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Pharmaceutical Nanotechnology

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

Research Article

Enhanced Oral Absorption of All-trans Retinoic Acid upon Encapsulation in Solid Lipid Nanoparticles

Author(s): Manoj Kumar, Garima Sharma, Dinesh Singla, Sukhjeet Singh, Vandita Kakkar, Jaspreet S. Gulati and Indu P. Kaur*

Volume 8, Issue 6, 2020

Page: [495 - 510] Pages: 16

DOI: 10.2174/2211738508999201027220825

Price: $65

Abstract

Background: All-trans retinoic acid (ATRA) is widely employed in the treatment of various proliferative and inflammatory diseases. However, its therapeutic efficacy is imperiled due to its poor solubility and stability. Latter was surmounted by its incorporation into a solid matrix of lipidic nanoparticles (SLNs).

Methods: ATRA loaded SLNs (ATRA-SLNs) were prepared using a novel microemulsification technique (USPTO 9907758) and an optimal composition and were characterized in terms of morphology, differential scanning calorimetry (DSC), and powder X-ray diffraction studies (PXRD). In vitro release, oral plasma pharmacokinetics (in rats) and stability studies were also done.

Results: Rod-shaped ATRA-SLNs could successfully incorporate 3.7 mg/mL of ATRA, increasing its solubility (from 4.7 μg/mL) by 787 times, having an average particle size of 131.30 ± 5.0 nm and polydispersibility of 0.283. PXRD, DSC, and FTIR studies confirmed the formation of SLNs. Assay/total drug content and entrapment efficiency of ATRA-SLNs was 92.50 ± 2.10% and 84.60 ± 3.20% (n=6), respectively, which was maintained even on storage for one year under refrigerated conditions as an aqueous dispersion. In vitro release in 0.01 M phosphate buffer (pH 7.4) with 3% tween 80 was extended 12 times from 2h for free ATRA to 24 h for ATRA-SLNs depicting Korsmeyer Peppas release. Oral administration in rats showed 35.03 times enhanced bioavailability for ATRA-SLNs.

Conclusion: Present work reports preparation and evaluation of bioenhanced ATRA-SLNs containing a high concentration of ATRA (>15 times than that reported by others). Latter is attributed to the novel preparation process and intelligent selection of components.

Lay Summary: All-trans retinoic acid (ATRA) shows an array of pharmacological activities but its efficacy is limited due to poor solubility, stability and side effects. In present study its solubility and efficacy is improved by 787 and 35.5 times, respectively upon incorporation into solid lipid nanoparticles (ATRA-SLNs). Latter extended its release by 12 times and provided stability for at least a year under refrigeration. A controlled and sustained release will reduce dose related side effects. ATRA-SLNs reported presently can thus be used in treatment /prophylaxis of disorders like cancers, tuberculosis, age related macular degeneration and acne and as an immune-booster.

Keywords: Bioavailability, cancers, extended release, immune booster, pharmacokinetics, rats, solubility.

