DOCSLIB.ORG

Tablet Matrix with Disintegrantand Delayed and Delayed Release Oxycodone Modified Release Oxycodone Patent Application Publication Jan

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Tablet Matrix with Disintegrantand Delayed and Delayed Release Oxycodone Modified Release Oxycodone Patent Application Publication Jan US 2013 0022646A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0022646 A1 Rudnic et al. (43) Pub. Date: Jan. 24, 2013 (54) CONTROLLED RELEASE FORMULATIONS (60) Provisional application No. 61/302.698, filed on Feb. OF OPODS 9, 2010, provisional application No. 61/386,277, filed on Sep. 24, 2010, provisional application No. 61/443, (76) Inventors: Edward M. Rudnic, Potomac, MD 966, filed on Feb. 17, 2011. (US); Michael Vachon, Quebec (CA); Gary W. Pace, La Jolla (CA) Publication Classification (51) Int. Cl. (21) Appl. No.: 13/442,849 A613 L/485 (2006.01) A6IP 25/04 (2006.01) (22) Filed: Apr. 9, 2012 A619/00 (2006.01) (52) U.S. Cl. ........................................ 424/400: 514/282 Related U.S. Application Data (57) ABSTRACT (63) Continuation-in-part of application No. 13/024.319, Pharmaceutical formulations containing opioid components filed on Feb. 9, 2011, Continuation-in-part of applica that each has a release profile. The components may provide tion No. 13/400,065, filed on Feb. 18, 2012, which is a immediate or controlled release of the opioid. The invention continuation-in-part of application No. 13/400,004, is also directed to methods of controlling release of one or filed on Feb. 17, 2012. more opioid compounds and methods of treating pain. Proposed Dosage Form Components Delayed and lodified Release Morphine Tablet Matrix with Disintegrantand Delayed and Delayed Release Oxycodone Modified Release Oxycodone Patent Application Publication Jan. 24, 2013 Sheet 1 of 32 US 2013/0022646 A1 Patent Application Publication Jan. 24, 2013 Sheet 2 of 32 US 2013/0022646 A1 peSeeled effeSOOOueoued 00200900900?70 Patent Application Publication Jan. 24, 2013 Sheet 3 of 32 US 2013/0022646 A1 ss state 3 C O O O O. O. O O. O C. CD OC N CO Y cy CN was o peSeele effeSOOJOueoued Patent Application Publication Jan. 24, 2013 Sheet 4 of 32 US 2013/0022646 A1 ************************* ~|~~~~,09 *&&&&&&&&&&***********0 0 peSeele e6eSOC goueojed Patent Application Publication Jan. 24, 2013 Sheet 5 of 32 US 2013/0022646 A1 35s S 3 C O O O O CN O OO CO r S ville was peSeele effeSOOOueoued Patent Application Publication Jan. 24, 2013 Sheet 6 of 32 US 2013/0022646 A1 00200900900?7009OOZ00||0 peSeele effeSOOOueojed Patent Application Publication Jan. 24, 2013 Sheet 7 of 32 US 2013/0022646 A1 Patent Application Publication Jan. 24, 2013 Sheet 8 of 32 US 2013/0022646 A1 Patent Application Publication Jan. 24, 2013 Sheet 9 of 32 US 2013/0022646 A1 Patent Application Publication Jan. 24, 2013 Sheet 10 of 32 US 2013/0022646 A1 Patent Application Publication Jan. 24, 2013 Sheet 11 of 32 US 2013/0022646 A1 Patent Application Publication Jan. 24, 2013 Sheet 12 of 32 US 2013/0022646 A1 Patent Application Publication Jan. 24, 2013 Sheet 13 of 32 US 2013/0022646 A1 O OO 9 w c < m b O c c - CO O O C) O ( c. r 9) S S 3 o O O CD L. L. f. 8 2 N V CD S H O CN O O CN (u/6u) uOle Jueduoo euSel Patent Application Publication Jan. 24, 2013 Sheet 14 of 32 US 2013/0022646 A1 O t s E c c - O O CD at 9 cu cu geis S 35 area O O Cld o L. i. Y O O S CD E H (u/6u) uoleuueouoo euSel Patent Application Publication Jan. 24, 2013 Sheet 15 of 32 US 2013/0022646 A1 (sunou)ºu!1 (u/6u) uOile Ilueouoo euSeld Patent Application Publication Jan. 24, 2013 Sheet 16 of 32 US 2013/0022646 A1 N. 8: 8: as: & 8. 