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US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 (54 ) ORAL DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) (71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U .S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC ...... A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 (22 ) Filed : Feb . 28 , 2019 (2013 .01 ); A61K 9 / 209 ( 2013 .01 ); A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1

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ORAL DRUG DOSAGE FORM COMPRISING erodible polymer . In certain embodiments , the thermoplastic DRUG IN THE FORM OF NANOPARTICLES material is selected from the group consisting of polyvinyl caprolactam - polyvinyl acetate - graft CROSS -REFERENCE TO RELATED copolymer 57 / 30 / 13 , - co - vinyl- acetate APPLICATIONS (PVP - VA ), polyvinylpyrrolidone -polyvinyl acetate copoly mer (PVP - VA ) 60 / 40 , polyvinylpyrrolidone (PVP ), polyvi [0001 ] This application is a continuation of U .S . patent nyl acetate (PVAc ) and polyvinylpyrrolidone (PVP ) 80 / 20 , application Ser. No . 16 / 028 , 305 , filed Jul. 5 , 2018 , and Ser . polyethylene glycol- polyvinyl graft copolymer No . 15 / 173 , 596 , filed Jun . 3 , 2016 , which claims priority to 25 / 75 , kollicoat IR - polyvinyl alcohol60 /40 , polyvinyl alco U . S . Provisional Patent Application Ser. Nos . 62 / 170 ,645 , hol (PVA or PV -OH ), poly ( vinyl acetate ) (PVAc ) , poly (butyl filed Jun . 3 , 2015 , 62 /296 , 087 , filed Feb . 17 , 2016 , and methacrylate- co - ( 2 -dimethylaminoethyl ) methacrylate - co 62 /313 , 092 , filed Mar. 24 , 2016 , the disclosures of which are methyl methacrylate ) 1 : 2 : 1 , poly (dimethylaminoethylmeth incorporated herein by reference in their entirety . acrylate - co -methacrylic ) , poly ( ethyl acrylate - co methyl methacrylate -co -trimethylammonioethyl FIELD OF THE INVENTION 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 ( oxide ) (PEO ) , poly (ethylene glycol ) (PEG ), hyperbranched polyesteramide , hydroxypro BACKGROUND pyl methylcellulose , 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 , 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 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 , , Polyvinyl Acetate forms, which shows more benefits in terms ofmanufactur 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 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 f0008 ] 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 , 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 , for developing dosage forms that provides controlled drug anti- Alzheimer' s disease drugs, , antipodagric , delivery systems, which may offer desired drug plasma anti -hypertensive drugs, antiarrhythmic drugs, levels , reduced side effects as well as improved patient drugs, drugs for treating diseases, drugs for treating compliance . pancreatic diseases, drugs, anti- allergic drugs , drugs, hormone drugs and contraceptive BRIEF SUMMARY OF THE INVENTION drugs, hypoglycemic drugs , anti - 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, , , xyloselactose , maltose , treha US 2019 /0192440 A1 Jun . 27 , 2019 lose , , , maltodextrins, raffinose, stachyose , [ 0024 ] FIG . 2B shows the release of the API from the fructo -oligosaccharides , water - soluble oligomers and poly dosage form illustrated in FIG . 2A . mers and a combination thereof. [ 0025 ] FIG . 3 shows an exemplary dosage form having a [0011 ] In certain embodiments , the compartment has an substrate that forms a compartment with another dosage aperture that is blocked and / or sealed by a plug. In certain form loaded into the compartment. embodiments , the plug is made from a porous polymer , an [0026 ] FIG . 4A shows an exemplary dosage form having erodible polymer, a pH sensitive polymer or natural occur a substrate forming a compartment of pie shape. ring material such as shellac . In certain embodiments , the [0027 ] FIG . 4B shows an exemplary dosage form having plug is made from a material selected from the group a substrate forming multiple compartments containing vari consisting of water - soluble polymers , erodible or dissolv ous sized openings. able polymers , wax like materials or saccharides or any [0028 ]. FIG . 4C shows an exemplary dosage form having materials mentioned above . a substrate forming an angled compartment. [0012 ] In certain embodiments , the dosage form com [0029 ] FIG . 4D shows an exemplary dosage form having prises a gas -generating component loaded into the first a substrate forming multiple compartments of different sized compartment . In certain embodiments , the gas -generating radius. component is selected from the group consisting of water [0030 ] FIG . 4E shows an exemplary dosage form having soluble , sulphites , , a substrate forming multiple compartments of different ate , sodium , sodium metabisulphite , geometric - shape that can be used to modulate release rate of , and combinations thereof, which on contact with the API. gastric fluid releases or sulphur dioxide gas . [0031 ] FIG . 5 shows the cross section of an exemplary In certain embodiments , the gas - generating component is a dosage form having a pie -shaped compartment. combination of sodium bicarbonate and organic acid ( e . g ., , 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 10036 ] 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 [ 00171 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 [0019 ] FIG . 1A shows a conventional dosage form com controlled release dosage form illustrated in FIG . 10A or prising a drug content. 10B when administered to a subject . 0020 ] FIG . 1B illustrates the release profile of the dosage [0041 ] FIG . 11 is a schematic workflow for using of a form of FIG . 1A when administered to a subject . three -dimensional printer for preparing patient specific dos [0021 ] FIG . 1C shows the plasma drug level when the age form . dosage form of FIG . 1A is administered to a subject. [0042 ] FIG . 12A shows an exemplary dosage form having [0022 ] FIG . 1D shows the plasma drug level of a con a three - layered substrate with different drug content embed trolled release dosage form having the zero - order drug ded into each layer . release profile when administered to a subject . [0043 ] FIG . 12B illustrates the release of three APIs from [0023 ] FIG . 2A shows an exemplary dosage form having the dosage form illustrated in FIG . 12A . a substrate that forms a compartment with a drug content (0044 ) FIG . 13A shows an exemplary dosage form having loaded into the compartment. a substrate forming three compartments , each of which US 2019 /0192440 A1 Jun . 27 , 2019 loaded with one drug content. The release profile of the drug and / or in the context of other particular aspects and embodi content can be controlled by the dissolution rate of the drug ments of the invention , and in the invention generally . content . 10064 ] The term “ comprises” and grammatical equivalents [ 0045 ] FIG . 13B illustrates the release profile of the APIs thereof are used herein to mean that other components , from the dosage form illustrated in FIG . 13A . ingredients , steps , etc . are optionally present. For example, [ 0046 ] FIG . 14A shows an exemplary dosage form having an article " comprising ” (or “ which comprises ” ) components a substrate having three pie - shaped segments , with drug A , B , and C can consist of (i . e . , contain only ) components content embedded into each segment . A , B , and C , or can contain not only components A , B , and [ 0047 ] FIG . 14B shows an exemplary dosage form having C but also one or more other components . a substrate having three pie - shaped segments wrapped with [0065 ] Where reference is made herein to a method com a shell structure. prising two or more defined steps , the defined steps can be 10048 ] FIG . 14C shows the release profile of the APIS carried out in any order or simultaneously ( except where the from the dosage forms illustrated in FIG . 8A and FIG . 8B . context excludes that possibility ) , and the method can (0049 ] FIG . 15A shows an exemplary dosage form having include one or more other steps which are carried out before a substrate forming a compartment filled with a drug con any of the defined steps , between two of the defined steps, tent. A second API is embedded in the substrate and is or after all the defined steps ( except where the context released when the substrate dissolves . excludes that possibility ) . [ 0050 ] FIG . 15B shows the controlled release of the APIs 10066 ] Where a range of value is provided , it is understood from the dosage form illustrated in FIG . 15A . that each intervening value, to the tenth of the unit of the [0051 ] FIG . 16A shows an exemplary dosage form having lower limit unless the context clearly dictate otherwise , a substrate forming three column - shaped compartments . between the upper and lower limit of that range and any Each compartment is loaded with one drug content. Each other stated or intervening value in that stated range , is drug content has a plug that blocks the opening of each encompassed within the disclosure , subject to any specifi compartment. The release of the drug content in each cally excluded limit in the stated range. Where the stated compartment can be controlled by the permeability , degrad range includes one or both of the limits , ranges excluding ability or erodibility of the plug . either or both of those included limits are also included in the disclosure . [0052 ] FIG . 16B shows the release profiles of the APIs 10067] 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 10062] FIG . 19D 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 US 2019 /0192440 A1 Jun . 27 , 2019

