Systematic Development of Sertraline Loaded Solid Lipid Nanoparticle (SLN) by Emulsification-Ultrasonication Method and Pharmacokinetic Study in Sprague-Dawley Rats

Author(s): Mohammad A. Rahman*, Ranjit K. Harwansh, Zeenat Iqbal.

Journal Name: Pharmaceutical Nanotechnology

Volume 7 , Issue 2 , 2019

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Graphical Abstract:


Abstract:

Objective: To circumvent the aforementioned problems and for the successful delivery of those newly discovered poorly soluble compounds, researchers have focused on the feasibility of biocompatible lipids such as Solid lipid nanoparticles (SLN) as carrier system.

Background: Sertraline (SRT) is commercially available as hydrochloride salt. Poor bioavailability (around 44%) of hydrochloride salt is considered to be conversion of salts to free base in the gastrointestinal tract which retard it’s absorption.

Methods: Different batches of solid lipid nanoparticles (SLN) were prepared and on the basis of particle size, polydispersity index (PDI), zeta potential (ZP), encapsulation efficiency (EE), and drug loading capacity (L) an optimum system was designed.

Results: The optimized formulation contains; 5% (w/v) Compritol® E ATO as lipids, 2.5% (w/v) Tween® 80 as surfactant and 0.1% (w/v) SRT as actives. The formulation was freeze-dried using mannitol as a cryoprotectant to control the aggregation of particles during redispersion process. SLN with <110 nm size, <0.2 PDI, >36 mV ZP, >72% EE, and nearly 0.7% L can be formed at appropriate formulation process conditions; homogenization time (HT) and sonication time (ST) at 5 min and 10 min, respectively. XRD studies indicated the presence of amorphous form of drug that is completely encapsulated within the nanoparticulate matrix system. The optimized SLN formulation have shown the highest value of zeta potential (-36.5 mV) confers stability of nanodispersion. Release of drug encapsulated in SLN showed a biphasic pattern and was extended upto 12 hours. The maximum plasma concentration (Cmax) and area under the curve (AUC) in case of sertraline loaded SLN were found 10-fold and 6-fold higher, respectively compared to pure drug.

Conclusion: The result depicted enhanced extent of absorption of sertraline from SLN compared to plain sertraline. Furthermore, sertraline-loaded SLN were found to be stable at 4°C for 6 months of study period. Hence, the SLN can be used as a potential carrier for successful delivery of poorly water-soluble drugs associated with poor oral bioavailability like sertraline.

Keywords: Bioavailability, drug loading, drug release, encapsulation, solid lipid nanoparticle, solubility, stability.