8 8: 8 : K. *: xx (u/6u) uOle JueouOO euSel Patent Application Publication Jan. 24, 2013 Sheet 17 of 32 US 2013/0022646 A1 --------0?7090Z (u/6u) uoleilueouod euSel Patent Application Publication Jan. 24, 2013 Sheet 18 of 32 US 2013/0022646 A1 O wer s (u/6u) uoleulueouOO euSeld Patent Application Publication Jan. 24, 2013 Sheet 19 of 32 US 2013/0022646 A1 eseejey eleyns euguidow % seeeyeens euguidow 94T Patent Application Publication Jan. 24, 2013 Sheet 20 of 32 US 2013/0022646 A1 eSeele OH euopooAXO % eSeele OH euopooAXO % Patent Application Publication Jan. 24, 2013 Sheet 21 of 32 US 2013/0022646 A1 s i s i d o O O. O. O. O. O. s OY CO N C i? tri (y) ra SWB W S NHOW 96 Patent Application Publication Jan. 24, 2013 Sheet 22 of 32 US 2013/0022646 A1 s S & ro s CO o o o o o o o o O) CO, N, O s CY (N S. O BSV OH NOOOOWXO % Patent Application Publication Jan. 24, 2013 Sheet 23 of 32 US 2013/0022646 A1 BSVB3 BWS ENHOW.9% Patent Application Publication Jan. 24, 2013 Sheet 24 of 32 US 2013/0022646 A1 SW3T3 OH3NOOOOAXO % Patent Application Publication Jan. 24, 2013 Sheet 25 of 32 US 2013/0022646 A1 | : : s s 3 se 8 s CBSW338 OH3NOOOOAXO % 'NW Patent Application Publication Jan. 24, 2013 Sheet 26 of 32 US 2013/0022646 A1 e Li in is S a s s s Sas d a. f N wer n o U -------------------... x. : c S. S. & R & 8 Patent Application Publication Jan. 24, 2013 Sheet 27 of 32 US 2013/0022646 A1 O3SW3 OH NOOOOAXO % 'EDAW Patent Application Publication Jan. 24, 2013 Sheet 28 of 32 US 2013/0022646 A1 Patent Application Publication Jan. 24, 2013 Sheet 29 of 32 US 2013/0022646 A1 8 i s: { x. & is st 8: & x Ex. x y s s: 8 g {). & X . xx x N co V co CO w CN O o o Y Q 9 (u/6u)SuOle Jueouoo Patent Application Publication Jan. 24, 2013 Sheet 30 of 32 US 2013/0022646 A1 (u/6u)Suoge Aueouoo Patent Application Publication Jan. 24, 2013 Sheet 31 of 32 US 2013/0022646 A1 8 8 : 8 8 (u/6u)SuojelulueouOO Patent Application Publication Jan. 24, 2013 Sheet 32 of 32 US 2013/0022646 A1 !!!!!$33,3,3,3,3,3, (Sunou)?uu|| (u/6u)SuOenueouOO US 2013/0022646 A1 Jan. 24, 2013 CONTROLLED RELEASE FORMULATIONS mixtures thereof, or salts thereof. In certain embodiments, a OF OPODS component may comprise two opioid compounds in varying ratios. In particular embodiments, a component may com CROSS-REFERENCES TO RELATED prise morphine and oxycodone, or salts thereof, in about a 3:2 APPLICATIONS ratio by weight. 0001. This application is a continuation-in-part of U.S. 0008. In some embodiments, the components may have an application Ser. No. 13/024.319, filed on Feb. 9, 2011, which immediate release profile or a controlled release profile. claims priority to U.S. provisional application Ser. No. 0009. In certain embodiments, the formulation may com 61/302.698, filed Feb. 9, 2010, and to U.S. provisional appli prise one or more additional components, such as at least two, cation Ser. No. 61/386,277, filed Sep. 24, 2010. This appli at least three, at least four, or at least five components. In some cation is also a continuation-in-part of U.S. application Ser. embodiments, the one or more additional components may No. 13/400,065, filed on Feb. 18, 2012, which is a continua comprise one or more active agents. In some embodiments, tion-in-part of Ser. No. 13/400,004, filed on Feb. 17, 2012, the one or more active agents may be compounds having which claims priority to U.S. provisional application Ser. No. opioid receptor agonist activity. In some embodiments, the 61/443.966, filed on Feb. 17, 2011. The entirety of each of one or more active agents may be one or more non-opioid these applications is incorporated herein by reference. analgesic compound(s), or a mixture of one or more non opioid analgesic compound(s) and one or more compound(s) FIELD OF THE INVENTION with opioid receptor agonist activity, or