Graphical Abstract
[1]
Mukherjee S, Date A, Patravale V, Korting HC, Roeder A, Weindl G. Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety. Clin Interv Aging 2006; 1(4): 327-48.
[http://dx.doi.org/10.2147/ciia.2006.1.4.327 PMID: 18046911]
[2]
Zhu YH, Ye N, Tang XF, et al. Synergistic effect of retinoic acid polymeric micelles and prodrug for the pharmacodynamic evaluation of tumor suppression. Front Pharmacol 2019; 10: 447.
[PMID: 31156425]
[3]
Kaidbey KH, Petrozzi JW, Kligman AM. Treatment of psoriasis with topically applied tretinoin and steroid ointment. Arch Dermatol 1975; 111(8): 1001-3.
[http://dx.doi.org/10.1001/archderm.1975.01630200061006] [PMID: 786170]
[4]
Kotori MG. Low dose vitamin A tablets treatment of acne vulgaris. Med Arh 2015; 69(1): 28-30.
[http://dx.doi.org/10.5455/medarh.2015.69.28-30] [PMID: 25870473]
[5]
Ascenso A, Ribeiro H, Marques HC, Oliveira H, Santos C, Simões S. Is tretinoin still a key agent for photoaging management? Mini Rev Med Chem 2014; 14(8): 629-41.
[http://dx.doi.org/10.2174/1389557514666140820102735] [PMID: 25141855]
[6]
Semba RD. Vitamin A, immunity, and infection. Clin Infect Dis 1994; 19(3): 489-99.
[http://dx.doi.org/10.1093/clinids/19.3.489 PMID: 7811869]
[7]
Pakasi TA, Karyadi E, Wibowo Y, et al. Vitamin A deficiency and other factors associated with severe tuberculosis in Timor and Rote Islands, East Nusa Tenggara Province, Indonesia. Eur J Clin Nutr 2009; 63(9): 1130-5.
[http://dx.doi.org/10.1038/ejcn.2009.25 PMID: 19471295]
[8]
Kaur IP, Verma MK. Process for preparing solid lipid sustained release nanoparticles for delivery of vitamins PCT/IB2013/050169. 2013.
[9]
Siddikuzzaman GC, Guruvayoorappan C, Berlin Grace VM. All trans retinoic acid and cancer. Immunopharmacol Immunotoxicol 2011; 33(2): 241-9.
[http://dx.doi.org/10.3109/08923973.2010.521507] [PMID: 20929432]
[10]
el Mansouri S, Tod M, Leclerq M, Petitjean O, Perret G, Porthault M. Time- and dose-dependent kinetics of all-trans-retinoic acid in rats after oral or intravenous administration(s). Drug Metab Dispos 1995; 23(2): 227-31.
[PMID: 7736916]
[11]
Hwang SR, Lim SJ, Park JS, Kim CK. Phospholipid-based microemulsion formulation of all-trans-retinoic acid for parenteral administration. Int J Pharm 2004; 276(1-2): 175-83.
[http://dx.doi.org/10.1016/j.ijpharm.2004.02.025] [PMID: 15113624]
[12]
Emami J, Rezazadeh M, Mashayekhi M, Rostami M, Jahanian-Najafabadi A. A novel mixed polymeric micelle for co-delivery of paclitaxel and retinoic acid and overcoming multidrug resistance: synthesis, characterization, cytotoxicity, and pharmacokinetic evaluation. Drug Dev Ind Pharm 2018; 44(5): 729-40.
[http://dx.doi.org/10.1080/03639045.2017.1411940] [PMID: 29235901]
[13]
Hollander D. Retinol lymphatic and portal transport: influence of pH, bile, and fatty acids. Am J Physiol 1980; 239(3): G210-4.
[PMID: 7435575]
[14]
Adamson PC, Pitot HC, Balis FM, Rubin J, Murphy RF, Poplack DG. Variability in the oral bioavailability of all-trans-retinoic acid. J Natl Cancer Inst 1993; 85(12): 993-6.
[http://dx.doi.org/10.1093/jnci/85.12.993 PMID: 8388479]
[15]
Takitani K, Nakao Y, Kosaka Y, et al. Low plasma level of all-trans retinoic acid after feeding tube administration for acute promyelocytic leukemia. Am J Hematol 2004; 76(1): 97-8.
[http://dx.doi.org/10.1002/ajh.20049] [PMID: 15114613]
[16]
Brisaert MG, Everaerts I, Plaizier-Vercammen JA. Chemical stability of tretinoin in dermatological preparations. Pharm Acta Helv 1995; 1995(70): 161-6.
[http://dx.doi.org/10.1016/0031-6865(95)00016-3]
[17]
