Amorphous Solid Dispersion Based Oral Disintegrating Film of Ezetimibe: Development and Evaluation

Author(s): Preethi Sudheer*, Sangam Shrestha, Kavitha A. Narayana

Journal Name: Drug Metabolism Letters

Volume 14 , Issue 1 , 2021


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: Ezetimibe is a cholesterol-lowering agent with an oral bioavailability of 50% by virtue of its poor solubility and extensive hepatic and intestinal metabolism.

Objective: The study aimed to overcome low bioavailability issues of ezetimibe by formulating an oral disintegrating film.

Methods: The low solubility of ezetimibe was undertaken, preparing solid dispersions using mannitol, β-cyclodextrin, and urea. The mannitol solid dispersion assimilated oral disintegrating film was prepared and optimized using 23 factorial design, where the concentration of film formers hydroxypropyl methylcellulose (K5& K15) (X1and X2) and super disintegrant, sodium starch glycolate (X3) was used as factors on the response disintegration time (Y). The films were evaluated for physical properties, time of disintegration, and drug release profiles.

Results: Mannitol solid dispersion (1:2 ratio) based on the superior drug content, solubility and in vitro release profile was preferred in film formation. The low crystalline nature of the solid dispersion was very evident by the absence of prominent peaks in the X-Ray diffraction pattern and the reduced peak intensity of melting endotherms. The correlation coefficient (R2) and statistical parameter analysis of variance specify the implication of linear factors on responses, which is apparent from confidence intervals (P-values) less than 0.05. The in vitro release profile of all the eight formulations (F1-F8) in a phosphate buffer solution of pH 6.8 revealed a significant increment in comparison to ezetimibe.

Conclusion: The study revealed that the formulation approach could overcome the biopharmaceutical challenge of solubility as well as low bioavailability issues of ezetimibe.

Keywords: Ezetimibe, HPMC, ODF, solid dispersion, BCS, mannitol, in vitro release, factors.