conventional solid dosage forms exhibit first - order drug hydroxypropylmethylcellulose , hydroxypropylcellulose , release profile ( FIG . 1B ) where the plasma level of the drug hydroxymethylcellulose , poly (meth )acrylic acid and /or the increases rapidly to an extremely high level after adminis derivatives thereof, such as the salts , or esters thereof tration and then decreases exponentially ( see FIG . 1C ) . This are suitable for use as thermoplastic materials . Physiologi poses disadvantages such as minimal therapeutic efficacy cally acceptable , hydrophobic materials that are known to due to reduced drug levels or drug toxicity which can occur the person skilled in the art , such as mono - or at high concentrations . This type of drug release does not ofC12 - C30 fatty acids and / or C12 - C30 fatty and /or allow for appropriate plasma drug level balance . The instant waxes or mixtures thereof may be used as thermoplastic invention relates to modified or controlled release oral drug material . Substrate prepared from hydrophobic materials , delivery system , which offers advantages over conventional such as hydrophobic polymers , waxes , fats, long - chain fatty systems, including increased patient compliance , selective acids , fatty alcohols or corresponding esters or or pharmacological action , reduced side effects and reduced mixtures thereof are also envisioned . dosing frequency . Controlled release offers prolonged deliv [ 0075 ] In certain embodiments , the thermoplastic material ery of drugs and maintenance of plasma levels within a is selected from the group consisting of polyvinyl capro therapeutic range. For example , a drug delivery system lactam -polyvinyl acetate -polyethylene glycol graft copoly exhibiting zero - order drug release profile ( FIG . 1D ) allows mer 57 /30 / 13 , polyvinylpyrrolidone -co -vinyl - acetate (PVP for a constant quantity of drug to be release over an extended VA ), polyvinylpyrrolidone -polyvinyl acetate copolymer period of time, resulting in uniform and sustained drug (PVP - VA ) 60 /40 , polyvinylpyrrolidone (PVP ) , polyvinyl delivery . As a result , zero -order release profile may be acetate (PVAc ) and polyvinylpyrrolidone (PVP ) 80 /20 , desired in delivery, the treatment of hypertension , polyethylene glycol- polyvinyl alcohol graft copolymer pain management, delivery and numerous 25 / 75, kollicoat IR - polyvinyl alcohol 60 /40 , polyvinyl alco other conditions that require constant plasma drug levels. hol (PVA or PV -OH ), poly ( vinyl acetate ) (PVAc ), poly (butyl 10070 ] Therefore , one aspect of the present disclosure methacrylate - co - ( 2 -dimethylaminoethyl ) methacrylate - co provides a stable solid pharmaceutical dosage form for oral methyl methacrylate ) 1 : 2 : 1 , poly (dimethylaminoethylmeth administration , which has a controlled release profile . In acrylate - co -methacrylic esters ), poly ( ethyl acrylate -co certain embodiments , the dosage form includes a substrate methyl m ethacrylate - co -trimethylammonioethyl forming at least one compartment and a drug content loaded methacrylate chloride ) , poly (methyl acrylate - co -methyl into the compartment. The dosage form is so designed that methacrylate -co -methacrylic acid ) 7: 3 : 1, poly (methacrylic the release of the active pharmaceutical ingredient of the acid -co -methylmethacrylate ) 1 :2 , poly (methacylic acid -co drug content can be controlled , e . g . , by opening the com ethyl acrylate ) 1 : 1 , poly (methacylic acid - co -methyl meth partment in a predetermined manner. acrylate ) 1 : 1 , poly ( ethylene oxide ) (PEO ), poly ( ethylene glycol ) (PEG ), hyperbranched polyesteramide , hydroxypro A . Substrate pyl methylcellulose phthalate , hypromellose phthalate , [0071 ] As used herein , “ substrate ” refers to a structure in hydroxypropyl methylcellulose or hypromellose (HMPC ), which a drug is enclosed or embedded . The substrate of a hydroxypropyl methylcellulose acetate succinate or dosage form of the instant invention can be of any size and hypromellose acetate succinate (HPMCAS ), poly ( lactide shape that are suitable for oral administration . In certain co - glycolide ) (PLGA ) , carbomer , poly (ethylene - co -vinyl embodiments , the substrate is a flat round tablet having a acetate ) , ethylene - vinyl acetate copolymer , polyethylene diameter of around 2 mm , 3 mm , 4 mm , 5 mm , 6 mm , 7 mm , (PE ) , and polycaprolactone ( PCL ), hydroxyl propyl cellu 8 mm , 9 mm , 10 mm , 11 mm 12 mm . In certain embodi lose (HPC ) , Polyoxyl40 Hydrogenerated Castor Oil, Methyl ments , the substrate is an oval tablet having a dimension of cellulose MC( ) , Ethyl cellulose (EC ) , Poloxamer, hydroxy around a mmxb mm , wherein a is 5 to 15 and b is 2 to 10 . propyl methylcellulose phthalate (HPMCP ) , Poloxamer , In certain embodiments , the substrate has a capsule shape . Hydrogenated Castor & Soybean Oil, Glyceryl Palmitoste [ 0072 ] In certain embodiments , the substrate is made of a arate , Carnauba Wax , polylactic acid ( PLA ) , polyglycolic hydrophilic polymer ( e . g . , hydroxypropylmethylcellulose acid ( PGA ), Cellulose acetate butyrate (CAB ), Colloidal (HPMC ) and poly ( ethylene oxide ) (PEO )) , a hydrophobic Silicon , Dioxide , Sucrose , Glucose , Polyvinyl Acetate polymer ( e . g ., ethylcellulose ( EC ) ) , a swellable polymer, a Phthalate ( PVAP ) and a combination thereof. non - swellable polymer , a porous polymer , a non - porous [ 0076 ] Properties and sources of various thermoplastic polymer, an erodible polymer , or a non - erodible polymer. materials are listed in Table 1 . [ 0073] In certain embodiments , the dosage form has a [0077 ] In certain embodiments , the thermoplastic material monolithic substrate. In certain embodiments , the substrate allows the dosage form to be made using an additive method consists of several pieces , each piece made of the same or such as fused deposition modeling ( FDM ) . In certain different material. embodiments , the substrate can be made by using a three 10074 ) In certain embodiments , the substrate is made of a dimensional printer ( 3D printer ) configured to extruding the thermoplastic material. As used herein , a “ thermoplastic thermoplastic material. Typically, the thermoplastic material material” refers to a material having the ability to be shaped is melted in the 3D printer before being extruded to form the using heat and pressure . In certain embodiments , the ther substrate . In certain embodiment , appropriate extruders moplastic materials may, for example , be hydrophilic , gel include without limitation , single or twin screw extruders forming materials , from which drug content release pro with the temperature within the extruder at a range from 50° ceeds mainly by diffusion , or hydrophobic materials , from C . to 180° C . and from 80° to 140° C . In general, the which drug content release proceeds mainly by diffusion extrusion process can be conducted at temperatures 10° to from the pores in the substrate. Polymers, particularly cel 40° C . above the glass transition ( Tg ) of the thermoplastic lulose ethers , cellulose esters and/ or acrylic resins can be material. Once at a suitable temperature for use in the used as hydrophilic thermoplastic materials . Ethylcellulose , three- dimensional printer, the thermoplastic material can be US 2019 /0192440 A1 Jun . 27 , 2019 deposited to the three - dimensional printing surface . The shape, a cylindrical shape , a cubic or cuboidal shape , a shape and size of the substrate and the compartment fabri triangular or polygonal prism shape , a tetrahedron and a cated by the thermoplastic material can be controlled by combination thereof. programming the three - dimensional printing process . [0084 ] In one embodiment, the compartment of the dosage [0078 ] In certain embodiments, the material of the sub form has different geometric shape. FIG . 4A shows an strate can be so selected to control the release profile of a exemplary dosage form having a substrate forming a com drug . For example, the substrate is made of a material having partment of pie shape . FIG . 4B shows an exemplary dosage desired erosion /dissolution rate , permeation rate so that form having a substrate forming multiple compartments when administered the compartment can be opened in a containing various sized openings. FIG . 4C shows an exem predetermined manner, and the drug content is release from plary dosage form having a substrate forming an angled the compartment at desired rate . In certain embodiments , the compartment. FIG . 4D shows an exemplary dosage form substrate is erodible or dissolvable and is embedded with an having a substrate forming multiple compartments of dif active pharmaceutical ingredient (API ) . The API is released ferent sized radius. when the substrate is eroded or dissolved [0085 ] The shape of the compartment can be used to [0079 ] The release of the drug content can also be con control the release profile of the dosage form . For example , trolled by adjusting the thickness of the substrate . For R . A . Lipper and W . I . Higuichi described a delivery system example , the substrate forming a compartment is made of a that provides zero -order release profile , which is illustrated soluble material. The opening of the compartment , thus the in FIG . 5 . FIG . 5 shows a cross -sectional view of the release of the drug content loaded within can be controlled delivery system having a pie - shaped compartment. The by adjusting the thickness of the walls that enclose the compartment communicates with the environment through a compartment . The thicker the wall , the slower the compart small opening . The compartment is loaded with a drug ment is open , and the later the drug content is released . content that dissolves to release an API. The API is then released to the environment through the small opening . The B . Compartment dissolution rate of the drug content positively correlates to [0080 ] 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 à . 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 à 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 . [0081 ] 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 content 103 is loaded in the compartment 102 by linking to C . Drug Content the internal wall of the compartment 102. The compartment 102 can provide a floating effect to the dosage form and [0086 ] As used herein , the term “ drug content” refers to a thereby extend its residence time in the stomach or in an composition comprising one or more active ingredient, aqueous or acidic environment. The residency time can be a including active pharmaceutical ingredient ( API) , cosmetic function of the erosion / dissolution rate of the materials of agent, biological agent, diagnostic agent and reagent for the substrate and result in a sustained release of API as scientific experiments . shown in FIG . 2B . [0087 ] As used herein , an API refers to an ingredient in a [ 0082 ] FIG . 3 illustrates another exemplary dosage form pharmaceutical drug that is biologically active . In certain with increased residence in the gastro intestinal tract . Refer embodiments , the API is selected from the groups consisting ring to FIG . 3 , a dosage form 200 has a configuration that the of local anesthetics , antiepileptic drugs and anticonvulsants , compartment 202 contains a second dosage form 203 ( e . g . , anti- Alzheimer 's disease drugs, analgesics, antipodagric , a tablet ) freely moving within the compartment 202 . The anti -hypertensive drugs, antiarrhythmic drugs , diuretic gastro intestinal residence time of a dosage form is limited . drugs, drugs for treating liver diseases, drugs for treating Using floating systems can allow the dosage form to stay in pancreatic diseases , antihistamine drugs , anti - allergic drugs , stomach and continuously release the drug at the upper part glucocorticoid drugs , drugs and contraceptive of GI tract and maximize the absorption in small intestine . drugs , hypoglycemic drugs , anti - osteoporosis drugs, antibi [0083 ] In certain embodiments , the shape of the compart otics, sulfonamides, quinolones , and other synthetic antibac ment is uniquely created so that the drug content can be terial drugs, anti - tuberculous drugs , antiviral drugs , anti released at a controlled rate . In certain embodiments , the neoplasm drugs, immune- modulators , cosmetically active compartment has a shape selected from the group consisting agents , traditional Chinese medicine ( TCM ) and TCM of a wedge shape , a pie shape , a cone shape, a pyramid extracts . US 2019 /0192440 A1 Jun . 27 , 2019

