Login Register Cart 0
Generic placeholder image

Pharmaceutical Nanotechnology

Editor-in-Chief

ISSN (Print): 2211-7385
ISSN (Online): 2211-7393

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Application of Statistical Tooling Techniques for Designing of Carvedilol Nanolipid Transferosomes and its Dermatopharmacokinetic and Pharmacodynamic Studies

Author(s): Brito R. Selvaraj*, Seshaiah K. Sridhar, Bhaskar R. Kesavan and Sucharitha Palagati

Volume 8, Issue 6, 2020

Page: [452 - 470] Pages: 19

DOI: 10.2174/2211738508666200928164820

Price: $65

Abstract

Background: The hypothesis is to augment the bioavailability and therapeutic potential of low bioavailable Carvedilol (25-35%) through Nanostructured Lipid Carrier (NLC) loaded Transdermal patch (Nanolipid Transferosomes).

Methods: Box-Behnken design was designed to formulate NLC through a hot homogenization technique. About 17 formulations (C1-C17) were formulated by varying the critical material attribute and critical process parameter. Optimization was done based on its critical quality attributes like particle size, zeta potential and entrapment efficiency. Selected NLC (C16) has been fabricated into a transdermal patch through solvent evaporation technique and estimated for thickness, weight variation, moisture content, folding endurance, drug content, in vitro drug release, ex vivo skin permeation studies 48 hrs, in vitro drug release kinetic studies and skin irritation studies. In vivo pharmacokinetics and pharmacodynamic study parameters were compared between carvedilol loaded NLC transdermal patch and a conventional formulation (Coreg CR).

Results: NLC (C16) was selected as the best formulation based on desirable, less particle size (201.1 ± 2.02 nm), more zeta potential (-37.2 ± 1.84mV) and maximum entrapment efficiency (87.54 ± 1.84%). Experimental investigations of in vivo dermatopharmacokinetic data shown statistically significant changes (p<0.05) in the parameter (increased AUC0-α, MRT with decreased Cmax, Tmax) when administered through the transdermal patch and on compared to the conventional dosage form. It was observed that there was a significant change with p<0.05 among the pharmacokinetic factors of conventional Carvedilol formulation, Carvedilol NLC and Carvedilol NLC loaded Transdermal patch with a maximum time of peak plasma concentration (Tmax) of 4 hrs, 8 hrs and 8 hrs; maximum peak plasma concentration (Cmax) of 0.258 μg/ml, 0.208 μg/ml and 0.108 μg/ml. Area Under Curve (AUC0-α) was established to be 125.127 μg/ml/h, 132.576 μg/ml.h and 841.032 μg/ml.h. Mean Residence Time (MRT0- α) of the drug was established to be 17 hrs, 19 hrs and 82 hrs, respectively. This data reveals the impact of NLC on the enhancement of bioavailability through a transdermal patch. In vivo pharmacodynamic studies confirm that NLC loaded transdermal patch (Nanolipid Transferosomes) shows a significant control in blood pressure for 48 hrs when compared to the conventional dosage form.

Conclusion: This research data concludes that NLC loaded transdermal patch (Nanolipid Transferosomes) was a suitable candidate to enhance the bioavailability of low bioavailable drug-like Carvedilol.

Lay Summary: It was inferred from the literature that NLC filled transdermal patches were a novel strategy to increase the solubility and permeability of Carvedilol, which has less bioavailability. It reveals that there was no reproducible preparation for the NLC. It also reveals that the option of formulation and process parameters for the formation of NLC is not clearly justified. On account of this, an uniquely validated and optimized formulation technique was developed for NLC with low soluble and poorly bioavailable carvedilol, tested in Albino wistar rats for enhancement of bioavailability, the same study has been performed and proved.

Keywords: Bioavailability, box-behnken design, nanostructured lipid carrier, pharmacodynamic, pharmacokinetic, transdermal patch.

