In vitro Controlled Release from Solid Pharmaceutical Formulations of two new Adamantane Aminoethers with Antitubercular Activity (I).

Abstract

The aim of the present investigation was to develop matrix tablet formulations for the in vitro controlled release of 2 new tuberculocidal adamantane aminoethers (compounds I and II), congeneric to the adamantane derivative SQ109, which is in final clinical trials, using carefully selected excipients, such as polyvinylpyrrolidone, sodium alginate and lactose. The tablets were prepared using the direct compression method and dissolution experiments were conducted using the US Pharmacopoeia type II apparatus (paddle method) in gastric and intestinal fluids. The results confirm that both analogues, albeit more lipophilic than SQ109, showed satisfactory in vitro release characteristics from solid pharmaceutical formulations. In conclusion, these formulations merit further assessment by conducting in the future bioavailability in vivo studies.

Key words

1,3-Bis[4-(2-morpholinoethoxy)phenyl]adamantane - 2,2-Bis[4-(2-morpholinoethoxy)phenyl]adamantane - antituberculars - drug delivery

• References

• 1 World Health Organization. World TB Day 2016: Unite to End TB. Geneva: WHO; 2016. Available at: http://www.who.int/campaigns/tb-day/2016/event/en/ (accessed February 18, 2016)
• 2 Debnath J, Siricilla S, Wan B. et al. Discovery of selective menaquinone biosynthesis inhibitors against Mycobacterium tuberculosis. J Med Chem 2012; 55: 3739-3755
• 3 Lia W, Obregón-Henao A, Wallach JB. et al. Therapeutic potential of the Mycobacterium tuberculosis mycolic acid transporter, MmpL3. Antimicrob Agents Chemother 2016; 60: 5198-207
• 4 Amani AM. Synthesis and biological activity of piperazine derivatives of phenothiazine. Drug Res 2015; 65: 5-8
• 5 Alegaon SG, Alagawadi KR, Dadwe DH. Synthesis and antitubercular activity of novel 3,5-diaryl-4,5-dihydro-1H-pyrazole derivatives. Drug Res 2014; 64: 553-558
• 6 Katagi MS, Bolakatti GS, Badiger AM. et al. Synthesis, spectral characterization and Antimicrobial Activity of Substituted Thiazolyl Derivatives of 2-Quinolones. Drug Res 2013; 63: 53-59
• 7 Protopopova M, Hanrahan C, Nikonenko B. et al. Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines. J Antimicrob Chemother 2005; 56: 968-974
• 8 Foss MH, Pou S, Davidson PM. et al. Diphenylether-modified 1,2-diamines with improved drug properties for development against Mycobacterium tuberculosis. ACS Infect Dis 2016; 2: 500-508
• 9 Panda G, Parai MK, Das SK. et al. Effect of substituents on diarylmethanes for antitubercular activity. Eur J Med Chem 2007; 42: 410-419
• 10 Foscolos A-S, Papanastasiou I, Tsotinis A. et al. Synthesis of adamantane aminoethers with antitubercular potential. Med Chem 2017; 13: 1-12
• 11 Lipinski CA, Lombardo F, Dominy BW. et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2001; 46: 3-26
• 12 Hiremath PS, Ranendra NS. Controlled release hydrophilic matrix tablet formulations of Isoniazid: design and in vitro studies. AAPS PharmSci 2008; 9: 1171-1178
• 13 Maestro, version 10.2, Schrödinger, LLC, New York, NY, 2015
• 14 LigPrep, version 3.4, Schrödinger, LLC, New York, NY, 2015
• 15 QikProp, version 4.4, Schrödinger, LLC, New York, NY, 2015
• 16 Shah VP, Tsong Y, Sathe P. et al. In vitro dissolution profile comparison (-) statistics and analysis of the similarity factor, f2. Pharm Res 1998; 15: 889-96
• 17 Costa P, Sousa Lobo JM. Modeling and comparison of dissolution profiles. Eur. J. Pharm Sci 2001; 13: 123-33