Exploring of Taguchi Design in the Optimization of Brinzolamide and Timolol Maleate Ophthalmic in-situ Gel Used in Treatment of Glaucoma

Author(s): Purvi Shah, Vaishali Thakkar*, Vishvas Anjana, Jenee Christian, Roma Trivedi, Kalpana Patel, Mukesh Gohel, Tejal Gandhi

Journal Name: Current Drug Therapy

Volume 15 , Issue 5 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Objective: The present research work focuses on experimental design assisted In-situ gel for fixed dose combination.

Significance: Brinzolamide(BZ) BCS class II drug and Timolol Maleate (TM), a BCS class I drug is formulated for obtaining the sustained effect, increased ocular bioavailability and reduction of dose leading to better patient compliance.

Methods: The material attributes were gelrite, hydroxy propyl methyl cellulose K4M(HPMC K4M) and HP-β-CD and critical quality attributes identified were gel strength, mucoadhesive index and percentage of drug release of both drugs. BZ and TM were successfully formulated in ion-triggered In-situ gelling system using Taguchi design with minimum trials.

Results: The final optimized formula 0.5 %w/v gelrite, 0.5 %w/v HPMC K4M, 1:2.5 Ratio of drug to HP-β-CD as well as 150rpm stirring rate exhibited acceptable results with enhanced solubility of BZ. The pharmacodynamic study revealed a decrease in intraocular pressure for In-situ gel (17.3) compared to conventional marketed suspension. Moreover, delayed mean residence time and high AUC (61.237 and 4523.65) of In-situ gel indicates prolonged residence time with sustained release.

Conclusion: In conclusion, excellent ocular tolerance and longer action of gelrite and HPMC K4M. In-situ gel for BZ and TM can be explored as potential alternative to marketed formulation reducing the frequency of administration and improving patient compliance in glaucoma.

Keywords: In-situ gel, HP-β-CD, taguchi design, in-vivo animal study, brinzolamide, Glaucoma.

