, fluticasone, fluticasone setron, dolutegravir, , donafenib tosylate, furoate, fluticasome propionate, flutrimazole, fluvastatin, flu donepezil, donepezil hydrochloride, , doravirine, voxamine, folic acid, folinate, foliumginkgo, fomepizole, US 2016/0354315 A1 Dec. 8, 2016 fonadelpar, fondaparinux sodium, foretinib, formestane, for ivacaftor, , ivosidenib, aflibercept, ixabepilone, moterol, fumarate, forddesine, fosamprenavir, ixazomib citrate, kallikrein, kangbeide, , ketan fosaprepitant, fosbretabulin, fosbretabulin disodium, fosflu serin, ketoconazole, ketoprofen, ketorolac, ketorolac conazole, fosfomycin, fosfomycindi sodium, fosfomycintro tromethamine, , kevetrin, kukoamine Brmesylate, metamol, fosinopril, fosinopril sodium, fosmidomycin, fos L-4-chlorokynurenine, , lacosamide, lactitol, , fospropofol, fosravuconazole, fostamatinib, ladarixin, ladostigil, laflumimus, , lamivudine, lam fostemsavir tromethamine, fotagliptin benzoate, fotemus otrigine, , landiolol hydrochloride, laninamivir time, , fruquintinib, fudosteine, fulvestrant, octanoate, lanoconazole, , lanthanum carbon , furosemide, fusidic acid, , gabapen ate, lapatinib, laquinimod, laromustine, , lasofox timenacarbil, gabexate mesylate, , gadobutrol, ifene, latanoprost, latanoprostenebunod, lauflumide, ledi gadoversetamide, gadoxetate disodium, galantamine, pasvir, lefamulin, leflunomide, lemborexant, lenalidomide, galeterone, galidesivir, gallium nitrate, galunisertib, gam lentinan, lentinansulfate, lentinanviral, lenvatinib mesylate, bogic acid, ganaxolone, ganciclovir, ganetespib, ganirelix , , leteprinim, letermovir, letrozole, acetate, garenoxacin, gatifloxacin, gatifloxacin mesylate, leucine, leuprorelin acetate, levalbuterol, levalbuterol gedatolisib, gefitinib, gemcabene, gemcitabine, gemcitabine hydrochloride, levamisole, levamlodipine, levamlodipine hydrochloride, gemfibrozil, gemifloxacin, gemigliptin, besylate, levamlodipine maleate, levetiracetam, levobupiva gemigliptintartaric acid, genistein, gentamicin, gentiopicrin, caine, levocabastine, levocabastine hydrochloride, levocar , gepotidacin, gestodene, gestrinone, mitine, levocetirizine dihydrochloride, levodopa, levodoxa maleate, gilteritinib, gimeracil, ginsenosideC-K, ginsenosi zosin mesylate, levofloxacin, levoketoconazole, deRg3, givinostat, glasdegib, glatiramer acetate, glecaprevir, levomilnacipran, levonadifloxacin arginine salt, levonorg glesatinib glycolate, , , , estrel, levonorgestrel butanoate, levo-phencynonate hydro , glufosfamide, glutamine, glutathionarsenoxide, chloride, levornidazole, levorphanol, levosimendan, levo glycerol phenylbutyrate, glycopyrronium, glycopyrronium thyroxime sodium, levotuss, L-glutamine, lidocaine, bromide, glycopyrronium tosylate, glycyrrhizi cacid, gan lifitegrast, ligustrazine hydrochloride, limaprost, linagliptin, glioside, golotimod, gosogliptin, , granisetron linezolid, liothyronine, liothyronine sodium, lipobean, lipo hydrochloride, grazoprevir, , guaimesal, guanfa somal curcumin, lipoteichoic acid, liranaftate, lisdexamfet cine, gusperimus trihydrochloride, haemophilusinfluenzae, amine, lisinopril, lisofylline, lisuridehydrogen maleate, lithi halobetasol propionate, halofantrine, halometasone, healon, umcitrate, lithiumsuccinate, lixivaptan, lobaplatin, , hemearginate, hemocoagulase acutus, lobeglitazone, lodenafil carbonate, , lomefloxacin, heparin, Herbiron, hetrombopag, hextend, higenaminehy lomerizine, lomerizine dihydrochloride, lomitapide, lona drochloride, histamine dihydrochloride, HPPHphotosensi farnib, lonidamine, , loperamideoxide, lopinavir, tizer, humanapotransferrin, humanplasminogen, huper loratadine, , , lorediplon, lorlatinib, zineA, hyaluronate sodium, hydralazine, hydrochloride, L-ornithinel-aspartate, lornoxicam, , losartan potas hydrochlorothiazide, hydrocodone, hydrocodone bitartrate, sium, losmapimod, loteprednoletabonate, lovastatin, loxap hydrocodone polistirex, hydrocortisone, hydrogenperoxide, ine, loxoprofen, L-praziquantel, lubiprostone, lucanthone, hydromorphone, hydromorphone hydrochloride, hydroxo lucerastat, lucinactant, lucitanib hydrochloride, lulicon cobalamin, hydroxycarbamide, hydroxychloroquine, azole, lumacaftor, sulfonate, lumefan hydroxyprogesterone caproate, hydroxysafilor yellowA, trine, lumiracoxib, lunacalcipol, , lurbinectedin, hylastan, hypericin, hypoestoxide, ibandronate, ibandronic luseogliflozin hydrate, lusutrombopag, lysine acetylsalicy acid, iberogastN, ibodutant, ibrutinib, ibudilast, ibuprofen, late, macimorelin, macitentan, mafenide, magnesium car , ibutilide fumarate, icaritin, iclaprim, icosabutate, bonate, magnesium isoglycyrrhizinate, mangafodipir, mani icosapent, icosapentethyl, icosapentethylester, icotinib dipine, dihydrochloride, mannitol, maraviroc, hydrochloride, , idasanutlin, idebenone, idelal maribavir, marizomib, masilukast, masitinib, mavoglurant, isib, idoxuridine, idronoxil, ifetroban, ifetrobansodium, igu maxacalcitol, mebendazole, mebiphon, mecamylamine, ratimod, ilansoprazole, , , iloprost, ilo mecamylamine hydrochloride, mechlorethamine, mecobala prostbetadexclathrate, imatinib, imatinibmesylate, min, medroxyprogesterone, medroxyprogesteroneacetate, imeglimin, imidafenacin, imidapril, salicylate, mefloquine, megestrol, megestrolacetate, meisuoshuli, imidol hydrochloride, imigliptin dihydrochloride, imi , meloxicam, melphalan, melphalanflufenamide penem, imiquimod, imisopasem manganese, impecoxib, hydrochloride, , memantine hydrochloride, incadronic acid, incobotulinumtoxin, , inda menadione sodium bisulfite, menatetrenone, mepacrine, caterol maleate, indapamide, indeloxazine, Indimitecan, meduinol, mercaptamine, mercaptamine bitartrate, mer indinavir, indisetron, indometacin, , indotecan, captamine hydrochloride, mercaptopurine, merestinib, indoximod, inecalcitol, infigratinib, Ingavirin, ingenolmebu meropenem, merotocin, mesalamine, , metacavir, tate, inhaled sodium nitrite, ferric carboxymaltose, , , metamizolesodium, metaxalone, , , iodiconazole, ipatasertib dihydrochloride, ipra metformin, metformin hydrochloride, methadone, methazo gliflozin, ipratropium, ipratropium bromide, iptakalim, irbe lamide, , methoxyflurane, methylaminolevuli sartan, irinotecan, irinotecan hydrochloride, irinotecan nate hydrochloride, methylmaltrexone bromide, methylmal sucrosofate, irofulven, iron isomaltoside1000, iron protein trexone, methylphenidate, methylphenidate hydrochloride, succinylate, irosustat, irsogladine maleate, isavuconazonium methylprednisolone, methylprednisolone aceponate, meth chloride/sulfate, isodibut, , isoniazid, isopropy ylthioninium chloride, metirosine, , meto lunoprostone, isosorbidedi nitrate, isosorbide mononitrate, prolol, succinate, metrifonate, metronidazole, isosteviol, isothiafludine, isotretinoin, , istarox metyrapone, , , , micon ime, , itacitinib, hydrochloride, itra azole nitrate, midazolam, midazolam hydrochloride, mido conazole, ivabradine hemisulfate, ivabradine hydrochloride, drine, midostaurin, mi?amurtide, mifepristone, migalastat, US 2016/0354315 A1 Dec. 8, 2016 miglitol, miglustat, milnacipran, milrinone, miltefosine, ozagrelsodium, , ozenoxacin, paclitaxel, paclitaxel minaprine, minocycline, minocycline hydrochloride, mino poliglumex, pacritinib, palbociclib, , paliperi dronic acid, , , miriplatin hydrate, done palmitate, palmidrol, palomosetron, palovarotene, mirodenafil, mirodenafil hydrochloride, , mir pamidronate disodium, pancrelipase, panipenem, panobin tazapine, , , mitomycin, mitoxan ostat, , paracetamol, parecoxib, paricalcitol, trone, mitoxantrone hydrochloride, mivotilate, mizolastine, paritaprevir, parnaparin sodium, parogrelil, parornomycin, mizoribine, mocetinostat dihydrobromide, moclobemide, paroxetine, paroxetine hydrochloride hemihydrate, parox , doxycycline, modipa?ant, moexipril, mofezolac, etine mesylate, patiromer calcium, patupilone, pazopanib, molidustat, hydrochloride, momelotinib, pazufloxacin, pazufloxacin mesylate, pefcalcitol, peficitinib, mometasone, monepantel, monoammonium glycyrrhizinate, pegylatedapo-filgrastim, pelubiprofen, pemafibrate, pem monobenzone, monosodium alphaluminol, monoterpene etrexed disodium, pemirolast, pemirolast potassium, pemi perillyl alcohol, montelukast, montelukast sodium, mont rolast sodium, penciclovir, penehyclidine hydrochloride, morillonite, moracizine, morinidazole, , morphine pentamidine, pentetate calcium trisodium, pentetatezinc tri glucuronide, morphine pitavastatin, morphine sulfate, mor sodium, pentetrazol, pentosan polysulfate sodium, pentosta phothiadine mesilate, , motolimod, moxidectin, tin, , peramivir, perampanel, perchlozone, moxifloxacin, moxifloxacin hydochloride, moxonidine, peretinoin, perflenapent, perflubronemulsion, perfluorooctyl