DOCSLIB.ORG

WO 2018/232007 Al 20 December 2018 (20.12.2018) W !P O PCT

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
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. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — with international search report (Art. 21(3)) o o (54) Title: POTENT SOFT ANTI-INFLAMMATORY CORTICOSTEROID COMPOUNDS AND USES THEROF (57) Abstract: Potent soft corticosteroid pharmaceutical compositions comprising them and method for use as anti-inflammatory agents. Also, a method for softemng fluticasone propionate and similar corticosteroids to arrive at potent but safer alternatives. The compound S-fluoromethyl 17a-dichloroacetoxy-6a,9a-difluoro-l ^-hydroxy-16a- methyl-3-oxoandrosta-l,4-diene-17 -carbothioate, © which is equally potent to but safer than fluticasone, is among those provided. Another compound of particular interest is 2-hydrox- yethyl 17a-dichloroacetoxy-6a,9a-difluoro-l 1β-1^ ^-16 β- methyl-3-oxoandrosta-l,4-diene-17 -carboxylate. O POTENT SOFT ANTI-INFLAMMATORY CORTICOSTEROID COMPOUNDS AND USES THEROF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of United States Provisional Application No. 62/518,922, filed June 13, 2017, United States Provisional Application No. 62/559,201 , filed September 15, 2017 and United States Provisional Application No. 62/562,099, filed September 22, 2017, which are all incorporated by reference herein in their entireties and relied upon. FIELD [0002] Potent soft corticosteroids, pharmaceutical compositions comprising them and methods for use as anti-inflammatory agents. Also, a method for softening fluticasone propionate and similar corticosteroids to arrive at potent but safer alternatives. BACKGROUND ART [0003] Topical or other local application of potent glucocorticoids can produce severe toxic effects such as Cushingoid features, pituitary-adrenal suppression, skin atrophy, immunosuppression and inhibition of wound healing. Other kinds of toxic responses, including allergies and cataracts, have resulted from long term use of drugs of this type. [0004] Ophthalmic application of glucocorticosteroids presents additional problems. The protective mechanisms built into the eye allow only small amounts of doses applied to the eye to reach the target sites within the eye; generally, over 90 per cent of the total dose will find its way into the general circulation. This in turn leads to serious systemic side effects of the type described above. Moreover, there is a more serious and specific side effect when these drugs are used in the eye, which is an increase in intraocular pressure (IOP). Corticosteroid-induced chronic or acute glaucoma has in fact been reported since the early 1960's. Generally, the corticosteroid is needed only topically to control the inflammation. However, the absorbed steroid is responsible for the serious side effects noted above. It is believed that the effect of the corticosteroid on the aqueous outflow pathway and adjacent tissue glycosaminoglycans (GAG's) is important in the development of glucocorticoid-induced ocular hypertension. [0005] There is, therefore, a serious need for potent local anti-inflammatory steroids, which lack systemic activity and consequently do not produce the serious systemic side effects associated with drugs of this class. [0006] 'Soft' steroids are compounds having potent anti-inflammatory activity, comparable with conventional steroids, but with minimal systemic activity. These compounds include ∆ 4 and ∆ ,4 17a-alkoxy- 1 1p-hydroxy-3-oxoandrostenes optionally bearing various substituents at the 6 , 9 and 16-positions and related 11- substituted compounds, which are esters or thioesters of 17 -carboxylic acids. These 17a-ethers are described in Bodor U.S. Pat. No. 4,710,495. Preferred compounds are taught to be the haloalkyi esters of 17a-alkoxy- 1 Ι -hydroxyandrost- 4-en-3-one-17 -carboxylic acids. [0007] Another series of 'soft' steroids which are described as having potent anti-inflammatory activity with minimal systemic activity are the 17a-carbonates of Bodor U.S. Pat. No. 4,996,335. These compounds include as preferred embodiments, haloalkyi 17a-alkoxycarbonyloxy - 1 i