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Das S, Lin HS, Ho PC, et al. The impact of aqueous solubility and dose on the pharmacokinetic profiles of resveratrol. Pharm Res 2008; 25: 2593-600.
[2]
Mehnert W, Mader K. Solid lipid nanoparticles: production, characterization and applications. Adv Drug Deliv Rev 2001; 47: 165-96.
[3]
Utreja P, Jain S, Tiwary AK. Novel drug delivery systems for sustained and targeted delivery of anti-cancer drugs: current status and future prospects. Curr Drug Deliv 2010; 7(2): 152-61.
[4]
Ravi Kumar MN. Nano and microparticles as controlled drug delivery devices. J Pharm Sci 2000; 3: 234-58.
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Muller RH, Maassen S, Weyhers H, et al. Phagocytic uptake and cytotoxicity of solid lipid nanoparticles (SLN) sterically stabilized with poloxamine 908 and poloxamer 407. J Drug Target 1996; 4: 161-70.
[6]
Yuan H, Huang LF, Du YZ, et al. Solid lipid nanoparticles prepared by solvent diffusion method in a nanoreactor system. Colloids Surf B Biointerfaces 2008; 61: 132-7.
[7]
Xie S, Zhu L, Dong Z, et al. Preparation, characteri-zation and pharmacokinetics of enrofloxacin-loaded solid lipid nanoparticles: influences of fatty acids. Colloids Surf B Biointerfaces 2011; 83: 382-7.
[8]
Pouton CW. Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci 2006; 29: 278-87.
[9]
Holm R, Mullertz A, Christensen E, et al. Comparison of total oral bioavailability and the lymphatic transport of halofantrine from three different unsaturated triglycerides in lymph-cannulated conscious rats. Eur J Pharm Sci 2001; 14: 331-7.
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Venkateswarlu V, Manjunath K. Preparation, characterization and in vitro release kinetics of clozapine solid lipid nanoparticles. J Control Release 2004; 95: 627-38.
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Muller RH, Runge S, Ravelli V, et al. Oral bioavailability of cyclosporine: solid lipid nanoparticles (SLN) versus drug nanocrystals. Int J Pharm 2006; 317: 82-9.
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Li H, Zhao X, Ma Y, et al. Enhancement of gastrointestinal absorption of quercetin by solid lipid nanoparticles. J Cont Release 2009; 133: 238-44.
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Muller RH, Mader K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery-a review of the state of the art. Eur J Pharm Biopharm 2000; 50: 161-77.
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Schwarz C, Mehnert W. Freeze-drying of drug-free and drug-loaded solid lipid nanoparticles (SLN). Int J Pharm 1997; 157: 171-9.
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Yuan H, Chen J, Du YZ, et al. Studies on oral absorption of stearic acid SLN by a novel fluorometric method. Colloids Surf B Biointerfaces 2007; 58: 157-64.
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Holm R, Porter CJH, Mullertz A, et al. Structured triglyceride vehicles for oral delivery of halofantrine: examination of intestinal lymphatic transport and bioavailability in conscious rats. Pharm Res 2002; 19: 1354-61.
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Chen CC, Tsai TH, Huang ZR. Effects of lipophilic emulsifiers on the oral administration of lovastatin from nanostructured lipid carriers: physicochemical characterization and pharmacokinetics. Eur J Pharm Biopharm 2010; 74: 474-82.
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Gohla SH, Dingler A. Scaling up feasibility of the production of solid lipid nanoparticles (SLN). Pharmazie 2001; 56: 61-3.
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Dingler S, Gohla S. Production of solid lipid nanoparticles (SLN): scaling up feasibilities. J Microencapsul 2002; 19: 11-6.
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Kaur IP, Bhandari R, Bhandari S, et al. Potential of solid lipid nanoparticles in brain targeting. J Control Release 2008; 127: 97-109.
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Rahman MA, Mujahid M, Hussain A, et al. Development and pharmacokinetic evaluation of spray-dried self-nanoemulsifying drug delivery system of sertraline. J Pharm Invest 2017; 44(4): 325-33.