moxonidine hydrochloride, mozavaptan, muparfostat bromide, , maleate, perifosine, perin sodium, mupirocin, mycobactovir, mycophenolatemofetil, dopril, perindopril arginine, , pevonedistat, pexi myristylnicotinate, nabilone, nabiximols, nabumetone, dartinib, PhagobioIDerm, phenchlobenpyrrone, phenethyl N-acetylcysteine, nacystelyn, nadifloxacin, , isothiocyanate, hydrochloride, phenter nadroparin calcium, naftifine hydrochloride, , nal mine, phentermine hydrochloride, mesylate, buphine, nalbuphine sebacate, maldemedine, malfurafine, phenylbutyrate, , phenylephrine hydrochlo malmefene, naloxegol, naloxone, naloxone hydrochloride, ride, phenytoin, phosphazid, pibrentasvir, picibanil, picroliv, maltrexone, maltrexone hydrochloride, , nandrolone picropodophyllin, pidotimod, pilocarpine, pilocarpine decanoate, napabucasin, , naphthoguine, hydrochloride, , pimasertib hydrochloride, pima naproxen, naproxen sodium, maquotinib mesylate, naratrip vanserin, pimecrolimus, pimobendan, pinocembrin, tan, narlaprevir, nasapaque, nasaruplase, nastorazepide cal pinometostat, pioglitazone, pioglitazone hydrochloride, cium, , navamepent, nazartinib, , necu pipamperone, pipecuronium, piperacillin, piperacillin paranib, medaplatin, nedocromil, nelarabine, nelfinavir, sodium, piperaquine, piperaquine phosphate, piperidone melotanserin, , nemonoxacin, neoandrogra hydrochloridum, piperine, piperphentonamine, piracetam, pholide, neosaxitoxin, neostigmine methylsulfate, pirarubicin, pirfenidone, pirmenol, , pirotinib, nepadutant, nepafenac, nepicastat, nepolong, neramexane, piroxicam, piroxicambetadex, pitavastatin, pitavastatin cal neratinib, meridronic acid, netarsudil, netilmicin, netupitant, cium, pitolisant, pixantrone, plazomicin, pleconaril, plerixa nevirapine, niacin, , , , nico for, plinabulin, pocapavir, hydromorphone, podofilox, pol tiflorin, nicotine, nicotinicacid, nicousamide, , aprezinc, polmacoxib, polydatin, polyoxidonium, , nifeviroc, Nifurtimox, , nikkomycin, pomaglumetad methionil, pomalidomide, ponatinib, pone nilotinib, nilutamide, , nimesulide, , simod, porfimer sodium, posaconazole, posiphen, potassium nimorazole, ningetinib, nintedanib, niraparib, , bicarbonate, potassium citrate, potassium clavulanate, pozi nitazoxanide, mitisinone, , nitricoxide, nitroglyc otinib, pracinostat, pradefovir, , pramipexole, erin, nitroglycerine, , nokxaban, nolatrexed, pramiracetam, pranlukast, pranlukast hydrate, prasterone, nomegestrol acetate, norelgestromin, , more , pravastatin, , prednimustine, predniso thindrone, norethindrone acetate, norethindrone enantate, lone, prednisoloneacetate, sodiumphosphate, norethisterone, norethisterone acetate, norfloxacin, norges , , prempro, presatovir, pretomanid, timate, , norursodeoxycholic acid, obeticholi previdersin, prexasertib, , prilocaine, pritelivir, cacid, octenidine, octohydroaminoacridine succinate, oct hydrochloride, , prochlorpera reotide, hydrochloride, odalasvir, odanacatib, zinemaleate, profezyme, , progestogen, proges odiparcil, ofioxacin, , olaparib, olesoxime, olic togendienogest, proguanil, , promitil, eridine, olmesartan, olmesartan cilexetil, olmesartan medox , propagermanium, propofol, , pro omil, olodaterol, olodaterol hydrochloride, olopatadine, olo pranolol hydrochloride, prostat, proxodolol, , patadine hydrochloride, olprinone, , oltipraz, prulifloxacin, prurisol, prussianblueinsoluble, pseudoephed omacetaxine mepesuccinate, omadacycline, omarigliptin, rine, hydrochloride, , puquitinib omaveloxolone, ombitasvir, omecamtivmecarbil, omega mesylate, , pyridoxamine dihydrochloride, 3carboxylicacids, , omigapil, omoconazole, pyridoxine hydrochloride, pyrimethamine, pyronaridine, onalespib, onapristone, , ondelopran, opica pyrroltinibmaleate, quazepam, fumarate, quetiap pone, , methylphenidate, orcinoside, orilotimod, ine, hydrochloride, quinapril hydrochloride, oritavancin, orlistat, ornithine phenylacetate, ornoprostil, sulfate, quinine sulfate, quinupristin, quisinostat, ortataxel, orteronel, orthovisc, orvepitant, oseltamivir, osi quizartinibdi hydrochloride, , rabeprazoleso lodrostat, osimertinib, Osiris Phleum pratense, ospenifene, dium, rabeximod, , radezolid, radotinib, ralfina oteracil potassium, oteseconazole, oxaliplatin, oxaloacetic mide, ralimetinib, ralinepag, raloxifene, raltegravir, ralti acid, oxandrolone, oxazepam, , oxfendazole, trexed, ramatroban, ramelteon, ramipril, , oxidizedglutathione sodium, oxiracetam, oxybutynin, oxy , ranitidine bismuth citrate, , rasagiline, butynin hydrochloride, oxycodone, oxycodone hydrochlo ravidasvir hydrochloride, raxatrigine, , rebas ride, , oxymetazoline hydrochloride, oxymor tinib, reboxetine, reboxetine mesylate, recilisib sodium, phone, oxytocin, ozagrel, ozagrel hydrochloride, recoflavone, redaporfin, ibuprofen, naproxen, glycopyrro US 2016/0354315 A1 Dec. 8, 2016 10 nium bromide, refametinib, regorafenib, relebactam, releno sodium, sulindac, Sulodexide, sulphamethoxazole, pride, relugolix, remeglurant, remifentanil, remifentanil sulthiame, , Sumatriptan succinate, Sunitinib, hydrochloride, remimazolam, remimazolam tosylate, remo sunstone, suplasyn, suplatast tosilate, sodium, Vera gliflozin etabonate, , reparixin, repirinast, aml pamil hydrochloride, rilpivirine, sutezolid, Suvorexant, exanox, hydrochloride, bucillamine, gua tacalcitol, tacrine, tacrolimus, tadalafil, tafamidis, tafeno nabenz, mazindol, naltrexone, mitisinone, ondansetron, quine, tafluprost, tafoxiparin sodium, taladegib, talapor?in, phacetoperane, , rosiglitazone, sodium phenylbu talazoparib, , taltirelin, tamibarotene, tamoxifen, tyrate, resiniferatoxin, residuimod, resminostat, resveratrol, , tamsulosin hydrochloride, , tane retagliptin, retapamulin, retigabine, retinoicacid, retosiban, spimycin, tapentadol, tarafenacin, tarenflurbil, tarloxotinib , revefenacin, reviparin sodium, rhein, rhenium bromide, taselisib, tasimelteon, tasquinimod, tavaborole, 186 etidronate, ribavirin, ribociclib, ricolinostat, ridinila tavilermide, tazarotene, tazemetostat, tazobactam, tazo zole, ridostin, rifabutin, rifampicin, rifamycin, rifapentine, bactam sodium, tebipenem pivoxil, tecarfarin, tecovirimat, , rigosertib sodium, rilapladib, rilpivirine, rilpiv tectorigenin sodiumsulfonate, , tedizolid phos irine hydrochloride, , , rimeporide, phate, tefinostat, tegafur, , teicoplanin, telaprevir, rimexolone, riociguat, ripasudil hydrochloride hydrate, rise telapristone acetate, telatinib, telbivudine, telithromycin, dronate sodium, , ritonavir, rivaroxaban, rivastig telmisartan, telotristatetiprate, temanogrel, temocapril, mine, rivipansel sodium, , rizatriptan benzoate, temopor?in, temozolomide, temsirolimus, tenalisib, tena rmulation, rociletinib, roflumilast, rokitamycin, rolapitant, panor, teneligliptin, tenofovir, tenofoviralafenamide, teno romurtide, ronacaleret, roneparstat, ronopterin, , fovirdipivoxil fumarate, tenofovir disoproxil aspartate, teno ropinirole hydrochloride, ropivacaine, rosebengal sodium, fovir disoproxil fumarate, tenoxicam, tepotinib, , rosiglitazone, rosiglitazone maleate, rosiglitazone sodium, terameprocol, , terbinafine, terbinafine hydrochlo rostafuroxin, rosuvastatin, rosuvastatin calcium, , ride, , teriflunomide, tesevatinib, tesofensine, tes rovatirelin, roxadustat, roxithromycin, rubitecan, rucaparib tosterone, testosterone undecanoate, tetrabenazine, tetra phosphate, , rufloxacin, rupatadine, ruxolitinib, caine, tetracaine hydrochloride, tetrahydrocannabidiol, S-(–)-ornidazole phosphate disodium, sabarubicin, sacu tetrathiomolybdate, , tezacaftor, thalidomide, the bitril, , , salbutamol sulfate, salicyclic liatinib, , therapeutic, , thienorphine acid, , salmeterol xinafoate, salubrinal, salvicine, hydrochloride, thiotepa, thrombin, thromboreductin, thyrox samarium(153 Sm) lexidronam, samidorphan, S-amlodipine ine, tiagabine, tianeptine, tibolone, , , nicotinate, sapacitabine, sapropterin, sapropterin dihydro tigecycline, tiludronatedi sodium, timolol, timolol maleate, chloride, saquinavir, Saracatinib, sarecycline, saroglitazar, tindamax, tinidazole, tinzaparin sodium, tioconazole, tio hydrochloride, savolitinib, saxagliptin, scopol pronin, tiotropium bromide, tiotropium bromide monohy amine, scorpionvenom, omega-3polyunsaturated fatty acid, drate, tipelukast, hibenzate, tipifarnib, tipiracil secnidazole, segesterone acetate, selegiline, selegiline hydrochloride, tipranavir, tirapazamine, tirasemtiv, tirilazad, hydrochloride, selepressin, selexipag, seliciclib, selinexor, tirofiban, tirofiban hydrochloride, tivantinib, tivozanib, tiza selisistat, selumetinib, selurampanel, sepranolone, seratro nidine, tobramycin, tocofersolan, tocoretinate, tofacitinib, dast, serlopitant, sertaconazole, sertaconazole nitrate, sertin