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US 20160354315A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0354315 A1 Li (43) Pub. Date: Dec. 8, 2016 (54) DOSAGE FORMS AND USE THEREOF Publication Classification (71) Applicant: Triastek, Inc., Nanjing (CN) (51) Int. Cl. A69/20 (2006.01) (72) Inventor: Xiaoling Li, Dublin, CA (US) A6IR 9/24 (2006.01) A63L/92 (2006.01) (52) U.S. Cl. (21) Appl. No.: 15/173,596 CPC ........... A61K 9/2031 (2013.01); A61K 9/2027 (2013.01); A61K 31/192 (2013.01); A61 K 9/209 (2013.01) (22) Filed: Jun. 3, 2016 (57) ABSTRACT The present disclosure provides a stable solid pharmaceuti Related U.S. Application Data cal dosage form for oral administration. The dosage form includes a Substrate that forms at least one compartment and (60) Provisional application No. 62/170,645, filed on Jun. a drug content loaded into the compartment. The dosage 3, 2015, provisional application No. 62/313,092, filed form is so designed that the active pharmaceutical ingredient on Mar. 24, 2016. of the drug content is released in a controlled manner. Patent Application Publication Dec. 8, 2016 Sheet 1 of 20 US 2016/0354315 A1 FG. A F.G. B. Peak carcetitration, tax ise F.G. C Patent Application Publication Dec. 8, 2016 Sheet 2 of 20 US 2016/0354315 A1 F.G. 2B Patent Application Publication Dec. 8, 2016 Sheet 3 of 20 US 2016/0354315 A1 F.G. 3 Patent Application Publication Dec. 8, 2016 Sheet 4 of 20 US 2016/0354315 A1 Patent Application Publication Dec. 8, 2016 Sheet 5 of 20 US 2016/0354315 A1 F.G. 4E F.G. 5 Patent Application Publication Dec. 8, 2016 Sheet 6 of 20 US 2016/0354315 A1 Patent Application Publication Dec. 8, 2016 Sheet 7 of 20 US 2016/0354315 A1 F.G. 8B Patent Application Publication Dec. 8, 2016 Sheet 8 of 20 US 2016/0354315 A1 F.G. 9 Patent Application Publication Dec. 8, 2016 Sheet 9 of 20 US 2016/0354315 A1 FIG 10B Patent Application Publication Dec. 8, 2016 Sheet 10 of 20 US 2016/0354315 A1 ti t t FIG 10C FIG. OD Patent Application Publication Dec. 8, 2016 Sheet 11 of 20 US 2016/0354315 A1 rescriptics: ------------------------------------------------------ it apexific itse and - - % dirig existic: \ey weighi ete/\: \"u/ ^ * FIG 11 Patent Application Publication Dec. 8, 2016 Sheet 12 of 20 US 2016/0354315 A1 --- - ^ --- *- ^. ---. \ --- FG, 12A FIG. 12B Patent Application Publication Dec. 8, 2016 Sheet 13 of 20 US 2016/0354315 A1 F.G. 13A FIG 3B Patent Application Publication Dec. 8, 2016 Sheet 14 of 20 US 2016/0354315 A1 FIG. 4C Patent Application Publication Dec. 8, 2016 Sheet 15 of 20 US 2016/0354315 A1 - s ---s: --- ^ * ----- 1. N r - - -- *r tra. f * . - S- --- e.Yas- -i.- 'w F.G. 1SA F.G. 1 SB Patent Application Publication Dec. 8, 2016 Sheet 16 of 20 US 2016/0354315 A1 1300 ^ 1 3 O 3 s w 2. x --- - 4. * 7- --- . 1304 C c/s (76 Crs) --- ar -l. aar, xx l Her -1 - 1301 k s as a *... F.G. 16B Patent Application Publication Dec. 8, 2016 Sheet 17 of 20 US 2016/0354315 A1 1401 1404. F.G. 17 A FG. 7B FIG. 17C Patent Application Publication Dec. 8, 2016 Sheet 18 of 20 US 2016/0354315 A1 F.G. 18A F.G. 18B :- 3eixeic acid reliease perceitsges assisgred a w by 3-is - My 83 */6ex P868000 reiesse areitage ( ^ geeksgress by gsi restice s 6 ? Citreatography i * 3 48 38 / s: s / * - 20 to so. 88 80 is kio 60 Beiease timefraits FIG. 18C Patent Application Publication Dec. 8, 2016 Sheet 19 of 20 US 2016/0354315 A1 FIG. 19A FIG. 19B Patent Application Publication Dec. 8, 2016 Sheet 20 of 20 US 2016/0354315 A1 O.30 0.25 0.20 5 O. 15 O. 10 O.05 O.OO O 2O 40 60 80 1OO 120 Time (min) FIG. 19C O.18 O. 16 0.14 O. 12 O. 10 É O.08 0.06 O.04 0.02 O.00 -0.02 O 20 40 60 8O 1 OO Time (min) FIG. 19) US 2016/0354315 A1 Dec. 8, 2016 DOSAGE FORMS AND USE THEREOF copolymer 57/30/13, polyvinylpyrrolidone-co-vinyl-acetate (PVP-VA), polyvinylpyrrolidone-polyvinyl acetate copoly CROSS-REFERENCE TO RELATED mer (PVP-VA) 60/40, polyvinylpyrrollidone (PVP), polyvi APPLICATIONS nyl acetate (PVAc) and polyvinylpyrrolidone (PVP) 80/20, polyethylene glycol-polyvinyl alcohol graft copolymer 0001. This application claims priority to U.S. Provisional 25/75, kollicoat IR-polyvinyl