DOCSLIB.ORG

Ep 1948596 B1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Ep 1948596 B1 (19) & (11) EP 1 948 596 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 207/10 (2006.01) C07D 451/10 (2006.01) 19.10.2011 Bulletin 2011/42 A61K 31/40 (2006.01) A61K 31/439 (2006.01) A61P 11/00 (2006.01) A61P 11/06 (2006.01) (2006.01) (2006.01) (21) Application number: 06837367.9 A61P 13/10 A61P 27/08 (22) Date of filing: 13.11.2006 (86) International application number: PCT/US2006/043858 (87) International publication number: WO 2007/058971 (24.05.2007 Gazette 2007/21) (54) SOFT ANTICHOLINERGIC ESTERS SANFTE ANTICHOLINERGE ESTER ESTERS ANTICHOLINERGIQUES MODERES (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR WO-A-2005/000815 WO-A-2006/066928 HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR • JI, F. ET AL: "Synthesis and pharmacological effects of new, N-substituted soft (30) Priority: 10.11.2005 US 735207 P anticholinergics based on glycopyrrolate" JOURNAL OF PHARMACY AND (43) Date of publication of application: PHARMACOLOGY , 57(11), 1427-1435 CODEN: 30.07.2008 Bulletin 2008/31 JPPMAB; ISSN: 0022-3573, 2005, XP009084050 • WU, WHEI-MEI ET AL: "Pharmacokinetic and (73) Proprietor: Bodor, Nicholas S. Pharmacodynamic Evaluations of the Bal Harbour, FL 33154 (US) Zwitterionic Metabolite of a New Series of N- Substituted Soft Anticholinergics" (72) Inventor: Bodor, Nicholas S. PHARMACEUTICAL RESEARCH , 22(12), Bal Harbour, FL 33154 (US) 2035-2044 CODEN: PHREEB; ISSN: 0724-8741, [Online] 26 September 2005 (2005-09-26), (74) Representative: Hedley, Nicholas James Matthew XP002426085 ISSN: 1573-904X Retrieved from et al the Internet: URL:http://www.springerlink.com/ Kilburn & Strode LLP content/tq 341467ww302m87/> [retrieved on 20 Red Lion Street 2007-03-19] London • BANHOLZER, R. ET AL: "Synthesis of WC1R 4PJ (GB) anticholinergically active N- alkylnorscopolamines and their quaternary salts with particular consideration of the bronchospasmolytic compound (-)-N- ethylnorscopolamine methobromide (Ba 253 BR)" ARZNEIMITTEL-FORSCHUNG , 35(1A), 217-28 CODEN: ARZNAD; ISSN: 0004-4172, 1985, XP001249054 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 948 596 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 948 596 B1 Description BACKGROUND 5 [0001] Various anticholinergic compounds have been previously described but are not optimal. [0002] Muscarinic receptor antagonists are frequently used therapeutic agents that inhibit the effects of acetylcholine by blocking its binding to muscarinic cholinergic receptors at neuroeffector sites on smooth muscle, cardiac muscle, and gland cells as well as in peripherial ganglia and in the central nervous system (CNS). However, their side effects, which can include dry mouth, photophobia, blurred vision, urinary hesitancy and retention, decreased sweating, drowsiness, 10 dizziness, restlessness, irritability, disorientation, hallucinations, tachycardia and cardiac arrhythmias, nausea, consti- pation, and severe allergic reactions, often limit their clinical use, and even topical anticholinergics can cause the same unwanted side effects. Glycopyrrolate and triotropium are among the quaternary ammonium anticholinergics, which have reduced CNS-related side effects as they cannot cross the blood-brain barrier; however, because glycopyrrolate (or, presumably, tiotropium) is eliminated mainly as unchanged drug or active metabolite in the urine, its administration 15 is problematic in young or elderly patients and especially in uraemic patients. To increase the therapeutic index of anticholinergics, the soft drug approach has been applied in a number of different designs starting from various lead compounds over the past 20 years, but there is a need for yet other new soft anticholinergics. These novel muscarinic antagonists, just as all other soft drugs, are designed to elicit their intended pharmacological effect at the site of application, but to be quickly metabolized into their designed-in, inactive metabolite upon entering the systemic circulation and rapidly 20 eliminated from the body, resulting in reduced systemic side effects and increased therapeutic index. [0003] Arzneimittel - Forschung, 35 (1A), 217 - 228, 1985, XP 001249054 discloses anticholinergic active quaternary salts of scopolamine derivaties. SUMMARY 25 [0004] New soft anticholinergic agents, pharmaceutical compositions containing them, processes for their preparation and methods for eliciting an anticholinergic response, especially for treating an obstructive disease of the respiratory tract or for treating overactive bladder, are provided. [0005] In one exemplary embodiment, there is provided a compound having the formula 30 35 40 45 - wherein R is C 1-C8 