tofogliflozin, tolcapone, , , tolterodine, dole, sertraline, sertraline hydrochloride, setipiprant, seve tolterodine tartrate, tolvaptan, tonabersat, , lamer carbonate, hydrochloride, seviteronel, topiroxostat, topotecan, topotecan hydrochloride, sevotlurane, sevuparin sodium, sibutramine maleate, torasemide, toreforant, toremifene, tosedostat, tosufloxacin, sibutramine mesylate, sildenafil, sildenafil citrate, silibinin totrombopag, tozadenant, trabectedin, trabodenoson, trad dihydrogen succinate, silmitasertib, , silver sulfa ipitant, , tramadol hydrochloride, trametinib, tran diazine, simeprevir, simmitecan hydrochloride, simotinib dolapril, tranexamic acid, tranilast, transcrocetinate-sodium, hydrochloride, simvastatin, sinotecean, siponimod, siroli transepithelial riboflavin, trantinterol hydrochloride, travo mus, sitafloxacin, sitagliptin, sitagliptinphosphate, sive prost, , trehalose, trelagliptin succinate, treosulfan, lestat, sizofiran, Smilagenin, S-modafinil, sobuzoxane, treprostinil, treprostinil diolamine, tretinoin, triamcinolone sodium aescinate, sodium ascorbate, sodium benzoate, acetonide, triapine, triazolam, tribendimidine, trichlormethi sodium bicarbonate, sodium chromoglycate, sodium ferric azide, triciribine, triclabendazole, triclocarban, trientine gluconate complex, sodium glycididazole, sodium hydrochloride, trifarotene, trifluridine, triflusal, triheptanoin, gualenate, sodium hyaluronate, sodium ibandronate, sodium trilostane, trimebutine3-thiocarbamoyl-benzenesulfonate, nitrate, sodium nitrite, sodium oxybate, sodium phenylac trimebutine tosylate, trimegestone, trimethoprim, trimetrex etate, sodium phenylbutyrate, sodium polysulthionate, ate, trinitrate, tripotassium dicitratobismuthate, trofinetide, sodium prasteronesulfate, sodium pyruvate, sodium tauro tropicamide, , trospiumchloride, trovafloxacin, cholate, sodium thiosulfate, sodium zirconiumcyclosilicate, , tucatinib, , tylerdipinehydrochloride, sofosbuvir, sofpironium bromide, , solifenacin, ubenimex, ubidecarenone, ubrogepant, udenafil, ulinastatin, solithromycin, sonidegib, sonolisib, sophocarpine, sophori ulipristal, ulixertinib, ulobetasol, umeclidinium, umecli dine hydrochloride, sorafenib, sorbitol, sotagliflozin, sotiri dinium bromide, upamostat, uprosertib, , , uri mod, Sotrastaurin, sotylize, sovaprevir, sparfloxacin, dimetriacetate, uroacitides, ursodeoxycholic acid, ursoli sparsentan, spebrutinib, spirapril, spironolactone, squala cacid, vaborbactam, Vadadustat, valaciclovir, Valaciclovir mine, stannsopor?in, stavudine, S-, stepronin, hydrochloride, , Valdecoxib, valganciclovir, stiripentol, streptozocin, strontium malonate, strontium valomaciclovir stearate, valproic acid, valrubicin, Valsartan, ranelate, succinic acid, , sucroferric oxyhydroxide, valsartan trisodium hemipentahydrate, , Vanco sufentanil, suftalanzinc, sugammadex, sulbactam, sulbactam mycin hydrochloride, vandetanib, vaniprevir, vanoxerine, sodium, sulcardine sulfate, sulfamethoxypyrazine, sulfasala vapendavir, Vardenafil hydrochloride, Varenicline, varithena, zine, sulfatinib, sulfonylurea, sulforaphane, sulfotanshinone varlitinib, Vatiquinone, vavelta, veliparib, velpatasvir, US 2016/0354315 A1 Dec. 8, 2016

, venurafenib, venetoclax, venlafaxine, Venlafax Bubali Cornu, Buddlejae Flos, Bufonis Venenum, Bungarus ine hydrochloride, vepoloxamer, , verapamil Parvus, Bupleuri Radix, Calamina, Callicarpae Caulis Et hydrochloride, verdinexor, Veregen, vericiguat, verinurad, Folium, Callicarpae Formosanae Folium, Callicarpae Mac vernakalant, vernakalant hydrochloride, verosudil, verte rophyllae Folium, Calomelas, Campsis Flos, Canarii Fruc por?in, verubecestat, verubulin, vesatolimod, Vesnarinone, tus, Canavaliae Semen, Cannabis Fructus, Capsici Fructus, , vicagrel, vigabatrin, , vilanterol trifena Carotae Fructus, Carpesii Fructus, Carthami Flos, tate, vilaprisan, , vildagliptin, Vincristine sulfate, Caryophylli Flos, Caryophylli Fructus, Cassiae Semen, Cas vinflumine, vinorelbine, vinpocetine, vintafolide, viralym-C, tor Oil, Catechu, Celosiae Cristatae Flos, Celosiae Semen, vismodegib, vistusertib, vitamin E nicotinicate, vizomitin, Centella Total Glucosides, Centellae Herba, Centipedae voglibose, volasertib, volixibat potassium ethanolate Herba, Cera Chinensis, Cera Flava, Cervi Cornu Degelati hydrate, fumarate, vorapaxar, Voriconazole, vor natum, Cervi Cornu Pantotrichum, Cervi Cornu, Cervi Cor inostat, , vortioxetine hydrobromide, vosaroxin, nus Colla, Chaenomelis Fructus, Changii Radix, Chebulae voxilaprevir, warfarin, xemilofiban, yimitasvir, yonkenafil. Fructus Immaturus, Chebulae Fructus, Chelidonii Herba, zabofloxacin, Zafirlukast, zalcitabine, zaleplon, zaltoprofen, Chinese Angelica Liquid Extract, Chloriti Lapis, Choero zamicastat, zanamivir, zemiStatin, Z-endoxifen hydrochlo spondiatis Fructus, Chrysanthemi Flos, Chrysanthemi Indici ride, zibotentan, zidebactam, zidovudine, zileuton, zincac Flos, Chuanxiong Rhizoma, Cibotii Rhizoma, Cicadae etate, zinostatin stimalamer, , zofenopril, Periostracum, Cichorii Herba,Cichorii Radix, Cimicifugae zogenix, zoledronate D.L-lysinemonohydrate, zoledronate Rhizoma, Cinnabaris, Cinnamomi Cortex, Cinnamomi disodium, zoledronic acid, zoliflodacin, , zolpi Ramulus, Cinnamon Oil, Cirsii Herba, Cirsii Japonici Herba dem, zolpidem tartrate, , zopiclone, , Carbonisata, Cirsii Japonici Herba, Cissampelotis Herba, Zucapsaicin, , and Zuretinol acetate. Cistanches Herba, Citri Exocarpium Rubrum, Citri Fructus, [0092] In certain embodiments, traditional Chinese medi Citri Grandis Exocarpium, Citri Reticulatae Pericarpium cine is selected from the group consisting of Abelmoschi Viride, Citri Reticulatae Pericarpium, Citri Reticulatae Corolla, Abri Herba, Abutili Semen, Acanthopanacis Cortex Semen, Citri Sarcodactylis Fructus, Clematidis Armandii Acanthopanacis Senticosi Radix Et Rhizoma Seu Caulis, Caulis, Clematidis Radix Et Rhizoma, Clinopodii Herba, Acanthopanax Extract, Achilleae Herba, Achyranthis Biden Cnidii Fructus, Codonopsis Radix, Coicis Semen, Commeli tatae Radix, Aconiti Kusnezoffii Folium, Aconiti Kusnezoffii nae Herba, Conyzae Herba, Coptidis Rhizoma, Cordyceps, Radix Cocta, Aconiti Kusnezoffii Radix, Aconiti Lateralis Corni Fructus, Corydalis Bungeanae Herba, Corydalis Radix Praeparata, Aconiti Radix Cocta, Aconiti Radix, Acori Decumbentis Rhizoma, Corydalis Rhizoma, Crataegi Calami Rhizoma, Acori Tatarinowii Rhizoma, Adenophorae Folium, Crataegi Fructus, Cremastrae Pseudobulbus, Pleio Radix, Aesculi Semen, Agkistrodon, Agrimoniae Herba, nes Pseudobulbus, Crinis Carbonisatus, Croci Stigma, Cro Ailanthi Cortex, Ajugae Herba, Akebiae Caulis, Akebiae tonis Fructus, Crotonis Semen Pulveratum, Curculiginis Fructus, Albiziae Cortex, Albiziae Flos, Alismatis Rhizoma, Rhizoma, Curcumae Longae Rhizoma, Curcumae Radix, Allii Macrostemonis Bulbus, Allii Sativi Bulbus, Allii Curcumae Rhizoma, Cuscutae Semen, Cyathulae Radix, Tuberosi Semen, Aloe, Alpiniae Katsumadai Semen, Cyclovirobuxine, Cynanchi Atrati Radix Et Rhizoma, Cyn Alpiniae Officinarum Rhizoma, Alpiniae Oxyphyllae Fruc anchi Paniculati Radix Et Rhizoma, Cynanchi Stauntonii tus, Alumen, Amomi Fructus Rotundus, Amomi Fructus, Rhizoma Et Radix, Cynomorii Herba, Cyperi Rhizoma, Ampelopsis Radix, Andrographis Herba, Andrographolides, Dahurian Rhododendron Leaf Oil, Dalbergiae Odoriferae Anemarrhenae Rhizoma, Anemones Raddeanae Rhizoma, Lignum, Daturae Flos, Dendrobii Caulis, Dendrobii Offici Angelicae Dahuricae Radix, Angelicae Pubescentis Radix, malis Caulis, Descurainiae Semenlepidii Semen, Desmodii Angelicae Sinensis Radix, Anisi Stellati Fructus, Apocyni Styracifolii Herba, Dianthi Herba, Dichroae Radix, Veneti Folium, Aquilariae Lignum Resinatum, Arcae Con Dictamni Cortex, Dioscorea Panthaicae Rhizoma, cha, Arctii Fructus, Ardisiae Crenatae Radix, Ardisiae Dioscoreae Hypoglaucae Rhizoma, Dioscoreae Nipponicae Japonicae Herba, Arecae Pericarpium, Arecae Semen Tos Rhizoma, Dioscoreae Rhizoma, Dioscoreae Spongiosae tum, Arecae Semen, Arisaema Cum Bil, Arisaematis Rhi Rhizoma, Dipsaci Radix, Draconis Sanguis, Drynariae Rhi zoma Preparatum, Arisaematis Rhizoma, Aristolochiae zoma, Dryopteridis Crassirhizomatis Rhizoma Carbonisa Fructus, Aristolochiae Herba, Armeniacae Semen Amarum, tum, Dryopteridis Crassirhizomatis Rhizoma, Echinopsis Arnebiae Radix, Artemisiae Annuae Herba, Artemisiae Radix, Ecliptae Herba, Entadae Semen, Entianae Rhodan Argyi Folium, Artemisiae Scopariae Herba, Asari Radix Et thae Herba, Ephedrae Herba, Ephedrae Radix Et Rhizoma, Rhizoma, Asiatic Moonseed Root Extract, Asini Corii Colla, Epimedii Folium, Epimedii Wushanensis Folium, Equiseti Asparagi Radix, Aspongopus, Asteris Radix Et Rhizoma, Hiemalis Herba, Erigerontis Herba, Eriobotryae