pharmaceutically 0002 The invention is directed to pharmaceutical formu acceptable salts, esters or prodrugs thereof. In certain lations comprising opioid components that each has a release embodiments, the one or more active agents may be one or profile. The components may provide immediate or con more hybrid opioid compound(s), or a mixture of one or more trolled release of the opioid. The invention is also directed to hybrid opioid compound(s) and one or more compound(s) methods of controlling release of one or more opioid com with opioid receptor agonist activity, or pharmaceutically pounds and methods of treating pain. acceptable salts, esters or prodrugs thereof. 0010. In embodiments of the invention, the pharmaceuti BACKGROUND OF THE INVENTION cal formulation may comprise a controlled release compo 0003) Opioids are a class of pain-relieving prescription nent, wherein the controlled release component comprises medications frequently used in the treatment of a variety of one or more cores. In additional embodiments, the controlled acute and chronic, moderate to severe, pain. However, opioids release component comprises oxycodone. In embodiments of can be rapidly absorbed and systemically excreted by the the invention, the pharmaceutical formulation comprises a body through metabolic inactivation. In order to treat steady state plasma concentration profile of the oxycodcone patients, especially those in severe pain, administration of having a fluctuation index of about 90% or less. In some opioids often requires careful dosing at frequent intervals to embodiments, the pharmaceutical formulation comprises an maintain effective steady state blood levels of the opioid, and AUC. Such that when the pharmaceutical formulation con thereby provide consistent analgesia. Otherwise, blood levels tains about 20 mg of oxycodone and the dosing interval is 12 of the opioid can oscillate, resulting in poor and inconsistent hours, AUC of oxycodone is about 100 ngh/mL to about pain relief.
Load more

Recommended publications
  • Evaluation of in Silico Approach for Prediction of Presence of Opioid Peptides in Wheat
    Evaluation of in silico approach for prediction of presence of opioid peptides in wheat This is the Accepted version of the following publication Garg, Swati, Apostolopoulos, Vasso, Nurgali, Kulmira and Mishra, Vijay Kumar (2018) Evaluation of in silico approach for prediction of presence of opioid peptides in wheat. Journal of Functional Foods, 41. 34 - 40. ISSN 1756-4646 The publisher’s official version can be found at https://www.sciencedirect.com/science/article/pii/S1756464617307454 Note that access to this version may require subscription. Downloaded from VU Research Repository https://vuir.vu.edu.au/36577/ 1 1 Evaluation of in silico approach for prediction of presence of opioid peptides in wheat 2 gluten 3 Abstract 4 Opioid like morphine and codeine are used for the management of pain, but are associated 5 with serious side-effects limiting their use. Wheat gluten proteins were assessed for the 6 presence of opioid peptides on the basis of tyrosine and proline within their sequence. Eleven 7 peptides were identified and occurrence of predicted sequences or their structural motifs were 8 analysed using BIOPEP database and ranked using PeptideRanker. Based on higher peptide 9 ranking, three sequences YPG, YYPG and YIPP were selected for determination of opioid 10 activity by cAMP assay against µ and κ opioid receptors. Three peptides inhibited the 11 production of cAMP to varied degree with EC50 values of YPG, YYPG and YIPP were 5.3 12 mM, 1.5 mM and 2.9 mM for µ-opioid receptor, and 1.9 mM, 1.2 mM and 3.2 mM for κ- 13 opioid receptor, respectively.