alkyl, straight or branched chain; and X is an anion with a single negative chargeor a mixture thereof. [0006] In other exemplary embodiments, processes for preparing the compounds are provided. [0007] In other exemplary embodiments, there are provided pharmaceutical compositions comprising one or more of the compounds of the foregoing formula and pharmaceutically acceptable carriers therefor; pharmaceutical combinations 50 comprising one or more of the compounds of the foregoing formula and an antiinflammatory corticosteroid, a betamimetic agent or an antialleric agent; also described are methods of using the subject compositions and combinations. BRIEF DESCRIPTION OF THE DRAWINGS 55 [0008] FIG. 1 is a graph of the heart rate in beats per minute versus time in minutes showing the protective effect of different anticholinergics, including Compound (w), on carbachol-induced bradycardia is anesthetized rats (n= 3-6). 2 EP 1 948 596 B1 FIG. 2 is a graph showing the time course of action of different anticholinergics, including Compounds (w) and (aa), on electrically stimulated guinea pig trachea. FIG. 3 is a graph showing the time course of the effect of different anticholingerics including Compounds (w) and (aa), after wash out of the test drug on electrically stimulated guinea pig trachea. 5 DETAILED DESCRIPTION [0009] Throughout this specification, the following definitions, general statements and illustrations are applicable: [0010] The patents, published applications, and scientific literature referred to herein establish the knowledge of those 10 with skill in the art. Any conflict between any reference cited herein and the specific teachings of this specification shall be resolved in favor of the latter. Likewise, any conflict between an art-understood definition of a word or phrase and a definition of the word or phrase as specifically taught in this specification shall be resolved in favor of the latter. [0011] As used herein, whether in a transitional phrase or in the body of a claim, the terms "comprise(s)" and "com- prising" are to be interpreted as having an open- ended meaning. That is, the terms are to be interpreted synonymously 15 with the phrases "having at least" or "including at least". When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a composition, the term "comprising" means that the composition includes at least the recited features or components, but may also include additional features or components. [0012] The terms "consists essentially of" or "consisting essentially of" have a partially closed meaning, that is, they 20 do not permit inclusion of steps or features or components which would substantially change the essential characteristics of a process or composition; for example, steps or features or components which would significantly interfere with the desired properties of the compounds or compositions described herein, i.e., the process or composition is limited to the specified steps or materials and those which do not materially affect the basic and novel characteristics of the invention. The basic and novel features herein are the provision of compounds of formula (Ib) and combinations of those compounds 25 with other drugs, particularly with antiinflammatory steroids, especially loteprednol etabonate or etiprednol dichloroac- etate, and most especially in the case of loteprenol etabonate (LE) further including an inactive metabolite enhancing agent for the LE as further defined hereinafter. [0013] The terms "consists of" and "consists" are closed terminology and allow only for the inclusion of the recited steps or features or components. 30 [0014] As used herein, the singular forms "a," "an" and "the" specifically also encompass the plural forms of the terms to which they refer, unless the content clearly dictates otherwise. [0015] The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" or "approximately" is used herein to modify a numerical 35 value above and below the stated value by a variance of 20%. [0016] As used herein, the recitation of a numerical range for a variable is intended to convey that the variable can be equal to any of the values within that range. Thus, for a variable which is inherently discrete, the variable can be equal to any integer value of the numerical range, including the end-points of the range. Similarly, for a variable which is inherently continuous, the variable can be equal to any real value of the numerical range, including the end- points of 40 the range. As an example, a variable which is described as having values between 0 and 2, can be 0, 1 or 2 for variables which are inherently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other real value for variables which are inherently continuous.