alcohol 60/40, polyvinyl alco Patent Applications Ser. Nos. 62/170,645, filed Jun. 3, 2015, hol (PVA or PV-OH), poly(vinyl acetate) (PVAc), poly(butyl 62/296,087, filed Feb. 17, 2016 and 62/313,092, filed Mar. methacrylate-co-(2-dimethylaminoethyl) methacrylate-co 24, 2016, the entire disclosures of which are incorporated methyl methacrylate) 1:2:1, poly(dimethylaminoethylmeth herein by reference. acrylate-co-methacrylic esters), poly(ethyl acrylate-co FIELD OF THE INVENTION methyl methacrylate-co-trimethylammonioethyl methacrylate 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 of manufactur Phthalate (PVAP) and a combination thereof. ing, packaging and shipping, and easy to identify and 0007. In certain embodiments, the compartment has a Swallow. After being administered into a living organism, a shape selected from the group consisting of a pie shape, a tablet undergoes interplay with the body in exerting phar cone shape, a pyramid shape, a cylindrical shape, a cubic or maceutical effects. The active pharmaceutical ingredient cuboidal shape, a triangular or polygonal prism shape, a must be released from the tablet before being absorbed into tetrahedron and a combination thereof. the blood circulation. The pharmaceutical ingredient then 0008. In certain embodiments, the first drug content is in disperses, disintegrates or dissolves throughout the fluids a form of nanoparticles, microneedles or forms a net. and tissues of the body. During drug absorption, disposition, 0009. In certain embodiments, the drug content com metabolism, and elimination process, dosage forms play a prises an active pharmaceutical ingredient (API). In certain critical role in determining the release profile and bioavail embodiments, the API is selected from the groups consisting ability of the drugs. Therefore, there is a continuing needs of local anesthetics, antiepileptic drugs and anticonvulsants, for developing dosage forms that provides controlled drug anti-Alzheimer's disease drugs, analgesics, antipodagric, delivery systems, which may offer desired drug plasma anti-hypertensive drugs, antiarrhythmic drugs, diuretic levels, reduced side effects as well as improved patient drugs, drugs for treating liver diseases, drugs for treating compliance. pancreatic diseases, antihistamine drugs, anti-allergic drugs, glucocorticoid drugs, hormone drugs and contraceptive BRIEF SUMMARY OF THE INVENTION drugs, hypoglycemic drugs, anti-osteoporosis drugs, antibi 0005. In one aspect, the present disclosure provides a otics, Sulfonamides, quinolones, and other synthetic antibac dosage form including a Substrate forming at least one terial drugs, anti-tuberculosis drugs, antiviral drugs, anti compartment and a drug content loaded into the compart neoplasm drugs, immune-modulators, cosmetically active ment. In certain embodiments, the drug content is operably agents and traditional Chinese medicine. In certain embodi linked to the substrate. In certain embodiments, the drug ments, the API is a biologically active agent, a diagnostic content is detached from the substrate and freely movable in agent, a reagent for Scientific research, a cosmetic agent, or the compartment. an agricultural/insecticide agent. 0006. In certain embodiments, the substrate is made from 0010. In certain embodiments, the drug content further a thermoplastic material selected from the group consisting comprises an excipient. In certain embodiments, the excipi of a hydrophilic polymer, a hydrophobic polymer, a ent is made from materials selected from the group consist Swellable polymer, a non-Swellable polymer, a porous poly ing of cocoa butter, polyethylene glycol (PEG), Sucrose, mer, a non-porous polymer, an erodible polymer, a non glucose, galactose, fructose, Xyloselactose, maltose, treha erodible polymer. In certain embodiments, the thermoplastic lose, Sorbitol, mannitol, maltodextrins, raffinose, stachyose, material is selected from the group consisting of polyvinyl fructo-oligosaccharides, water-soluble oligomers and poly caprolactam-polyvinyl acetate-polyethylene glycol graft mers and a combination thereof.