« Previous Next »
Graphical Abstract

[1]
Hathout RM, Elshafeey AH. Development and characterization of colloidal soft nano-carriers for transdermal delivery and bioavailability enhancement of an angiotensin II receptor blocker. Eur J Pharm Biopharm 2012; 82(2): 230-40.
[http://dx.doi.org/10.1016/j.ejpb.2012.07.002] [PMID: 22820090]
[2]
Sharma G, Thakur K, Raza K, Singh B, Katare OP. Nanostructured lipid carriers: a new paradigm in topical delivery for dermal and transdermal applications. Crit Rev Ther Drug Carrier Syst 2017; 34(4): 355-86.
[http://dx.doi.org/10.1615/CritRevTherDrugCarrierSyst.2017019047] [PMID: 29199589]
[3]
Zhang Y, Cun D, Kong X, Fang L. Design and evaluation of a novel transdermal patch containing diclofenac and teriflunomide for rheumatoid arthritis therapy. Asian J Pharm Sci 2014; 9: 251-9.
[http://dx.doi.org/10.1016/j.ajps.2014.07.007]
[4]
Bhaskar K, Anbu J, Ravichandiran V, Venkateswarlu V, Rao YM. Lipid nanoparticles for transdermal delivery of flurbiprofen: formulation, in vitro, ex vivo and in vivo studies Lipids Health Dis 2009; 8(6): 6.
[http://dx.doi.org/10.1186/1476-511X-8-6] [PMID: 19243632]
[5]
Jadupati M, Amites G, Kumar NA. Transfersome: an opportunistic carrier for transdermal drug delivery system. IRJP 2012; 3(3): 35-8.
[6]
Lei Wei, Yu Chuqin, Lin Huaqing, Zhou Xiaoyuan. Development of tacrolimus-loaded transfersomes for deeper skin penetration enhancement and therapeutic effect improvement in vivo 2013; 8(6): 336-45.
[http://dx.doi.org/10.1016/j.ajps.2013.09.005]
[7]
Jensen LB, Petersson K, Nielsen HM. in vitro penetration properties of solid lipid nanoparticles in intact and barrier-impaired skin. Eur J Pharm Biopharm 2011; 79(1): 68-75.
[http://dx.doi.org/10.1016/j.ejpb.2011.05.012] [PMID: 21664463]
[8]
Vitorino C, Almeida J, Gonçalves LM, Almeida AJ, Sousa JJ, Pais AA. Co-encapsulating nanostructured lipid carriers for transdermal application: from experimental design to the molecular detail. J Control Release 2013; 167(3): 301-14.
[http://dx.doi.org/10.1016/j.jconrel.2013.02.011] [PMID: 23454133]
[9]
Abdel-Mottaleb MM, Neumann D, Lamprecht A. Lipid nanocapsules for dermal application: a comparative study of lipid-based versus polymer-based nanocarriers. Eur J Pharm Biopharm 2011; 79(1): 36-42.
[http://dx.doi.org/10.1016/j.ejpb.2011.04.009] [PMID: 21558002]
[10]
Brunton LL, Parker KL. Goodman and Gilman’s manual of pharmacology and therapeutics New York: McGraw-Hill 2008; pp. 549-, 563, 580, 622-626..
[11]
Michael J. Reiter. Cardiovascular Drug Class Specificity: Blockers Prog Cardiovasc Dis 2004; 47(1): 11-33.
[PMID: 15517513]
[12]
Uprit S, Kumar Sahu R, Roy A, Pare A. Preparation and characterization of minoxidil loaded nanostructured lipid carrier gel for effective treatment of alopecia. Saudi Pharm J 2013; 21(4): 379-85.
[http://dx.doi.org/10.1016/j.jsps.2012.11.005] [PMID: 24227958]
[13]
Kong X, Zhao Y, Quan P, Fang L. Development of a topical ointment of Betamethasone dipropionate loaded nanostructured lipid carrier. Asian J Pharm Sci 2015; 11(2): 1-7.
[14]
Pratap SB, Brajesh K, Jain SK. Shafaat Kausar. Development and characterization of a nanoemulsion gel formulation for transdermal delivery of carvedilol. Int J Drug Development & Res 2012; 4(1): 151-61.
[15]
Ahad A, Aqil M, Kohli K, Sultana Y, Mujeeb M, Ali A. Formulation and optimization of nanotransfersomes using experimental design technique for accentuated transdermal delivery of valsartan. Nanomedicine (Lond) 2012; 8(2): 237-49.