Folium, Astragali Complanati Semen, Astragali Radix Praeparata Eriocauli Flos, Erodii Herba Geranii Herba, Erycibes Caulis, Cum Melle, Astragali Radix, Atractylodis Macrocephalae Eucalyptus Oil, Eucommiae Cortex, Eucommiae Folium, Rhizoma, Atractylodis Rhizoma, Aucklandiae Radix, Euodiae Fructus, Eupatorii Herba, Eupatorii Lindleyani Aurantii Fructus Immaturus, Aurantii Fructus, Bambusae Herba, Euphorbiae Ebracteolatae Radix, Euphorbiae Hirtae Caulis In Taenias, Bambusae Concretio Silicea, Baphica Herba, Euphorbiae Humifusae Herba, Euphorbiae Pekinen canthis Cusiae Rhizoma Et Radix, Belamcandae Rhizoma, sis Radix, Euphorbiae Semen Pulveratum, Euphorbiae Belladonna Extract, Belladonna Liquid Extract, Belladon Semen, Eupolyphaga Steleophaga, Euryales Semen, Fag nae Herba, Benincasae Exocarpium, Benzoinum, Berberidis opyri Dibotryis Rhizoma, Farfarae Flos, Ferulae Resina, Radix, Bergeniae Rhizoma, Bergenin, Bistortae Rhizoma, Fibraureae Caulis, Fibriuretinin, Fluoritum, Foeniculi Fruc Bletillae Rhizoma, Bolbostemmatis Rhizoma, Bombyx tus, Forsythiae Fructus, Fraxini Cortex, Fritillariae Cirrho Batryticatus, Borneolum Syntheticum, Borneolum, Bovis sae Bulbus, Fritillariae Hupehensis Bulbus, Fritillariae Pal Calculus Artifactus, Bovis Calculus Sativus, Bovis Calculus, lidiflorae Bulbus, Fritillariae Thunbergii Bulbus, Fritillariae Breviscapine, Broussonetiae Fructus, Bruceae Fructus, Ussuriensis Bulbus, Galangae Fructus, Galla Chinensis, US 2016/0354315 A1 Dec. 8, 2016

Galli Gigerii Endothelium Corneum, Ganoderma, Capillary Rhizoma, Peppermint Oil, Perillae Caulis, Perillae Folium, Wormwood Extract, Gardeniaefructus Praeparatus, Garde Perillae Fructus, Periplocae Cortex, Persicae Ramulus, Per niae Fructus, Gastrodiae Rhizoma, Gecko, Gei Herba, Gen sicae Semen, Peucedani Decursivi Radix, Peucedani Radix, darussae Herba, Genkwa Flos, Gentianae Macrophyllae Pharbitidis Semen, Phellodendri Amurensis Cortex, Phello Radix, Gentianae Radix Et Rhizoma, Ginger Liquid Extract, dendri Chinensis Cortex, Pheretima, Phragmitis Rhizoma, Ginkgo Folium, Ginkgo Leaves Extract, Ginkgo Semen, Phyllanthi Fructus, Physalis Calyx. Seu Fructus, Ginseng Folium, Ginseng Radix Et Rhizoma Rubra, Gin Physochlainae Radix, Phytolaccae Radix, Picrasmae Ramu seng Radix Et Rhizoma, Glabrous Sarcandra Extract, lus Et Folium, Picriae Herba, Picrorhizae Rhizoma, Pinelliae Glechomae Herba, Gleditsiae Fructus Abnormalis, Gledit Rhizoma Praeparatum Cum Alumine, Pinelliae Rhizoma siae Sinensis Fructus, Gleditsiae Spina, Glehniae Radix, Praeparatum Cum Zingibere Et Alumine, Pinelliae Rhizoma Glycyrrhizae Radix Et Rhizoma Praeparata Cum Melle, Praeparatum, Pinelliae Rhizoma, Pini Lignum Nodi, Pini Glycyrrhizae Radix Et Rhizoma, Gossampini Flos, Granati Pollen, Piperis Fructus, Piperis Kadsurae Caulis, Piperis Pericarpium, Gypsum Fibrosum, Gypsum Ustum, Haemati Longi Fructus, Plantaginis Herba, Plantaginis Semen, Platy tum, Haliotidis Concha, Halitum, Halloysitum Rubrum, cladi Cacumen, Platycladi Semen, Platycodonis Radix, Hawthorn Leave Extract, Hedysari Radix Praeparata Cum Pogostemonis Herba, Polygala Liquid Extract, Polygalae Melle, Hedysari Radix, Hibisci Mutabilis Folium, Hip Japonicae Herba, Polygalae Radix, Polygonati Odorati Rhi pocampus, Hippophae Fructus, Hirudo, Homalomenae Rhi zoma, Polygonati Rhizoma, Polygoni Avicularis Herba, zoma, Hordei Fructus Germinatus, Houttuyniae Herba, Polygoni Cuspidati Rhizoma Et Radix, Polygoni Multiflori Hydrargyri Oxydum Rubrum, Hyoscyami Semen, Hyperici Caulis, Polygoni Multiflori Radix Praeparata, Polygoni Mul Perforati Herba, Ilicis Chinensis Folium, Ilicis Cornutae tiflori Radix, Polygoni Orientalis Fructus, Polygoni Perfo Folium, Ilicis Rotundae Cortex, Ulicii Cortex, Impatientis liati Herba, Polygoni Tinctorii Folium, Polyporus, Poria, Semen, Imperatae Rhizoma, Indigo Naturalis, Inulae Flos, Poriae Cutis, Portulacae Herba, Potentillae Chinensis Herba, Inulae Herba, Inulae Radix, Iridis Tectori Rhizoma, Isatidis Potentillae Discoloris Herba, Powerdered Buffalo Horn Folium, Isatidis Radix, Juglandis Semen, Jujubae Fructus, Extract, Prinsepiae Nux, , Prunellae Spica, Pruni Junci Medulla, Kadsurae Caulis, Kaempferiae Rhizoma, Semen, Psammosilenes Radix, Pseudolaricis Cortex, Pseu Kaki Calyx, Kansui Radix, Knoxiae Radix, Kochiae Fruc dostellariae Radix, Psoraleae Fructus, Pterocephali Herba, tus, Lablab Semen Album, Laggerae Herba, Lagotidis Puerariae Lobatae Radix, Puerariae Thomsonii Radix, Pul Herba, Laminariae Thallus Eckloniae Thallus, Lamiophlo satillae Radix, Pyritum, Pyrolae Herba, Pyrrosiae Folium, mis Herba, Lasiosphaera Calvatia, Leonuri Fructus, Leonuri Quisqualis Fructus, Rabdosiae Rubescentis Herba, Ranae Herba, Leonurus Liquid Extract, Licorice Extract, Licorice Oviductus, Ranunculi Ternati Radix, Raphani Semen, Real Liquid Extract, Ligustici Rhizoma Et Radix, Ligustri Lucidi gar, Rehmanniae Radix Praeparata, Rehmanniae Radix, Fructus, Lilii Bulbus, Limonitum, Linderae Radix, Lini Rhapontici Radix, Rhei Radix Et Rhizoma, Rhodiolae Semen, Liquidambaris Fructus, Liquidambaris Resina, Liri Crenulatae Radix Et Rhizoma, Rhododendri Daurici opes Radix, Litchi Semen, Litseae Fructus, Lobeliae Chin Folium, Rhododendri Mollis Flos, Rhubarb Extract, Rhu ensis Herba, Longan Arillus, Lonicerae Flos, Lonicerae barb Liquid Extract, Ricini Semen, Rosae Chinensis Flos, Japonicae Caulis, Lonicerae Japonicae Flos, Lophatheri Rosae Laevigatae Fructus, Rosae Rugosae Flos, Rubi Fruc Herba, Luffae Fructus Retinervus, Lycii Cortex, Lycii Fruc tus, Rubiae Radix Et Rhizoma, Saigae Tataricae Cornu, tus, Lycopi Herba, Lycopodii Herba, Lygodii Spora, Lysi Salvia Total Phenolic Acids, Salviae Miltiorrhizae Radix Et machiae Herba, Lysionoti Herba, /-Borneolum, /-Menthol, Rhizoma, Sanguisorbae Radix, Santali Albi Lignum, Magnetitum, Magnoliae Flos, Magnoliae Officinalis Cortex, Saposhnikoviae Radix, Sappan Lignum, Sarcandrae Herba, Magnoliae Officinalis Flos, Mahoniae Caulis, Malvae Fruc Sargassum, Sargentodoxae Caulis, Sauropi Folium, Saururi tus, Manis Squama, Mantidis OOTheca, Margarita, Marga Herba, Saussureae Involucratae Herba, Schisandrae Chin ritifera Concha, Marsdeniae Tenacissimae Caulis, Mel, ensis Fructus, Schisandrae Sphenantherae Fructus, Schi Melanteritum, Meliae Cortex, Melo Semen, Menispermi zonepetae Herba Carbonisata, Schizonepetae Herba, Schi Rhizoma, Menthae Haplocalycis Herba, Meretricis Concha, zonepetae Spica Carbonisata, Schizonepetae Spica, Cyclinae Concha, Micae Lapis Aureus, Microctis Folium, Scolopendra, Scorpio, Scrophulariae Radix, Scutellaria Mirabilitum Praeparatum, Momordicae Semen, Mori Cor Extract, Scutellariae Barbatae Herba, Scutellariae Radix, tex, Mori Folium, Mori Fructus, Mori Ramulus, Morindae Sedi Herba, Selaginellae Herba, Semiaquilegiae Radix, Officinalis Radix, Moschus, Moslae Herba, Moutan Cortex, Senecionis Scandentis Hebra, Sennae Folium, Sepiae Endo Mume Flos, Mume Fructus, Murrayae Folium Et Cacumen, concha, Serpentis Periostracum, Sesame Oil, Sesami Semen Mylabris, Myristicae Semen, Myrrha, Nardostachyos Radix Nigrum, Setariae Fructus Germinatus, Siegesbeckiae Herba, Et Rhizoma, Natrii Sulfas Exsiccatus, Natrii Sulfas, Nelum Silybi Fructus, Sinapis Semen, Sinomenii Caulis, Sinopo binis Folium, Nelumbinis Plumula, Nelumbinis Receptacu dophylli Fructus, Siphonostegiae Herba, Siraitiae Fructus, lum, Nelumbinis Rhizomatis Nodus, Nelumbinis Semen, Smilacis Chinae Rhizoma, Smilacis Glabrae Rhizoma, Nelumbinis Stamen, Nigellae Semen, Notoginseng Radix Et Sojae Semen Germinatum, Sojae Semen Nigrum, Sojae Rhizoma, Notoginseng Total Saponins, Notoginseng Triol Semen Praeparatum, Solidaginis Herba, Sophorae Flaves Saponins, Notopterygii Rhizoma Et Radix, Ocimum Grat centis Radix, Sophorae Flos, Sophorae Fructus, Sophorae issimum Oil, Olibanum, Omphalia, Ophicalcitum, Oph Tonkinensis Radix Et Rhizoma, Sparganii Rhizoma, iopogonis Radix, Orostachyis Fimbriatae Herba, Oroxyli Spatholobi Caulis, Spiceleaf Kernel Oil, Spirodelae Herba, Semen, Oryzae Fructus Germinatus, Osmundae Rhizoma, Stachyuri Medulla Helwingiae Medulla, Stalactitum, Star Ostreae Concha, Paeoniae Radix Alba, Paeoniae Radix Anise Oil, Stauntoniae Caulis Et Folium, Stellariae Radix, Rubra, Panacis Japonici Rhizoma, Panacis Majoris Rhi Stemonae Radix, Stephaniae Tetrandrae Radix, Sterculiae zoma, Panacis Quinquefolii Radix, Papaveris Pericarpium Lychnophorae Semen, Strychni Semen Pulveratum, SI, Paridis Rhizoma, Patchouli Oil, Pegaeophyti Radix Et Strychni Semen, Styrax, Suis Fellis Pulvis, Sulfur, Swertiae US 2016/0354315 A1 Dec. 8, 2016