Lin HS, Chan SY, Low KSY, Shoon ML, Ho PC. Kinetic study of a 2-hydroxypropyl-β-cyclodextrin-based formulation of all-trans-retinoic acid in Sprague-Dawley rats after oral or intravenous administration. J Pharm Sci 2000; 89(2): 260-7.
[http://dx.doi.org/10.1002/(SICI)1520-6017(200002)89:2<260:AID-JPS13>3.0.CO;2-Q] [PMID: 10688755]
[18]
Chen Z, Xiea Y, Guana P, et al. Enhanced oral bioavailability of all-trans-retinoic acid by 2-hydroxypropyl-β-cyclodextrin inclusion complex pellets prepared by fluid-bed coating technique. Asian J Pharm Sci 2011; 6(5): 202-7.
[19]
Tinoco LMS, Oliveira da Silva FL, Ferreira LAM, Leite EA, Carneiro G. Hyaluronic acid-coated nanoemulsions loaded with a hydrophobic ion pair of all trans retinoic acid for improving the anticancer activity. Braz J Pharm Sci 2018; 54(4)e17361
[http://dx.doi.org/10.1590/s2175-97902018000417361]]
[20]
Ourique AF, Pohlmann AR, Guterres SS, Beck RCR. Tretinoin-loaded nanocapsules: Preparation, physicochemical characterization, and photostability study. Int J Pharm 2008; 352(1-2): 1-4.
[http://dx.doi.org/10.1016/j.ijpharm.2007.12.035] [PMID: 18249513]
[21]
Rahman SA, Abdelmalak NS, Badawi A, Elbayoumy T, Sabry N, El Ramly A. Formulation of tretinoin-loaded topical proniosomes for treatment of acne: in vitro characterization, skin irritation test and comparative clinical study. Drug Deliv 2015; 22(6): 731-9.
[http://dx.doi.org/10.3109/10717544.2014.896428] [PMID: 24670094]
[22]
Yamaguchi Y, Igarashi R. NANOEGG technology for drug delivery. In: Kumar SSR, ed Nanotechnologies for the life sciences. Weinheim: Wiley-VCH 2007; pp. 310-41.
[23]
Errico C, Gazzarri M, Chiellini F. A novel method for the preparation of retinoic acid-loaded nanoparticles. Int J Mol Sci 2009; 10(5): 2336-47.
[PMID: 19564952]
[24]
Tang J, Wang X, Wang T, Chen F, Zhou J. In vivo pharmacokinetics, biodistribution and antitumor effect of amphiphilic poly(L-amino acids) micelles loaded with a novel all-trans retinoic acid derivative. Eur J Pharm Sci 2014; 51: 157-64.
[http://dx.doi.org/10.1016/j.ejps.2013.09.016] [PMID: 24076464]
[25]
Ozpolat B, Lopez-Berestein G, Adamson P, Fu CJ, Williams AH. Pharmacokinetics of intravenously administered liposomal all-trans-retinoic acid (ATRA) and orally administered ATRA in healthy volunteers. J Pharm Pharm Sci 2003; 6(2): 292-301.
[PMID: 12935441]
[26]
Douer D, Estey E, Santillana S, et al. Treatment of newly diagnosed and relapsed acute promyelocytic leukemia with intravenous liposomal all-trans retinoic acid. Blood 2001; 97(1): 73-80.
[http://dx.doi.org/10.1182/blood.V97.1.73 PMID: 11133744]
[27]
Kawano K, Isoda Y, Toma H, Fukasawa A, Yonemochi E, Hattori Y. Effect of all-trans retinoic acid-loaded liposomes on adipogenesis of obese mice. Int J Pharm Sci Res 2017; 4: 121.
[28]
Chen XJ, Zhang XQ, Tang MX, Zho G. PD-l1 conjugated all-trans retinoic acid nanoparticles for targeted treatment of oral dysplasia and oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol 2020; 129(1): e198-9.
[http://dx.doi.org/10.1016/j.oooo.2019.07.059]
[29]
Cui C, Zhang Y, Wang L, Liu H, Cui G. Enhanced anticancer activity of glutamate prodrugs of all-trans retinoic acid. J Pharm Pharmacol 2009; 61(10): 1353-8.
[http://dx.doi.org/10.1211/jpp.61.10.0012 PMID: 19814868]
[30]
Narvekar M, Xue HY, Wong HL. A novel hybrid delivery system: polymer-oil nanostructured carrier for controlled delivery of highly lipophilic drug all-trans-retinoic acid (ATRA). Int J Pharm 2012; 436(1-2): 721-31.
[http://dx.doi.org/10.1016/j.ijpharm.2012.07.042] [PMID: 22850294]
[31]