[0088 ] In certain embodiments , the API is selected from tidine, , azelaicacid , , azelastine hydro the groups consisting of ( R ) - folitixorin , , 11- di chloride , azeliragon , , azilsartan , azilsartan deutero -ethyllinoleate , 16 -dehydro - , 17 -beta medoxomil potassium , azilsartan trimethylethanolamine , , 2 - iminobiotin , 3 , 5 - diiodothyropropionicacid , , azithromycin , azithromycin lactobionate , aztreo 5 - fluoro - 2 -deoxycytidine , 6 - , edotreotide, nam , aztreonam , azvudine, , bafetinib , Baica , abalone haemocyanin , abametapir, , abe lein , , BAK - freelatanoprost, , balsalaz maciclib , , abiraterone , acalabrutinib , acampro ide , sodium , , barasertib , sate , acamprosatecalcium , acarbose, acebilustat, , bardoxolone methyl , , , , , acehytisine hydrochloride, acemannan , ace batefenterol succinate, , beclabuvir, beclometa neuramic acid , acetaminophen , , acetylki sone dipropionate , beclomethasone dipropionate , bedaqui tasamycin , acetyl- L -carnitinehydrochloride , acetylsalicyli line, bedoradrine , , beloranib , , bempe cacid , aciclovir , , acitazanolast, acitretin , doic acid , benapenem , benazepril , bencycloquidium aclidinium , aclidinium , , acorafloxacin , bromide , , bendamustine hydrochloride, beni , , actarit , adapalene , adapalene, dipine, benserazide , bentamapimod , , adefovirdipivoxil, ademetionine , adoair , , afimox , benznidazole , , benzoylper ifene , afuresertib , , aildenafilcitrate , aladorian , oxide , benzydamineHCL , , bepotastine calcium alalevonadifloxacin mesylate , alarelin acetate , dihydrate , bepotastine salicylate , beractant, mesylate , , albuterol , albuterpenoids, sodium , , besifovir , besipirdine , beta - elemene , , aldoxorubicin , , alendronate , alendro , betaine anhydrous, , betametha nate sodium , alendronate sodiumhydrate, , sone butyrate propionate , betamethasonedipropionate , alfacalcidol, , , , alisertib , betamethasone valerate , betamipron , , betaxolol aliskiren , alisporivir , , allantoin , allisartaniso hydrochloride, , , , bexa proxil , allopurinol, , alogliptin , alogliptin benzo gliflozin , , , biafungin , biapenem , ate , , , alphaketoglutarate , alphalipoic acid , , bicizar , , bicyclol, , - lantitrypsin , alpha -cyclodextrin - stabilized sul , , biotin , birabresibdihydrate, biska foraphane , , alprostadil , alprostadil alfadex , alti lcitrate potassium , bismuth subgallate , bismuthyl ecabet, ratinib , , , aluminum sulfate , alvimo bisnorcymserine, , bisoprolol fumarate , bitespi pan , , , amantadine hydrochloride , ramycin , bixalomer, , , boanmycin , ambroxol, ambroxol hydrochloride , amcaser hydrochloride , boceprevir, , , bosentan tib , amfetamine , amfetamine polistirex , , ami hydrate , , bovactant, , briciclib fampridinephosphate , ami fostine , amikacin , , ami sodium , , , brimapitide, , nolevulinic , , aminolevulinic acid brincidofovir , , brivanibalaninate , brivarac hydrochloride , , , amiselimod , etam , brivudine , , , , , hydrochloride, , aml bromfenac sodium , , bronchostat, , exanox , , amlodipine , amlodipinebesilate , amlo bryostatin - 1 , , , , , dipine besylate , amlodipine camsylate , amlodipine maleate , bufiomedil, bulaquin , , buparlisib , , amlodipine nicotinate , amlodipine orotate , lac bupivacaine hydrochloride , , buprenorphine tate, , , , amoxicillin , hydrochloride , , bupropion hydrochloride , burixa amoxicillin hydrate , , amphetamine aspartate , for, acetate , , buspirone hydrochloride , amphetamine sulfate , amphotericinB , amphotericinB cho , busulfex , , tartrate , butyl lesterylsulfate , amphotericinB lipid complex , ampicillin phthalide, , , , cabozan sodium , , , , amtolmet tinib S -malate , , cadrofloxacin , , caffeine inguacil , , anagliptin , , , citrate , cafnea , cafusertib hydrochloride, calcipotriol, calcit , , , andrographolide , anecortave , riol, calcium acetate , calciumfolinate , calcium levofolinate , , , , anlotinib , antazo calcium polycarbophil, calfactant , calmangafodipir , calsurf , line , , antineoplaston A - 10 , antineoplaston , camostat mesylate , , canagliflozin , AS2 - 1 , antofloxacin hydrochloride , antroquinonol, apabeta candesartan , candesartan cilexetil , canfosfamide , , lone , , apatinib mesylate , apaziquone , apilimod , , , , captopril, mesylate , , , apomorphine hydrochlo , carbetocin , carbidopa , , car ride, , , , aramchol, arani bocysteine , , cardidopa , , carglumi dipine , arasertaconazole , arasertaconazolenitrate , arba cacid , , , , carotegastm clofen , , arbekacin , arbekacin sulfate , ethyl, , carteolol hydrochloride , carumonam , , , , arhalofenate , , carvedilolphosphate , , , arimoclomol, , , , , 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 cefminox , cefoperazone , cefoperazone sodium , cefoselis , luren , , atazanavir sulfate , , , cefotaxime, cefotaxime sodium , cefotiam , cefozopran , cef , atorvastatin calcium , atorvastatin , pirome, cefpodoxime, cefprozil, ceftaroline, ceftaroline fos , , , auranofin , auriclosene , amil , ceftazidime, ceftibuten , ceftobiprole medocaril , avacincaptadpegol sodium , avacopan , , avatrom ceftolozane sulfate, ceftriaxone , ceftriaxone sodium , cefu bopag, avibactam , avibactam sodium , AvidinOx , aviptadil , roxime, cefuroxime sodium , , celgosivir , celip avitinib , avoralstat , , , , azacy rolol , cellprotect, cenestin , , censavudine , cen US 2019 /0192440 A1 Jun . 27 , 2019 tanafadine, , ceralifimod , cerdulatinib , hydrochloride, dimesna , , , , ceriumnitrate , cetilistat, , , cevi dinoprostone , diphenylcyclopropenone , , meline , , chlocibutamine, chlorhexi , diquafosoltetra sodium , dirithromycin , dis dine , acetate , chlorogenicacid , chloroquine , ufenton sodium , disulfiram , dithranol, d - , docar chloroxoquinoline, chlorpheniramine, chlorpheniramine pamine , , dociparstat , docosanol, , dola maleate , chlorpheniramine polistirex , , chlo setron , , , donafenib tosylate , rthalidone , cholecalciferol, , alfoscerate , , donepezil hydrochloride , , , choline diepalrestat, choline , , doripenem , , dorzolamide hydrochloride , dos ciclopiroxolamine , , cidofovir , , cilas malfate , , , doxazosin mesy tatin , cilazapril , , , , cinacal late , hydrochloride, doxercalciferol, , cet , maleate , cinhyaluronate sodium , , , doxorubicin hydrochloride, doxy tartrate , cipargamin , , , ciprofloxa cycline , doxycycline hyclate , succinate , dron cin hydrochloride , ciraparantag , circadin , cisatracurium abinol, , , , D - tagatose , besilate , , , citalopram hydrobromide, , duloxetine hydrochloride, , , , citrulline , , , clavulanate , , ebselen , ecabet , econazolenitrate , potassium , clavulanic acid , clazosentan , , clevu , edaravone , , edonerpic maleate , dine, , clindamycin hydrochloride , clindamycin , efatutazone, , , eflornith phosphate , , , clobetasolpropionate , clo ine , efonidipin hydrochloride, egualen sodium , eicosapen betasolpropionatefoam , , , clofaz taenoic acid monoglycerides , elafibranor, , , , clomipramine hydrochloride , clonaze elamipretide, , eldecalcitol, eleclazine , pam , , clonidine hydrochloride , , sodium , , eliglustattartrate , elobixibat , eltrom clopidogrel besylate , clopidogrel bisulfate , clopidogrel cam bopag , dihydrochloride , , emdogain , sylate , clopidogrel hydrogensulfate , clopidogrel napadisi , emeramide, emixustat, emodepside , empagli late, clopidogrel resinate , , , cobama flozin , emricasan , , enalapril, enalaprilmaleate , mide , , , cobiprostone , , , , citrate , , codeine polistirex , colchicine , colecalciferol, , , , gluconate , enoxaparin , daropate , , colis sodium , , entacapone , entasobulin , entecavir , ente timethate sodium , , , copperhistidine , cavir maleate , , entospletinib , , enzalu cortexolone 17alpha -propionate , cositecan , , cri tamide , enzastaurin , epacadostat, epalrestat , , epe danimod sodium , , , , traborole , sulfate , hydrochloride , crolibulin , , cromolyn sodium , epinephrine, , epirubicin hydrochloride, episal dihydrochloride , , lactate , van , epitinib , , epoprostenol, epristeride , eprodi hydrochloride , , cyclo sate , eprosartan , eptaplatin , eravacycline , erdafitinib , phosphamide monohydrate , cyclosporin , , erdosteine , mesylate , , ertapenem , erte , , cytarabine ocfosfate , dab berel, ertugliflozin , , erythromycin acistrate , igatran etexilate , , daclatasvir , , dal erythromycin stinoprate , , , esket bavancin , , dalfampridine , dalfopristin , hydrochloride, , , sodium , , danirixin , hydrochloride , , esomeprazole , danoprevir , sodium , danusertib , dapaconazole , esomeprazole strontium , esomeprazole , , estradiol, dapagliflozin , dapagliflozin propanediol, , dapi , , , virine, , daprodustat, , , dari estrodiol, , esuberaprost sodium , , naparsin , , dasabuvir , , das?traline , etamicastat, ethambutol hydrochloride , ethaselen , ethi , , decuprate, defactinib , deferasirox , nylestradiol, ethylhydrogenfumarate calcium , ethylhydro deferiprone , deferoxamine mesylate , , deflexifol, genfumarate magnesium , ethylhydrogenfumara tezinc , ethy , delamanid , delapril , delapril hydrochloride , nylestradiol, etidronicacid , etimicin sulfate , , denibulin , deoxyandrographolide , dermatansul etirinotecanpegol, , , , etopo fate , , hydrochloride, , side , phosphate , , , etripamil, desmopressin , desmopressin acetate , , , eupatilin , hydrochloride , , evofosf , deudextromethorphan hydrobromide, deu , evogliptin , , exendin ( 9 - 39 ) , exeporfinium teporfin , deuterated levodopa , deuteratedvenlafaxine , deu chloride , ezatiostat , , ezutromid , fadolmidine , , , dexamethasone acetate , dex , faldaprevir , falecalcitriol, famciclovir , famitinib , amethasone cipecilate , dexamethasone palmitate , , fampridine , faropenem , fasitibant chloride , faso dexamethasone sodiumphosphate , dexamfetamine, dex , , fasudil hydrochloride, fasudil mesylate , anabinol, dexferrum , trometamol, dexlanso favipiravir , , febuxostat, fedovapagon , felbam prazole, , , dex ate , trometamol, , femitra , , dexrazoxane, dexsotalol, hydrochloride , , fenofibrate , fenofibric acid , saccharate , dextroamphetamine sulfate , , , , fenretinide , , fentanyl cit dextromethorphan hydrobromide , , rate , , fermagate , ferriccitrate , ferricmaltol, diacerein , diamorphine hydrochloride , dianhydrogalactitol, ferumoxytol, fumarate, , fexinida , diazoxidecholine , , diclofenac potas zole , , fibrinsealant, fibrinogen , fibrinogenseal sium , diclofenac sodium , , , ant, , filanesib , , filociclovir , , , , digoxin , dihomog fimaporfin , fimasartan , , finafloxacin hydrochlo amma- linolenic acid , dihydroergocristine, dihydroergot ride , , finerenone , , fipamezole, firte amine , mesylate , , diltiazem canpegol, , , , flomoxef , US 2019 /0192440 A1 Jun . 27 , 2019

, fluazolepali , , , fluma sucrosofate , irofulven , iron isomaltoside1000 , iron protein tinib , , , acetonide, fluo succinylate , irosustat, maleate, cinonide, fluorapacin , , , fluoxetine chloride/ sulfate , isodibut, , , isopropy hydrochloride , , , flurbiprofenaxetil, lunoprostone , isosorbidedi , isosorbide mononitrate , flurbiprofen sodium , flurithromycin , , fluticasone isosteviol, isothiafludine , , , istarox furoate , , , , flu ime , istradefylline , itacitinib , hydrochloride, itra voxamine , folic acid , folinate , foliumginkgo , fomepizole , conazole , ivabradine hemisulfate , ivabradine hydrochloride , fonadelpar, sodium , , , for , , ivosidenib , , , moterol, fumarate , , , citrate , kallikrein , kangbeide , , ketan , fosbretabulin , fosbretabulin disodium , fosflu serin , , , , Ketorolac conazole , fosfomycin , fosfomycindi sodium , fosfomycintro tromethamine , , kevetrin , kukoamine Bmesylate , metamol , fosinopril , fosinopril sodium , fosmidomycin , fos L - 4 - chlorokynurenine, , , , , , fosravuconazole , fostamatinib , ladarixin , , laflunimus, , , lam tromethamine, fotagliptin benzoate , fotemus otrigine , , landiolol hydrochloride , laninamivir tine, , fruquintinib , fudosteine , , octanoate , lanoconazole , , carbon , , , , gabapen ate , , , laromustine , , lasofox tinenacarbil , gabexate mesylate , , , ifene , , latanoprostenebunod , lauflumide, ledi , gadoxetate disodium , , pasvir , lefamulin , , , , , galidesivir , nitrate , galunisertib , gam lentinan , lentinansulfate , lentinanviral, mesylate , bogic acid , , ganciclovir , ganetespib , , lesinurad , leteprinim , letermovir, , acetate , , , gatifloxacin mesylate , , acetate , levalbuterol, levalbuterol gedatolisib , , gemcabene , , gemcitabine hydrochloride , , , levamlodipine hydrochloride , , , gemigliptin , besylate , levamlodipine maleate , , levobupiva gemigliptintartaric acid , , gentamicin , gentiopicrin , caine , , levocabastine hydrochloride , levocar , , , , nitine , dihydrochloride , levodopa , levodoxa maleate , gilteritinib , gimeracil , ginsenosideC - K , ginsenosi zosin mesylate , , , deRg3 , , glasdegib , glatiramer acetate , glecaprevir , , levonadifloxacin arginine , levonorg glesatinib glycolate , , , , estrel , butanoate , levo - phencynonate hydro , , , glutathionarsenoxide , chloride , levornidazole , , levosimendan , levo phenylbutyrate , glycopyrronium , glycopyrronium thyroxine sodium , levotuss, L - glutamine , lidocaine , bromide , glycopyrronium tosylate , glycyrrhizi cacid , gan , ligustrazine hydrochloride , limaprost, linagliptin , glioside , golotimod , gosogliptin , , granisetron , liothyronine , liothyronine sodium , lipobean , lipo hydrochloride , , , guaimesal, guanfa somal , lipoteichoic acid , liranaftate, lisdexamfet cine , gusperimus trihydrochloride, haemophilusinfluenzae, amine, lisinopril, , lisuridehydrogen maleate , lithi halobetasol propionate , halofantrine , , healon , umcitrate , lithiumsuccinate , lixivaptan , lobaplatin , , hemearginate , hemocoagulase acutus , lobeglitazone , carbonate , , , , Herbiron , hetrombopag , hextend , higenaminehy , lomerizine dihydrochloride, , lona drochloride , dihydrochloride , HPPHphotosensi farnib , , , loperamideoxide, , tizer, humanapotransferrin , humanplasminogen , huper , , , , , zineA , hyaluronate sodium , hydralazine , hydrochloride, L - ornithineL - aspartate , , losartan , losartan potas , , hydrocodone bitartrate , sium , losmapimod , loteprednoletabonate, , loxap hydrocodone polistirex , , hydrogenperoxide , ine , , L - , , , , hydromorphone hydrochloride, hydroxo lucerastat, lucinactant, lucitanib hydrochloride , lulicon cobalamin , , hydroxychloroquine , , , sulfonate , lumefan hydroxyprogesterone caproate , hydroxysafflor yellowA , trine , , lunacalcipol, , lurbinectedin , hylastan , , hypoestoxide , ibandronate , ibandronic luseogliflozin hydrate , lusutrombopag , lysine acetylsalicy acid , iberogastN , ibodutant, ibrutinib , , , late , , , , magnesium car , ibutilide fumarate , icaritin , , icosabutate , bonate , magnesium isoglycyrrhizinate , , mani icosapent, icosapentethyl, icosapentethylester , dipine , dihydrochloride , mannitol, , hydrochloride , , idasanutlin , idebenone , idelal maribavir , marizomib , masilukast, , , isib , idoxuridine, idronoxil , , ifetrobansodium , igu maxacalcitol, , mebiphon , , ratimod , ilansoprazole , , , , ilo mecamylaminehydrochloride ,mechlorethamine , mecobala prostbetadexclathrate , , imatinibmesylate , min , , medroxyprogesteroneacetate , imeglimin , , imidapril, salicylate , , , megestrolacetate , meisuoshuli , imidol hydrochloride, imigliptin dihydrochloride, imi , , , melphalanflufenamide penem , imiquimod , imisopasem manganese , imrecoxib , hydrochloride , , memantine hydrochloride , , incobotulinumtoxin , , inda menadione sodium bisulfite , , , caterol maleate , , , Indimitecan , , mercaptamine , mercaptamine bitartrate , mer , indisetron , , , indotecan , captamine hydrochloride , mercaptopurine , merestinib , indoximod , inecalcitol, , Ingavirin , ingenolmebu meropenem , merotocin ,mesalamine , , metacavir, tate, inhaled sodium nitrite , ferric carboxymaltose , inosine , , metamizolesodium , , , , iodiconazole , ipatasertib dihydrochloride, ipra metformin , metformin hydrochloride , methadone , methazo gliflozin , ipratropium , , iptakalim , irbe - lamide, , , methylaminolevuli sartan , , irinotecan hydrochloride, irinotecan nate hydrochloride , bromide, methylnal US 2019 /0192440 A1 Jun . 27 , 2019

