Development of Bosentan Hydrochloride - Loaded Solid Self-Micro Emulsifying Drug Delivery System (SMEDDS) For the Treatment of Pulmonary Hypertension
DOI:
https://doi.org/10.63682/jns.v14i25S.6155Keywords:
Bioavailability, Self-nanoemulsifying drug delivery systems, Bosentan, oral solid dosage form, solubilityAbstract
The main purpose of this research study was to investigate the potential of self- micro-emulsifying drug delivery system (SMEDDS) in improving the bioavailability of Bosentan (BOS) and its therapeutic effect. In this study the S-SMEDDS of BOS powder was prepared by spray drying technology. It contains S-SMEDDS of BOS (59.57%), anhydrous lactose (11.4%), pregelatinized starch (3%), microcrystalline cellulose (22%), Magnesium stearate (2%) and Talc (2%) were selected and final weight of tablet was 965 mg. The S-SMEDDS consists of well separated particle with smooth surface observed from SEM. Both the DSC and XRD analysis suggest that BOS in S-SMEDDS may be in molecular dispersion state. In-vitro dissolution test shows that S-SMEDDS of BOS tablet had faster release rate. Formulation (F3) released 99.80% BOS within 30 min. The similarity factor found between F3 and marketed formulation was 18.19 therefore it confirmed F3 formulation better release pattern than the marketed formulation and pure drug. Release profile treated with different kinetic equations it indicated S-SMEDDS tablet best fit to Zero order model, non Fickian confirms the release of drug by diffusion mechanism. In-vivo Adsorption study in rat showed that S-SMEDDS tablet (F3) increased significant bioavailability of BOS compared to the pure drug. The “%”relative bioavailability of F3 formulation was found to be 159 % compared to pure drug and marketed formulation of BOS. Thus the S-SMEDDS provide a useful oral solid dosage form for poorly water soluble and higher molecular weight drug BOS.
Methods: PubMed and Embase databases have been searched, and related studies are compiled and summarized.
Conclusion: The study successfully developed a solid self-microemulsifying drug delivery system (S-SMEDDS) for BOS using spray-drying technology, with an optimal composition of Campul MCM (30%), Tween 20 (50%), and propylene glycol (20%) in the liquid SMEDDS (L-SMEDDS). The S-SMEDDS powder exhibited well-separated, smooth-surfaced particles while retaining self-emulsifying properties. DSC and XRD analyses indicated that BOS was molecularly dispersed within the system. When formulated into tablets (F3), the S-SMEDDS demonstrated significantly faster drug release (99.80% within 30 minutes) compared to the marketed formulation and pure drug, as evidenced by a low similarity factor (f₂ = 18.19). Drug release followed zero-order kinetics with non-Fickian diffusion, suggesting a combined diffusion-based mechanism. These findings highlight the potential of S-SMEDDS tablets to enhance the dissolution and bioavailability of BOS.
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References
Cui S, Nie S, Li L, Wang C, Pan W, Sun J. Preparation and Evaluation of Self-Microemulsifying Drug Delivery System Containing Vinpocetine. Drug Development and Industrial Pharmacy 2009; 35:5: 603-611.
Kohali K, Chopra S, Dhar D, Khar RK. Self-emulsifying drug delivery system: an approach to enhance oral bioavailability. Drug discovery today 2010; 15: 958-965.
Funke C, Farr M, Werner B, Dittmann S, Uberla K, Piper C, Niehaus K, Horstkotte D. Antiviral effect of Bosentan and Valsartan duringcoxsackievirus B3 infection of human endothelial cells. Journal of General Virology 2010; 91: 1959-1970.
Parekh JM, Shah DK, Sanyal M, Yadav M, Shrivastav PS. Development of an SPE-LC–MS/MS method for simultaneous quantification of bosentan and its active metabolite hydroxybosentan in human plasma to support a bioequivalence study. Journal of Pharmaceutical and Biomedical Analysis 2012; 70: 462-470.
Reddy KT, Younus DM, Reddy RY, Kumar AG, Sarvan S. RP-HPLC Method Devlopment and Valdation of Bosentan drug Presents in Tablets. International Journal of Pharmacy and Technology 2010; 2: 577-587.
Bhorghade BV, Nair HA, Hegde DD. 'Development and Characterization of Self-Microemulsifying Drug Delivery System of Tacrolimus for Intravenous Administration'. Drug Development and Industrial Pharmacy 2009; 35: 619- 630.
Choi HG, Balkrishnan P, Lee BJ, Oh DH, Kim JO, Hong JO, Jee JP, Kim JA, Yoo BK, Woo JS, Yong CS. Enhance oral bioavailability of dexibuprofen by a novel solid self-emulsifying drug delivery system (SEDDS). European Journal of Pharmaceutics and Biopharmaceutics 2009; 72: 539-545.