Zhang J, Han J, Zhang X, et al. Polymeric nanoparticles based on chitooligosaccharide as drug carriers for co-delivery of all-trans-retinoic acid and paclitaxel. Carbohydr Polym 2015; 129: 25-34.
[PMID: 26050884]
[32]
Kakkar V, Mishra AK, Chuttani K, Kaur IP. Proof of concept studies to confirm the delivery of curcumin loaded solid lipid nanoparticles (C-SLNs) to brain. Int J Pharm 2013; 448(2): 354-9.
[PMID: 23558314]
[33]
Singh H, Bhandari R, Kaur IP. Encapsulation of Rifampicin in a solid lipid nanoparticulate system to limit its degradation and interaction with Isoniazid at acidic pH. Int J Pharm 2013; 446(1-2): 106-11.
[PMID: 23410991]
[34]
Hu L, Tang X, Cui F. Solid lipid nanoparticles (SLNs) to improve oral bioavailability of poorly soluble drugs. J Pharm Pharmacol 2004; 56(12): 1527-35.
[http://dx.doi.org/10.1211/0022357044959] [PMID: 15563759]
[35]
Arana L, Bayón-Cordero L, Sarasola LI, Berasategi M, Ruiz S, Alkorta I. Solid lipid nanoparticles surface modification modulates cell internalization and improves chemotoxic treatment in an oral carcinoma cell line. Nanomaterials (Basel) 2019; 9(3): 1-17.
[http://dx.doi.org/10.3390/nano9030464 PMID: 30897724]
[36]
Das S, Ng WK, Kanaujia P, Kim S, Tan RBH. Formulation design, preparation and physicochemical characterizations of solid lipid nanoparticles containing a hydrophobic drug: effects of process variables. Colloids Surf B Biointerfaces 2011; 88(1): 483-9.
[http://dx.doi.org/10.1016/j.colsurfb.2011.07.036] [PMID: 21831615]
[37]
Kaur I, Verma M. Solid nanolipidic particulates of vitamin D3 and retinoic acid India Patent 79/DEL/ 20122012,. 2012.
[38]
Kumar M, Sharma G, Singla D, et al. Development of a validated UPLC method for simultaneous estimation of both free and entrapped (in solid lipid nanoparticles) all-trans retinoic acid and cholecalciferol (vitamin D3) and its pharmacokinetic applicability in rats. J Pharm Biomed Anal 2014; 91: 73-80.
[http://dx.doi.org/10.1016/j.jpba.2013.12.011] [PMID: 24440824]
[39]
Subongkot T, Ngawhirunpat T. Development of a novel microemulsion for oral absorption enhancement of all-trans retinoic acid. Int J Nanomedicine 2017; 12: 5585-99.
[http://dx.doi.org/10.2147/IJN.S142503 PMID: 28831254]
[40]
Moghimipour E, Salimi A, Leis F. Preparation and evaluation of tretinoin microemulsion based on pseudo-ternary phase diagram. Adv Pharm Bull 2012; 2(2): 141-7.
[PMID: 24312785]
[41]
Kumar M, Kakkar V, Mishra AK, Chuttani K, Kaur IP. Intranasal delivery of streptomycin sulfate (STRS) loaded solid lipid nanoparticles to brain and blood. Int J Pharm 2014; 461(1-2): 223-33.
[http://dx.doi.org/10.1016/j.ijpharm.2013.11.038] [PMID: 24286922]
[42]
Kumar A, Sahoo SK, Padhee K, Kochar P, Sathapathy A, Pathak N. Review on solubility enhancement techniques for hydrophobic drugs Pharmacie Globale 2011; 3(3): 001-7..
[43]
Sharma D, Soni M, Kumar S, Gupta G. Solubility enhancement-eminent role in poorly soluble drugs. Res J Pharm Technol 2009; 2(2): 220-4.
[44]
Krishnaiah YS. Pharmaceutical technologies for enhancing oral bioavailability of poorly soluble drugs. J Bioequivalence Bioavailab 2010; 2(2): 28-36.
[http://dx.doi.org/10.4172/jbb.1000027]
[45]
Pople PV, Singh KK. Development and evaluation of topical formulation containing solid lipid nanoparticles of vitamin A. AAPS PharmSciTech 2006; 7(4): 91.
[http://dx.doi.org/10.1208/pt070491] [PMID: 17285742]
[46]
Lim SJ, Lee MK, Kim CK. Altered chemical and biological activities of all-trans retinoic acid incorporated in solid lipid nanoparticle powders. J Control Release 2004; 100(1): 53-61.