trexone, , methylphenidate hydrochloride , lodrostat, , Osiris Phleum pratense , , , methylprednisolone aceponate , meth oteracil potassium , oteseconazole , , oxaloacetic ylthioninium chloride, , , meto acid , , , , oxfendazole, prolol, succinate , , , oxidizedglutathione sodium , , , oxy , , , , micon butynin hydrochloride , , oxycodone hydrochlo azole nitrate , , midazolam hydrochloride , mido ride , , oxymetazoline hydrochloride , oxymor drine , midostaurin , mifamurtide, , migalastat, phone, , , Ozagrel hydrochloride, miglitol , miglustat , , , , ozagrelsodium , , ozenoxacin , , paclitaxel , , minocycline hydrochloride, mino poliglumex , pacritinib , , , paliperi dronic acid , , , miriplatin hydrate , done palmitate , palmidrol, , palovarotene , , mirodenafil hydrochloride , , mir pamidronate disodium , pancrelipase , panipenem , panobin tazapine , , , mitomycin , mitoxan ostat, , , , paricalcitol, trone , hydrochloride , mivotilate , , paritaprevir, , parogrelil, , , dihydrobromide , , , paroxetine hydrochloride hemihydrate , parox , doxycycline , modipafant, moexipril , , etine mesylate , patiromer calcium , patupilone, , , hydrochloride , momelotinib , , pazufloxacin mesylate , pefcalcitol, peficitinib , , monepantel, monoammonium glycyrrhizinate , pegylatedapo - , pelubiprofen , , pem , monosodium alphaluminol, monoterpene etrexed disodium , , pemirolast potassium , pemi perillyl alcohol , , montelukast sodium , mont rolast sodium , penciclovir , penehyclidine hydrochloride , morillonite , , morinidazole , , morphine , pentetate calcium trisodium , pentetatezinc tri glucuronide , morphine , morphine sulfate , mor sodium , pentetrazol, pentosan polysulfate sodium , pentosta phothiadine mesilate , , motolimod , , tin , , peramivir , , perchlozone , , moxifloxacin hydochloride , moxonidine , peretinoin , , perflubronemulsion , perfluorooctyl moxonidine hydrochloride , , muparfostat bromide , , maleate , perifosine, perin sodium , , mycobactovir , mycophenolatemofetil , dopril , perindopril arginine , , pevonedistat, pexi myristylnicotinate , , , , dartinib , PhagoBioDerm , phenchlobenpyrrone, phenethyl N - acetylcysteine , nacystelyn , , , , hydrochloride , phenter , hydrochloride , , nal mine , hydrochloride , mesylate , buphine , sebacate , , , phenylbutyrate , , phenylephrine hydrochlo , , , naloxone hydrochloride , ride, phenytoin , phosphazid , pibrentasvir, picibanil, picroliv , , naltrexone hydrochloride , , picropodophyllin , pidotimod , , pilocarpine decanoate , napabucasin , , naphthoquine , hydrochloride, , pimasertib hydrochloride, pima , naproxen sodium , naquotinib mesylate , naratrip vanserin , , , , tan , narlaprevir , nasapaque, nasaruplase , nastorazepide cal pinometostat, pioglitazone , pioglitazone hydrochloride, cium , , navamepent, nazartinib , , necu , pipecuronium , piperacillin , piperacillin paranib , , , , , sodium , piperaquine, piperaquine phosphate , piperidone , , , neoandrogra hydrochloridum , , piperphentonamine, , pholide, , methylsulfate , , , pirmenol, , pirotinib , , nepafenac , nepicastat , nepolong , , , piroxicambetadex, pitavastatin , pitavastatin cal , , , netilmicin , , cium , , , plazomicin , pleconaril , plerixa , , , , , nico for , plinabulin , pocapavir, hydromorphone, podofilox , pol tiflorin , , nicotinicacid , nicousamide , , aprezinc , , polydatin , polyoxidonium , , nifeviroc , Nifurtimox , , nikkomycin , methionil , , , pone , , , , , simod , , , posiphen , potassium , ningetinib , , , , bicarbonate , potassium citrate , potassium clavulanate , pozi nitazoxanide, nitisinone, , nitricoxide , nitroglyc otinib , , pradefovir , , pramipexole , erin , nitroglycerine , , nokxaban , nolatrexed , , , pranlukast hydrate , , acetate , , , nore , , , , predniso thindrone , norethindrone acetate , norethindrone enantate , lone, prednisoloneacetate , sodiumphosphate , , , , norges , , prempro , presatovir , pretomanid , timate , , norursodeoxycholic acid , obeticholi previdersin , prexasertib , , , pritelivir, cacid , octenidine , octohydroaminoacridine succinate , oct hydrochloride, , prochlorpera reotide , hydrochloride , odalasvir , , zinemaleate , profezyme, , , proges odiparcil, , , , olesoxime, olic togendienogest , proguanil , , promitil , eridine , olmesartan , olmesartan cilexetil , olmesartan medox , propagermanium , , , pro omil, , olodaterol hydrochloride, , olo pranolol hydrochloride , prostat , proxodolol, , patadine hydrochloride , , , oltipraz , , prurisol, prussianblueinsoluble , pseudoephed omacetaxine mepesuccinate, omadacycline , omarigliptin , rine , hydrochloride , , puquitinib omaveloxolone , ombitasvir, omecamtivmecarbil, omega mesylate , pyrazinamide, pyridoxamine dihydrochloride, 3carboxylicacids , , omigapil , , pyridoxine hydrochloride , pyrimethamine , pyronaridine , onalespib , , , ondelopran , opica pyrroltinibmaleate, , fumarate , quetiap pone , , methylphenidate , orcinoside, orilotimod , ine , hydrochloride , quinapril hydrochloride , oritavancin , , ornithine phenylacetate , ornoprostil, sulfate , sulfate , quinupristin , , , , orthovisc , , oseltamivir, osi quizartinibdi hydrochloride, , rabeprazoleso US 2019 /0192440 A1 Jun . 27 , 2019