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    Advances in therapeutic peptides targeting G protein-coupled receptors Anthony P. Davenport1Ϯ Conor C.G. Scully2Ϯ, Chris de Graaf2, Alastair J. H. Brown2 and Janet J. Maguire1 1Experimental Medicine and Immunotherapeutics, Addenbrooke’s Hospital, University of Cambridge, CB2 0QQ, UK 2Sosei Heptares, Granta Park, Cambridge, CB21 6DG, UK. Ϯ Contributed equally Correspondence to Anthony P. Davenport email: [email protected] Abstract Dysregulation of peptide-activated pathways causes a range of diseases, fostering the discovery and clinical development of peptide drugs. Many endogenous peptides activate G protein-coupled receptors (GPCRs) — nearly fifty GPCR peptide drugs have been approved to date, most of them for metabolic disease or oncology, and more than 10 potentially first- in-class peptide therapeutics are in the pipeline. The majority of existing peptide therapeutics are agonists, which reflects the currently dominant strategy of modifying the endogenous peptide sequence of ligands for peptide-binding GPCRs. Increasingly, novel strategies are being employed to develop both agonists and antagonists, and both to introduce chemical novelty and improve drug-like properties. Pharmacodynamic improvements are evolving to bias ligands to activate specific downstream signalling pathways in order to optimise efficacy and reduce side effects. In pharmacokinetics, modifications that increase plasma-half life have been revolutionary. Here, we discuss the current status of peptide drugs targeting GPCRs, with a focus on evolving strategies to improve pharmacokinetic and pharmacodynamic properties. Introduction G protein-coupled receptors (GPCRs) mediate a wide range of signalling processes and are targeted by one third of drugs in clinical use1. Although most GPCR-targeting therapeutics are small molecules2, the endogenous ligands for many GPCRs are peptides (comprising 50 or fewer amino acids), which suggests that this class of molecule could be therapeutically useful.
  • Vasopressin, Norepinephrine, and Vasodilatory Shock After Cardiac Surgery Another “VASST” Difference?

    Vasopressin, Norepinephrine, and Vasodilatory Shock After Cardiac Surgery Another “VASST” Difference?

    Vasopressin, Norepinephrine, and Vasodilatory Shock after Cardiac Surgery Another “VASST” Difference? James A. Russell, A.B., M.D. AJJAR et al.1 designed, Strengths of VANCS include H conducted, and now report the blinded randomized treat- in this issue an elegant random- ment, careful follow-up, calcula- ized double-blind controlled trial tion of the composite outcome, of vasopressin (0.01 to 0.06 U/ achieving adequate and planned Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/126/1/9/374893/20170100_0-00010.pdf by guest on 01 October 2021 min) versus norepinephrine (10 to sample size, and evaluation of 60 μg/min) post cardiac surgery vasopressin pharmacokinetics. with vasodilatory shock (Vaso- Nearly 20 yr ago, Landry et al.2–6 pressin versus Norepinephrine in discovered relative vasopressin defi- Patients with Vasoplegic Shock ciency and benefits of prophylactic After Cardiac Surgery [VANCS] (i.e., pre cardiopulmonary bypass) trial). Open-label norepinephrine and postoperative low-dose vaso- was added if there was an inad- pressin infusion in patients with equate response to blinded study vasodilatory shock after cardiac drug. Vasodilatory shock was surgery. Previous trials of vasopres- defined by hypotension requiring sin versus norepinephrine in cardiac vasopressors and a cardiac index surgery were small and underpow- greater than 2.2 l · min · m-2. The “[The use of] …vasopressin ered for mortality assessment.2–6 primary endpoint was a compos- Vasopressin stimulates arginine ite: “mortality or severe complica- infusion for treatment of vasopressin receptor 1a, arginine tions.” Patents with vasodilatory vasodilatory shock after vasopressin receptor 1b, V2, oxy- shock within 48 h post cardiopul- tocin, and purinergic receptors monary bypass weaning were eli- cardiac surgery may causing vasoconstriction (V1a), gible.