Herba, Swertiae Mileensis Herba, Syngnathus, Syringae [0099] The size of the nanoparticles ranges from 1 nm to Cortex, Talci Pulvis, Talcum; Tamaricis Cacumen, Tanshi 900 nm in size (preferable 100-800 nm, 100-700 nm, nones, Taraxaci Herba, Taxilli Herba, Tea-Seed Oil, Termi 100-600 nm, 100-500 nm, 100-400 nm, 100-300 nm, 100 maliae Belliricae Fructus, Testudinis Carapacis Et Plastri 200 nm, 1 nm, 2 nm, 3 nm, nm, 5 nm, 6 mm, 7 mm, 8 nm, Colla, Testudinis Carapax Et Plastrum, Tetrapanacis 9 mm, 10 nm, 11 nm, 12 nm, 13 nm, 14 nm, 15 nm, 16 nm, Medulla, Thlaspi Herba, Thunberg Fritillary Liquid Extract, 17 nm, 18 nm, 19 mm, 20 nm, 100 nm, 200 nm, 300 nm, 400 Tinosporae Radix, Toatal Ginsenoside Of Ginseng Stems nm, 500 nm, 600 nm, 700 nm, 800 nm, 900 nm in size). The And Leaves, Toosendan Fructus, Torreyae Semen, Total size of nanoparticles can be controlled by selecting appro Ginsenoside Ginseng Root, Toxicodendri Resina, Trache lospermi Caulis Et Folium, Trachycarpi Petiolus, Tribuli priate synthesis mcthods and/or systems. To obtain nano Fructus, Trichosanthis Fructus, Trichosanthis Pericarpium, particles within a desired size range, the synthesis conditions Trichosanthis Radix, Trichosanthis Semen Tostum, Tricho may be properly controlled or varied to provide for, e.g., a santhis Semen, Trigonellae Semen, Trionycis Carapax, Tsa desired solution concentration or a desired cavity range (a oko Fructus, Turpentine Oil, Turpiniae Folium, Typhae detailed review can be found at, e.g., Vincenzo Liveri, Pollen, Typhonii Rhizoma, Uncariae Ramulus Cum Uncis, Controlled synthesis of nanoparticles in microheterogeneous Vaccariae Semen, Valerianae Jatamansi Rhizoma Et Radix, systems, Published by Springer, 2006). Verbenae Herba, Vespae Nidus, Vignae Semen, Violae [0100] In certain embodiments, the drug content is in the Herba, Visci Herba, Vitex Oil, Viticis Fructus, Viticis form of microneedles as illustrated in FIG. 7. The Negundo Folium, Vladimiriae Radix, Weeping Forsythia microneedle would be printed in conjunction with the dos Extract, Wenyujin Rhizoma Concisum, Xanthii Fructus, age form or inserted into the dosage form during the Zanthoxyli Pericarpium, Zanthoxyli Radix, Zaocys, Zedo three-dimensional printing of the dosage form. The ary Turmeric Oil, Zingiberis Rhizoma Praeparatum, Zingib microneedles can be composed of a saccharide, a PLGA eris Rhizoma Recens, Zingiberis Rhizoma, Ziziphi Spinosae polymer or an API or a combination thereof. The Semen. microneedle can assist in the penetration of an API into the [0093] In certain embodiments, the drug content further circulatory system of a patient when administered either comprises a medium. The medium can be associated with parenteral or enteric. the API, i.e., the medium is in physical contact with the API. [0101] In certain embodiments, the drug content forms a In certain embodiments, the API is embedded in the network. As shown in FIG. 8A, a dosage form has a substrate medium. In certain embodiments, the API is dispersed forming a compartment loaded with a drug content. The within the medium. In certain embodiments, the medium is drug content has a substrate forming a network. The frame made of a thermoplastic material as disclosed herein. structure of tablet is made of a material that dissolves [0094] In certain embodiments, the medium comprises a between 1-10 minutes, and the substrate dissolves in 2-60 water-soluble excipient selected from the group consisting seconds, preferably in 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, of cocoa butter, polyethylene glycol (PEG), sucrose, glu 55, 60 seconds. As shown in FIG. 8B, the API can be cose, galactose, fructose, xyloselactose, maltose, trehalose, released in seconds after the dosage form is administered. In sorbitol, mannitol, maltodextrins, raffinose, stachyose, certain embodiments, the substrate also forms a network, fructo-oligosaccharides and a combination thereof. In cer which can further accelerate the release of the API. tain embodiments, the substrate further comprises a plasti C17er. [0102] The drug content can be made using an additive [0095] The drug content can be of any suitable shape and method such as fused deposition modeling (FDM). In cer size to be loaded into the compartment. tain embodiments, the drug content can be made by using a [0096] In certain embodiments, the drug content is oper three-dimensional printer (3D printer) configured to extrud ably linked to the compartment via covalent bond, non ing a mixture of API and the excipient. The API can be covalent interactions or through a linker. Thus, the drug melted and mixed homogenously with the melted substrate content and the substrate can be made separately and asso before being extruded. Alternatively, the API in a solid form ciate together through a covalent bond or non-covalent (e.g., powder) can be mixed with and dispersed in the melted interactions. In certain embodiments, dosage form is made substrate before being extruded. In general, the extrusion by producing the drug content and the substrate in a single process can be conducted at temperatures 10° to 40° C. process using 3D printing methods. above the glass transition (Tg) of the substrate and a [0097] In certain embodiments, the drug content is formed temperature close to the melting point of the API. Once at a in the shape of a compressed tablet, an oval tablet, a pill, or suitable temperature for use in the three-dimensional printer, a capsulet. In certain embodiments, the shape of the drug the substrate can be deposited to the three-dimensional content matches the shape of the compartment. For example, printing surface. The shape and size of the drug content can when the compartment is a pie-shape, the drug content is be controlled by programing the three-dimensional printing also of a pie-shape, e.g., to fill the compartment. process. In certain embodiments, the drug content is fabri [0098] In certain embodiments, the drug content is in the cated in the same process of the substrate. In certain embodi form of nanoparticles as illustrated in FIG. 6. The drug ments, the drug content is fabricated before the making of content can be mixed with solution in which the API is either the substrate and loaded into the compartment during or dissolved or suspended. The solution is then atomized/ after the substrate is fabricated. sprayed atop a printing layer during the course of the [0103] In certain embodiments, when the drug content is three-dimensional printing of the dosage form. Once the loaded into the compartment, it is associated with the solution containing the drug content dries, the drug content substrate, e.g., embedded or fixed in the substrate. In certain is dispersed in the dosage form. Nanoparticles have large embodiments, the drug content is detachable from the sub surface area and will have high dissolution rate. strate when loaded into the compartment. US 2016/0354315 A1 Dec. 8, 2016

[0104] D. Controlled Release API in the second compartment is completely released, the [0105] The dosage form disclosed herein can offer various third plug dissolves to release the API from the third release profiles after oral administration. In certain embodi compartment. As a result, the plasma drug level reaches the ments, the dosage form provides a constant release profile, first peak when the drug content in the first compartment is pulsatile or delayed delivery, or non-linear drug release. In released. When the API released from the first compartment certain embodiments, the dosage form provides a zero-order starts to be eliminated, the plasma drug level starts to release kinetics. decrease (see FIG. 10D). Before the plasma drug level falls [0106] A proper release profile may offer benefits to below the critical level (the horizontal line, below which the certain drug therapy regimes. For example, a pulsatile drug would be ineffective), the API from the second com release profile offers controlled absorption with resultant partment is released, and the plasma drug level increases reduction in peak through ratios, targeted release of the drug again. When the API released from the second compartment to specific areas within the gastro intestinal tract, and reaches the second peak and starts to be eliminated, the plug absorption independent of the feeding state, thus may be of the third compartment dissolves to open the compartment. used to prevent tolerance, reduce the side-effects and As a result, the plasma API level is maintained above the improve patient compliance, which is desirable to treat critical level for a long time, which benefits certain diseases. diseases like ADHD. For another example, a release profile [0110] The consecutive release manner can also be with a loading dose followed by a maintenance dose may be achieved through another exemplary dosage form having good for treating chronic conditions such as hypertension several