dium , rabeximod , , radezolid , , ralfina sparsentan , spebrutinib , spirapril, , squala mide, ralimetinib , ralinepag , , , ralti mine , stannsoporfin , , S - , stepronin , trexed , , , ramipril , , , streptozocin , strontium malonate , strontium , ranitidine bismuth citrate , , rasagiline , ranelate, succinic acid , , sucroferric oxyhydroxide , ravidasvir hydrochloride , raxatrigine , , rebas , suftalanzinc , , sulbactam , sulbactam tinib , , reboxetine mesylate , recilisib sodium , sodium , sulcardine sulfate , sulfamethoxypyrazine , sulfasala recoflavone , redaporfin , ibuprofen , naproxen , glycopyrro zine , sulfatinib , sulfonylurea , , sulfotanshinone nium bromide , refametinib , , relebactam , releno sodium , , , sulphamethoxazole , pride , , remeglurant , , remifentanil sulthiame, , sumatriptan succinate , , hydrochloride , , remimazolam tosylate , remo sunstone , suplasyn , suplatast tosilate , sodium , vera gliflozin etabonate , , reparixin , repirinast, aml pamil hydrochloride , , sutezolid , , exanox , hydrochloride , bucillamine, gua tacalcitol, , , , , tafeno nabenz , , naltrexone , nitisinone , ondansetron , quine , , tafoxiparin sodium , taladegib , , phacetoperane, , rosiglitazone , sodium phenylbu , , , , , tyrate , , resiquimod , , , , tamsulosin hydrochloride, , tane retagliptin , retapamulin , retigabine , retinoicacid , retosiban , spimycin , , tarafenacin , , tarloxotinib , , , rhein , rhenium bromide , taselisib , , tasquinimod , , 186 etidronate , ribavirin , , ricolinostat, ridinila , tazarotene , tazemetostat, tazobactam , tazo zole , ridostin , , , , , bactam sodium , tebipenem pivoxil , tecarfarin , tecovirimat, , rigosertib sodium , rilapladib , rilpivirine, rilpiv sodiumsulfonate , , phos irine hydrochloride, , , rimeporide, phate , tefinostat, , , teicoplanin , telaprevir, , riociguat, hydrochloride hydrate , rise acetate , telatinib , telbivudine, telithromycin , dronate sodium , , , , rivastig , telotristatetiprate , temanogrel, temocapril , mine , rivipansel sodium , , rizatriptan benzoate , , , , tenalisib , tena rmulation , , , rokitamycin , , panor , teneligliptin , tenofovir , tenofoviralafenamide , teno romurtide , ronacaleret, roneparstat, ronopterin , , fovirdipivoxil fumarate , aspartate , teno ropinirole hydrochloride , , rosebengal sodium , fovir disoproxil fumarate , , , , rosiglitazone , rosiglitazone maleate , rosiglitazone sodium , terameprocol, , , terbinafine hydrochlo rostafuroxin , , rosuvastatin calcium , , ride , , , , , tes rovatirelin , , , , tosterone , undecanoate , tetrabenazine , tetra phosphate , , , , ruxolitinib , caine , hydrochloride, tetrahydrocannabidiol, S - ( - ) - phosphate disodium , sabarubicin , sacu tetrathiomolybdate , , , , the bitril, , , salbutamol sulfate , salicyclic liatinib , , therapeutic , , acid , , salmeterol xinafoate , salubrinal, salvicine , hydrochloride , , , thromboreductin , thyrox samarium ( 153Sm ) lexidronam , , S - amlodipine ine , , , , , , nicotinate , , sapropterin , sapropterin dihydro tigecycline , tiludronatedi sodium , timolol , timololmaleate , chloride, , saracatinib , sarecycline, saroglitazar, tindamax , , , , tio hydrochloride, , saxagliptin , scopol pronin , , tiotropium bromide monohy amine , scorpionvenom , omega - 3polyunsaturated fatty acid , drate , tipelukast, hibenzate , , tipiracil secnidazole , acetate , , selegiline hydrochloride , , tirapazamine , tirasemtiv , , hydrochloride , selepressin , , , selinexor, , tirofiban hydrochloride, , , tiza selisistat, , , sepranolone , seratro nidine, tobramycin , tocofersolan , tocoretinate , , dast, , , sertaconazole nitrate , sertin tofogliflozin , tolcapone, , , , dole , , sertraline hydrochloride , , seve tolterodine tartrate , , tonabersat, , lamer carbonate , sevelamer hydrochloride , , topiroxostat, , topotecan hydrochloride , , sevuparin sodium , maleate , , toreforant, , tosedostat, , sibutramine mesylate , , sildenafil citrate , totrombopag , tozadenant, , trabodenoson , trad dihydrogen succinate , silmitasertib , , silver sulfa ipitant, , tramadol hydrochloride, , tran diazine , , simmitecan hydrochloride , simotinib dolapril , tranexamic acid , tranilast, transcrocetinate - sodium , hydrochloride , , sinotecean , , siroli transepithelial riboflavin , trantinterol hydrochloride , travo mus, , sitagliptin , sitagliptinphosphate , sive prost , , trehalose , trelagliptin succinate , , lestat, sizofiran , smilagenin , S -modafinil , sobuzoxane , , treprostinil diolamine , , sodium aescinate , sodium ascorbate , sodium benzoate , acetonide , triapine , , , trichlormethi sodium bicarbonate , sodium chromoglycate , sodium ferric azide , triciribine , , , trientine gluconate complex , sodium glycididazole , sodium hydrochloride, trifarotene , trifluridine , , triheptanoin , gualenate , sodium hyaluronate , sodium ibandronate , sodium , trimebutine3 -thiocarbamoyl -benzenesulfonate , nitrate , sodium nitrite , , sodium phenylac tosylate , , , trimetrex etate , , sodium polysulthionate , ate , trinitrate , tripotassium dicitratobismuthate , , sodium prasteronesulfate , sodium pyruvate , sodium tauro , , trospiumchloride , , cholate , , sodium zirconiumcyclosilicate , , , , tylerdipinehydrochloride , , , , , , ubidecarenone, , , ulinastatin , solithromycin , sonidegib , sonolisib , sophocarpine, sophori ulipristal, ulixertinib , , umeclidinium , umecli dine hydrochloride , , sorbitol, sotagliflozin , sotiri dinium bromide , upamostat, uprosertib , uracil, , uri mod , sotrastaurin , sotylize , sovaprevir , , dinetriacetate , uroacitides, , ursoli US 2019 /0192440 A1 Jun . 27 , 2019 cacid , vaborbactam , , valaciclovir , valaciclovir Belladonna Extract, Belladonna Liquid Extract, Belladon hydrochloride , , , valganciclovir , nae Herba, Benincasae Exocarpium , Benzoinum , Berberidis valomaciclovir stearate , valproic acid , , valsartan , Radix , Bergeniae Rhizoma, Bergenin , Bistortae Rhizoma, valsartan trisodium hemipentahydrate , , vanco Bletillae Rhizoma , Bolbostemmatis Rhizoma , Bombyx mycin hydrochloride, , vaniprevir , , Batryticatus , Borneolum Syntheticum , Borneolum , Bovis vapendavir , hydrochloride , , varithena , Calculus Artifactus , Bovis Calculus Sativus, Bovis Calculus, varlitinib , vatiquinone, vavelta , , velpatasvir, Breviscapine , Broussonetiae Fructus, Bruceae Fructus, , , , , 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 hydrochloride , verosudil , verte rophyllae Folium , Calomelas, Campsis Flos, Canarii Fruc porfin , , verubulin , vesatolimod , , tus , Canavaliae Semen , Fructus, Capsici Fructus, , vicagrel, , , vilanterol trifena Carotae Fructus , Carpesii Fructus, Carthami Flos, tate, , , vildagliptin , sulfate , Caryophylli Flos, Caryophylli Fructus, Cassiae Semen , Cas , , , , 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 , , , vor natum , Cervi Cornu Pantotrichum , Cervi Cornu , Cervi Cor inostat , , vortioxetine hydrobromide, vosaroxin , nus Colla , Chaenomelis Fructus, Changii Radix , Chebulae voxilaprevir , , xemilofiban , yimitasvir , yonkenafil , Fructus Immaturus, Chebulae Fructus , Chelidonii Herba , zabofloxacin , , , , , Chinese Angelica Liquid Extract, Chloriti Lapis , Choero Zamicastat , zanamivir , zemiStatin , Z - endoxifen hydrochlo spondiatis Fructus , Chrysanthemi Flos, Chrysanthemi Indici ride , , zidebactam , , , 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 , , zoliflodacin , , zolpi Ramulus, Oil , Cirsii Herba , Cirsii Japonici Herba dem , tartrate , , , , Carbonisata , Cirsii Japonici Herba , Cissampelotis Herba , , , and zuretinol acetate . Cistanches Herba , Citri Exocarpium Rubrum , Citri Fructus , [0089 ] 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 CalamiRhizoma , 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 , nalis 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 US 2019 /0192440 A1 Jun . 27 , 2019

Semen , Eupolyphaga Steleophaga, Euryales Semen , Fag issimum Oil, Olibanum , Omphalia , Ophicalcitum , Oph opyri Dibotryis Rhizoma, Farfarae Flos , Ferulae Resina , iopogonis Radix , Orostachyis Fimbriatae Herba , Oroxyli Fibraureae Caulis , Fibriuretinin , Fluoritum , Foeniculi Fruc Semen , Oryzae Fructus Germinatus , Osmundae Rhizoma, tus , Forsythiae Fructus, Fraxini Cortex , Fritillariae Cirrho Ostreae Concha , Paeoniae Radix Alba , Paeoniae Radix sae Bulbus, Fritillariae Hupehensis Bulbus , Fritillariae Pal Rubra , Panacis Japonici Rhizoma, Panacis Majoris Rhi lidiflorae Bulbus, Fritillariae Thunbergii Bulbus, Fritillariae zoma, Panacis Quinquefolii Radix , Papaveris Pericarpium Ussuriensis Bulbus , Galangae Fructus, Galla Chinensis , SI, Paridis Rhizoma, Patchouli Oil , Pegaeophyti Radix Et Galli Gigerii Endothelium Corneum , Ganoderma, Capillary Rhizoma, Oil , Perillae Caulis , Perillae Folium , Wormwood Extract, Gardeniae Fructus Praeparatus , Garde Perillae Fructus , Periplocae Cortex , Persicae Ramulus , Per niae Fructus , Gastrodiae Rhizoma, Gecko , Gei Herba, Gen sicae Semen , PeucedaniDecursivi Radix , Peucedani Radix , darussae Herba , Genkwa Flos, Gentianae Macrophyllae Pharbitidis Semen , Phellodendri Amurensis Cortex , Phello Radix ,Gentianae Radix Et Rhizoma, 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 , PolygoniMul 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 , Propolis , 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 , / - , 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 , 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 , Notoginseng Triol Semen Praeparatum , Solidaginis Herba, Sophorae Flaves Saponins, Notopterygii Rhizoma Et Radix , Ocimum Grat centis Radix , Sophorae Flos, Sophorae Fructus , Sophorae US 2019 /0192440 A1 Jun . 27 , 2019 13

Tonkinensis Radix Et Rhizoma, Sparganii Rhizoma content can be mixed with solution in which the API is either Spatholobi Caulis , Spiceleaf Kernel Oil, Spirodelae Herba , dissolved or suspended . The solution is then atomized / Stachyuri Medulla Helwingiae Medulla , Stalactitum , Star sprayed atop a printing layer during the course of the Anise Oil, Stauntoniae Caulis Et Folium , Stellariae Radix , three -dimensional printing of the dosage form . Once the Stemonae Radix , Stephaniae Tetrandrae Radix , Sterculiae solution containing the drug content dries, the drug content Lychnophorae Semen , Strychni Semen Pulveratum , is dispersed in the dosage form . Nanoparticles have large Strychni Semen , Styrax , Suis Fellis Pulvis , , Swertiae surface area and will have high dissolution rate . Herba, Swertiae Mileensis Herba , Syngnathus , Syringae [0096 ] 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 naliae Belliricae Fructus , Testudinis Carapacis Et Plastri 200 nm , 1 nm , 2 nm , 3 nm , 4 nm , 5 nm , 6 nm , 7 nm , 8 nm , Colla Testudinis Carapax Et Plastrum , Tetrapanacis 9 nm , 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 nm , 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 priate synthesis methods and /or systems. To obtain nano lospermi Caulis Et Folium , Trachycarpi Petiolus, Tribuli particles within a desired size range , the synthesis conditions Fructus, Trichosanthis Fructus , Trichosanthis Pericarpium , may be properly controlled or varied to provide for, e . g ., a Trichosanthis Radix , Trichosanthis Semen Tostum , Tricho desired solution concentration or a desired cavity range ( a santhis Semen , Trigonellae Semen , Trionycis Carapax , Tsa detailed review can be found at, e . g ., Vincenzo Liveri, oko Fructus , Turpentine Oil, Turpiniae Folium , Typhae Controlled synthesis of nanoparticles in microheterogeneous Pollen , Typhonii Rhizoma, Uncariae Ramulus Cum Uncis , systems, Published by Springer , 2006 ) . Vaccariae Semen , Valerianae Jatamansi Rhizoma Et Radix , [0097 ] In certain embodiments , the drug content is in the Verbenae Herba , Vespae Nidus, Vignae Semen , Violae form of microneedles as illustrated in FIG . 7 . The Herba , Visci Herba , Vitex Oil , Viticis Fructus , Viticis microneedle would be printed in conjunction with the dos Negundo Folium , Vladimiriae Radix , Weeping Forsythia age form or inserted into the dosage form during the Extract, Wenyujin Rhizoma Concisum , Xanthii Fructus , three- dimensional printing of the dosage form . The Zanthoxyli Pericarpium , Zanthoxyli Radix , Zaocys, Zedo microneedles can be composed of a saccharide, a PLGA ary Oil, Zingiberis Rhizoma Praeparatum , Zingib polymer or an API or a combination thereof. The eris Rhizoma Recens, Zingiberis Rhizoma, Ziziphi Spinosae microneedle can assist in the penetration of an API into the Semen . circulatory system of a patient when administered either [ 0090 ] In certain embodiments , the drug content further parenteral or enteric . comprises a medium . The medium can be associated with [0098 ] In certain embodiments , the drug content forms a the API, i . e ., the medium is in physical contact with the API. network . As shown in FIG . 8A , a dosage form has a substrate In certain embodiments , the API is embedded in the forming a compartment loaded with a drug content. The medium . In certain embodiments , the API is dispersed drug content has a substrate forming a network . The frame within the medium . In certain embodiments , the medium is structure of tablet is made of a material that dissolves made of a thermoplastic material as disclosed herein . between 1 - 10 minutes , and the substrate dissolves in 2 -60 10091 ] In certain embodiments , the medium comprises a seconds, preferably in 2 , 5 , 10 , 15 , 20 , 25 , 30 , 35 , 40 , 45 , 50 , water - soluble excipient selected from the group consisting 55 , 60 seconds. As shown in FIG . 8B , the API can be of cocoa butter , polyethylene glycol ( PEG ) , sucrose , glu released in seconds after the dosage form is administered . In cose , galactose , fructose , xyloselactose , maltose , trehalose , certain embodiments , the substrate also forms a network , sorbitol, mannitol, maltodextrins , raffinose , stachyose , which can further accelerate the release of the API. fructo -oligosaccharides and a combination thereof. In cer [0099 ] The drug content can be made using an additive tain embodiments , the substrate further comprises a plasti method such as fused deposition modeling (FDM ) . In cer cizer . tain embodiments , the drug content can be made by using a [ 0092 ] The drug content can be of any suitable shape and three - dimensional printer (3D printer ) configured to extrud size to be loaded into the compartment . ing a mixture of API and the excipient. The API can be 10093 ]. In certain embodiments , the drug content is oper melted and mixed homogenously with the melted substrate ably linked to the compartment via covalent bond , non before being extruded . Alternatively , the API in a solid form covalent interactions or through a linker. Thus , the drug ( e . g ., powder ) can be mixed with and dispersed in themelted content and the substrate can be made separately and asso substrate before being extruded . In general, the extrusion ciate together through a covalent bond or non - covalent process can be conducted at temperatures 10° to 40° C . interactions . In certain embodiments , dosage form is made above the glass transition ( Tg ) of the substrate and a by producing the drug content and the substrate in a single temperature close to the of the API . Once at a process using 3D printing methods. suitable temperature for use in the three - dimensional printer, [ 0094 ) In certain embodiments , the drug content is formed the substrate can be deposited to the three - dimensional in the shape of a compressed tablet, an oval tablet, a pill, or printing surface . The shape and size of the drug content can a capsule . In certain embodiments , the shape of the drug be controlled by programming the three - dimensional print contentmatches the shape of the compartment. For example , ing process . In certain embodiments , the drug content is when the compartment is a pie - shape , the drug content is fabricated in the same process of the substrate . In certain also of a pie - shape , e . g . , to fill the compartment. embodiments , the drug content is fabricated before the 10095 ) In certain embodiments , the drug content is in the making of the substrate and loaded into the compartment form of nanoparticles as illustrated in FIG . 6 . The drug during or after the substrate is fabricated . US 2019 /0192440 A1 Jun . 27 , 2019 14