Load more

Recommended publications
  • WO 2018/232007 Al 20 December 2018 (20.12.2018) W !P O PCT
    (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 2018/232007 Al 20 December 2018 (20.12.2018) W !P O PCT (51) International Patent Classification: A61K 31/56 (2006.01) C07J 3/00 (2006.01) A61K 31/569 (2006.01) A61P 29/00 (2006.01) (21) International Application Number: PCT/US2018/037366 (22) International Filing Date: 13 June 2018 (13.06.2018) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/5 18,922 13 June 2017 (13.06.2017) US 62/559,201 15 September 2017 (15.09.2017) US 62/562,099 22 September 2017 (22.09.2017) US (71) Applicant: BODOR LABORATORIES, INC. [US/US]; 4400 Biscayne Boulevard, Suite 980, Miami, FL 33 137 (US). (72) Inventor: BODOR, Nicholas, S.; 10225 Collins Avenue, Units 1002-1004, Bal Harbour, FL 33 154 (US). (74) Agent: BRUEHS, Martin A.; Dentons US LLP, 233 South Wacker Drive, Suite 5900, Chicago, Illinois 60606 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
    [Show full text]
  • HPLC Separation of Related Impurities in Etiprednol Dicloacetate, a Novel Soft Corticosteroid
    ORIGINAL ARTICLES IVAX Drug Research Institute Ltd., Budapest, Hungary HPLC separation of related impurities in etiprednol dicloacetate, a novel soft corticosteroid M. Patthy, G. Seres, A´ . Csana´di, T. Szekeres, Z. Zubovics, N. Bodor Received October 29, 2003, accepted November 12, 2003 Miklos Patthy, 1045 Budapest, Berlini u. 47-49, Hungary [email protected] Pharmazie 59: 382–386 (2004) Etiprednol dicloacetate (ethyl 17a-dichloroacetoxy-11b-hydroxy-androsta-1,4-diene-3-one-17b-carboxy- late, code-named: BNP-166) has been prepared in a 3-step synthesis from prednisolone as starting material. The primary aim of the present work was to develop HPLC methods for the separation of all the impurities found in experimental pilot plant batches of BNP-166 at concentrations 0.10 area %. Besides BNP-166, a total of 19 compounds, eight of them potential impurities, were involved in the HPLC studies in which several HPLC systems were examined and tested to optimize the separation. Of the parameters influencing chromatographic behaviour column type, the nature and composition of the mobile phase and column temperature were varied, while the pH of the eluent was kept constant at 4.5, a pH value at which stability of the BNP-166 ester bonds was found to be the highest. A comparison of the RRT values obtained allowed some conclusions to be drawn concerning the physi- co-chemical forces governing separation. The isocratic reversed-phase HPLC system (V02) chosen to be used for various GXP studies on BNP-166 affords baseline separation of nearly all the compounds concerned, and also the quantitation of the drug candidate (BNP-166).