drug contents packed in the form of layers as and diabetes. illustrated in FIG. 10B. The API can be released in a [0107] Some of the mechanisms to control the release sustained manner by having each layer dissolving in syn profile using the dosage from disclosed herein have been chrony to provide a continuous, sustained release of API as discussed above. For example, by manipulating the exposed depicted in FIG. 10C. In certain embodiments, the outer surface area of the substrate that erodes constantly over time, layers of the dosage form dissolve immediately and release the drug content embedded in the substrate is able to deliver the embedded drug content when the dosage form is admin a constant amount of drug over time. In addition, the release istered. But the layers sandwiched in the middle do not profile can be controlled by the size of compartment opening dissolve or dissolve much slower because the outer layers and/or by the geometric shape of the compartment. block their interface with the environment. The dissolution [0108] In certain embodiments, the release profile can be of the outer layers exposes the layers sandwiched in the controlled by the design of a compartment having an aper middle and expedites their dissolution, thus providing a ture that is sealed or blocked by a plug. The plug is made of consecutive release profile as illustrated in FIG. 10C. a water-soluble, porous, or erodible material or pH sensitive [0111] In certain embodiments, the dosage form comprises materials or hydrophobic material that will undergo attrition a gas-generating component loaded into the first compart when the dosage form passing the GI tract. When the dosage ment. In certain embodiments, the gas-generating compo form is administered to a subject, the plug is dissolved, ment is selected from the group consisting of organic acid permeated or eroded, thus releasing the drug content from and carbonates, sulphites, bicarbonates, sodium carbonate, the compartment. The release profile of the drug content can sodium bicarbonate, sodium metabisulphite, calcium car be controlled by choosing a plug of proper erosion/dissolu bonate, and combinations thereof, which on contact with tion rate or permeation rate. Alternatively, the release profile gastric fluid releases carbon dioxide or sulphur dioxide gas. of the drug content can be controlled by using the shape When the substrate is dissolved, permeated or eroded in and/or the size of the plug (e.g., a rod shape of proper stomach, the gas generating component is exposed to the length). The release profile can also be controlled by the acid environment or water penetrate into compartment to number of the compartment. FIG. 9 shows an exemplary induce the reaction between acid and sodium bicarbonate dosage form having a substrate forming a plurality of and generates gas to release the drug content in an effer column-shaped compartments residing on both sides of the VeScent manner. dosage form. Each compartment is loaded with a drug [0112] The dosage form disclosed herein may comprise content. Each compartment has an aperture that is blocked one or more drug content at least partially in delayed-release by a rod-shaped plug. The plugs have different dissolution form, wherein the delayed release may be achieved with the rate. Depending on the size, shape and dissolution rate of the assistance of conventional materials and methods known to plug, the APIs can be released in a sustained, continuous, the person skilled in the art, for example by embedding the simultaneous, consecutive or pulsatile manner. API in a delayed-release substrate/substrate or by the appli [0109] FIG. 10A shows an exemplary dosage form pro cation of one or more delayed-release coatings. Through viding a consecutive release profile. Referring FIG. 10A, the delayed release, API release may be so controlled that twice dosage form 700 has a substrate 701 forming three column or once daily administration of the dosage form is sufficient, shaped compartments 702~704. Each compartment is which is advantageous in particular in the case of a need for loaded with a drug content of the same API. Each compart a sustained level active compound, e.g., for combatting pain. ment has an aperture that is blocked by a rod-shaped plug [0113] In certain embodiments, the dosage form intends to 705–707. The plugs are made of the same material but have release the active ingredients in oral cavity instantly. One different length. Consequently, it takes different amount of example is to be given to oral cavity or take sublingual time to dissolve the plugs and to open the compartments to region. release the drug content. As illustrated in FIG. 10C, the [0114] In certain embodiments, the drug form can further shortest plug dissolves first, releasing the API from the first comprise conventional auxiliary substances known to the compartment. When the API in the first compartment is person skilled in the art, preferably selected from the group completely released, the plug of the median length dissolves, consisting of glyceryl monostearate, semi-synthetic triglyc releasing the API from the second compartment. When the eride derivatives, semi-synthetic glycerides, hydrogenated US 2016/0354315 A1 Dec. 8, 2016

castor oil, glyceryl palmitostearate, glyceryl behenate, poly derivation from a solid CAD model, or other means specific vinylpyrrolidone, gelatin, magnesium stearate, stearic acid, to the 3D printing machine’s computer interface and appli sodium stearate, talcum, sodium benzoate, boric acid and cation software. These instructions may include information colloidal silica, fatty acids, substituted triglycerides, glyc on the number and spatial placement of droplets, and on erides, polyoxyalkylene glycols and the derivatives thereof. general print parameters such as the drop spacing in each linear dimension (X, Y, Z), and volume or mass of fluid per Manufacture of the Dosage Form droplet. For a given set of materials, these parameters may [0115] The controlled release dosage forms disclosed be adjusted in order to refine the quality of structure created. herein can be manufactured using any appropriate process. The overall resolution of the structure created is a function In certain embodiments, the dosage forms are produced of the powder particle size, the fluid droplet size, the print using three-dimensional printing (3D printing). parameters, and the material properties. [0116] As used herein, 3D printing refers to a process that [0120) Because of its ability of handling a range of phar produce 3D objects layer-by-layer from digital designs. The maceutical materials and control both composition and basic process of 3D printing has been described in U.S. Pat. architecture locally, 3D printing is well suited to the fabri Nos. 5,204,055; 5,260,009; 5,340,656; 5,387.380; 5,503, cation of dosage forms with complex geometry and com 785; and 5,633,021. Additional U.S. patents and applications position in accordance with the present invention. related to 3D printing include: U.S. Pat. Nos. 5,490,962; [012.1] Manufacturing the dosage forms using 3D printing 5,518,690; 5,869,170; 6,530,958; 6,280.771; 6,514,518; methods also facilitate personalized medicine. Personalized 6,471,992: 8,828,411; U.S. PG Pub. Nos: 2002/0015728; medicine refers to stratification of patient populations based 002/0106412; 2003/0143268; 2003/0198677; 2004/ on biomarkers to aid therapeutic decisions and personalized 0005360. Reference can be made to the patents and appli dosage form design. Modifying digital designs is easier than cations listed above for a detailed description of 3D printing. modifying physical equipment. Also, automated, small-scale [0117| Different 3D printing methods have been devel 3D printing may have negligible operating cost. Hence, 3D oped for dosage form manufacturing in terms of raw mate printing can make multiple small, individualized batches rials, equipment and solidification. These 3D printing meth economically feasible and enable personalized dosage forms ods include binder deposition (see L Gibson et al. (2015) designed to improve adherence. Additive Manufacring Technologies: 3D Printing, Rapid [0122) Personalized dosage foriii allows for tailoring the Prototyping, and Direct Digital Manufacturing. 2 ed. amount of drug delivered based on a patient’s mass and Springer, New York; W. E. Katstra et al. (2000) Oral dosage metabolism. 