Elnaggar YSR, Magda A, Massik E, Abdallah OY. Self-nanoemulsifying drug delivery system of tamoxifen citrate: Design and optimization. International Journal of Pharmaceutics 2009; 380: 131-141.
Sillhart C, Kuentz M. Comparison of high resolution ultrasonic resonator technology and raman spectroscopy as a novel process analytical tools for drug quantification in self-emulsifying drug delivery system. Journal Pharmaceutical and Biomedical Analysis 2012; 59: 29-37.
Clinical Pharmacology and Biopharmaceutics Review, Office of Clinical Pharmacology and Biopharmaceutics New Drug Application Filing and Review Form. NDA: 21-290, IND: 49-73.
Lausecker, B.; Hess, B.; Fischer, G.; Mueller, M.; Hopfgartner, G. Simultaneous determination of bosentan and its three major metabolites in various biological matrices and species using narrow bore liquid chromatography with ion spray tandem mass spectrometric detection. J.Chromatogr.B 2000;749: 67–83.
Sweethman SC. Martindale the complete drug reference, thirty six edition, published by pharmaceutical press 2009:1235-2
http://www.emea.europa.eu, Assessment report for Tracleer, International non- proprietary name/Common name: Bosentan, Procedure No. EMEA/H/C/000401/X/0039. Date of Access 13 Aug 2010.
Technical data sheet of Abitech Corporation USA, an ABF ingredient company. 2012:1-2. Available at: http://www.abitechcorp.com/doi/abs/1355148844CapmulMCMC8EPTDSI6. Accessed on 12 July 2012.
Rowe CR, Sheskey PJ, Quinn ME. Handbook of Pharmaceutical Excipients, 5th edition, American Pharmaceutical Association, Washington 2006: 580-584.
Rowe CR, Sheskey PJ, Owen SC. Handbook of Pharmaceutical Excipients, 5th edition, American Pharmaceutical Association, Washington 2006: 624-626.
www.evonic.com. Date of access 16 August 2010.
United States Pharmacopoeia XXIV NF 19, United States Pharmacopoeial Convention, Rockville 2000: 1685.
Rowe CR, Sheskey PJ, Weller PJ. Handbook of Pharmaceutical Excipients, 4th edition, American Pharmaceutical Association, Washington 2003: 659-660.
Rowe CR, Sheskey PJ, Weller PJ. Handbook of Pharmaceutical Excipients, 4th edition, American Pharmaceutical Association, Washington 2003: 474-479.
United States Pharmacopoeia XXIV NF 19, United States Pharmacopoeial Convention, Rockville, 2000: 2500.
Indian Pharmacopoeia, Volume II, Appendix 13.2, Controller of publications, Ministry of Health and Welfare, Govt. of India, Delhi, 1996: A-138.
Indian Pharmacopoeia, Volume II, Appendix 13.2, Controller of publications, Ministry of Health and Welfare, Govt. of India, Delhi, 1996: A-147.
Rowe CR, Sheskey PJ, Weller PJ. Handbook of Pharmaceutical Excipients, 4th edition, American Pharmaceutical Association, Washington 2003: 479-483.
Elnaggar YSR, Magda A, Massik E, Abdallah OY. Self-nanoemulsifying drug delivery system of tamoxifen citrate: Design and optimization. International Journal of Pharmaceutics 2009; 380: 131-141.
Kommuru TR, Gurley B, Khan MA, Reddy I.K. Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: formulation development and bioavailability assessment. International Journal of Pharmaceutics 2001; 212 (2): 233-246.
Dixit AR, Rajput SJ, Patel SG. Preparation and bioavailability assessment of SMEDDS containing valsartan. AAPS PharmSciTech 2010; 11: 314-321.
Nagarsenker MS, Date AA. Design and evaluation of Self nanoemulsifying drug delivery system (SNEDDS) for Cefpodoxime Proxetil. International Journal of Pharmaceutics 2007; 329: 166-172.
Bajaj A, Rao MRP, Khole I, Munjapara G. Self-nanoemulsifying drug delivery system of cefpodoxime proxetil containing tocopherol polyethylene glycol succinate. Drug Development and Industrial Pharmacy 2013; 39: 635-645.
Chakraborty S, Shukla D, Mishra B, Singh S. Lipid an emerging platform for oral delivery of drugs with poor bioavailability. Eur. J. Pharm. Biopharm 2009; 73: 1-15. (42)
He Z, Wang Z, Sun J, Wang Y, Liu X, Liu Y, Fu Q, Meng P. Solid self-emulsifying nitredipine pellets: preparation and in vitro/ in vivo evaluation. International Journal of Pharmaceutics 2010; 383: 1-6.