[0100 ] In certain embodiments , when the drug content is time to dissolve the plugs and to open the compartments to loaded into the compartment, it is associated with the release the drug content. As illustrated in FIG . 10C , the substrate , e . g . , embedded or fixed in the substrate . In certain shortest plug dissolves first , releasing the API from the first embodiments , the drug content is detachable from the sub compartment. When the API in the first compartment is strate when loaded into the compartment. completely released , the plug of the median length dissolves, releasing the API from the second compartment. When the D . Controlled Release API in the second compartment is completely released , the [ 0101 ] 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 [ 0102] 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 reduction in peak through ratios, targeted release of the drug partment is released , and the plasma drug level increases to specific areas within the gastro intestinal tract, and again . When the API released from the second compartment absorption independent of the feeding state, thus may be reaches the second peak and starts to be eliminated , the plug used to prevent tolerance , reduce the side - effects and of the third compartment dissolves to open the compartment. improve patient compliance , which is desirable to treat As a result , the plasma API level is maintained above the diseases like ADHD . For another example , a release profile critical level for a long time, which benefits certain diseases . with a loading dose followed by a maintenance dose may be [0106 ] The consecutive release manner can also be good for treating chronic conditions such as hypertension achieved through another exemplary dosage form having and diabetes . several drug contents packed in the form of layers as [ 0103 ] Some of the mechanisms to control the release illustrated in FIG . 10B . The API can be released in a profile using the dosage from disclosed herein have been sustained manner by having each layer dissolving in syn discussed above . For example , by manipulating the exposed chrony to provide a continuous , sustained release of API as surface area of the substrate that erodes constantly over time, depicted in FIG . 10C . In certain embodiments , the outer the drug content embedded in the substrate is able to deliver layers of the dosage form dissolve immediately and release a constant amount of drug over time. In addition , the release profile can be controlled by the size of compartment opening the embedded drug content when the dosage form is admin and / or by the geometric shape of the compartment. istered . But the layers sandwiched in the middle do not 0104 ] In certain embodiments , the release profile can be dissolve or dissolve much slower because the outer layers controlled by the design of a compartment having an aper block their interface with the environment. The dissolution ture that is sealed or blocked by a plug. The plug is made of of the outer layers exposes the layers sandwiched in the a water - soluble , porous , or erodible material or pH sensitive middle and expedites their dissolution , thus providing a materials or hydrophobic material that will undergo attrition consecutive release profile as illustrated in FIG . 10C . when the dosage form passing the GI tract . When the dosage [0107 ] In certain embodiments , the dosage form com form is administered to a subject, the plug is dissolved , prises a gas- generating component loaded into the first permeated or eroded , thus releasing the drug content from compartment. In certain embodiments , the gas - generating the compartment. The release profile of the drug content can be controlled by choosing a plug of proper erosion /dissolu component is selected from the group consisting of organic tion rate or permeation rate . Alternatively , the release profile acid and carbonates , sulphites , bicarbonates , sodium carbon of the drug content can be controlled by using the shape ate , sodium bicarbonate , sodium metabisulphite , calcium and / or the size of the plug ( e . g ., a rod shape of proper carbonate , and combinations thereof, which on contact with length ) . The release profile can also be controlled by the gastric fluid releases carbon dioxide or sulphur dioxide gas . number of the compartment. FIG . 9 shows an exemplary When the substrate is dissolved , permeated or eroded in dosage form having a substrate forming a plurality of stomach , the gas generating component is exposed to the column - shaped compartments residing on both sides of the acid environment or water penetrate into compartment to dosage form . Each compartment is loaded with a drug induce the reaction between acid and sodium bicarbonate content. Each compartment has an aperture that is blocked and generates gas to release the drug content in an effer by a rod - shaped plug. The plugs have different dissolution vescent manner . rate . Depending on the size , shape and dissolution rate of the [0108 ] The dosage form disclosed herein may comprise plug , the APIs can be released in a sustained , continuous , one or more drug content at least partially in delayed - release simultaneous , consecutive or pulsatile manner. form , wherein the delayed release may be achieved with the [0105 ] FIG . 10A shows an exemplary dosage form pro assistance of conventional materials and methods known to viding a consecutive release profile . Referring FIG . 10A , the the person skilled in the art, for example by embedding the dosage form 700 has a substrate 701 forming three column API in a delayed - release substrate / substrate or by the appli shaped compartments 702 ~ 704 . Each compartment is cation of one or more delayed - release coatings . Through loaded with a drug content of the same API . Each compart delayed release , API release may be so controlled that twice ment has an aperture that is blocked by a rod - shaped plug or once daily administration of the dosage form is sufficient , 705 – 707 . The plugs are made of the same material but have which is advantageous in particular in the case of a need for different length . Consequently , it takes different amount of a sustained level active compound , e. g. , for combating pain . US 2019 /0192440 A1 Jun . 27 , 2019 15

[0109 ] In certain embodiments , the dosage form intends to common type of extrusion printing is fused deposition release the active ingredients in oral cavity instantly . One modeling , which uses solid polymeric filaments for printing . example is to be given to oral cavity or take sublingual In fused deposition modeling , a gear system drives the region . filament into a heated nozzle assembly for extrusion (see L 0110 ] In certain embodiments, the drug form can further Gibson et al . ( 2015 ) Additive Manufacturing Technologies : comprise conventional auxiliary substances known to the 3D Printing , Rapid Prototyping , and Direct Digital Manu person skilled in the art, preferably selected from the group facturing . 2 ed . Springer, New York ). consisting of glyceryl monostearate , semi- synthetic triglyc [0115 ] The manufacturing instructions for a print job may eride derivatives , semi- synthetic glycerides , hydrogenated be generated a variety of ways , including direct coding , 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 [0111 ] 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 . [ 0112 ]. As used herein , 3D printing refers to a process that [0116 ] 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 ; 101171 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 [0113 ] 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 Manufacturing Technologies: 3D Printing , Rapid [0118 ] Personalized dosage form 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 . chusetts Institute of Technology ; H . Lipson et al. ( 2013 ) [0119 ] 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 Manufacturing Tech The instruction is then sent to a 3D printer to manufacture nologies: 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 ). [0114 ] In certain embodiments , the dosage forms dis [0120 ] The dosage form and methods disclosed herein can closed herein are manufactured using extrusion methods . In be used to control release of two or more drugs in order to an extrusion process , material is extruded from robotically optimize the drug combinations in certain therapeutic actuated nozzles. Unlike binder deposition , which requires a regimes. For example , a tablet to treat powder bed , extrusion methods can print on any substrate . A can be designed to offer immediate release of Atorvastatin variety ofmaterials can be extruded for 3D printing , includ calcium and extended release of nicotinic acid . In another ing thermoplastic materials disclosed herein , pastes and example , a non - steroidal anti - inflammatory drug (NSAID ) colloidal suspensions, silicones and other semisolids . One for pain relief may be designed to provide sustained release US 2019 /0192440 A1 Jun . 27 , 2019 16 of NSAID and a rapid release of H2- antagonist for [0127 ] FIG . 17A shows an exemplary dosage form having preventing NSAID - induced mucosal damage . a simultaneous release profile or sequential release profile . [0121 ] In certain embodiments , the substrate forms mul Referring to FIG . 17A , the dosage form 1400 has a substrate tiple compartments , each loaded with a drug content. In containing four segments 1701 – 1704 having different dis certain embodiments , the multiple compartments are con solution rate . In certain embodiments , as illustrated in FIG . nected . In certain embodiments , the multiple compartments 17B , the drug contents are embedded in the segments are disconnected . In certain embodiments , the drug contents 1701 – 1704 and are released simultaneously when the sub loaded into different compartments are the same. In certain strate dissolves . In certain embodiments , each segment embodiments , the drug contents loaded into different com contains a compartment where a drug content is loaded . As partments are different . The dosage form can be so designed illustrated in FIG . 17C , the drug contents are released in a to provide simultaneous or sequential release of multiple sequential manner when the substrate dissolves . drug content to exert synergistic therapeutic effects . [ 0122 ] FIG . 12A shows an exemplary dosage form that Example 1 can release APIs simultaneously . Referring to FIG . 12A , the dosage form 800 includes three stacked layers 801 - 803, [0128 ] This example illustrates a design of dosage form each of which is embedded with a different drug content. As that has controlled release profile . illustrated in FIG . 12B , when the dosage form 800 is [ 0129 ] As shown in FIG . 18A , the dosage form comprised administered , the drug contents are released simultaneously a flat tablet substrate forming a pie shaped compartment. but at different rates as the layers dissolve . The substrate was made of PEG8000 . was used [ 0123 ] FIG . 13A depicts another exemplary dosage form as a module drug content. of simultaneous release profile . Referring to FIG . 13A , the 10130 ]. The release profile of the benzoic acid from the dosage form 900 includes three column shaped compart dosage form was measured as the following method . ments 901 - 903 , in which three drug contents are loaded . Na HPO4 solution of pH 8 was prepared as dissolvent of Each drug content contains an API embedded in a substrate benzoic acid . Benzoic acid solution of 120 ug /mL was of different dissolution rate . As illustrated in FIG . 13B , when serially diluted to 30 ug /mL , 15 ug / m , 7 . 5 ug/ m , 3 . 75 ug /mL , the dosage form 900 is administered , the three APIs are and 1 .875 ug /mL solutions, whose absorbance at 226 nm released simultaneously but at different rates as the sub was measured using a UV spectrophotometer . The numbers strates of the drug contents dissolve . The release rate of the obtained were treated with linear regression to generate a standard curve of benzoic acid concentration with the for APIs can also be controlled by the shape of the compart mula y = 0 .0599x + 0 .0347 . To measure the released amount of ments or the size of the opening of the compartments . benzoic acid , the dosage form was dissolved in degassed pH [0124 ] FIGS. 14A and 14B depict additional exemplary 8 Na HPO , solution at 37° C . + 0 . 5° C . and centrifuged at 100 dosage forms of simultaneous release profile of three APIs . rpm . 5 mL solution was collected from the solution at each Referring to FIG . 14A , the dosage form 1000 contains three time point to measure the concentration of benzoic acid with pie - shaped segments 1001 - 1003 wherein drug contents are 5 mL dissolvent added back to the solution . The collected embedded . As illustrated in FIG . 14C , the drug contents solution was filtered through 0 . 45 um membrane before release simultaneously as the segments dissolve , and the transferred to an UV spectrophotometer for measuring the release rate of the drug contents can be controlled by the dissolution rate of the segments . Referring to FIG . 14B , the absorbance at 226 nm . The percentage of benzoic acid dosage form 1100 contains three pie - shaped segments released was calculated using the following formula : 1101 - 1103 , which are wrapped by a shell 1104 that dis solves slower than the segments . The release rates of the drug contents embedded in the segments are reduced as the Benzoic acid released ( % ) = CAVA + VECn- 1 x 100 shell 1104 blocks the interface of the segments 1101 - 1103 Qbenzoic acid with the environment . [0125 ] FIG . 15A shows an exemplary dosage form of [0131 ] Wherein sequential release profile of two APIs . Referring to FIG . [0132 ] C , means concentrate measured , V , means total 15A , the dosage form 1200 includes a substrate 1201 solution volume, V means sample volume, Qbenzoic acid forming a compartment that is filled by a drug content 1202 . means amount of benzoic acid in the dosage form The substrate 1201 contains a first API, and the drug content [0133 ] The release of PEG8000 is measured using the 1202 contains a second API. As illustrated in FIG . 15B , the following method . To prepare a standard curve of PEG8000 , first API releases as the substrate dissolves when the dosage 0 . 1275 g PEG8000 standard sample was dissolved in water form is administered . The second API does not release until in a 25 mL volumetric flask . Transferring 1 mL , 2 mL 5 mL the substrate dissolves to expose the drug content, providing and 10 mL to 10 mL volumetric flask , respectively , and a sequential release profiles of the APIs . diluted in water to prepare the control solution . Injecting 50 [0126 ] FIG . 16A shows another exemplary dosage form of ul control solutions to a liquid chromatography (three Waters sequential release profiles . Referring to FIG . 16A , the dos UltrahydrogelTM 120 /250 / 500 connected in series, flow age form 1300 has a substrate 1301 forming three column speed at 0 . 5 ml/ min , temperature at 40° C . , measured by a shaped compartments 1302 ~ 1304 loaded with three drug differential refraction detector ). The areas of the volume contents . The compartments 1302 - 1304 have an aperture were measured and used as y -axis . The log numbers of the that are blocked by rod -shaped plugs that have different control solution concentration were used as X -axis . A stan length and /or dissolution rate . As illustrated in FIG . 16B , the dard curve of PEG8000 was generated with the formula of APIs are released in a sequential manner as the plugs y = 1 .024x + 8 . 918 . The percentage of PEG800 released was dissolve sequentially to open the compartments . calculated using the following formula : US 2019 /0192440 A1 Jun . 27 , 2019 17