[http://dx.doi.org/10.1016/j.jconrel.2004.07.032 PMID: 15491810]
[47]
Lim SJ, Kim CK. Formulation parameters determining the physicochemical characteristics of solid lipid nanoparticles loaded with all-trans retinoic acid. Int J Pharm 2002; 243(1-2): 135-46.
[http://dx.doi.org/10.1016/S0378-5173(02)00269-7] [PMID: 12176302]
[48]
Morales JO, Valdés K, Morales J, Oyarzun-Ampuero F. Lipid nanoparticles for the topical delivery of retinoids and derivatives. Nanomedicine (Lond) 2015; 10(2): 253-69.
[http://dx.doi.org/10.2217/nnm.14.159 PMID: 25600970]
[49]
Aggarwal D, Garg A, Kaur IP. Development of a topical niosomal preparation of acetazolamide: preparation and evaluation. J Pharm Pharmacol 2004; 56(12): 1509-17.
[http://dx.doi.org/10.1211/0022357044896 PMID: 15563757]
[50]
des Rieux A, Fievez V, Garinot M, Schneider Y-J, Préat V. Nanoparticles as potential oral delivery systems of proteins and vaccines: a mechanistic approach. J Control Release 2006; 116(1): 1-27.
[http://dx.doi.org/10.1016/j.jconrel.2006.08.013 PMID: 17050027]
[51]
Kaur IP, Bhandari R, Bhandari S, Kakkar V. Potential of solid lipid nanoparticles in brain targeting. J Control Release 2008; 127(2): 97-109.
[http://dx.doi.org/10.1016/j.jconrel.2007.12.018 PMID: 18313785]
[52]
Champion JA, Mitragotri S. Role of target geometry in phagocytosis. Proc Natl Acad Sci USA 2006; 103(13): 4930-4.
[http://dx.doi.org/10.1073/pnas.0600997103] [PMID: 16549762]
[53]
Gratton SEA, Ropp PA, Pohlhaus PD, et al. The effect of particle design on cellular internalization pathways. Proc Natl Acad Sci USA 2008; 105(33): 11613-8.
[http://dx.doi.org/10.1073/pnas.0801763105] [PMID: 18697944]
[54]
Hao N, Li L, Zhang Q. The shape effect of PEGylated mesoporous silica nanoparticles on cellular uptake pathway in Hela cells. Micropor Mesopor Mat 2012; pp. 14-23.
[55]
Sadeghi B, Garmaroudi FS, Hashemi M, et al. Comparison of the anti-bacterial activity on the nanosilver shapes: nanoparticles, nanorods and nanoplates. Adv Powder Technol 2012; 23(1): 22-6.
[http://dx.doi.org/10.1016/j.apt.2010.11.011]
[56]
Ren X, Mao X, Si L, et al. Pharmaceutical excipients inhibit cytochrome P450 activity in cell free systems and after systemic administration. Eur J Pharm Biopharm 2008; 70(1): 279-88.
[http://dx.doi.org/10.1016/j.ejpb.2008.03.019] [PMID: 18499414]
[57]
Christiansen A, Backensfeld T, Denner K, Weitschies W. Effects of non-ionic surfactants on cytochrome P450-mediated metabolism in vitro. Eur J Pharm Biopharm 2011; 78(1): 166-72.
[http://dx.doi.org/10.1016/j.ejpb.2010.12.033] [PMID: 21220010]
[58]
Taha E, Ghorab D, Zaghloul AA. Bioavailability assessment of vitamin A self-nanoemulsified drug delivery systems in rats: a comparative study. Med Princ Pract 2007; 16(5): 355-9.
[http://dx.doi.org/10.1159/000104808 PMID: 17709923]
[59]
Le Doze F, Debruyne D, Albessard F, Barre L, Defer GL. Pharmacokinetics of all-trans retinoic acid, 13-cis retinoic acid, and fenretinide in plasma and brain of Rat. Drug Metab Dispos 2000; 28(2): 205-8.
[PMID: 10640519]
[60]
Lu Y, Chen SC. Micro and nano-fabrication of biodegradable polymers for drug delivery. Adv Drug Deliv Rev 2004; 56(11): 1621-33.
[http://dx.doi.org/10.1016/j.addr.2004.05.002] [PMID: 15350292]
[61]
Khalil S, Bardawil T, Stephan C, et al. Retinoids: a journey from the molecular structures and mechanisms of action to clinical uses in dermatology and adverse effects. J Dermatolog Treat 2017; 28(8): 684-96.
[http://dx.doi.org/10.1080/09546634.2017.1309349] [PMID: 28318351]

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