Sillhart C, Kuentz M. Comparison of high resolution ultrasonic resonator technology and raman spectroscopy as a novel process analytical tools for drug quantification in self emulsifying drug delivery system. Journal Pharmaceutical and Biomedical Analysis 2012; 59: 29-37.
Lee D, Cheon NH, Song C. Measurements of two-phase mixture level using an ultrasonic method. Experimental Thermal and fluid science 2005; 29: 609-614.
Aminabhavi TM, Aralaguppi MI, Haragoppad SB, Balundgi RH. Prediction of Molecular Radius of Liquids from Density, Refractive index and Sound Velocity Measurements. Indian Journal of Technology 1993; 31: 32-33.
Gupta M, Singh RD, Singh S, Vibhu I, Shukla JP. Thermoacoustical response of 1, 4-dioxane with carboxylic acids. Physics and Chemistry of Liquids 2008; 46: 349-357.
Rajulu AV, Sreenivasulu G, Raghuraman KS. Ultrasonic attenuation in aqueous dispersion of polytetrafluoro ethylene. Indian Journal of Chemical Technology 1994; 1: 302-304.
N. Parmar, N. Singla, S. Amin, K. Kohli. Study of cosurfactant effect on nanoemulsifying area and development of lercanidipine loaded (SNEDDS) self-nanoemulsifying drug delivery system. Colloids Surf. B Biointerfaces 2011; 86: 327-338. (45)
S.V. Biradar, R.S. Dhumal, A. Paradkar. Rheological investigation of self-emulsification process. J. Pharm. Pharm. Sci 2009; 12: 17-31.
Bandari S, Kallakunta VR, Jukanti R, Reddy PV. Oral self-emulsifying powder of lercanidipine hydrochloride: Formulation and evaluation. Powder Technology 2012; 221: 375-382.
Bachynsky MO, Shah NH, Patel CI, Malick AW. 'Factors Affecting the Efficiency of a Self-Emulsifying Oral Delivery System. Drug Development and Industrial Pharmacy 1997; 23(8): 809-816.
Warisnoicharoen W, Lansley AB, Lawrence MJ. Nonionic oil-in-water microemulsions: the effect of oil type on phase behavior. Int. J. Pharm 2000; 198:1-7.
Chena F, Wanga Y, Zhenga F, Wub Y, Liangb W. Studies on cloud point of agrochemical microemulsions. Colloids Surf. A: Physicochem. Eng. Aspects 2000; 175: 257-265.
Dixit AR, Rajput SJ, Patel SG. Preparation and bioavailability assessment of SMEDDS containing valsartan. AAPS PharmSciTech 2010; 11: 314-321. (44)
Yi T, Wan J, Xu H, Yang X. A new solid Self-microemulsifying formulation prepared by spray drying to improve the bioavailability of poorly water soluble drugs. European Journal of Pharmaceutics and Biopharmaceutics 2008; 70: 439-444.
Beckett AH, Stenlake JB. Practical pharmaceutical chemistry, 4 th edition part-II, CBS publisher 2007:379-405.
Mandawgade SD, Sharma S, Pathak S, Patravale VB. Development of SMEDDS using natural lipophile: Application to Beta Artemether delivery. International Journal of Pharmaceutics 2008; 362: 179–183.
Kang JH, Oh DH, Oh YK, Yong CS, Choi HG. Effect of Solid carrier on the crystalline properties, Dissolution and bioavailability of flurbiprofen in solid self-nanoemulsifying drug delivery system (solid SNEDDS). European Journal of Pharmaceutics and Biopharmaceutics 2012; 80: 289-297.
Choi HG, Balkrishnan P, Lee BJ, Oh DH, Kim JO, Hong JO, Jee JP, Kim JA, Yoo BK, Woo JS, Yong CS. Enhance oral bioavailability of dexibuprofen by a novel solid self-emulsifying drug delivery system (SEDDS). European Journal of Pharmaceutics and Biopharmaceutics 2009; 72: 539-545.
Wang L, Cui FD, Sunada H. Improvement of the dissolution rate of nitrendipine using a new pulse combustion drying method. Chem. Pharm. Bull 2006; 54: 1119-1125.
Ito Y, Arai H, Uchino K, Iwasaki K, Shibata N, Takada K. Effect of adsorbents on the Adsorption of lansoprazole with surfactant. Int. J. Pharm 2005; 289: 69-77.
Rizwan M, Beg S, Jena S, Patra C, Swain S, Shruti J, Bhanojirao ME, Singh B. Development of Solid Self-nanoemulsifying granules (SSEGs) of Ondensteron hydrochloride with enhanced bioavailability potential. Colloids and surfaces B: Biointerfaces 2013; 101: 414-423.
Nazzal S, Smalyukh II, Lavrentovich OD and Khan MA. Preparation and in vitro characterization of a eutectic based semisolid self-nanoemulsified drug delivery system (SNEDDS) of ubiquinone: mechanism and progress of emulsion formation. Int J Pharm 2002; 235(1-2): 247-65.