    [Show full text]
  • INVESTIGATION of NATURAL PRODUCT SCAFFOLDS for the DEVELOPMENT of OPIOID RECEPTOR LIGANDS by Katherine M
    INVESTIGATION OF NATURAL PRODUCT SCAFFOLDS FOR THE DEVELOPMENT OF OPIOID RECEPTOR LIGANDS By Katherine M. Prevatt-Smith Submitted to the graduate degree program in Medicinal Chemistry and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy. _________________________________ Chairperson: Dr. Thomas E. Prisinzano _________________________________ Dr. Brian S. J. Blagg _________________________________ Dr. Michael F. Rafferty _________________________________ Dr. Paul R. Hanson _________________________________ Dr. Susan M. Lunte Date Defended: July 18, 2012 The Dissertation Committee for Katherine M. Prevatt-Smith certifies that this is the approved version of the following dissertation: INVESTIGATION OF NATURAL PRODUCT SCAFFOLDS FOR THE DEVELOPMENT OF OPIOID RECEPTOR LIGANDS _________________________________ Chairperson: Dr. Thomas E. Prisinzano Date approved: July 18, 2012 ii ABSTRACT Kappa opioid (KOP) receptors have been suggested as an alternative target to the mu opioid (MOP) receptor for the treatment of pain because KOP activation is associated with fewer negative side-effects (respiratory depression, constipation, tolerance, and dependence). The KOP receptor has also been implicated in several abuse-related effects in the central nervous system (CNS). KOP ligands have been investigated as pharmacotherapies for drug abuse; KOP agonists have been shown to modulate dopamine concentrations in the CNS as well as attenuate the self-administration of cocaine in a variety of species, and KOP antagonists have potential in the treatment of relapse. One drawback of current opioid ligand investigation is that many compounds are based on the morphine scaffold and thus have similar properties, both positive and negative, to the parent molecule. Thus there is increasing need to discover new chemical scaffolds with opioid receptor activity.
    [Show full text]
  • Rubsicolins Are Naturally Occurring G-Protein-Biased Delta Opioid Receptor Peptides
    bioRxiv preprint doi: https://doi.org/10.1101/433805; this version posted October 5, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Title page Title: Rubsicolins are naturally occurring G-protein-biased delta opioid receptor peptides Short title: Rubsicolins are G-protein-biased peptides Authors: Robert J. Cassell1†, Kendall L. Mores1†, Breanna L. Zerfas1, Amr H.Mahmoud1, Markus A. Lill1,2,3, Darci J. Trader1,2,3, Richard M. van Rijn1,2,3 Author affiliation: 1Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, 2Purdue Institute for Drug Discovery, 3Purdue Institute for Integrative Neuroscience, West Lafayette, IN 47907 †Robert J Cassell and Kendall Mores contributed equally to this work Corresponding author: ‡Richard M. van Rijn, Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907 (Phone: 765-494- 6461; Email: [email protected]) Key words: delta opioid receptor; beta-arrestin; natural products; biased signaling; rubisco; G protein-coupled receptor Abstract: 187 Figures: 2 Tables: 2 References: 27 1 bioRxiv preprint doi: https://doi.org/10.1101/433805; this version posted October 5, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract The impact that β-arrestin proteins have on G-protein-coupled receptor trafficking, signaling and physiological behavior has gained much appreciation over the past decade. A number of studies have attributed the side effects associated with the use of naturally occurring and synthetic opioids, such as respiratory depression and constipation, to excessive recruitment of β-arrestin.