[1]
Taupitz, T.; Dressman, J.B.; Klein, S. New formulation approaches to improve solubility and drug release from fixed dose combinations: case examples pioglitazone/glimepiride and ezetimibe/simvastatin. Eur. J. Pharm. Biopharm., 2013, 84(1), 208-218.
[http://dx.doi.org/10.1016/j.ejpb.2012.11.027] [PMID: 23246797]
[2]
Irfan, M.; Rabel, S.; Bukhtar, Q.; Qadir, M.I.; Jabeen, F.; Khan, A. Orally disintegrating films: A modern expansion in drug delivery system. Saudi Pharm. J., 2016, 24(5), 537-546.
[http://dx.doi.org/10.1016/j.jsps.2015.02.024] [PMID: 27752225]
[3]
Yan, Z.; Yin, L.; Yang, L.; Qin, C. Preparation and evaluation of orally disintegrating film containing donepezil for Alzheimer disease. J. Drug Deliv. Sci. Technol., 2019, 54, 134-142.
[4]
Sharma, R.; Kamboj, S.; Singh, G.; Rana, V. Development of aprepitant loaded orally disintegrating films for enhanced pharmacokinetic performance. Eur. J. Pharm. Sci., 2016, 84, 55-69.
[http://dx.doi.org/10.1016/j.ejps.2016.01.006] [PMID: 26780381]
[5]
Scarpa, M.; Paudel, A.; Kloprogge, F.; Hsiao, W.K.; Bresciani, M.; Gaisford, S.; Orlu, M. Key acceptability attributes of orodispersible films. Eur. J. Pharm. Biopharm., 2018, 125, 131-140.
[http://dx.doi.org/10.1016/j.ejpb.2018.01.003] [PMID: 29355687]
[6]
Łyszczarz, E.; Hofmanová, J.; Szafraniec-Szczęsny, J.; Jachowicz, R. Orodispersible films containing ball milled aripiprazole-poloxamer®407 solid dispersions. Int. J. Pharm., 2020, 575, 118955.
[http://dx.doi.org/10.1016/j.ijpharm.2019.118955] [PMID: 31843552]
[7]
Maher, E.M.; Ali, A.M.A.; Salem, H.F.; Abdelrahman, A.A. In vitro/in vivo evaluation of an optimized fast dissolving oral film containing olanzapine co-amorphous dispersion with selected carboxylic acids. Drug Deliv., 2016, 23(8), 3088-3100.
[http://dx.doi.org/10.3109/10717544.2016.1153746] [PMID: 26960680]
[8]
Ganesan, P.; Soundararajan, R.; Shanmugam, U. Development characterization and solubility enhancement of comparative dissolution study of second generation of solid dispersions and microspheres for poorly water soluble drug. Asian J. Pharm. Sci, 2015, 10, 433-441.
[http://dx.doi.org/10.1016/j.ajps.2015.05.001]
[9]
Zielińska, A.; Martins-Gomes, C.; Ferreira, N.R.; Silva, A.M.; Nowak, I.; Souto, E.B. Anti-inflammatory and anti-cancer activity of citral: Optimization of citral-loaded solid lipid nanoparticles (SLN) using experimental factorial design and LUMiSizer®. Int. J. Pharm., 2018, 553(1-2), 428-440.
[http://dx.doi.org/10.1016/j.ijpharm.2018.10.065] [PMID: 30385373]
[10]
Baghel, S.; Cathcart, H.; O’Reilly, N.J. Polymeric amorphous solid dispersions: a review of amorphization, crystallization, stabilization, solid-state characterization, and aqueous solubilization of biopharmaceutical classification system class II drugs. J. Pharm. Sci., 2016, 105(9), 2527-2544.
[http://dx.doi.org/10.1016/j.xphs.2015.10.008] [PMID: 26886314]
[11]
Choi, J.S.; Lee, S.E.; Jang, W.S.; Byeon, J.C.; Park, J.S. Tadalafil solid dispersion formulations based on PVP/VA S-630: Improving oral bioavailability in rats. Eur. J. Pharm. Sci., 2017, 106, 152-158.
[http://dx.doi.org/10.1016/j.ejps.2017.05.065] [PMID: 28579005]
[12]
Ng, C.L.; Lee, S.E.; Lee, J.K.; Kim, T.H.; Jang, W.S.; Choi, J.S.; Kim, Y.H.; Kim, J.K.; Park, J.S. Solubilization and formulation of chrysosplenol C in solid dispersion with hydrophilic carriers. Int. J. Pharm., 2016, 512(1), 314-321.
[http://dx.doi.org/10.1016/j.ijpharm.2016.08.062] [PMID: 27593897]
[13]
Solaiman, A.; Suliman, A.S.; Shinde, S.; Naz, S.; Elkordy, A.A. Application of general multilevel factorial design with formulation of fast disintegrating tablets containing croscaremellose sodium and Disintequick MCC-25. Int. J. Pharm., 2016, 501(1-2), 87-95.
[http://dx.doi.org/10.1016/j.ijpharm.2016.01.065] [PMID: 26827922]
[14]
Pethe, A.M.; Desai, R.B. Formulation, optimization & evaluation of mouth dissolving film of nifedipine by using design of experiment. Asian J. Pharm. Sci., 2016, 11, 74-76.
[http://dx.doi.org/10.1016/j.ajps.2015.10.059]
[15]
Abdelbary, A.; Bendas, E.R.; Ramadan, A.A.; Mostafa, D.A. Pharmaceutical and pharmacokinetic evaluation of a novel fast dissolving film formulation of flupentixol dihydrochloride. AAPS Pharm. Sci. Tech. , 2014, 15(6), 1603-1610.
[http://dx.doi.org/10.1208/s12249-014-0186-8] [PMID: 25142820]
[16]
Liew, K.B. Fung, Tan Y.T, Peh K.K. Effect of polymer, plasticizer and filler on oral disintegarting film. Drug Dev. Ind. Pharm., 2014, 40, 110-119.
[http://dx.doi.org/10.3109/03639045.2012.749889] [PMID: 23311593]
[17]
Choudhary, D.R.; Patel, V.A.; Chhalotiya, U.K.; Patel, H.V.; Kundawala, A.J. Development and characterization of pharmacokinetic parameters of fast-dissolving films containing levocetirizine. Sci. Pharm., 2012, 80(3), 779-787.
