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(12) Patent Application Publication (10) Pub. No.: US 2008/0124279 A1 Andremont Et Al

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US 2008O124279A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0124279 A1 Andremont et al. (43) Pub. Date: May 29, 2008 (54) COLONIC DELIVERY USING ZN/PECTIN (52) U.S. Cl. .......................................... 424/9.1; 424/493 BEADS WITH AEUDRAGT COATING (76) Inventors: Antoine Andremont, Malakoff (FR); Helene Huguet, Paris (FR) (57) ABSTRACT Correspondence Address: Drug delivery systems that can deliver therapeutic and/or INTELLECTUAL PROPERTY f TECHNOLOGY diagnostic agents to the colon are disclosed. The systems LAW include pectin beads crosslinked with Zinc or any divalent PO BOX 14329 cation of interest, which beads are then coated with RESEARCH TRIANGLE PARK, NC 27709 Eudragit R-type polymers. The drug delivery systems are orally administrable, but can deliver the active agents to the (21) Appl. No.: 11/985.465 colon. In some embodiments, they can administer the agents to various positions in the gastro-intestinal tract, including the (22) Filed: Nov. 15, 2007 colon. The agent can be a small molecule, peptide, protein, nucleic acid, or complex structures of natural, recombinant or Related U.S. Application Data synthetic origin. In still other embodiments, the agent is a diagnostic agent. The agents can be used to diagnose, treat or (60) Provisional application No. 60/859,600, filed on Nov. investigate humans and animals for a variety of conditions, 17, 2006. including infectious diseases, inflammatory diseases, cancers O O and the like. Colon-specific delivery is obtained by formulat Publication Classification ing a prophylactic, therapeutic, and/or diagnostic agent with (51) Int. Cl. specific polymers that degrade in the colon, Such as pectin. A6 IK 49/00 (2006.01) The pectin is gelled/crosslinked with a cation Such as a Zinc A6 IK 9/14 (2006.01) cation. The formulation, typically in the form of ionically A6IP35/00 (2006.01) crosslinked pectin beads, is Subsequently coated with a spe A6IPI/00 (2006.01) cific polymer such as a EudragitR) polymer. Processes for A6IP 43/00 (2006.01) obtaining Such beads are also disclosed. SEM pictures of beads with cross section showing approximate thickness of Eudragit layer Patent Application Publication May 29, 2008 Sheet 1 of 6 US 2008/0124279 A1 Figure I : Efficiency of water rinsing to renove excess in etallic cation for formulation of As-Lacatamase LI E 16 9. 14 ') E 12 S 10 a 8 6 g 4. 5 2 O 0 supernatant after first wash Second wash third wash gelification Sample --Gelification in 6% Zn(Ac)2 bath -- Gelification in 12% Zn(Ac)2 bath Patent Application Publication May 29, 2008 Sheet 2 of 6 US 2008/O124279 A1 Beads mean weight (mg : s Number of rising 2 time of rinsing (min) t Time of gelification (min). 1. Figure 2: Effect of Gelification Time, Rinsing Process, and Drying Time on Recovery of b-Lactamase Ll Activity Patent Application Publication May 29, 2008 Sheet 3 of 6 US 2008/0124279 A1 Linearity of the L1 assay using CENTA y = 0.029a + 0.004 R 0.999 y = 0.028x + 0.006 R - G S. y = 0.033: + .001 R = (.99g L1 Concentration (ughini) Figure 3: Linearity of the assay of the enzymatic activity of B-lactamase Ll using CENTA as a substrate. Patent Application Publication May 29, 2008 Sheet 4 of 6 US 2008/0124279 A1 Figure 4: SEM pictures of beads with cross section showing approximate thickness of Endragit layer Release Kinetics from uncoated beads, or Eudragit-coated beads with or without HPMC pre-coating 150 180 210 240 270 300 Time (min) Figure 5: release kinetics of B-lactamase Ll from uncoated beads, and Eudragit-coated beads with or without HPMC pre-coating. Blue triangles: uncoated beads, red circles: beads coated with 40% Eudragit L30D-55 without pre coating; green squares: beads pre-coated with 5% HPMC and coated with 40% Eudragit L30D-55. Patent Application Publication May 29, 2008 Sheet 5 of 6 US 2008/0124279 A1 withfrom without uncoated HPMC beads, pre-coat or Tirne nin Figure 6: Hydrolysis of amoxicillin by uncoated, and Eudragit-coated beads with or without HPMC pre-coating. Blue triangles: uncoated beads, red circles: beads coated with 40% Eudragit L30D-55 without pre-coating, green squares: beads pre coated with HPMC and coated with Eudragit L30D-55. Patent Application Publication May 29, 2008 Sheet 6 of 6 US 2008/0124279 A1 Effect of beta-lactamase-containing beads on the emergence of bacterial resistance 80 . 