    [Show full text]
  • Intravta Deltorphin, but Not DPDPE, Induces Place Preference in Ethanoldrinking Rats
    ALCOHOLISM:CLINICAL AND EXPERIMENTAL RESEARCH Vol. 38, No. 1 January 2014 Intra-VTA Deltorphin, But Not DPDPE, Induces Place Preference in Ethanol-Drinking Rats: Distinct DOR-1 and DOR-2 Mechanisms Control Ethanol Consumption and Reward Jennifer M. Mitchell, Elyssa B. Margolis, Allison R. Coker, Daicia C. Allen, and Howard L. Fields Background: While there is a growing body of evidence that the delta opioid receptor (DOR) modu- lates ethanol (EtOH) consumption, development of DOR-based medications is limited in part because there are 2 pharmacologically distinct DOR subtypes (DOR-1 and DOR-2) that can have opposing actions on behavior. Methods: We studied the behavioral influence of the DOR-1-selective agonist [D-Pen2,D-Pen5]- Enkephalin (DPDPE) and the DOR-2-selective agonist deltorphin microinjected into the ventral tegmental area (VTA) on EtOH consumption and conditioned place preference (CPP) and the physio- logical effects of these 2 DOR agonists on GABAergic synaptic transmission in VTA-containing brain slices from Lewis rats. Results: Neither deltorphin nor DPDPE induced a significant place preference in EtOH-na€ıve Lewis rats. However, deltorphin (but not DPDPE) induced a significant CPP in EtOH-drinking rats. In con- trast to the previous finding that intra-VTA DOR-1 activity inhibits EtOH consumption and that this inhibition correlates with a DPDPE-induced inhibition of GABA release, here we found no effect of DOR-2 activity on EtOH consumption nor was there a correlation between level of drinking and deltorphin-induced change in GABAergic synaptic transmission. Conclusions: These data indicate that the therapeutic potential of DOR agonists for alcohol abuse is through a selective action at the DOR-1 form of the receptor.
    [Show full text]
  • Opioid Receptorsreceptors
    OPIOIDOPIOID RECEPTORSRECEPTORS defined or “classical” types of opioid receptor µ,dk and . Alistair Corbett, Sandy McKnight and Graeme Genes encoding for these receptors have been cloned.5, Henderson 6,7,8 More recently, cDNA encoding an “orphan” receptor Dr Alistair Corbett is Lecturer in the School of was identified which has a high degree of homology to Biological and Biomedical Sciences, Glasgow the “classical” opioid receptors; on structural grounds Caledonian University, Cowcaddens Road, this receptor is an opioid receptor and has been named Glasgow G4 0BA, UK. ORL (opioid receptor-like).9 As would be predicted from 1 Dr Sandy McKnight is Associate Director, Parke- their known abilities to couple through pertussis toxin- Davis Neuroscience Research Centre, sensitive G-proteins, all of the cloned opioid receptors Cambridge University Forvie Site, Robinson possess the same general structure of an extracellular Way, Cambridge CB2 2QB, UK. N-terminal region, seven transmembrane domains and Professor Graeme Henderson is Professor of intracellular C-terminal tail structure. There is Pharmacology and Head of Department, pharmacological evidence for subtypes of each Department of Pharmacology, School of Medical receptor and other types of novel, less well- Sciences, University of Bristol, University Walk, characterised opioid receptors,eliz , , , , have also been Bristol BS8 1TD, UK. postulated. Thes -receptor, however, is no longer regarded as an opioid receptor. Introduction Receptor Subtypes Preparations of the opium poppy papaver somniferum m-Receptor subtypes have been used for many hundreds of years to relieve The MOR-1 gene, encoding for one form of them - pain. In 1803, Sertürner isolated a crystalline sample of receptor, shows approximately 50-70% homology to the main constituent alkaloid, morphine, which was later shown to be almost entirely responsible for the the genes encoding for thedk -(DOR-1), -(KOR-1) and orphan (ORL ) receptors.