[http://dx.doi.org/10.1016/j.nano.2011.06.004] [PMID: 21704600]
[16]
Gönüllü Ü, Üner M, Yener G, Karaman EF, Aydoğmuş Z. Formulation and characterization of solid lipid nanoparticles, nanostructured lipid carriers and nanoemulsion of lornoxicam for transdermal delivery. Acta Pharm 2015; 65(1): 1-13.
[http://dx.doi.org/10.1515/acph-2015-0009] [PMID: 25781700]
[17]
Müller RH, Radtke M, Wissing SA. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations. Adv Drug Deliv Rev 2002; 54(1)(Suppl. 1): S131-55.
[http://dx.doi.org/10.1016/S0169-409X(02)00118-7] [PMID: 12460720]
[18]
Guo R, Du X, Zhang R, Deng L, Dong A, Zhang J. Bioadhesive film formed from a novel organic-inorganic hybrid gel for transdermal drug delivery system. Eur J Pharm Biopharm 2011; 79(3): 574-83.
[http://dx.doi.org/10.1016/j.ejpb.2011.06.006] [PMID: 21723945]
[19]
Cevc G, Vierl U. Nanotechnology and the transdermal route: a state of the art review and critical appraisal. J Control Release 2010; 141(3): 277-99.
[http://dx.doi.org/10.1016/j.jconrel.2009.10.016] [PMID: 19850095]
[20]
Akhlaq M, Arshad MS, Mudassir AM, et al. Formulation and evaluation of anti-rheumatic dexibuprofen transdermal patches: a quality-by-design approach. J Drug Target 2016; 24(7): 603-12.
[http://dx.doi.org/10.3109/1061186X.2015.1116538] [PMID: 26586147]
[21]
Patil-Gadhe A, Pokharkar V. Montelukast-loaded nanostructured lipid carriers: part I oral bioavailability improvement. Eur J Pharm Biopharm 2014; 88(1): 160-8.
[http://dx.doi.org/10.1016/j.ejpb.2014.05.019] [PMID: 24878424]
[22]
Chen G, Hao B, Ju D, et al. Pharmacokinetic and pharmacodynamic study of triptolide-loaded liposome hydrogel patch under microneedles on rats with collagen-induced arthritis. Acta Pharm Sin B 2015; 5(6): 569-76.
[http://dx.doi.org/10.1016/j.apsb.2015.09.006] [PMID: 26713272]
[23]
Thakur R, Anwer MK, Shams MS, et al. Proniosomal transdermal therapeutic system of losartan potassium: development and pharmacokinetic evaluation. J Drug Target 2009; 17(6): 442-9.
[http://dx.doi.org/10.1080/10611860902963039] [PMID: 19527115]
[24]
Bhalekar R. Mangesh, Upadhaya Prashant, Madgulkar Ashwini. Solid lipid nanoparticles incorporated transdermal patch for improving the permeation of piroxicam. Asian J Pharm 2016; 10(1): 45-50.
[25]
Bagchi A, Dey BK. Formulation, in vitro evaluations and skin irritation study of Losartan Potassium transdermal patches. Iran J Pharm Sci 2010; 6(3): 163-70.
[26]
Prabhakara P, Koland M, Vijaynarayana K, et al. Preparation and evaluation of transdermal patches of papaverine hydrochloride. Int J Res Pharm Sci 2010; 1(3): 259-66.
[27]
Saxena M, Mutalik S, Reddy MS. Formulation and evaluation of transdermal patches of metoclopramide hydrochloride. Ind Drugs 2006; 43(9): 740-5.
[28]
Pratap SB, Brajesh K, Jain SK. Shafaat Kausar. Development and characterization of a nanoemulsion gel formulation for transdermal delivery of carvedilol. Int J Drug Deliv 2012; 4(1): 151-61.
[29]
Vashisth I, Ahad A. Mohd. Aqil, Suraj P Agarwal. Investigating the potential of essential oils as penetration enhancer for transdermal losartan delivery: effectiveness and mechanism of action. Asian J Pharm Sci 2014; 9: 260-7.
[http://dx.doi.org/10.1016/j.ajps.2014.06.007]
[30]
Kong M, Xi GC. Dong Keon Kweon, Hyun Jin Park. Investigations on skin permeation of hyaluronic acid based nanoemulsion as transdermal carrier. Carbohydr Polym 2011; 86: 837-43.
[http://dx.doi.org/10.1016/j.carbpol.2011.05.027]
[31]