Firat PG, Samdanci E, Doganay S, Cavdar M, Sahin N, Gunduz A. Short-term effect of topical brinzolamide-timolol fixed combination on ocular surface of glaucoma patients. Int J Ophthalmol 2012; 5(6): 714-8.
[PMID: 23275906]
Gupta SK, Niranjan DG, Agrawal SS, Srivastava S, Saxena R. Recent advances in pharmacotherapy of glaucoma. Indian J Pharmacol 2008; 40(5): 197-208.
[http://dx.doi.org/10.4103/0253-7613.44151] [PMID: 20040958]
Khouri AS, Realini T, Fechtner RD. Use of fixed-dose combination drugs for the treatment of glaucoma. Drugs Aging 2007; 24(12): 1007-16.
[http://dx.doi.org/10.2165/00002512-200724120-00004 PMID: 18020533]
Zhang Y, Ren K, He Z, et al. Development of inclusion complex of brinzolamide with hydroxypropyl-β-cyclodextrin. Carbohydr Polym 2013; 98(1): 638-43.
[http://dx.doi.org/10.1016/j.carbpol.2013.06.052] [PMID: 23987393]
Loftssona T, Järvinen T. Cyclodextrins in ophthalmic drug delivery. Adv Drug Deliv Rev 1999; 36(1): 59-79.
[http://dx.doi.org/10.1016/S0169-409X(98)00055-6] [PMID: 10837709]
Dubey A, Prabhu A. Formulation and evaluation of stimuli-sensitive hydrogels of timolol maleate and brimonidinetar-trate. Int J Pharm Investig 2014; 4(3): 112-8.
[http://dx.doi.org/10.4103/2230-973X.138340] [PMID: 25126524]
Kuno N, Fujii S. Recent advances in ocular drug delivery systems. Polymers 2011; 3(1): 193-221.
Patel N, Shinde G, Rajesh K. Formulation and evaluation of ophthalmic in-situ gel of brinzolamide. Inventi Rapid-Pharm Tech 2014; p. 955.
Li J, Liu H, Liu LL, Cai CN, Xin HX, Liu W. Design and evaluation of a brinzolamide drug-resin in situ thermosensitive gelling system for sustained ophthalmic drug delivery. Chem Pharm Bull 2014; 62(10): 1000-8.
[http://dx.doi.org/10.1248/cpb.c14-00451] [PMID: 25099146]
Ikuta Y, Aoyagi S, Tanaka Y, et al. Creation of nano eye-drops and effective drug delivery to the interior of the eye. Sci Rep 2017; 7: 44229.
[http://dx.doi.org/10.1038/srep44229] [PMID: 28290486]
Lad S, Bajaj A. Thermosensitive in situ gel of brinzolamide for sustained ocular drug delivery. Int J Pharma Bio Sci 2015; 4(3): 378-97.
Jagdale S, Shewale N, Bhanudas S. Optimization of thermoreversible in situ nasal gel of Timolol maleate In. Scientifica 2016; pp. 1-11.
Gupta S, Vyas SP. Carbopol/chitosan based pH triggered in situ gelling system for ocular delivery of timolol maleate. Sci Pharm 2010; 78(4): 959-76.
[http://dx.doi.org/10.3797/scipharm.1001-06] [PMID: 21179328]
Gupta H, Aqil M, Khar RK, et al. Development and characterization of 99mTc-timolol maleate for evaluating efficacy of in situ ocular drug delivery system. AAPS PharmSciTech 2009; 10(2): 540-6.
[http://dx.doi.org/10.1208/s12249-009-9238-x] [PMID: 19424806]
Kumar S, Balaji A, Marupaka K. Optimization and in vivo evaluation of timolol maleate in situ gels for ocular drug de-livery. World J Pharm Pharm Sci 2015; 4(3): 978-89.
Gupta H, Velpandian T, Jain S. Ion- and pH-activated novel in-situ gel system for sustained ocular drug delivery. J Drug Target 2010; 18(7): 499-505.
[http://dx.doi.org/10.3109/10611860903508788] [PMID: 20055752]
Gould S, Scott RC. 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD): a toxicology review. Food Chem Toxicol 2005; 43(10): 1451-9.
[http://dx.doi.org/10.1016/j.fct.2005.03.007] [PMID: 16018907]
Panda AK, Singh RK. Optimization of process parameters by taguchi method: Catalytic degradation of polypropylene to liquid fuel. Int J Multidisci Curr Res 2013; 1: 50-4.
Garg NK, Sharma G, Singh B, et al. Quality by Design (QbD)-enabled development of aceclofenac loaded-nano structured lipid carriers (NLCs): An improved dermatokinetic profile for inflammatory disorder(s). Int J Pharm 2017; 517(1-2): 413-31.
[http://dx.doi.org/10.1016/j.ijpharm.2016.12.010] [PMID: 27956192]
Bragagni M, Bozdag M, Carta F, et al. Cyclodextrin complexation highly enhances efficacy of arylsulfonylureido benzenesulfonamide carbonic anhydrase inhibitors as a topical antiglaucoma agents Bioorg Med Chem 201 5; 23(18): 6223-7.
[http://dx.doi.org/10.1016/j.bmc.2015.07.047 ] [PMID: 26319622]
Wei G, Xu H, Ding PT, Li SM, Zheng JM. Thermosetting gels with modulated gelation temperature for ophthalmic use: the rheological and gamma scintigraphic studies. J Control Release 2002; 83(1): 65-74.