    [Show full text]
  • Soft Anticholinergic Zwitterions Weiche Anticholinerge Zwitterionen Zwitterions Anticholinergiques Moderes
    (19) & (11) EP 1 957 451 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 207/10 (2006.01) C07D 451/10 (2006.01) 19.10.2011 Bulletin 2011/42 A61K 31/40 (2006.01) A61K 31/439 (2006.01) A61P 11/00 (2006.01) A61P 11/06 (2006.01) (2006.01) (2006.01) (21) Application number: 06837428.9 A61P 13/10 A61P 27/08 (22) Date of filing: 13.11.2006 (86) International application number: PCT/US2006/043966 (87) International publication number: WO 2007/059021 (24.05.2007 Gazette 2007/21) (54) SOFT ANTICHOLINERGIC ZWITTERIONS WEICHE ANTICHOLINERGE ZWITTERIONEN ZWITTERIONS ANTICHOLINERGIQUES MODERES (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR WO-A-2005/000815 WO-A-2006/066928 HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR • WU, WHEI-MEI ET AL: "Pharmacokinetic and Pharmacodynamic Evaluations of the (30) Priority: 10.11.2005 US 735206 P Zwitterionic Metabolite of a New Series of N- Substituted Soft Anticholinergics" (43) Date of publication of application: PHARMACEUTICAL RESEARCH , 22(12), 20.08.2008 Bulletin 2008/34 2035-2044 CODEN: PHREEB; ISSN: 0724-8741, [Online] 26 September 2005 (2005-09-26), (73) Proprietor: Bodor, Nicholas S. XP002426085 ISSN: 1573-904X Retrieved from Bal Harbour, FL 33154 (US) the Internet: URL:http://www.springerlink.com/ content/tq 341467ww302m87/> [retrieved on (72) Inventor: Bodor, Nicholas S. 2007-03-19] Bal Harbour, FL 33154 (US) • BANHOLZER, R.
    [Show full text]
  • Retrometabolic Drug Design: Principles and Recent Developments*
    Pure Appl. Chem., Vol. 80, No. 8, pp. 1669–1682, 2008. doi:10.1351/pac200880081669 © 2008 IUPAC Retrometabolic drug design: Principles and recent developments* Nicholas Bodor1,‡ and Peter Buchwald2 1Center for Drug Discovery, University of Florida, Health Science Center, P.O. Box 100497, Gainesville, FL 32610, USA; 2Molecular and Cellular Pharmacology and Diabetes Research Institute, University of Miami, Miami, FL 33136, USA Abstract: Retrometabolic drug design incorporates two major systematic approaches: the de- sign of soft drugs (SDs) and of chemical delivery systems (CDSs). Both aim to design new, safe drugs with an improved therapeutic index by integrating structure–activity and –metab- olism relationships; however, they achieve it by different means: whereas SDs are new, ac- tive therapeutic agents that undergo predictable metabolism to inactive metabolites after ex- erting their desired therapeutic effect, CDSs are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a de- signed sequential metabolism that involves several steps. General principles and recent de- velopments are briefly reviewed with various illustrative examples from different therapeu- tic areas with special focus on soft corticosteroids and on brain targeting. Keywords: drug design; metabolism; brain targeting; hydrolysis; oxime. INTRODUCTION Despite major advancement in the elucidation of the molecular/biochemical mechanisms of drug ac- tions and in our abilities to screen compounds and identify highly active hits, there was no correspon- ding increase in launched new chemical entities (NCEs) approved by regulatory agencies. This is most likely due to our limited understanding as to what makes ultimately a good drug as well as to increas- ing difficulties caused by the existing stringent regulations.