Wei L, Li J, Guo L, Nie S, Pan W, Sun P, Liu H. 'Investigations of a Novel Self-Emulsifying Osmotic Pump Tablet Containing Carvedilol'. Drug Development and Industrial Pharmacy 2007; 33: 990-998.
Lachman L, Lieberman HA, Kanig JL. The theory and practice of Industrial Pharmacy, III rd edition, Varghese publishing house Bombay. 1987: 296.
Lachman L, Lieberman HA, Kanig JL. The theory and practice of Industrial Pharmacy, III rd edition, Varghese publishing house Bombay 1987: 297.
Sinko PJ. Martin’s Physical Pharmacy and Pharmaceutical Analysis, fifth edition, lippinecott Williams & wilkins N. Delhi 2008:533-560.
Indian Pharmacopoeia, Volume I, Pharmaceutical method, Controller of publications, Ministry of Health and Welfare, Govt. of India, Delhi 2007: 182.
Indian Pharmacopoeia, Volume I, Pharmaceutical method, Controller of publications, Ministry of Health and Welfare, Govt. of India, Delhi 2007: 182-183.
Indian Pharmacopoeia, Volume I, Pharmaceutical method, Controller of publications, Ministry of Health and Welfare, Govt. of India, Delhi 2007: 183.
Indian Pharmacopoeia, Volume I, Pharmaceutical method, Controller of publications, Ministry of Health and Welfare, Govt. of India, Delhi 2007: 177-179.
Indian Pharmacopoeia, Volume I, Pharmaceutical method, Controller of publications, Ministry of Health and Welfare, Govt. of India, Delhi 2007: 179-181.
Brenner GS, Ellison DK, Kaufman MJ, Brittain HG. Analytical profiles of drug substances and excipients, Klaus Flory, Published by Academia Press. 2005; 21: 277-305.
Costa P, Manuel J, Lobo S. Modeling and comparison of dissolution profiles. Eur. J. Pharm. Sci 2003; 13: 123-133.
Fukui A, FujiI R, Yonizawa Y, Sunada H. Analysis of the release process of pheny lprpanolamine hydrochloride from ethyl cellulose matrix granules. Chem. Pharm. Bull 2002; 50(11): 1439-1442.
Jantzen GM, Robinsin JR. Diffusion-Controlled Matrix Systems. In: Kydonieus (II nd Ed), Treatise on controlled drug delivery. A Marcel Dekker Inc. New York 1992: 172-175.
Yadav AV, Yadav VB, Shete AS. Experimental Biopharmaceutics and Pharmacokinetics, First edition, Nirali prakashan Mumbai. 2011: 1.11-1.21
Lachman L, Lieberman HA, Kanig JL. The theory and practice of Industrial Pharmacy, III rd edition, Varghese publishing house Bombay. 1987, pp 760-803.
ICH Q1A (R2), Stability testing guidelines: Stability testing of new drug substance and products. The European agency for the evaluation of medicinal products. CPMP/ICH/2736/99, 2003: 4-20.
Pugh J. Kinetics and product stability, In: M. Aulton (Ed.) Pharmacutics: the science of dosage form design, IInd ed. Churchill livingstone, 2002: 101-112.
Holm R, Müllertz A , Tonsberg H, Jorgensen EB, Abedinpour P, Farsad S. Influence of bile on the Adsorption of halofantrine from lipid-base formulations. European Journal of Pharmaceutics and Biopharmaceutics 2012; 81: 281-287.
Onoue S, Uchida A, Kuriyama K, Nakamura T, Seto Y, Kato M, Hatanaka J, Tanaka T, Miyoshi H, Yamada S. Novel solid self-emulsifying drug delivery system of coenzyme Q10 with improved Photochemical and Pharmacokinetic behaviours. European Journal of Pharmaceutical Science 2012; 46: 492-499.
Yanyu X, Shan W, Yinan C, Qineng P. Self-emulsifying bifendate pellets: preparation, characterization and oral bioavailability in rats. Drug Development and Industrial Pharmacy 2013; 39: 724-732.
Bandivadekar M, Pancholi S, Ghanekar RK, Choudhari A, Koppikar S. Single non-ionic surfactant based self-nanoemulsifying drug delivery systems: formulation, characterization, cytotoxicity and permeability enhancement study. Drug Development and Industrial Pharmacy 2013; 39: 696-703.
Bhatt S, Trivedi P. Taste Masking of Ondansetron Hydrochloride and Formulation of Fast Dissolving Tablets. Chem. Pharm. Res 2011; 3: 472-484.
Taha EI. Development and Characterization of New Indomethacin Self-Nanoemulsifying Formulations. Sci. Pharm 2009; 77: 443-451.
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