[http://dx.doi.org/10.1016/S0168-3659(02)00175-X] [PMID: 12220839]
Jain D, Kumar V, Singh S, Mullertz A, Bar-Shalom D. Newer trends in In situ gelling systems for controlled ocular drug delivery. J Anal Pharm Res 2016; 2(3): 00022.
Shastri DH, Prajapati ST, Patel LD. Thermoreversible mucoadhesive ophthalmic in situ hydrogel: Design and optimization using a combination of polymers. Acta Pharm 2010; 60(3): 349-60.
[http://dx.doi.org/10.2478/v10007-010-0029-4] [PMID: 21134868]
Kumar S, Haglund BO, Himmelstein KJ. In situ-forming gels for ophthalmic drug delivery. J Ocul Pharmacol 1994; 10(1): 47-56.
[http://dx.doi.org/10.1089/jop.1994.10.47] [PMID: 8207344]
Katariya DC, Poddar SS. In-situ ophthalmic gel of timololma-letae: Formulation rheological studies, in-vitro and in-vivo evaluation. Indo Am J Pharm Res 2014; 4(11): 5165-84.
Tong L, Su C, Wang C. The optimization of multi- response problems in the Taguchi method. Int J Qual Reliab Manage 1997; 14(4): 367-80.
Shravani D, Lakshmi PK, Balasubramaniam J. Preparation and optimization of various parameters of enteric coated pellets using the Taguchi L9 orthogonal array design and their characterization. Yao Xue Xue Bao 2011; 1(1): 56-63.
Liu Y, Liu J, Zhang X, Zhang R, Huang Y, Wu C. In situ gelling gelrite/alginate formulations as vehicles for ophthalmic drug delivery. AAPS PharmSciTech 2010; 11(2): 610-20.
[http://dx.doi.org/10.1208/s12249-010-9413-0] [PMID: 20354916]
Franzesi GT, Ni B, Ling Y, Khademhosseini A. A controlled-release strategy for the generation of cross-linked hydrogel microstructures. J Am Chem Soc 2006; 128(47): 15064-5.
[http://dx.doi.org/10.1021/ja065867x] [PMID: 17117838]
El-Kamel A, El-Khatib M. Thermally reversible in situ gelling carbamazepine liquid suppository. Drug Deliv 2006; 13(2): 143-8.
[http://dx.doi.org/10.1080/10717540500316003] [PMID: 16423803]
Shah P, Kadikar A, Katira R, Patel K, Gandhi T. Simultaneous determination of brinzolamide and Timolol maleate using three different Spectrophotometric methods. World J Pharm Pharm Sci 2014; 3(2): 1955-67.
Mayol L, Quaglia F, Borzacchiello A, Ambrosio L, La Rotonda MI. A novel poloxamers/hyaluronic acid in situ forming hydrogel for drug delivery: rheological, mucoadhesive and in vitro release properties. Eur J Pharm Biopharm 2008; 70(1): 199-206.
[http://dx.doi.org/10.1016/j.ejpb.2008.04.025] [PMID: 18644705]
Srividya B, Cardoza RM, Amin PD. Sustained ophthalmic delivery of ofloxacin from a pH triggered in situ gelling system. J Control Release 2001; 73(2-3): 205-11.
[http://dx.doi.org/10.1016/S0168-3659(01)00279-6] [PMID: 11516498]
Zignani M, Tabatabay C, Gurny R. Topical semi-solid drug delivery: Kinetics and tolerance of ophthalmic hydrogels. Adv Drug Deliv Rev 1995; 16: 51-60.
Weil CS, Scala RA. Study of intra and interlaboratory variability in the results of rabbit eye and skin irritation tests. Toxicol Appl Pharmacol 1971; 19(2): 276-360.
[http://dx.doi.org/10.1016/0041-008X(71)90112-8] [PMID: 5570968]
Mcnally S, Brien CJO. Drug discovery in glaucoma and the role of animal models. Drug Discov Today Dis Models 2014; 30(20): 1-8.
Ammar HO, Salama HA, Ghorab M, Mahmoud AA. Nanoemulsion as a potential ophthalmic delivery system for dorzolamide hydrochloride. AAPS PharmSciTech 2009; 10(3): 808-19.
[http://dx.doi.org/10.1208/s12249-009-9268-4] [PMID: 19536653]
International Conference on Harmonization Q1C: Stability testing for new dosage forms EU: FDA: Published in the Federal Register 1997; 62(90): 25634-5.
Biswal S, Sahoo J, Murthy PN, Giradkar RP, Avari JG. Enhancement of dissolution rate of gliclazide using solid dispersions with polyethylene glycol 6000. AAPS PharmSciTech 2008; 9(2): 563-70.
[http://dx.doi.org/10.1208/s12249-008-9079-z] [PMID: 18459056]
Pralhad T, Rajendrakumar K. Study of freeze-dried quercetin-cyclodextrin binary systems by DSC, FT-IR, X-ray diffraction and SEM analysis. J Pharm Biomed Anal 2004; 34(2): 333-9.
[http://dx.doi.org/10.1016/S0731-7085(03)00529-6] [PMID: 15013147]
Nair KA, Somashekara N, Venkata M, et al. Development of curcumin based ophthalmic formulation research and development. Am J Infect Dis 2012; 8(1): 41-9.

open access plus

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Page: [524 - 542]
Pages: 19
DOI: 10.2174/1574885514666190916151506

Article Metrics

PDF: 25