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • A Abacavir Abacavirum Abakaviiri Abagovomab Abagovomabum
    A abacavir abacavirum abakaviiri abagovomab abagovomabum abagovomabi abamectin abamectinum abamektiini abametapir abametapirum abametapiiri abanoquil abanoquilum abanokiili abaperidone abaperidonum abaperidoni abarelix abarelixum abareliksi abatacept abataceptum abatasepti abciximab abciximabum absiksimabi abecarnil abecarnilum abekarniili abediterol abediterolum abediteroli abetimus abetimusum abetimuusi abexinostat abexinostatum abeksinostaatti abicipar pegol abiciparum pegolum abisipaaripegoli abiraterone abirateronum abirateroni abitesartan abitesartanum abitesartaani ablukast ablukastum ablukasti abrilumab abrilumabum abrilumabi abrineurin abrineurinum abrineuriini abunidazol abunidazolum abunidatsoli acadesine acadesinum akadesiini acamprosate acamprosatum akamprosaatti acarbose acarbosum akarboosi acebrochol acebrocholum asebrokoli aceburic acid acidum aceburicum asebuurihappo acebutolol acebutololum asebutololi acecainide acecainidum asekainidi acecarbromal acecarbromalum asekarbromaali aceclidine aceclidinum aseklidiini aceclofenac aceclofenacum aseklofenaakki acedapsone acedapsonum asedapsoni acediasulfone sodium acediasulfonum natricum asediasulfoninatrium acefluranol acefluranolum asefluranoli acefurtiamine acefurtiaminum asefurtiamiini acefylline clofibrol acefyllinum clofibrolum asefylliiniklofibroli acefylline piperazine acefyllinum piperazinum asefylliinipiperatsiini aceglatone aceglatonum aseglatoni aceglutamide aceglutamidum aseglutamidi acemannan acemannanum asemannaani acemetacin acemetacinum asemetasiini aceneuramic
    [Show full text]
  • A New Withanolide from the Roots of Withania Somnifera
    Indian Journal of Chemistry Vol. 47B, May 2008, pp. 721-733 Advances in Contemporary Research Retrometabolism based drug targeting- Soft drug approach C S Ramaa*, Rhea Mohan, A S Mundada & V J Kadam Bharati Vidyapeeth’s College of Pharmacy, Sector 8, C.B.D-Belapur, Navi Mumbai 400 614, India E-mail: [email protected] Received 11 August 2006; accepted (revised) 10 March 2008 Despite considerable progress in medicinal chemistry in the last century, rational drug design that allows the development of effective pharmaceutical agents with minimal side effects is still an elusive goal. The primary causes for side effects are the generalized effect of drug on receptors present throughout the body and uncontrolled drug metabolism. Thus, it has become evident that targeting and metabolism considerations should be an integral part of any drug design process and that the focus should be on increasing activity as well as therapeutic index of the potential drug candidate. Various ideas have been suggested over the years to come up with an ideal approach to drug design. In this review, we shall be dealing with one such approach, that is, the soft drug approach. A soft drug is pharmacologically active as such, and it undergoes a predictable and controllable metabolism to nontoxic and inactive metabolites. The main concept of soft drug design is to avoid oxidative metabolism as much as possible and to use hydrolytic enzymes to achieve predictable and controllable drug metabolism. The discussion shall present an overview on the need for the development of soft drugs, associated terminologies and the different classes of soft drugs.
    [Show full text]
  • Recent Advances in the Design and Development of Soft Drugs
    REVIEW Diabetes Research Institute1 and Department of Molecular and Cellular Pharmacology2, University of Miami, Miami, FL, USA and Center for Drug Discovery3, University of Florida, Gainesville, FL, USA Recent advances in the design and development of soft drugs P. Buchwald 1,2, N. Bodor 3 Received November 4, 2013, accepted November 29, 2013 Prof. Dr. Nicholas Bodor, Center for Drug Discovery, University of Florida, Health Science Center, P.O. Box 100497, Gainesville, FL 32610-0497, USA [email protected] Pharmazie 69: 403–413 (2014) doi: 10.1691/ph.2014.3911R This paper summarizes recent developments in the field of soft drug development as collected and reviewed for the 9th Retrometabolism-Based Drug Design and Targeting Conference. Soft drugs are still often con- fused with prodrugs because they both require metabolic transformations; however, they are conceptual opposites: whereas, prodrugs are pharmacologically inactive and are converted by a predictable mecha- nism to the active drug, soft drugs are active therapeutic agents as such and are designed to undergo a predictable and controllable metabolic deactivation after exerting their desired therapeutic effect. Several rationally designed soft drug examples including clinically approved ones (e.g., clevidipine, esmolol, lan- diolol, loteprednol etabonate, and remifentanil) as well as others that have reached clinical investigations within different therapeutic areas (e.g., budiodarone, naronapride, remimazolam, tecarfarine) are briefly summarized. Anesthesiology, which requires a high degree of pharmacologic control during the surgical procedure to maintain the anesthetic state together with a quick return to responsiveness at the end of this procedure, is a particularly well-suited area for soft drug development.