[http://dx.doi.org/10.3797/scipharm.1205-15] [PMID: 23008821]
[18]
Vuddanda, P.R.; Montenegro-Nicolini, M.; Morales, J.O.; Velaga, S. Effect of surfactants and drug load on physico-mechanical and dissolution properties of nanocrystalline tadalafil-loaded oral films. Eur. J. Pharm. Sci., 2017, 109, 372-380.
[http://dx.doi.org/10.1016/j.ejps.2017.08.019] [PMID: 28823854]
[19]
Nagaraju, T.; Gowthami, R.; Rajashekar, M.; Sandeep, S.; Mallesham, M.; Sathish, D.; Kumar, Y.S. Comprehensive review on oral disintegrating films. Curr. Drug Deliv., 2013, 10(1), 96-108.
[http://dx.doi.org/10.2174/1567201811310010016] [PMID: 22920576]
[20]
Zhang, H.; Han, M.G.; Wang, Y. Development of oral fast disintegrating levothyroxine films for management of hypothyroidism in pediatrics. Trop. J. Pharm. Res., 2015, 14, 1755-1762.
[http://dx.doi.org/10.4314/tjpr.v14i10.4]
[21]
Khadra, I.; Obeid, M.A.; Dunn, C.; Watts, S.; Halbert, G.; Ford, S.; Mullen, A. Characterisation and optimisation of diclofenac sodium orodispersible thin film formulation. Int. J. Pharm., 2019, 561, 43-46.
[http://dx.doi.org/10.1016/j.ijpharm.2019.01.064] [PMID: 30772459]
[22]
Rençber, S.; Karavana, S.Y.; Yilmaz, F.F.; Eraç, B.; Nenni, M. Formulation and evaluation of fluconazole loaded oral strips for local treatment of oral candidiasis. J. Drug Deliv. Sci. Technol., 2019, 49, 615-621.
[http://dx.doi.org/10.1016/j.jddst.2018.12.035]
[23]
Speer, I.; Preis, M.; Breitkreutz, J. Dissolution testing of oral film preparations: Experimental comparison of compendial and non-compendial methods. Int. J. Pharm., 2019, 561, 124-134.
[http://dx.doi.org/10.1016/j.ijpharm.2019.02.042] [PMID: 30826424]
[24]
Giordani, B.; Abruzzo, A.; Prata, C.; Nicoletta, F.P.; Dalena, F.; Cerchiara, T.; Luppi, B.; Bigucci, F. Ondansetron buccal administration for paediatric use: A comparison between films and wafers. Int. J. Pharm., 2020, 580, 119228.
[http://dx.doi.org/10.1016/j.ijpharm.2020.119228] [PMID: 32184180]
[25]
Nayak, A.K.; Pal, D.; Santra, K. Swelling and drug release behavior of metformin HCl-loaded tamarind seed polysaccharide-alginate beads. Int. J. Biol. Macromol., 2016, 82, 1023-1027.
[http://dx.doi.org/10.1016/j.ijbiomac.2015.10.027] [PMID: 26472516]
[26]
Mendyk, A.; Jachowicz, R.; Fijorek, K. KinetDS: an open source software for dissolution test data analysis. Dissolut. Technol., 2012, 19, 6-11.
[http://dx.doi.org/10.14227/DT190112P6]
[27]
Fu, Y.; Kao, W.J. Drug release kinetics and transport mechanisms of non-degradable and degradable polymeric delivery systems. Expert Opin. Drug Deliv., 2010, 7(4), 429-444.
[http://dx.doi.org/10.1517/17425241003602259] [PMID: 20331353]
[28]
Hussain, A.; Latif, S.; Abbas, N. Hydroxy propyl cellulose based orally disintegrating films of promethazine HCl for the treatment of motion sickness. Trop. J. Pharm. Res., 2018, 7, 991-996.
[http://dx.doi.org/10.4314/tjpr.v17i6.2]
[29]
Nishimura, M.; Matsuura, K.; Tsukioka, T.; Yamashita, H.; Inagaki, N.; Sugiyama, T.; Itoh, Y. In vitro and in vivo characteristics of prochlorperazine oral disintegrating film. Int. J. Pharm., 2009, 368(1-2), 98-102.
[http://dx.doi.org/10.1016/j.ijpharm.2008.10.002] [PMID: 18992311]
[30]
Lai, K.L.; Fang, Y.; Han, H.; Li, Q.; Zhang, S.; Li, H.Y.; Chow, S.F.; Lam, T.N.; Lee, W.Y.T. Orally-dissolving film for sublingual and buccal delivery of ropinirole. Colloids Surf. B Biointerfaces, 2018, 163, 9-18.
[http://dx.doi.org/10.1016/j.colsurfb.2017.12.015] [PMID: 29268211]
[31]
Bohrey, V.C.S.; Pandey, A. Formulation, optimization, characterization and in vitro drug release kinetics of atenolol loaded PLGA nanoparticles using 33 factorial design for oral delivery. Material Discov., 2016, 5, 1-13.
[http://dx.doi.org/10.1016/j.md.2016.12.002]
[32]
Bulbul, E.O.; Mesut, B.; Cevher, E.; Ozta, E.; Ozsoy, Y. Product transfer from lab-scale to pilot-scale of quetiapine fumarate orodispersible films using quality by design approach. J. Drug Deliv. Sci. Technol., 2019, 54, 101358.
[http://dx.doi.org/10.1016/j.jddst.2019.101358]
[33]
Mazumder, S.; Pavurala, N.; Manda, P.; Xu, X.; Cruz, C.N.; Krishnaiah, Y.S.R. Quality by Design approach for studying the impact of formulation and process variables on product quality of oral disintegrating films. Int. J. Pharm., 2017, 527(1-2), 151-160.
[http://dx.doi.org/10.1016/j.ijpharm.2017.05.048] [PMID: 28549972]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 14
ISSUE: 1
Year: 2021
Published on: 01 September, 2020
Page: [66 - 79]
Pages: 14
DOI: 10.2174/1872312814666200901182517
Price: $65

Article Metrics

PDF: 431
HTML: 2