Alexander A, Dwivedi S, Ajazuddin TK, et al. Approaches for breaking the barriers of drug permeation through transdermal drug delivery. J Control Release 2012; 164(1): 26-40.
[http://dx.doi.org/10.1016/j.jconrel.2012.09.017] [PMID: 23064010]
[32]
Lei W, Yu C, Lin H, Zhou X. Development of tacrolimus-loaded transfersomes for deeper skin penetration enhancement and therapeutic effect improvement in vivo. Asian J Pharm Sci 2013; 8: 336-45.
[http://dx.doi.org/10.1016/j.ajps.2013.09.005]
[33]
Kshirsagar RV, Patil SG. Mathematical models for drug release characterization: a review. World J Pharm Res 2015; 4(4): 324-38.
[34]
Dash S, Murthy PN, Nath L, Chowdhury P. Kinetic modeling on drug release from controlled drug delivery systems. Acta Pol Pharm 2010; 67(3): 217-23.
[PMID: 20524422]
[35]
Yong-tai zhang, Zhong-hua wu, Kai zhang. An in vitro and in vivo comparison of solid and liquid–oil cores in transdermal aconitine nanocarriers. J Pharm Sci 2014; 103: 3602-10.
[http://dx.doi.org/10.1002/jps.24152] [PMID: 25187419]
[36]
Bhaskar Reddy K, Jyostna M, Audinarayana N, Madhavi Latha C, Mohanambal E. The enhancement effect of surfactants on the penetration of Nitrendipine through rat skin. Indian J Nov Drug Deliv 2012; 4(1): 38-42.
[37]
Priano L, Zara GP, El-Assawy N, et al. Baclofen-loaded solid lipid nanoparticles: preparation, electrophysiological assessment of efficacy, pharmacokinetic and tissue distribution in rats after intraperitoneal administration. Eur J Pharm Biopharm 2011; 79(1): 135-41.
[http://dx.doi.org/10.1016/j.ejpb.2011.02.009] [PMID: 21352914]
[38]
Kim S-H, Sang HL, Lee HJ. Rapid and sensitive Carvedilol assay in human plasma using a high-performance liquid chromatography with mass/mass spectrometer detection employed for a bioequivalence study. Am J Anal Chem 2010; 1: 135-43.
[http://dx.doi.org/10.4236/ajac.2010.13017]
[39]
Wu P-C. Yaw-vBin Huang, Judy Jui-Fen Chang, Jui-Sheng Chang, Yi-Hung Tsai. Evaluation of pharmacokinetics and pharmacodynamic of captopril from transdermal hydrophilic gels in normotensive rabbits and spontaneously hypertensive rats. Int J Pharm 2000; 209: 87-94.
[http://dx.doi.org/10.1016/S0378-5173(00)00557-3] [PMID: 11084249]
[40]
Bertera FM, Mayer MM, Opezzo JAW, Taira CA, Bramuglia GF, Hocht C. Pharmacokinetic-pharmacodynamic modeling of diltiazem in spontaneously hypertensive rats: A microdialysis study. J Pharmacol Tox Met 2007; 56: 290-9.
[http://dx.doi.org/10.1016/j.vascn.2007.04.001]
[41]
Abubakar MG, Ukwuani AN, Mande UU. Antihypertensive activity of Hibiscus sabdariffa aqueous calyx extract in Albino rats. Sky J Biochem Res 2015; 4(3): 16-20.
[42]
In-Chan Seol. Chang-Gue Son. Interpretation of animal dose and human equivalent dose for drug development. Korean J Orient Med 2010; 31(3): 1-7.
[43]
Badyal DK, Lata H, Dadhich AP. Animal models of hypertension and effect of drugs. Indian J Pharmacol 2003; 35: 349-62.
[44]
Manpreet kaur, Rana AC, Sunil Kumar. Induction of hypertension by various animal models. Int J Pharma Bio Sci 2011; 1(3): 335-40.
[45]
Mushtaq MN, Akhtar MS, Alamgeer TA, et al. Evaluation of antihypertensive activity of Sonchus Asper L. in Rats. Acta Pol Pharm 2016; 73(2): 425-31.
[PMID: 27180435]
[46]
Alamgeer, Muhamamd S Akhtar, Qaiser Jabeen, Muhammad Akram. Antihypertensive activity of aqueous-methanol extract of Berberis Orthobotrys Bien Ex Aitch in rats. Trop J Pharm Res 2013; 12(3): 393-9.

Rights & Permissions Print Cite
Article Metrics
25
© 2024 Bentham Science Publishers | Privacy Policy