    [Show full text]
  • Anti-Inflammatory Effect and Soft Properties of Etiprednol Dicloacetate (BNP-166), a New, Anti-Asthmatic Steroid
    ORIGINAL ARTICLES IVAX Drug Research Institute1, Budapest Hungary; Ivax Corporation2 Miami, Fl. USA Anti-inflammatory effect and soft properties of etiprednol dicloacetate (BNP-166), a new, anti-asthmatic steroid I. Kurucz1,K.Ne´meth1,S.Me´sza´ros1,K.To¨ro¨k1, Z. Nagy1, Z. Zubovics1, K. Horva´th1, N. Bodor1, 2 Received October 29. 2003, accepted December 1, 2003 Istva´n Kurucz, Department of Immunopharmacology, IVAX Drug Research Institute, 47–49 Berlini utca, H-1045 Budapest, Hungary Pharmazie 59: 412–416 (2004) In vitro and in vivo anti-inflammatory properties and soft characteristics of etiprednol dicloacetate (BNP-166) a new steroid, which has been developed for the treatment of asthma, were investigated in this study. The compound effectively decreased cytokine production in lipopolysaccharide stimu- lated lymphocytes and attenuated lectin-induced proliferation of blood mononuclear cells in tissue culture. In an animal model of allergen sensitized and challenged Brown Norway rats, using topical treatment, etiprednol dicloacetate substantially attenuated the extent of allergen induced bronchoal- veolar fluid eosinophilia. At every examined parameter its pharmacological effects were comparable to those of budesonide. By means of in vitro biological and analytical methods the soft character of BNP-166 was also investigated. The anti-inflammatory effect of etiprednol dicloacetate in vitro was shown to be the function of the quantity of serum components, present in the assay. This loss of activity was most likely the result of the fast metabolism of etiprednol dicloacetate, which in the presence of sera could have been demonstrated by LC/MS/MS. Our data indicate that the sig- nificant local effect of the compound will very likely be accompanied with a drastically reduced systemic activity indicating an encouraging selectivity of the pharmacological action of etiprednol dicloacetate.
    [Show full text]
  • CASE STUDY 6 Steroidal Anti-Inflammatory Agents
    ■ CASE STUDY 6 Steroidal anti-infl ammatory agents CS6.1 Introduction to steroids Steroids are hydrophobic compounds owing to their extensive hydrocarbon skeleton. Th is is an important Steroids are important endogenous hormones found in characteristic as the hormonal steroids have to cross cell many life forms. Th ey all share a common tetracyclic membranes in order to interact with intracellular steroid structure, as shown in Figure CS6.1, but they vary in receptors (see section 4.9 and Box 8.2). All of the impor- the substituents and functional groups that are present. tant endogenous steroids have polar functional groups, Th e stereochemistry of the rings in fully saturated ster- such as alcohols, phenols, and ketones. Th ese play a cru- oids is identical in mammalian steroids, where the three cial role in the binding of steroids to their target recep- 6-membered rings have chair conformations. Th ere are tors, but their presence does not alter the hydrophobic several asymmetric centres present, but only one stereo- nature of the molecule as a whole. Because most steroids isomer occurs naturally for any particular steroid. For are hormones, they are present in very small quantities example, cortisol has seven asymmetric centres, but only in the body (less than 1 mg). Th e exception is cholesterol, the stereoisomer shown in Figure CS6.1 exists naturally. which is present in much larger quantities (250 g) and Some of the terminology used in the nomenclature of has a number of non-hormonal roles (Case study 1). steroids is worth explaining at this point.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2007/0299044 A1 Faring Et Al