compartments were enclosed by walls having a thickness of PEG8000 released ( % ) = -ChV1 + VsCn - 1 x 100 0 . 75 mm and 2 . 25 mm , respectively. QPEG8000 10140 ] To detect the release ofthe drug content, the dosage form was added to 900 ml phosphate buffer of pH6 . 8 at 100 rpm . The UV absorption of the buffer was assayed to [0134 ] wherein Cn means concentration measured , determine the release of the drug content. [0135 ] Vémeans volume of solution , V , means sample [0141 ] The results of the release assays were illustrated in volume, FIGS . 19C and 19D . As shown in FIG . 19C , when the first [ 0136 ] PEGS000 means amount of PEG8000 in the dosage dosage form was added to the buffer for 20 min , the first form compartment was open , and the drug content in the first [ 0137 ] Results : as illustrated in FIG . 18C , the release compartment was released . The second compartment was profile of the benzoic acid matches a model profile accord not open till 40 min after the dosage form was added to the ing to D . Brooke and R . J . Washkuhn ( Zero -Order Drug buffer. For the second dosage form , whose results were Delivery System : Theory and Preliminary Testing , J Pharm illustrated in FIG . 19D , the second compartment was not Sci ., 1977 , 66 : 159 - 162 ) and was controlled by the interface . open till 60 min after the dosage form was added to the Therefore , a controlled release profile can be designed buffer . Therefore , the release profile of the dosage form can according to the dosage forms disclosed herein . be controlled through the thickness of the wall that encloses a compartment. Example 2 [0142 ] While the principles of this invention have been [0138 ] This example illustrates a design of dosage form described in connection with specific embodiments , it that controls release of drug contents from different com should be understood clearly that these descriptions are partments . made only by way of example and are not intended to limit [0139 ] Dosage design : two dosage forms were produced the scope of the invention . What has been disclosed herein using fused deposition modeling methods . The substrate of has been provided for the purposes of illustration and the dosage forms was made of Copovidone ( Kollidon® description . It is not intended to be exhaustive or to limit VA64 ) 72 % , PEG1500 18 % and Soluplus® 10 % . The drug what is disclosed to the precise forms described . Many content was consisted of Moxifloxacin Hydrochloride 30 % , modifications and variations will be apparent to the practi PEG1000 70 % . The schematic of the dosage forms are tioner skilled in the art . What is disclosed was chosen and illustrated in FIGS . 19A and 19B . Referring to FIGS. 19A described in order to best explain the principles and practical and 19B , the dosage form 1600 contained a substrate 1601 application of the disclosed embodiments of the art that forms two compartments 1602 and 1603 . The compart described , thereby enabling others skilled in the art to ments were enclosed by a wall 1604 and 1605 , respectively. understand the various embodiments and various modifica For the first dosage form , the two compartments were tions that are suited to the particular use contemplated . It is enclosed by walls having a thickness of 0 . 75 mm and 1 . 5 intended that the scope of what is disclosed be defined by the mm , respectively . For the second dosage form , the two following claims and their equivalence . TABLE 1 Commercial Water Polymer Vendor Name Chemical Structure Polyvinyl caprolactam BASF SE , Soluplus HO 25 w / w % polyvinyl acetate Germany polyethylene glycol graft copolymer 57 / 30 / 13

theof

Amphiphilic Soluplus + 10 % | CH31 40 w / w % Plasticizer ( freely Kolliphor P 188 tot TOH???? soluble ) US 2019 /0192440 A1 Jun . 27 , 2019

TABLE 1 - continued Commercial Water Polymer Vendor Name Chemical Structure Solubility Soluplus + 10 % n / a poorly Plasticizer soluble Kolliphor RH40 Soluplus + 10 % soluble Plasticizer PEG HL ? / In OH 1500 , ?? Polyvinylpyrrolidone International PVP / VA 40 w / w % co -vinyl - acetate Specialty ( freely (PVP - VA ) Products soluble ) Inc. , Manchester, UK International Plasdone S -630 40 w / w % Specialty - CH - CH2 - CH - CH27 ( freely Products Inc ., soluble ) Wayne , NJ, C = 0 USA ?H? |

Polyvinylpyrrolidone BASF SE , Kollidon VA 64 40 w / w % polyvinyl acetate Germany ( freely copolymer soluble ) (PVP - VA ) 60 /40 Polyvinylpyrrolidone BASF SE , Kollidon VA 64 + 40 w / w % polyvinyl acetate Germany 10 % Plasticizer ( freely copolymer Kolliphor P 188 H How to???? soluble ) (PVP - VA ) 60 /40 Polyvinylpyrrolidone BASF SE , Kollidon VA 64 + n / a poorly polyvinyl acetate Germany 10 % Plasticizer soluble copolymer Kolliphor RH40 ( PVP - VA ) 60 /40 Polyvinylpyrrolidone BASF SE , Kollidon VA 64 + soluble Germany polyvinyl acetate 10 % Plasticizer at themIn 'OH copolymer PEG 1500 ( PVP - VA ) 60 /40 Polyvinylpyrrolidone International Plasdone K - 29 / 32 soluble ( PVP ) Specialty PVP K30 Products Inc . , Wayne , NJ , USA PVP polyvinyl soluble pyrrolidone k30 PVP Polyvinyl soluble pyrrolidone K25 ( PVP K25 ) PVP PVP K25 + soluble Plasticizer dibutyl sebacate (DBS )

PVP PVP K25 + Plasticizer Triethyl citrate ( TEC ) Kollidon 12 PF PVP Kollidon 12 PF + CH3 ] 40 w / w % 10 % Plasticizer LO ( freely Kolliphor P 188 I LOV TOH soluble ) US 2019 /0192440 A1 Jun . 27 , 2019 19

TABLE 1 - continued Commercial Water Polymer Vendor Name Chemical StructureStructure Solubility PVP Kollidon 12 PF + n / a 40 w / w % 10 % Plasticizer ( freely Kolliphor RH40 soluble ) PVP Kollidon 12 PF + poorly 10 % Plasticizer H - L In 'OH soluble PEG 1500 tortion PVP Kollidon 17 PF soluble PVP Kollidon 17 PF + CH ; 1 40 w / w % 10 % Plasticizer ( freely Kolliphor P 188 Ato tout torton12 ?? soluble ) PVP Kollidon 17 PF + n / a 40 w / w % 10 % Plasticizer ( freely Kolliphor RH40 soluble ) PVP Kollidon 17 PF + poorly 10 % Plasticizer soluble PEG 1500 htºvaIn OH Spray formulated BASF SE , Kollidon SR 0 (Because mixture of polyvinyl Germany PVAc is acetate (PVAc ) and lipophilic polyvinylpyrrolidone and water (PVP ) 80 / 20 insoluble ? )

Spray formulated BASF SE , Kollidon SR + CH21 40 w / w % mixture of polyvinyl Germany 10 % Plasticizer ( freely acetate (PVAc ) and Kolliphor P 188 soluble ) polyvinylpyrrolidone Z OH (PVP ) 80 /20 te to thewton Spray formulated BASF SE , Kollidon SR + n / a poorly mixture of polyvinyl Germany 10 % Plasticizer soluble acetate (PVAc ) and Kolliphor RH40 polyvinylpyrrolidone (PVP ) 80 /20 Spray formulated BASF SE , Kollidon SR + soluble mixture of polyvinyl Germany 10 % Plasticizer acetate (PVAc ) and PEG 1500 to ton polyvinylpyrrolidone (PVP ) 80 / 20 Polyethylene BASF SE , Kollicoat IR 40 w / w % glycol- polyvinyl Germany Hº ( freely alcohol graft copolymer the ton soluble ) 25 / 75

pH

Polyethylene glycol BASF SE , Kollicoat IR + soluble polyvinyl alcohol graft Germany 10 % Plasicizer Loa copolymer 25 / 75 PEG 1500 H7 V ???? Kollicoat IR -polyvinyl BASF SE , Kollicoat 25 w / w % alcohol 60 / 40 Germany Protect H MotorOH

buhpH to US 2019 /0192440 A1 Jun . 27 , 2019 20

TABLE 1 - continued Commercial Water Polymer Vendor Name Chemical Structure Solubility Kollicoat IR -polyvinyl BASF SE , Kollicoat soluble alcohol 60 / 40 Germany Protect + 10 % Plasticizer ut hon PEG 1500

Polyvinyl Alcohol DuPont Elvanol ® soluble ( PVA or PV Company , OH ) Wilmington , Delaware USA

Hydroxypropyl cellulose Ashland Klucel EF soluble (HPC ) Aqualon Functional Ingredients , Wilmington, DE , USA R = H or CH2CH (OH )CH3

Klucel ELF R = H or CH2CH (OH )CH3

Ethyl cellulose (EC ) Dow Ethocel ® soluble Chemical, - 0 - C2H57 Midland , MI, US E01??

0 - C2H5_ ,

Poly ( ethylene Sigma- Aldrich Polyox® WSR soluble oxide ) ( PEO ) Ltd , Poole , Dorset , UK utºtooN un OH

Poly ( ethylene Dow Carbowax ® soluble glycol) (PEG ) Chemical, tortoroIn OH Midland , MI, US

Hyperbranched Polymer Hybrane S1200 ?? . OH Soluble Polyesteramide Factory , Stockholm , Sweden N HO OH

HO ??

