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 DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (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 FIG . 1A *Release FIG . 1B Postabsorption . Plasmadruglevel groupon.www Blimination hoolimason Absorption cocinio concentration , Coax Time FIG . 1C Patent Application Publication Jun . 27 , 2019 Sheet 2 of 20 US 2019 /0192440 A1 Plasmadruglevel FIG . 1D over 1011 FIG . 2A %Release FIG . 2B Patent Application Publication Jun . 27 , 2019 Sheet 3 of 20 US 2019 /0192440 A1 203 202 201 * W e want to enter FIG . 3 Patent Application Publication Jun . 27 , 2019 Sheet 4 of 20 US 2019 /0192440 A1 ETVE WORLD 2X41 ter FIG . 4A HAFA 2222222222222222222 FIG . 4B WASCETTEV 2222 XaN FIG . 4C t. MAR res FIG . 4D Patent Application Publication Jun . 27 , 2019 Sheet 5 of 20 US 2019 /0192440 A1 ** * FIG . 4E yung ** * *** * * D L . SOLODRUG FLUID ansan k FIG . 5 Patent Application Publication Jun . 27 , 2019 Sheet 6 of 20 US 2019 /0192440 A1 300 ve 301 - 304 exames 302 LEEY T 'INNYA T?rne 1 DT FIG . 6 - 401 FIG . 7 Patent Application Publication Jun . 27 , 2019 Sheet 7 of 20 US 2019 /0192440 A1 *** * * * * * **22 * * * FIG . SA Kelease FIG . SB Patent Application Publication Jun . 27 , 2019 Sheet 8 of 20 US 2019 /0192440 A1 wordmoet wwwm . a son FIG . 9 Patent Application Publication Jun . 27 , 2019 Sheet 9 of 20 US 2019 /0192440 A1 700 -707 705 TTT 103 canli smo FIG . 10A FIG . 10B Patent Application Publication Jun . 27, 2019 Sheet 10 of 20 US 2019 /0192440 A1 *Release ti t2t3 FIG . 10C Plasandruglevel FIG . 10D Patent Application Publication Jun . 27, 2019 Sheet 11 of 20 US 2019 /0192440 A1 Prescription With Bacific doso said .* 19 ** * Patient FIG . 11 Patent Application Publication Jun . 27, 2019 Sheet 12 of 20 US 2019 /0192440 A1 XXXV FIG . 12A spot misrae***** *Release sünnitaminwist ir E FIG . 12B Patent Application Publication Jun . 27, 2019 Sheet 13 of 20 US 2019 /0192440 A1 900 900 - 902. 901 903 | | || TL II FIG . 13A rimitrittsitsi *Release p insmásitseine FIG . 13B Patent Application Publication Jun . 27, 2019 Sheet 14 of 20 US 2019 /0192440 A1 1000 - w . 1001 1002 - 1003 FIG . 14A CA 1102 _ 11031 FIG . 14B iero **** * *Release ingen susitsit FIG . 14C Patent Application Publication Jun . 27, 2019 Sheet 15 of 20 US 2019 /0192440 A1 1200 - 1201 JO . FIG . 15A Release uti . FIG . 15B Patent Application Publication Jun . 27, 2019 Sheet 16 of 20 US 2019 /0192440 A1 1300 1302 1303 wwware 1304 0918011301 www FIG . 16A *ReleaseSA FIG . 16B Patent Application Publication Jun . 27, 2019 Sheet 17 of 20 US 2019 /0192440 A1 1402 1400 1403 * 1401 imeno 1404 FIG . 17A re E * * rfsmeistos Release ** FIG . 17B *Release FIG . 17C Patent Application Publication Jun . 27, 2019 Sheet 18 of 20 US 2019 /0192440 A1 1500 1503 1502 ** Y : * FIG . 18A FIG . 18B Benzoic acid release percentage measured PBC8000 release percentage DRESUred by Gel Perseatich ReleasePercentage(%) Chronstography sazin?ts Helo se tice / & * X FIG . 18C Patent Application Publication Jun . 27, 2019 Sheet 19 of 20 US 2019 /0192440 A1 1600 FIG . 19A 1602 ***** * * * ** ***** * YKY FIG . 19B Patent Application Publication Jun . 27, 2019 Sheet 20 of 20 US 2019 /0192440 A1 0 . 30 0 . 25 0 . 20 Abs 0 . 15 0 . 10 0 .05 0 . 