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Olbrich C, Muller RH. Enzymatic degradation of SLN-effect of surfactant and surfactant mixture. Int J Pharm 1999; 180: 31-9.
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Das S, Ng WK, Kanaujia P, et al. 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.
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Joshi M, Patravale V. Formulation and evaluation of nanostructured lipid carrier (NLC)-based gel of valdecoxib. Drug Dev Ind Pharm 2006; 32: 911-8.
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Helgason T, Awad TS, Kristbergsson K, et al. Effect of surfactant surface coverage on formation of solid lipid nanoparticles (SLN). J Colloid Interface Sci 2009; 334: 75-81.
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Rahman MA, Mujahid M. Development of self-nanoemulsifying tablet (SNET) for bioavailability enhancement of sertraline. Braz J Pharm Sci 2018; 54(1): 17232.
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Pradhan M, Singh D, Singh MR. Influence of selected variables on fabrication of triamcinolone acetonide loaded solid lipid nanoparticles for topical treatment of dermal disorders. Artif Cells Nanomed Biotechnol 2016; 44(1): 392-400.
[29]
Hu L, Tang X, Cui F. Solid lipid nanoparticles (SLNs) to improve oral bioavailability of poorly soluble drugs. J Pharm Pharmacol 2004; 56: 1527.
[30]
Parveen R, Baboota S, Ali J, et al. Oil based nanocarrier for improved oral delivery of silymarin: in vitro and in vivo studies. Int J Pharm 2011; 413(1-2): 245-53.
[31]
Muthu MS, Rawat MK, Mishra A, et al. PLGA nanoparticle formulations of risperidone: preparation and neuropharmacological evaluation. Nanomedicine 2009; 5(3): 323-33.
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Das S, Chaudhury A. Recent advances in lipid nanoparticle formulations with solid matrix for oral drug delivery. AAPS PharmSciTech 2011; 12: 62-76.
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Liu J, Hu W, Chen H, et al. Isotretinoin-loaded solid lipid nanoparticles with skin targeting for topical delivery. Int J Pharm 2007; 328: 191-5.
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Shahgaldian P, Gualbert J, Aissa K, et al. A study of the freeze-drying conditions of calixarene based solid lipid nanoparticles. Eur J Pharm Biopharm 2003; 55: 181-4.
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Kim BD, Na K, Choi H. Preparation and characterization of solid lipid nanoparticles (SLN) made of cacao butter and curdlan. Eur J Pharm Sci 2005; 24(2-3): 199-205.
[36]
Cavalli R, Caputo O, Carlotti ME, et al. Sterilization and freeze-drying of drug-free and drug-loaded solid lipid nanoparticles. Int J Pharm 1997; 148: 47-54.
[37]
Pozo-Rodriguez AD, Solinis MA, Gascon AR, et al. Short- and long-term stability study of lyophilized solid lipid nanoparticles for gene therapy. Eur J Pharm Biopharm 2008; 71: 181-9.
[38]
Subedi RK, Kang KW, Choi H. Preparation and characterization of solid lipid nanoparticles loaded with doxorubicin. Eur J Pharm Sci 2009; 37(3-4): 508-13.
[39]
Pradhan M, Singh D, Murthy SN, et al. Design, characterization and skin permeating potential of fluocinoloneacetonide loaded nanostructured lipid carriers for topical treatment of psoriasis. Steroids 2015; 101: 56-63.
[40]
Chakraborty S, Shukla D, Mishra B, et al. Lipid-an emerging platform for oral delivery of drugs with poor bioavailability. Eur J Pharm Biopharm 2009; 73: 1-15.
[41]
Nanjwade K, Patel DJ, Udhani RA, et al. Functions of lipids for enhancement of oral bioavailability of poorly water-soluble drugs. Pharm Sci 2011; 79: 705-27.
[42]
Porter J, Trevaskis NL, Charman WN. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat Rev Drug Discov 2007; 6: 231-48.
[43]
Tayrouz Y, Ding R, Burhenne J, et al. Pharmacokinetic and pharmaceutic interaction between digoxin and Cremophor RH40. Clin Pharmacol Ther 2003; 73: 397-405.
[44]
Zhao Y, Wang C, Chow AH, et al. Self-nanoemulsi-fying drug delivery system (SNEDDS) for oral delivery of Zedoary essential oil: formulation and bioavai-lability studies. Int J Pharm 2010; 383(1-2): 170-7.
[45]