3D printed dosage forms could ensure accurate forms fabricated by three dimensional printing, J. Control dosing in growing children and permit personalized dosing Release 66: 1-9; W.E. Katstra et al. (2001) Fabrication of of highly potent drugs. Personalized dosage forms can also complex oral delivery forms by three dimensional printing, combine all of patients’ into a single daily dose, Dissertation in Materials Science and Engineering, Massa thus improve patients’ adherence to . chussetts Institute of Technology; H. Lipson et al. (2013) [0123] FIG. 11 illustrates a process of using 3D printing to Fabricated: The New World of 3D printing, John Wiley & manufacture personalized dosage forms. For each patient, a Sons, Inc.; G. Jonathan, A. Karim (2016) 3D printing in variety of clinical testing results can be obtained, including pharmaceutics: a new tool for designing customized drug body weight, age, metabolism indicator and genomic bio delivery systems, Int. J. Pharm. 499; 376-394), material markers, etc. The clinical testing results are input into jetting (see G. Jonathan, A. Karim (2016) 3D printing in computer software. The information is combined with the pharmaceutics: a new tool for designing customized drug prescription of physician and pharmaco-kinetic model to delivery systems, Int. J. Pharm. 499; 376-394), extrusion design a dosage form of specific dose and drug combination. (see L Gibson et al. (2015) Additive Manufacring Technolo The instruction is then sent to a 3D printer to manufacture gies: 3D Printing, Rapid Prototyping, and Direct Digital the dosage form designed, which is administered to the Manufacturing. 2 ed. Springer, New York) and photopoly patient. merization (see F. P. Melchels et al. (2010) A review on stereolithography and its application in biomedical engineer Controlled Release of Multiple Drugs ing. Biomaterials 31: 6121–30). [012.4] The dosage form and methods disclosed herein can [0118] In certain embodiments, the dosage forms dis be used to control release of two or more drugs in order to closed herein are manufactured using extrusion methods. In optimize the drug combinations in certain therapeutic an extrusion process, material is extruded from robotically regimes. For example, a tablet to treat hypercholesterolemia actuated nozzles. Unlike binder deposition, which requires a can be designed to offer immediate release of Atorvastatin powder bed, extrusion methods can print on any substrate. A calcium and extended release of nicotinic acid. In another variety of materials can be extruded for 3D printing, includ example, a non-steroidal anti-inflammatory drug (NSAID) ing thermoplastic materials disclosed herein, pastes and for pain relief may be designed to provide sustained release colloidal suspensions, silicones and other semisolids. One of NSAID and a rapid release of H2- antagonist for common type of extrusion printing is fused deposition preventing NSAID-induced mucosal damage. modeling, which uses solid polymeric filaments for printing. [0125] In certain embodiments, the substrate forms mul In fused deposition modeling, a gear system drives the tiple compartments, each loaded with a drug content. In filament into a heated nozzle assembly for extrusion (see L certain embodiments, the multiple compartments are con Gibson et al. (2015) Additive Manfacturing Technologies: nected. In certain embodiments, the multiple compartments 3D Printing, Rapid Prototyping, and Direct Digital Manu are disconnected. In certain embodiments, the drug contents facturing. 2 ed. Springer, New York). loaded into different compartments are the same. In certain [0119) The manufacturing instructions for a print job may embodiments, the drug contents loaded into different com be generated a variety of ways, including direct coding, partments are different. The dosage form can be so designed US 2016/0354315 A1 Dec. 8, 2016

to provide simultaneous or sequential release of multiple EXAMPLE 1 drug content to exert synergistic therapeutic effects. [0132] This example illustrates a design of dosage form [0126] FIG. 12A shows an exemplary dosage form that that has controlled release profile. can release APIs simultaneously. Referring to FIG. 12A, the [0133) As shown in FIG. 18A, the dosage form comprised dosage form 800 includes three stacked layers 801~803, a flat tablet substrate forming a pie shaped compartment. each of which is embedded with a different drug content. As The substrate was made of PEG8000. Benzoic acid was used illustrated in FIG. 12B, when the dosage form 800 is as a module drug content. administered, the drug contents are released simultaneously [0134] The release profile of the benzoic acid from the but at different rates as the layers dissolve. dosage form was measured as the following method. [0127] FIG. 13A depicts another exemplary dosage form Na2HPO, solution of pH 8 was prepared as dissolvent of of simultaneous release profile. Referring to FIG. 13A, the benzoic acid. Benzoic acid solution of 120 pg/mL was dosage form 900 includes three column shaped compart serially diluted to 30 pig?mL, 15 pig?m, 7.5 pig?m, 3.75 pig?mL, ments 901~903, in which three drug contents are loaded. and 1.875 pig?m.L solutions, whose absorbance at 226 mm Each drug content contains an API embedded in a substrate was measured using a UV spectrophotometer. The numbers of different dissolution rate. As illustrated in FIG. 13B, when obtained were treated with linear regression to generate a the dosage form 900 is administered, the three APIs are standard curve of benzoic acid concentration with the for released simultaneously but at different rates as the sub mula y=0.0599x+0.0347. To measure the released amount of strates of the drug contents dissolve. The release rate of the benzoic acid, the dosage form was dissolved in degassed pH APIs can also be controlled by the shape of the compart 8 Na2HPO, solution at 37°C.:-0.5°C. and centrifuged at 100 ments or the size of the opening of the compartments. rpm. 5 mL solution was collected from the solution at each [0128] FIG. 14A and 14B depict additional exemplary time point to measure the concentration of benzoic acid with dosage forms of simultaneous release profile of three APIs. 5 mL dissolvent added back to the solution. The collected Referring to FIG. 14A, the dosage form 1000 contains three solution was filtered through 0.45 um membrane before pie-shaped segments 1001~1003 wherein drug contents are transferred to an UV spectrophotometer for measuring the embedded. As illustrated in FIG. 14C, he drug contents absorbance at 226 mm. The percentage of benzoic acid release simultaneously as the segments dissolve, and the released was calculated using the following formula: release rate of the drug contents can be controlled by the dissolution rate of the segments. Referring to FIG. 14B, the dosage form 1100 contains three pie-shaped segments C, V, + V.). Cn-1 1101~1103, which are wrapped by a shell 1104 that dis Benzoic acid released (%) = × 1()() solves slower than the segments. The release rates of the 2benzoic acid drug contents embedded in the segments are reduced as the shell 1104 blocks the interface of the segments 1101~1103 [0135] Wherein with the environment. [0136] C, means concentrate measured, V, means total [0129] FIG. 15A shows an exemplary dosage form of solution volume, V, means sample volume, Qºomeone a..., sequential release profile of two APIs. Referring to FIG. means amout of benzoic acid in the dosage form 15A, the dosage form 1200 includes a substrate 1201 [0137] The release of PEG8000 is measured using the forming a compartment that is filled by a drug contcnt 1202. following method. To prepare a standard curve of PEG8000, The substrate 1201 contains a first API, and the drug content 0.1275 g PEG8000 standard sample was dissolved in water 1202 contains a second API. As illustrated in FIG. 15B, the in a 25 mL volumetric flask. Transferring 1 mL, 2 mL 5 mL first API releases as the substrate dissolves when the dosage and 10 mL to 10 mL volumetric flask, respectively, and form is administered. The second API does not release until diluted in water to prepare the control solution. Injecting 50 the substratc dissolves to expose the drug content, providing ul control solutions to a liquid chromatography (three Waters a sequential release profiles of the APIs. UltrahydrogelTM 120/250/500 connected in series, flow [0130] FIG. 16A shows another exemplary dosage form of speed at 0.5 ml/min, temperature at 40°C., measured by a sequential release profiles. Referring to FIG. 16A, the dos differential refraction detector). The areas of the volume age form 1300 has a substrate 1301 forming three column were measured and used as y-axis. The log numbers of the shaped compartments 1302~1304 loaded with three drug control solution concentration were used as x-axis. A stan contents. The compartments 1302~4304 have an aperture dard curve of PEG8000 was generated with the formula of that are blocked by rod-shaped plugs that have different y=1.024x+8.918. The percentage of PEG800 released was length and/or dissolution rate. As illustrated in FIG. 16B, the calculated using the following formula: APIs are released in a sequential manner as the plugs dissolve sequentially to open the compartments. [0131] FIG. 17A shows an exemplary dosage form having PEG8000 released (%) = × 1 ()() a simultaneous release profile or sequential release profile. QPEG8000 Referring to FIG. 17A, the dosage form 1400 has a substrate containing four segments 1701~1704 having different dis solution rate. In certain embodiments, as illustrated in FIG. [0138] wherein C, means concentration measured, V, 17B, the drug contents are embedded in the segments means volume of solution, V, means sample volume, 1701–1704 and are released simultaneously when the sub [0139| Qezesooo means amount of PEG8000 in the dosage strate dissolves. In certain embodiments, each segment form contains a compartment where a drug content is loaded. As [0140] Results: as illustrated in FIG. 18C, the release illustrated in FIG. 17C, the drug contents are released in a profile of the benzoic acid matches a model profile accord sequential manner when the substrate dissolves. ing to D. Brooke and R. J. Washkuhn (Zero-Order Drug US 2016/0354315 A1 Dec. 8, 2016