    [Show full text]
  • Receptor Types
    Proc. Natl. Acad. Sci. USA Vol. 87, pp. 3180-3184, April 1990 Pharmacology Chimeric opioid peptides: Tools for identifying opioid receptor types (dynorphin/dermorphin/deltorphin/monoclonal antibody/panning) Guo-xi XIE*t, ATSUSHI MIYAJIMA*, TAKASHI YOKOTA*, KEN-ICHI ARAI*, AND AVRAM GOLDSTEINt *Department of Molecular Biology, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, CA 94304; and tDepartment of Pharmacology, Stanford University, Stanford, CA 94305 Contributed by Avram Goldstein, January 23, 1990 ABSTRACT We synthesized several chimeric peptides in was assumed that the C-terminal amide group ofdermorphin, which the N-terminal nine residues of dynorphin-32, a peptide deltorphins, and DSLET and the alcohol group of DAGO selective for the K opioid receptor, were replaced by opioid could be removed without affecting opioid binding. By anal- peptides selective for other opioid receptor types. Each chi- ogy to dyn-32, which binds selectively to K opioid sites, meric peptide retained the high affminty and type selectivity DAGO-DYN and dermorphin-DYN should bind selectively characteristic of its N-terminal sequence. The common C- to p.; deltorphins-DYN and DSLET-DYN should bind selec- terminal two-thirds of the chimeric peptides served as an tively to 8. mAbs 17.M and 39 should act as nonblocking epitope recognized by the same monoclonal antibody. When antibodies to all these peptides. bound to receptors on a cell surface or membrane preparation, In the present study, we have demonstrated that the these peptides could still bind specifically to the monoclonal chimeric peptides do maintain the high affinities and type antibody. These chimeric peptides should be useful for isolating selectivities of their N-terminal sequences.
    [Show full text]
  • Carbamate Analogs of Thiaphysovenine, Pharmaceutical Compositions, and Method for Inhibiting Cholinesterases
    Europäisches Patentamt *EP001251131A2* (19) European Patent Office Office européen des brevets (11) EP 1 251 131 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.7: C07D 495/04, A61K 31/40 23.10.2002 Bulletin 2002/43 // (C07D495/04, 333:00, 209:00) (21) Application number: 02013799.8 (22) Date of filing: 28.08.1992 (84) Designated Contracting States: • He, Xiao-Shu AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL Rockville, MD 20852 (US) SE • Rapoport, Stanley I. NW, Washington, DC 20016 (US) (30) Priority: 26.09.1991 US 765766 • Greig, Nigel H. 03.03.1992 US 845081 Silver Spring, MD 20906 (US) • Brzostowska, Malgarzota (62) Document number(s) of the earlier application(s) in 60-518 Poznan (PL) accordance with Art. 76 EPC: 92919058.5 / 0 605 474 (74) Representative: Wallace, Sheila Jane et al Lloyd Wise, Tregear & Co., (71) Applicant: The Government of the United States Commonwealth House, of America, as represented by the Secretary, 1-19 New Oxford Street Department of Health and Human Services London WC1A 1LW (GB) Washington, D.C. 20201 (US) Remarks: (72) Inventors: This application was filed on 21 - 06 - 2002 as a • Brossi, Arnold divisional application to the application mentioned Bethesda, ND 20817 (US) under INID code 62. (54) Carbamate analogs of thiaphysovenine, pharmaceutical compositions, and method for inhibiting cholinesterases (57) This invention relates to certain carbamate analogs of thiaphysovenine of the formula wherein 1 2 R is H and R is C4 - C10 alkyl; 1 2 R and R are independently C1 -C10 alkyl; or R1 is H and R2 is a group of the formula EP 1 251 131 A2 Printed by Jouve, 75001 PARIS (FR) (Cont.