Rahman M, Laurent S, Tawil N, Yahia L, Mahmoudi M. Protein-nanoparticle interactions. Berlin, Germany: Springer 2013.
[46]
Westesen K, Bunjes H. Do nanoparticles prepared from lipids solid at room temperature always possess a solid lipid matrix? Int J Pharm 1995; 115: 129-31.
[47]
Westesen K, Siekmann B, Koch MHJ. Investigations on the physical state of lipid nanoparticles by synchrotron radiation X-ray diffraction. Int J Pharm 1993; 93: 189-99.
[1]
Das S, Lin HS, Ho PC, et al. The impact of aqueous solubility and dose on the pharmacokinetic profiles of resveratrol. Pharm Res 2008; 25: 2593-600.
[2]
Mehnert W, Mader K. Solid lipid nanoparticles: production, characterization and applications. Adv Drug Deliv Rev 2001; 47: 165-96.
[3]
Utreja P, Jain S, Tiwary AK. Novel drug delivery systems for sustained and targeted delivery of anti-cancer drugs: current status and future prospects. Curr Drug Deliv 2010; 7(2): 152-61.
[4]
Ravi Kumar MN. Nano and microparticles as controlled drug delivery devices. J Pharm Sci 2000; 3: 234-58.
[5]
Muller RH, Maassen S, Weyhers H, et al. Phagocytic uptake and cytotoxicity of solid lipid nanoparticles (SLN) sterically stabilized with poloxamine 908 and poloxamer 407. J Drug Target 1996; 4: 161-70.
[6]
Yuan H, Huang LF, Du YZ, et al. Solid lipid nanoparticles prepared by solvent diffusion method in a nanoreactor system. Colloids Surf B Biointerfaces 2008; 61: 132-7.
[7]
Xie S, Zhu L, Dong Z, et al. Preparation, characteri-zation and pharmacokinetics of enrofloxacin-loaded solid lipid nanoparticles: influences of fatty acids. Colloids Surf B Biointerfaces 2011; 83: 382-7.
[8]
Pouton CW. Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci 2006; 29: 278-87.
[9]
Holm R, Mullertz A, Christensen E, et al. Comparison of total oral bioavailability and the lymphatic transport of halofantrine from three different unsaturated triglycerides in lymph-cannulated conscious rats. Eur J Pharm Sci 2001; 14: 331-7.
[10]
Venkateswarlu V, Manjunath K. Preparation, characterization and in vitro release kinetics of clozapine solid lipid nanoparticles. J Control Release 2004; 95: 627-38.
[11]
Muller RH, Runge S, Ravelli V, et al. Oral bioavailability of cyclosporine: solid lipid nanoparticles (SLN) versus drug nanocrystals. Int J Pharm 2006; 317: 82-9.
[12]
Li H, Zhao X, Ma Y, et al. Enhancement of gastrointestinal absorption of quercetin by solid lipid nanoparticles. J Cont Release 2009; 133: 238-44.
[13]
Muller RH, Mader K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery-a review of the state of the art. Eur J Pharm Biopharm 2000; 50: 161-77.
[14]
Schwarz C, Mehnert W. Freeze-drying of drug-free and drug-loaded solid lipid nanoparticles (SLN). Int J Pharm 1997; 157: 171-9.
[15]
Yuan H, Chen J, Du YZ, et al. Studies on oral absorption of stearic acid SLN by a novel fluorometric method. Colloids Surf B Biointerfaces 2007; 58: 157-64.
[16]
Holm R, Porter CJH, Mullertz A, et al. Structured triglyceride vehicles for oral delivery of halofantrine: examination of intestinal lymphatic transport and bioavailability in conscious rats. Pharm Res 2002; 19: 1354-61.
[17]
Chen CC, Tsai TH, Huang ZR. Effects of lipophilic emulsifiers on the oral administration of lovastatin from nanostructured lipid carriers: physicochemical characterization and pharmacokinetics. Eur J Pharm Biopharm 2010; 74: 474-82.
[18]
Gohla SH, Dingler A. Scaling up feasibility of the production of solid lipid nanoparticles (SLN). Pharmazie 2001; 56: 61-3.
[19]
Dingler S, Gohla S. Production of solid lipid nanoparticles (SLN): scaling up feasibilities. J Microencapsul 2002; 19: 11-6.
[20]
Manjunath K, Ready JS, Venkateswarlu V. Solid lipid nanoparticles as drug delivery systems. Methods Find Exp Clin Pharmacol 2005; 27: 127-44.
[21]
Kaur IP, Bhandari R, Bhandari S, et al. Potential of solid lipid nanoparticles in brain targeting. J Control Release 2008; 127: 97-109.
[22]
Rahman MA, Mujahid M, Hussain A, et al. Development and pharmacokinetic evaluation of spray-dried self-nanoemulsifying drug delivery system of sertraline. J Pharm Invest 2017; 44(4): 325-33.
[23]
Olbrich C, Muller RH. Enzymatic degradation of SLN-effect of surfactant and surfactant mixture. Int J Pharm 1999; 180: 31-9.
[24]