7t, 60 Treatment2 duration4 (dayss post Dose 1) Figure 7: Effect of Eu dragit-coated pectin beads containing B-lactamase L1 on the emergence of antibiotic-resistant bacteria in piglets treated with amoxicitlin. Blue triangles: untreated animals (n=12), red diamonds: animals treated with amoxicillin and placebo pectin beads (n=12); green squares: animals treated with amoxicillin together with Eudragit-coated pectin beads containing B-lactamase Ll (n=4). US 2008/O124279 A1 May 29, 2008 COLONIC DELVERY USING ZNAPECTIN bacterial species; more than 10' bacteria per gram of colonic BEADS WITH AEUDRAGIT COATING content) which will be affected by the arrival of active anti biotic residues. The following can be observed: REFERENCE TO RELATED APPLICATION 0007 1. Flora imbalance which is the main cause of banal diarrhea occurring following antibiotic treatments (Bartlett J. 0001. This application claims priority to U.S. Ser. No. G. (2002) Clinical practice. Antibiotic associated diarrhea, 60/859,600, filed on Nov. 17, 2006, the contents of which are New England Journal of Medicine, 346,334). Even though hereby incorporated by reference. this diarrhea is generally not serious and ceases rapidly, either spontaneously, or upon completion of the antibiotic treat FIELD OF THE INVENTION ment, it is adversely perceived by patients and adds to the 0002 The present invention is in the area of oral drug discomfort of the original illness for which the antibiotic was delivery systems to administer active agents to the colon. prescribed: 0008 2. interference with the resistance to colonization by BACKGROUND OF THE INVENTION exogenic bacteria (or “barrier effect”) with possible risk of 0003 Drug delivery systems that specifically deliver infection, such as alimentary salmonella intoxication (Holm active agents to the colon have been recognized as having berg S. D. et al. (1984) Drug resistant Salmonella from ani important therapeutic advantages. A large number of colonic mals fed antimicrobials, New England Journal of Medicine, conditions could effectively be treated more efficaciously if 311, 617); the active ingredient is released locally. Examples of Such 0009. 3. selection of microorganisms resistant to the anti colonic disorders include Crohn's disease, ulcerative colitis, biotic. These microorganisms can be of various types: colorectal cancer and constipation. 0010 a) first they can be pathogenic bacteria such as for 0004 Colonic release can also benefit patients when, from example, Clostridium difficile, a species capable of secreting atherapeutic point of view, a delay in absorption is necessary. toxins causing a form of colitis known as pseudomembranous colitis (Bartlett J. G. (1997) Clostridium difficle infection: Examples include the treatment of disorders such as noctur pathophysiology and diagnosis, Seminar in Gastrointestinal nal asthma or angor (Kinget R. et al. (1998), Colonic Drug Disease, 8, 12); Targeting, Journal of Drug Targeting, 6. 129). 0.011 b) they can also be microorganisms that are rela 0005 Colonic release can also be used to administer thera tively weakly pathogenic, but whose multiplication can peutically active polypeptides. Polypeptides are typically lead to an associated infection (vaginal Candidosis or administered by injection, because they are degraded in the Escherichia coli resistant cystitis). stomach. Because injection is painful, research efforts have 0012 c) they can finally be non-pathogenic commensal focused on using the colon as a site of absorption for active drug-resistant bacteria whose multiplication and fecal elimi polypeptides, including analgesics, contraceptives, vaccines, nation will increase dissemination of antibiotic resistance in insulin, and the like. The absorption of polypeptides in the the environment. It is well documented that antibiotic resis colon appears to be more effective than in other sites in the tance genes are carried by mobile or transposable genetic digestive tract. This is particularly due to the relatively weak elements that may contain up to 5 or 6 antibiotic resistance proteolytic activity in the small intestine and the absence of genes, and are readily transmitted to other bacteria, even peptidase activity associated with the membrane of the across species. Consequently, these resistant commensal bac colonic epithelial cells. teria may constitute an important source leading to drug resis 0006 Following their oral administration, antibiotics pass tance for pathogenic species. This risk is currently considered through the stomach and are then absorbed in the Small intes seminal in terms of the disquieting character of the evolution tine to diffuse in the whole organism and treat the infectious towards drug multiresistance by numerous species patho outbreak site(s) for which they have been administered. All genic for humans. the same, a fraction of antibiotics ingested (the importance of 0013. It would therefore be desirable to have drugs and this fraction varies with the characteristics of each antibiotic) drug delivery systems that would act to reduce the quantity of is not absorbed and continues its progress to the colon before residual antibiotics reaching the colon following oral or being eliminated in the stool. These residual antibiotics are parenteral antibiotic therapy. To this end, it would be advan combined, in the large intestine, with a fraction of the antibi tageous to have drug delivery systems which enable to admin otics absorbed, but which are re-excreted in the digestive tract ister the active agents to the colon. by means of biliary elimination. This fraction is of variable 0014) Numerous strategies exploiting the diverse physi importance as a function of metabolism and elimination path ological parameters of the digestive tract have been devised ways for each antibiotic.
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  • Rubsicolins Are Naturally Occurring G-Protein-Biased Delta Opioid Receptor Peptides

    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.