    US 20070299044A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0299044 A1 Faring et al. (43) Pub. Date: Dec. 27, 2007 (54) CORTICOSTEROID TOPICAL DISPERSION Related U.S. Application Data WITH LOW CONTENT OF SURFACTANT (60) Provisional application No. 60/610,139, filed on Sep. (76) Inventors: Richard K. Farng, East Brunswick, NJ 15, 2004. (US); Chung-Tsin Chiu, Miami, FL (US); Ba Cuong Tu, Miami, FL (US); Publication Classification Kenneth W. Kwochka, St. Joseph, MO (51) Int. Cl. (US) A6II 3/56 (2006.01) A6IP 29/00 (2006.01) Correspondence Address: (52) U.S. Cl. .............................................................. S14/178 LERNER, DAVID, LITTENBERG, KRUMHOLZ. & MENTLIK (57) ABSTRACT 6OO SOUTHAVENUE WEST The invention provides novel compositions of water-in WESTFIELD, NJ 07090 (US) soluble corticosteroid drug in combination with antimicro (21) Appl. No.: 11/662,538 bial agents and very low concentrations of polymers and Surfactants for topical, otic and ophthalmic treatment. The (22) PCT Filed: Sep. 15, 2005 invention provides stable aqueous Suspension where the ingredients remain in Such a state so as to allow for imme (86). PCT No.: PCT/USOS/32641 diate re-suspension, when desired, even after extended peri ods of settling. The invention provides also a method for S 371(c)(1), treating inflammation with low systemic absorption and (2), (4) Date: Jul. 23, 2007 side-effects of the corticosteroid. US 2007/0299044 A1 Dec. 27, 2007 CORTICOSTEROID TOPCAL DISPERSON WITH provides formulations having ionic polymers and very low LOW CONTENT OF SURFACTANT concentrations of Surfactants. It is Surprisingly found that at the low concentrations of non-ionic polymers (e.g., 0.005% BACKGROUND OF THE INVENTION to 0.2% w/w), the re-suspension of the drug substance is better than the formulation comprising conventional con 0001 Typically topical, otic, or ophthalmic products con centrations (i.e., 0.2-2% w/w) of non-ionic polymers.
    [Show full text]
  • Poison Or Antibiotic? a Guide to "Class" Entries
    Poison or Antibiotic? A Guide to “Class” Entries Preface Most entries in the Poisons List, i.e. the Schedule 10, and the Schedules 1, 2 and 3 to the Pharmacy and Poisons Regulations (Cap. 138A) are in the form of individual drugs and their salts, e.g. “Abacavir; its salts”. However, some entries are in the form of a “class”, e.g. “Barbituric acid; its salts; its derivatives …”. In such cases, it is not always clear which drugs are members of the class (e.g. amobarbital, barbital, pentobarbital, phenobarbital, etc. are poisons, being derivatives of barbituric acid). Likewise, the Antibiotics Ordinance (Cap. 137) applies to the substances specified in Schedule 1 to the Antibiotics Regulations, to their salts and derivatives, and to the salts of such derivatives. Again, it is not always clear which drugs are derivatives of an antibiotic named in the Schedule (e.g. demeclocycline, doxycycline, tigecycline, etc. are antibiotics, being derivatives of “Tetracycline” named in the Schedule). This Guide provides a list of such drugs which are available as registered pharmaceutical products in Hong Kong. Drugs which are not available as registered pharmaceutical products in Hong Kong are also included in this Guide as far as possible. It should be noted that it is not possible to compile a complete list of all these drugs, simply because there is no limit to the number of “derivatives” a parent chemical can have. This Guide should be read in conjunction with the Schedules 1, 2, 3, and 10 to the Pharmacy and Poisons Regulations, and Schedule 1 to the Antibiotics Regulations, if the poison/antibiotic classification of a particular pharmaceutical product is to be determined.
    [Show full text]