Das S, Ng WK, Kanaujia P, et al. 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.
[25]
Joshi M, Patravale V. Formulation and evaluation of nanostructured lipid carrier (NLC)-based gel of valdecoxib. Drug Dev Ind Pharm 2006; 32: 911-8.
[26]
Helgason T, Awad TS, Kristbergsson K, et al. Effect of surfactant surface coverage on formation of solid lipid nanoparticles (SLN). J Colloid Interface Sci 2009; 334: 75-81.
[27]
Rahman MA, Mujahid M. Development of self-nanoemulsifying tablet (SNET) for bioavailability enhancement of sertraline. Braz J Pharm Sci 2018; 54(1): 17232.
[28]
Pradhan M, Singh D, Singh MR. Influence of selected variables on fabrication of triamcinolone acetonide loaded solid lipid nanoparticles for topical treatment of dermal disorders. Artif Cells Nanomed Biotechnol 2016; 44(1): 392-400.
[29]
Hu L, Tang X, Cui F. Solid lipid nanoparticles (SLNs) to improve oral bioavailability of poorly soluble drugs. J Pharm Pharmacol 2004; 56: 1527.
[30]
Parveen R, Baboota S, Ali J, et al. Oil based nanocarrier for improved oral delivery of silymarin: in vitro and in vivo studies. Int J Pharm 2011; 413(1-2): 245-53.
[31]
Muthu MS, Rawat MK, Mishra A, et al. PLGA nanoparticle formulations of risperidone: preparation and neuropharmacological evaluation. Nanomedicine 2009; 5(3): 323-33.
[32]
Das S, Chaudhury A. Recent advances in lipid nanoparticle formulations with solid matrix for oral drug delivery. AAPS PharmSciTech 2011; 12: 62-76.
[33]
Liu J, Hu W, Chen H, et al. Isotretinoin-loaded solid lipid nanoparticles with skin targeting for topical delivery. Int J Pharm 2007; 328: 191-5.
[34]
Shahgaldian P, Gualbert J, Aissa K, et al. A study of the freeze-drying conditions of calixarene based solid lipid nanoparticles. Eur J Pharm Biopharm 2003; 55: 181-4.
[35]
Kim BD, Na K, Choi H. Preparation and characterization of solid lipid nanoparticles (SLN) made of cacao butter and curdlan. Eur J Pharm Sci 2005; 24(2-3): 199-205.
[36]
Cavalli R, Caputo O, Carlotti ME, et al. Sterilization and freeze-drying of drug-free and drug-loaded solid lipid nanoparticles. Int J Pharm 1997; 148: 47-54.
[37]
Pozo-Rodriguez AD, Solinis MA, Gascon AR, et al. Short- and long-term stability study of lyophilized solid lipid nanoparticles for gene therapy. Eur J Pharm Biopharm 2008; 71: 181-9.
[38]
Subedi RK, Kang KW, Choi H. Preparation and characterization of solid lipid nanoparticles loaded with doxorubicin. Eur J Pharm Sci 2009; 37(3-4): 508-13.
[39]
Pradhan M, Singh D, Murthy SN, et al. Design, characterization and skin permeating potential of fluocinoloneacetonide loaded nanostructured lipid carriers for topical treatment of psoriasis. Steroids 2015; 101: 56-63.
[40]
Chakraborty S, Shukla D, Mishra B, et al. Lipid-an emerging platform for oral delivery of drugs with poor bioavailability. Eur J Pharm Biopharm 2009; 73: 1-15.
[41]
Nanjwade K, Patel DJ, Udhani RA, et al. Functions of lipids for enhancement of oral bioavailability of poorly water-soluble drugs. Pharm Sci 2011; 79: 705-27.
[42]
Porter J, Trevaskis NL, Charman WN. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat Rev Drug Discov 2007; 6: 231-48.
[43]
Tayrouz Y, Ding R, Burhenne J, et al. Pharmacokinetic and pharmaceutic interaction between digoxin and Cremophor RH40. Clin Pharmacol Ther 2003; 73: 397-405.
[44]
Zhao Y, Wang C, Chow AH, et al. Self-nanoemulsi-fying drug delivery system (SNEDDS) for oral delivery of Zedoary essential oil: formulation and bioavai-lability studies. Int J Pharm 2010; 383(1-2): 170-7.
[45]
Rahman M, Laurent S, Tawil N, Yahia L, Mahmoudi M. Protein-nanoparticle interactions. Berlin, Germany: Springer 2013.
[46]
Westesen K, Bunjes H. Do nanoparticles prepared from lipids solid at room temperature always possess a solid lipid matrix? Int J Pharm 1995; 115: 129-31.
[47]
Westesen K, Siekmann B, Koch MHJ. Investigations on the physical state of lipid nanoparticles by synchrotron radiation X-ray diffraction. Int J Pharm 1993; 93: 189-99.


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Article Details

VOLUME: 7
ISSUE: 2
Year: 2019
Page: [162 - 176]
Pages: 15
DOI: 10.2174/2211738507666190327145628

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