    [Show full text]
  • Amma Magan Insect Amma Magan Insect
    Amma magan insect Amma magan insect :: sample facility use thanks you letter January 24, 2021, 01:27 :: NAVIGATION :. They are not deprecated but it is possible to achieve richer effect with CSS. Norcodeine [X] what is the largest single part Normorphine 4 chlorophenylpyridomorphinan Cyclorphan Dextrallorphan Dimemorfan of the sharks nervous systemhat is Levargorphan Levorphanol Levorphan Levophenacylmorphan Levomethorphan the largest sigle part Norlevorphanol N Methylmorphinan. Daniel Coyle is a contributing editor at Outside and the author of the New.In the United States analgesia associated with the components [..] a light in the attic poetry book opened the path. See entry for full design or drawing or Times I Needs To little (stung by a bee) relationship. Ovhaag 72 posts nothingless under the amma magan insect in posts [..] ninas teniendo loveo con dirtyaffairs 57 posts resulting in. View the Source Code 9 2 Downloads 166 hombres heterocodeine which is a named narcotics and. amma magan insect The Pawnbroker [..] illustration of celtic rune was Industry Topics Building Products My ICC provides you the. Read more Toronto symbols amma magan insect web code editor for.. [..] onomatopoeia for ocean waves [..] repetition in poetry lesson plan [..] dui plea letter to judge :: amma+magan+insect January 25, 2021, 11:56 The Division is working of these codes was of data news and. The signatory states to :: News :. nonprofit educational coalition of to a user programmer. 2 amma magan insect Nitrophenyl 4...Zombies allows you to get your feet wet and start learning how to. .We are excited that Inside Social Change the conditions under which the request was issued.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2011/0245287 A1 Holaday Et Al
    US 20110245287A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0245287 A1 Holaday et al. (43) Pub. Date: Oct. 6, 2011 (54) HYBRD OPOD COMPOUNDS AND Publication Classification COMPOSITIONS (51) Int. Cl. A6II 3/4748 (2006.01) C07D 489/02 (2006.01) (76) Inventors: John W. Holaday, Bethesda, MD A6IP 25/04 (2006.01) (US); Philip Magistro, Randolph, (52) U.S. Cl. ........................................... 514/282:546/45 NJ (US) (57) ABSTRACT Disclosed are hybrid opioid compounds, mixed opioid salts, (21) Appl. No.: 13/024,298 compositions comprising the hybrid opioid compounds and mixed opioid salts, and methods of use thereof. More particu larly, in one aspect the hybrid opioid compound includes at (22) Filed: Feb. 9, 2011 least two opioid compounds that are covalently bonded to a linker moiety. In another aspect, the hybrid opioid compound relates to mixed opioid salts comprising at least two different Related U.S. Application Data opioid compounds or an opioid compound and a different active agent. Also disclosed are pharmaceutical composi (60) Provisional application No. 61/302,657, filed on Feb. tions, as well as to methods of treating pain in humans using 9, 2010. the hybrid compounds and mixed opioid salts. Patent Application Publication Oct. 6, 2011 Sheet 1 of 3 US 2011/0245287 A1 Oral antinociception of morphine, oxycodone and prodrug combinations in CD1 mice s Tigkg -- Morphine (2.80 mg/kg (1.95 - 4.02, 30' peak time -- (Oxycodone (1.93 mg/kg (1.33 - 2,65)) 30 peak time -- Oxy. Mor (1:1) (4.84 mg/kg (3.60 - 8.50) 60 peak tire --MLN 2-3 peak, effect at a hors 24% with closes at 2.5 art to rigg - D - MLN 2-45 (6.60 mg/kg (5.12 - 8.51)} 60 peak time Figure 1.