00 0 20 40 60 80 100 120 Time (min ) FIG . 190 Abs - 0 .02 20 40 60 80 100 Time (min ) FIG . 19D US 2019 /0192440 A1 Jun . 27 , 2019 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 - polyethylene glycol graft CROSS -REFERENCE TO RELATED copolymer 57 / 30 / 13 , polyvinylpyrrolidone - 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 alcohol 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 esters ) , poly ( ethyl acrylate - co methyl methacrylate -co - trimethylammonioethyl FIELD OF THE INVENTION methacrylate chloride ) , poly (methyl acrylate - co -methyl [ 0002] The present invention generally relates to a phar methacrylate - co -methacrylic acid ) 7 : 3 : 1 , poly (methacrylic maceutical dosage form and controlled release of biologi acid - co -methylmethacrylate ) 1 : 2 , poly (methacylic acid - co cally active agents , diagnostic agents , reagents , cosmetic ethyl acrylate ) 1 : 1 , poly (methacylic acid - co -methyl meth agents , and agricultural/ insecticide agents . acrylate ) 1 : 1 , poly ( ethylene oxide ) (PEO ) , poly ( ethylene glycol ) (PEG ), hyperbranched polyesteramide , hydroxypro BACKGROUND pyl methylcellulose phthalate , hypromellose phthalate , [ 0003] Pharmaceutical drug products must be manufac hydroxypropyl methylcellulose or hypromellose (HMPC ) , tured into dosage forms in order to be marketed for use . hydroxypropyl methylcellulose acetate succinate or Conventional dosage forms typically involve a mixture of hypromellose acetate succinate (HPMCAS ) , poly ( lactide active pharmaceutical ingredients and inactive components co - glycolide ) (PLGA ) , carbomer, poly ( ethylene -co - vinyl ( excipients ) , along with other non - reusable materials such as acetate ), ethylene - vinyl acetate copolymer , polyethylene a capsule shell. Categories of dosage forms include liquid (PE ) , and polycaprolactone (PCL ) , hydroxyl propyl cellu dosage forms ( e . g ., solutions , syrups , elixirs , suspensions lose (HPC ) , Polyoxyl 40 Hydrogenerated Castor Oil, Methyl and emulsions ) , solid dosage forms ( e . g ., tablets , capsules , cellulose (MC ) , Ethyl cellulose ( EC ) , Poloxamer , hydroxy caplets and gel - caps ) , and semi- solid dosage form ( e . g ., propyl methylcellulose phthalate (HPMCP ) , Poloxamer, ointments and suppositories ), among which solid dosage Hydrogenated Castor & Soybean Oil, Glyceryl Palmitoste forms are more advantages to administer drugs in systemic arate , Carnauba Wax , polylactic acid ( PLA ), polyglycolic effect through oral route . acid (PGA ) , Cellulose acetate butyrate (CAB ) , Colloidal [0004 ] Tablets are most commonly used solid dosage Silicon , Dioxide , Sucrose , Glucose, Polyvinyl Acetate forms, which shows more benefits in terms 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 tablet undergoes interplay with the body in exerting phar cone shape , a pyramid shape, a cylindrical shape , a cubic or maceutical effects . The active pharmaceutical ingredient cuboidal shape , a triangular or polygonal prism shape , a must be released from the tablet before being absorbed into tetrahedron and a combination thereof. the blood circulation . The pharmaceutical ingredient then 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 metabolism , and elimination process , dosage forms play a prises