HO CH US 2019 /0192440 A1 Jun . 27 , 2019 21

TABLE 1 - continued Commercial Water Polymer Vendor Name Chemical Structure Solubility Hydroxypropyl Dow Methocel ® Soluble Methylcellulose or Chemical, E4M , K4M , Hypromellose (HMPC ) Midland , K15M CH3 MI, US + CH2 - H? H O HOL OH HOO HO H CH2 CH2CHCH : À CH2 CH2CHCH3L n = 2 CHZ ?? CH3 Hydroxyprapyl Methylcellulose METHOCEL E , METHOCEL F , METHOCEL J, AND METHOLCEL K brand products

Hydroxypropyl Colorcon Inc ., HPMC ( 2910 Soluble Methylcellulose or Shanghai, grade ) OH Hypromellose (HMPC ) China

ROROK O LR

TOR ORRO OR

R = H , CH3 or t o HPMC

Hydroxypropyl Syntapharm Pharmacoat ® OR OH Soluble Methylcellulose or GmbH , 603 and 615 Hypromellose (HMPC ) Mülheim Ruhr, Germany ROH

P ór br Ró OR JR

R = H , CH3 or t HPMC

Hydroxypropyl Shin - Etsu Co . , Pharmacoat ® OR 1 Soluble Methylcellulose or Ltd . , 603 ?? Hypromellose (HMPC ) Niigata , (2910 grade ) RO 20

O OR ROOR ,

R = H , CHz or HPMC US 2019 /0192440 A1 Jun . 27 , 2019

TABLE 1 - continued Commercial Water Polymerpabernet Vendor Name Solubility vendor amenecial Chemical Structure Structure Carbomer Lubrizol Carbopol ® T H H ] Soluble Advanced 974P + Materials Inc ., Eudragit L - C - 0 Cleveland , 100 - 55 OH , US CEO

OH din

Lactose Quest Lactose OH soluble International, Anhydrate ?? / Hoffman DT NF OH Estates , O HO OH IL , USA HO OH OH|

Microcrystalline cellulose FMC , Avicel ® HO soluble (MCC ) Philadelphia , PH 101 PA , USA - 00H OH 00 OH HO

OH

Dibasic calcium phosphate Penwest Emcompress ® O= soluble Pharma Dibuie satin shophone ceuticals , 0 - P - OH Patterson , NY CartCa 2+ 6 Xanthan gum CP Kelco XANTURAL ® CH2OH soluble U . S . Inc ., 180 CH2OH Chicago , - ON IL , USA OH

COOH OH HC HzC R6

OR

R40 COOH - ON OH OH ON O R409 OH

Poly (methyl acrylate - co Evonik R€ohm Eudragit ® methyl methacrylate - co GmbH , 4135F + methacrylic acid ) 7 : 3 : 1 Darmstadt, Plasticizer Germany PEG8000

O OH CH3 US 2019 /0192440 A1 Jun . 27 , 2019 23

TABLE 1 - continued

Commercial Water Polymer Vendor Name Chemical Structure Solubility Poly (methyl acrylate -co Evonik Rohm Eudragit ® CH3 CH3 soluble at methyl methacrylate -co GmbH , 4155F pH > 7 methacrylic acid ) 7 : 3 : 1 Darmstadt, ( freeze dried Germany EUDRAGIT ® FS 30 D ) O OH CH3 CH3

Poly (methacrylic acid - co Evonik Eudragit ® S methylmethacrylate ) 1 : 2 Industries , Piscataway, New Jersey , USA

Poly (methacrylic acid -co Evonik Eudragit ® S + CHE CHE methylmethacrylate ) 1 : 2 Industries , Plasticizer Piscataway, Triethyl citrate New Jersey , ( TEC ) USA OH 0 CH3

Poly (methacrylic acid -co Evonik Eudragit ® S + methylmethacrylate ) 1: 2 Industries, Plasticizer PEG Piscataway, 8000 New Jersey , USA Poly (methacrylic acid - co Evonik Eudragit ® S + soluble at methylmethacrylate ) 1: 2 Industries , Plasticizer pH > 7 [36 ] Piscataway, methylparaben New Jersey, USA

Poly (methacylic Evonik Eudragit L Soluble at acid -co - ethyl Degussa 100 - 55 pH > 5 . 5 acrylate ) 1 : 1 Piscataway, NJ To OH O C2H5

Poly (methacylic acid - co Evonik Eudragit CH3 CH3 Soluble at methyl methacrylate ) 1 : 1 Degussa L - 100 pH > 6 . 0 Piscataway, NJ

OH O C2H5 US 2019 /0192440 A1 Jun . 27 , 2019 24

TABLE 1 - continued Commercial Water Polymer Vendor Name Chemical Structure Solubility Hydroxypropyl Shin - Etsu Co . , HP -55F Soluble at Methylcellulose Ltd . , Niigata , LOR pH > 5 . 5 Phthalate or Japan Hypromellose phthalate

- 0 0 OR OR

OR CH3

R = H , CH3 or CH2 or

- OH or

HO O CH3 CH3

Hydroxypropyl Shin - Etsu Co ., Shin - Etsu OR CHOR Soluble at Methylcellulose Acetate Ltd ., Niigata , Aqoat MF pH > 6 . 0 Succinate or Japan Hypromellose OR OR Acetate Succinate OL (HPMCAS ) CHOR OR Jn R = - H – CH2CH ( CH3) OH - COCH3 - COCH2CH2COOH - CH2CH (CH3 ) OCOH3 - CH2CH ( CH3) OCOCH ,CH2COOH Hydroxypropyl Shin - Etsu Co . , Shin - Etsu Soluble at Methylcellulose Acetate Ltd . , Niigata , Aqoat LF pH > 5 . 5 Succinate or Hypromellose Japan Acetate Succinate (HPMCAS ) Poly (dimethylaminoethyl Rohm Eudragit E Soluble at methacrylate -co GmbH & Co ., pH < 5 methacrylic esters ) Darmstadt , Germany Hydroxypropyl Shin - Etsu Co . , Shin - Etsu Soluble at Methylcellulose Acetate Ltd ., Niigata , Aqoat MF pH > 6 . 0 Succinate or Hypromellose Japan Acetate Succinate (HPMCAS ) Poly ( lactide- co - glycolide ) Birmingham PLGA insoluble Polymers , Inc. , Birmingham , AL , USA Bart US 2019 /0192440 A1 Jun . 27 , 2019 25

TABLE 1 -continued Commercial Water Polymer Vendor Name Chemical Structure Solubility

Elvax ® insoluble 40W : EV28 TKY O CH3

Elvax ? insoluble 40W : EVO TAM 0 CH3

Evatane ® THY insoluble CH3

Polyethylene (PE ) Scientific PE1400 insoluble

Polymer n Products Inc . , Ontario , NY Polycaprolactone ( PCL ) Scientific — insoluble Polymer Products Inc . , Ontario , NY

Carnauba Wax Noda n / a insoluble Wax Co . , Japan Glyceryl Palmitostearate Gattefosse, Precirol ® insoluble Cedex , France ATO 5 Hydrogenated Castor & Abitec Sterotex ? K n / a insoluble Soybean Oil Corporation , Janesville WI, USA

Cellulose acetate butyrate Eastman CAB 381- 0 . 5 RO . insoluble (CAB ) Chemical Company, Kingsport, -00 + R Tennessee , USA 0 0 ORV OR

OR 12 R = H or

CH3 or

CH3 US 2019 /0192440 A1 Jun . 27 , 2019

TABLE 1 - continued Commercial Water Polymer Vendor Name Chemical Structure Solubility

CAB FMC , CAB 500 - 1 RO insoluble Newark , DE , USA - 00 + R

OR

RO OR R = H or

CH3 or

CH3

Poly (vinyl acetate ) (PVAc ) Scientific Sentry ® plus insoluble Polymer Products Inc . , Ontario , NY H3C

Poly ( ethyl acrylate Rohm Eudragit CH3 CH3 insoluble co -methyl GmbH & RS PO methacrylate - co Co. , ( 1 : 2 : 0 . 1 ) trimethylammonioethyl Darmstadt, methacrylate chloride) Germany

CH2 CH3 C2H5 H2C Cl- | N + HzCCHE CH3

Poly( ethyl acrylate Rohm Eudragit CH3 CH3 insoluble co -methyl GmbH & RL PO methacrylate - co Co ., ( 1 : 2 : 0 . 2 ) Ky trimethylammonioethyl Darmstadt, methacrylate chloride) Germany

CH2 CH3 C2H5 HC

CH3 US 2019 /0192440 A1 Jun . 27 , 2019 27

TABLE 1 - continued Commercial Water Polymer Vendor Name Chemical Structure Solubility Poly (butyl methacrylate Evonik CH3 CH3 CH3 co - ( 2 Industries , dimethylaminoethyl) Essen , methacrylate - co -methyl Germany methacrylate ) 1 : 2 : 1 CH3 0 CH2 CH2 C4H , CH3 Evonik EUDRAGIT ® Industries , E PO Piscataway, New Jersey , USA

What is claimed is : comprises a drug in the form of nanoparticles disposed 1 . An oral drug dosage form comprising a plurality of between at least two of the plurality of layers , the method layers , wherein each layer comprises a substrate , and comprises : wherein the oral drug dosage form comprises a drug in the a ) printing a first layer by three - dimensional ( 3D ) print form of nanoparticles disposed between at least two of the ing ; plurality of layers . b ) atomizing or spraying atop of the first layer a solution 2 . The oral drug dosage form of claim 1 , comprising a first comprising the drug to form a plurality ofnanoparticles layer , a second layer , a third layer , a first drug in the form of on top of the first layer; and nanoparticles disposed between the first layer and the second c ) printing a second layer by 3D printing . layer , and a second drug in the form of nanoparticles 15 . The method of claim 14 , wherein the oral drug dosage disposed between the second layer and the third layer . form comprises at least three layers, wherein the oral drug 3. The oral drug dosage form of claim 2 , wherein the first dosage form comprises a first and a second drug in the form drug and the second drug are different. of nanoparticles disposed between the at least three of the 4 . The oral drug dosage form of claim 2 , wherein the first plurality of layers , and wherein the method comprises : drug and the second drug are the same. a ) printing a first layer by 3D printing ; 5 . The oral drug dosage form of claim 1, wherein the b ) atomizing or spraying atop of the first layer a solution substrate is erodible . comprising the first drug to form a plurality of nano 6 . The oral drug dosage form of claim 1 , wherein the particles on top of the first layer, substrate thickness is different among each layer . c ) printing a second layer by 3D printing ; 7 . The oral drug dosage form of claim 1 , wherein the d ) atomizing or spraying atop of the second layer a substrate thickness is the same among each layer . solution comprising the second drug to form a plurality 8 . The oral drug dosage form of claim 1 , wherein the of nanoparticles on top of the second layer; and substrate comprises a drug embedded therein . e ) printing a third layer by 3D printing . 9 . The oral drug dosage form of claim 8 , wherein the drug 16 . The method of claim 15 , wherein the first drug and the embedded within the substrate of each layer is different. second drug are different. 10 . The oral drug dosage form of claim 8 , wherein the 17 . The method of claim 15 , wherein the first drug and the drug embedded within the substrate of each layer is the second drug are the same . same. 18 . The method of claim 14 , further comprising mixing 11 . The oral drug dosage form of claim 1 , wherein the size the drug with the solution in which the drug is either of the nanoparticles is from about 1 nm to about 900 nm . dissolved or suspended before step a ) . 12 . The oral drug dosage form of claim 1 , wherein the size 19 . Themethod of claim 14 , further comprising drying the of the nanoparticles is from about 100 nm to about 500 nm . solution containing the drug . 13 . The oral drug dosage form of claim 1 , wherein the size 20 . The method of claim 14 , wherein the substrate is of the nanoparticles is from about 100 nm to about 200 nm . erodible . 14 . A method of preparing an oral drug dosage form 21 . The method of claim 14 , wherein the substrate com comprising a plurality of layers , wherein each layer com prises a drug embedded therein . prises a substrate, and wherein the oral drug dosage form