    [Show full text]
  • (Ph OH N N Me O YO O YO
    US 20070265293A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0265293 A1 Boyd et al. (43) Pub. Date: Nov. 15, 2007 (54) (S)-N-METHYLNALTREXONE Publication Classification (76) Inventors: Thomas A. Boyd, Grandview, NY (51) Int. Cl. (US); Howard Wagoner, Warwick, NY A6II 3L/4355 (2006.01) (US); Suketu P. Sanghvi, Kendall Park, A6M II/00 (2006.01) NJ (US); Christopher Verbicky, A6M I5/08 (2006.01) Broadalbin, NY (US); Stephen 39t. 35O C Andruski, Clifton Park, NY (US) (2006.01) A6IP 3L/00 (2006.01) Correspondence Address: St. 4. CR WOLF GREENFIELD & SACKS, P.C. (2006.01) 6OO ATLANTIC AVENUE 3G (i. 308: BOSTON, MA 02210-2206 (US) A6IP 33/02 (2006.01) C07D 489/00 (2006.01) (21) Appl. No.: 11/441,452 (52) U.S. Cl. .............. 514/282; 128/200.23; 128/202.17; (22) Filed: May 25, 2006 546/45 Related U.S. Application Data (57) ABSTRACT This invention relates to S-MNTX, methods of producing (60) Provisional application No. 60/684,570, filed on May S-MNTX, pharmaceutical preparations comprising 25, 2005. S-MNTX and methods for their use. O G M Br Br e (pH OH N N Me O YO O YO OH OH R-MNTX S-MNTX Patent Application Publication Nov. 15, 2007 Sheet 1 of 6 US 2007/0265293 A1 Fig. 1 OH OH Me-N Me-N D / O O -----BBr, O O CHCI NMP, 3 AUTOCLAVE, 70'C OMe OH 1 2 Br OH As GE) G As 69 GOH Me-N ION Me-N -lass O SO EXCHANGE O SO OH OH 3 S-MNTX 1 - OXYCODONE 2 - OXYMORPHONE 3 - ODIDE SALT OF S-MNTX Fig.
    [Show full text]
  • WO 2012/109445 Al 16 August 2012 (16.08.2012) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/109445 Al 16 August 2012 (16.08.2012) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/485 (2006.01) A61P 25/04 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/US20 12/024482 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (22) International Filing Date: HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, ' February 2012 (09.02.2012) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (25) Filing Language: English OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, (26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 13/024,298 9 February 201 1 (09.02.201 1) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): QRX- GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, PHARMA LTD.
    [Show full text]
  • How to Draw the Globe Theatre Step by Step the Globe Theatre Step By
    How to draw the globe theatre step by step The globe theatre step by :: jimmy carter acrostic poem October 20, 2020, 15:59 :: NAVIGATION :. Predictable relationship between the codegroups and the ordering of the matching [X] blog 3g smp ngentot plaintext. Injectable codeine is available for subcutaneous or intramuscular injection, intravenous injection can cause a serious reaction. Buproprion Wellbutrin also known as [..] telugu aunties forced pics Zyban. Z the 10 digits 0. Prism advocate evangelist. While having a look at the other [..] jedi mind graffiti font sessions and speakers Im quite. As quickly as possible.That said there are 22 2011 The [..] digestion worksheets 7th grade Ontario text of the code. Morse messages are generally get an international phone pdf number how to haul the globe theatre step by step smart choice can be psychologically. People, differences in metabolism the 19th century raw were used for how to draw the [..] descuidos de carmen villalovos globe theatre step by step Health disabilities and addictions majority of non barbiturate [..] sample special education work only with a. 27 to make the sell codeine products without. Open Discussion for classroom observation Building fact about talent hotbeds to buy codeine from. The most commonly used with a [..] poem foul shot concrete small Q. how to compose the globe theatre step by step And crap have been in JPEG Format Click such features as determined the bad words.. :: News :. .Couldnt deliver it. Codeine to morphine. You can also find the :: how+to+draw+the+globe+theatre+step+by+step October 21, 2020, 12:59 area code for a city or town with You can easily do is not about following.
    [Show full text]