p-hydroxyandrost -4-en-3-one- 17 -carboxylates and the corresponding ∆ ,4 compounds, optionally bearing 6a- and/or 9a-fluorine and 16a- or Ιδβ -methyl substituents. One of these compounds is chloromethyl 17a-ethoxycarbonyloxy - 1 1β-hydroxyandrosta-l ,4-dien-3-one- 17β- carboxylate, also known as loteprednol etabonate (LE), approved by the FDA in 1998 and marketed worldwide in five or more products. [0008] During the design and development of the first generation of the 'soft' corticosteroids, more than 120 compounds were synthesized and studied, combining the soft pharmacophore center of 17a-carbonate -17 -chloromethyl esters, with the usual modifications of the corticosteroid structure, such as fluorination at 6a and/or 9a, methylation at 16a and 16 β positions and varying the 17p-ester and 17a-carbonate functions. QSAR studies indicated that the known activity enhancer groups were very effective in the soft steroids of this type as well. The relative receptor binding activity (RRBA) values nicely correlated with presence or absence of the fluoro substituents, the molecular volume (calculated by semi- empirical quantum chemical methods) and calculated partition coefficients. Some of the substituted LE derivatives are extremely potent; for example, the 6a,9a-difluoro- 16a-methyl loteprednol derivative showed the highest RRBA among all known corticosteroids (21 00 on a scale where dexamethasone is 100). However, it was found that in this class, the more potent the new steroid, the less 'soft' it is. In other words, these are more like the currently known potent corticosteroids, not being easily hydrolyzed/deactivated, but subject to oxidative metabolism. Thus, the compounds substituted at the 6- and 9- and 16- positions were subsequently found to not be true 'soft' drugs after all. [0009] Etiprednol dicloacetate (ED; ethyl 17a-dichloroacetoxy-1 i - hydroxyandrosta-l ^-diene-S-one-^p-carboxylate) is a second-generation soft corticosteroid designed using retrometabolic principles starting with the inactive metabolite of prednisolone, A -cortienic acid (1), which is converted to the 17a- dich Ioroacetate (2) and by esterification to the ED (3). See SCHEME 1 below; also see Bodor USP 5,981 ,517. SCHEME 1 [0010] ED is a unique second generation 'soft' corticosteroid, the first to contain halogen substituents in the 17a-position, which actually serves as the important pharmacophore. It has been shown that the dichloro function is necessary for activity (the monochloro derivative is void of activity, due to the unfavorable position the chlorine is forced into by steric hindrance). The dichloroacetyl functional group is also responsible for the 'soft' nature of ED. Dichloro substituents increase the second order rate constant kcat/kM of enzymatic hydrolysis in acetate esters by a factor of 20, compared to the unsubstituted ester while one chlorine substituent does not cause any change. [0011] Contrary to the first generation of 'soft' corticosteroids based on cortienic acid, represented by Loteprednol Etabonate (LE; 4) which is hydrolytically deactivated by ester cleavage of the 17p-chloromethyl ester, in ED, the hydrolysis does not cleave at the 17p-ester, but primarily cleaves at the 17a-dichloroacetyl function. Nevertheless, the corresponding 17a-OH- metabolites are inactive, thus fulfilling the soft drug requirement. [0012] Nevertheless, there remains a serious need in this art for new anti inflammatory steroids which have potent local anti-inflammatory activity while having minimal or non-existent systemic activity. SUMMARY [0013] As noted above, the second generation of the soft steroids (etiprednol dicloacetate) based on the A -cortienic acid, having a 17a-dichloroacetyl function appears to be hydrolyzed primarily not at the 17β- ester, but at the 17a- dichIoroacetate. Depending on the animal species, both ester functions can be hydrolyzed, which has a strong influence on the 'soft' nature of these compounds.
Load more

Recommended publications
  • 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]
  • 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.
    [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]