Delivery System: Theory and Preliminary Testing, J Pharm [0144] The results of the release assays were illustrated in Sci., 1977, 66: 159-162) and was controlled by the interface. FIG. 19C and 19D. As shown in FIG. 19C, when the first Therefore, a controlled release profile can be designed dosage form was added to the buffer for 20 min, the first according to the dosage forms disclosed herein. compartment was open, and the drug content in the first compartment was released. The second compartment was EXAMPLE 2 not open till 40 min after the dosage form was added to the buffer. For the second dosage form, whose results were [0141] This example illustrates a design of dosage form illustrated in FIG. 19L), the second compartment was not that controls release of drug contents from different com open till 60 min after the dosage form was added to the partments. buffer. Therefore, the release profile of the dosage form can [0142] Dosage design: two dosage forms were produced be controlled through the thickness of the wall that encloses using fused deposition modeling methods. The substrate of a compartment. the dosage forms was made of Copovidone (Kollidon R [0145] While the principles of this invention have been VA64) 72%, PEG1500 18% and Soluplus R 10%. The drug described in connection with specific embodiments, it content was consisted of Moxifloxacin Hydrochloride 30%, should be understood clearly that these descriptions are PEG1000 70%. The schematic of the dosage forms are made only by way of example and are not intended to limit illustrated in FIG. 19A and 19B. Referring to FIG. 19A and the scope of the invention. What has been disclosed herein 19B, the dosage form 1600 contained a substrate 1601 that has been provided for the purposes of illustration and forms two compartments 1602 and 1603. The compartments description. It is not intended to be exhaustive or to limit were enclosed by a wall 1604 and 1605, respectively. For the what is disclosed to the precise forms described. Many first dosage form, the two compartments were enclosed by modifications and variations will be apparent to the practi walls having a thickness of 0.75 mm and 1.5 mm, respec tioner skilled in the art. What is disclosed was chosen and tively. For the second dosage form, the two compartments described in order to best explain the principles and practical were enclosed by walls having a thickness of 0.75 mm and application of the disclosed embodiments of the art 2.25 mm, respectively. described, thereby enabling others skilled in the art to [0143] To detect the release of the drug content, the dosage understand the various embodiments and various modifica form was added to 900 ml phosphate buffer of pH6.8 at 100 tions that are suited to the particular use contemplated. It is rpm. The UV absorption of the buffer was assayed to intended that the scope of what is disclosed be defined by the determine the release of the drug content. following claims and their equivalence. US 2016/0354315 A1 Dec. 8, 2016 18

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What is claimed is: 16. The dosage from of claim 14, wherein the first 1. A dosage form comprising: compartment has a first aperture which is covered by a first a substrate that forms a compartment; and plug, and the second compartment has a second aperture a drug content loaded into the compartment. which is covered by a second plug. 2. The dosage form of claim 1, wherein the drug content 17. The dosage form of claim 16, wherein the first plug is is operably linked to the substrate. longer than the second plug. 3. The dosage form of claim 1, wherein the drug content 18. The dosage form of claim 16, wherein the first plug is detached from the substrate. has a first permeation rate and the second plug has a second permeation rate, wherein the first permeation rate is different 4. The dosage form of claim 1, wherein the substrate is from the second permeation rate. made from at least one thermoplastic material. 19. The dosage form of claim 16, wherein the first plug 5. The dosage form of claim 4, wherein the thermoplastic has a first erosion/dissolution rate and the second plug has a material is selected from the group consisting of a hydro second erosion/dissolution rate, wherein the first erosion/ philic polymer, a hydrophobic polymer, a swellable poly dissolution rate is different from the second erosion/disso mer, a non-swellable polymer, a porous polymer, a non lution rate. porous polymer, an erodible polymer, a non-erodible 20. The dosage form of claim 14, wherein the first polymer. compartment is enclosed by a first wall, and the second 6. The dosage form of claim 1, wherein the compartment compartment is enclosed by a second wall. has a shape selected from the group consisting of a pie 21. The dosage form of claim 20, wherein the first wall is shape, a cone shape, a pyramid shape, a cylindrical shape, a thicker or more permeable than the second wall. cubic or cuboidal shape, a triangular or polygonal prism 22. The dosage form of claim 20, wherein the first wall shape, a tetrahedron and a combination thereof. erodes/dissolves faster than the second wall. 7. The dosage form of claim 1, wherein the drug content 23. A dosage form comprising: comprises an active pharmaceutical ingredient (API). two or more matrix layers stacked together, wherein at 8. The dosage form of claim 7, wherein the drug content least one of the two or more matrix layers is loaded further comprises a medium. with at least one drug content, respectively. 9. The dosage form of claim 8, wherein the medium is 24. The dosage form of claim 23, wherein the two or more made from a thermoplastic material. matrix layers are detachable from each other. 10. The dosage form of claim 8, wherein the medium has 25. The dosage form of claim 23, wherein the two or more a higher erosion/dissolution rate than the API. matrix layers are made from at least one thermoplastic 11. The dosage form of claim 8, wherein the medium has material. a higher erosion/dissolution rate than the substrate. 26. The dosage form of claim 23, wherein the two or more 12. The dosage form of claim 1, wherein the compartment matrix layers have different thickness. has an aperture which is blocked by a plug. 27. The dosage form of claim 23, wherein the two or more 13. The dosage form of claim 12, wherein the plug is matrix layers have different erosion/dissolution rates. made from a material selected from the group consisting of 28. The dosage form of claim 23, wherein the two or more a water-soluble polymer, an erodible or dissolvable polymer, matrix layers are configured that the loaded each of the at a wax like material, saccharides or a combination thereof. least one drug content is released in an aqueous solution 14. A dosage form comprising: based on a predetermined release profile. a substrate that forms at least a first compartment and a 29. The dosage form of claim 23, wherein the two or more second compartment; and matrix layers comprise a first matrix layer loaded with a first a first drug content loaded into the first compartment and drug content and a second matrix layer loaded with a second a second drug content loaded into the second compart drug content and positioned outer than the first matrix layer, ment. such that the second drug content is released prior to the first 15. The dosage form of claim 14, wherein the first drug drug content. content is different from the second drug content.