Quality by Design approach for development and characterization of gabapentin-loaded solid lipid nanoparticles for intranasal delivery: In vitro, ex vivo, and histopathological evaluation

Document Type : Original Article


1 Department of Pharmaceutical Technology, Dicle University, Diyarbakır, Turkey

2 Department of Histology and Embryology, Dicle University, Diyarbakır, Turkey

3 Department of Pharmaceutical Technology, Ege University, İzmir, Turkey


Objective(s): ”Quality by Design” (QbD) is a novel approach to product development that involves understanding the product and process, as well as the relationship between critical quality attributes (CQA) and critical process parameters (CPP). This study aimed to optimize the gabapentin-loaded solid lipid nanoparticle formulation (GP-SLN) using a QbD approach and evaluate in vitro and ex vivo performance.
Materials and Methods: The GP-SLN formulation was created using the microemulsion method by combining Gelucire 48/16, Tween 80, and Plurol Oleique CC 497. The Box-Behnken experimental design was adopted to investigate the effects of independent factors on dependent factors. The GP-SLN formulation was assessed based on particle size and distribution, zeta potential, morphology, entrapment efficiency, release kinetics, permeation parameters, stability, and nasal toxicity.
Results: The nanoparticles had a cubical shape with a particle size of 185.3±45.6 nm, a zeta potential of -24±3.53 mV, and an entrapment efficiency of 82.57±4.02%. The particle size and zeta potential of the GP-SLNs remained consistent for 3 months and followed Weibull kinetics with a significantly higher ex vivo permeability (1.7 fold) than a gabapentin solution (GP-SOL). Histopathology studies showed that intranasal administration of the GP-SLN formulation had no harmful effects.
Conclusion: The current study reports the successful development of a GP-SLN formulation using QbD. A sustained release of GP was achieved and its nasal permeability was increased. Solid lipid nanoparticles with optimum particle size and high entrapment efficiency may offer a promising approach for the intranasal delivery of drugs.


Main Subjects

1. Thurman DJ, Beghi E, Begley CE, Berg AT, Buchhalter JR, Ding D, et al. Standards for epidemiologic studies and surveillance of epilepsy. Epilepsia 2011; 52:2-26.
2. Cameron A, Bansal A, Dua T, Hill SR, Moshe SL, Mantel-Teeuwisse AK, et al. Mapping the availability, price, and affordability of antiepileptic drugs in 46 countries. Epilepsia 2012; 53:962-969.
3. Duncan JS, Sander JW, Sisodiya SM, Walker MC. Adult epilepsy. Lancet 2006; 367:1087-1100.
4. Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, et al. Epileptic seizures and epilepsy: Definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 2005; 46:470-472.
5. Meyer AC, Dua T, Ma J, Saxena S, Birbeck G. Global disparities in the epilepsy treatment gap: A systematic review. Bull World Health Organ 2010; 88:260-266.
6. Gidal BE, DeCerce J, Bockbrader HN, Gonzalez J, Kruger S, Pitterle ME, et al. Gabapentin bioavailability: Effect of dose and frequency of administration in adult patients with epilepsy. Epilepsy Res 1998; 31:91-99.
7. Goa KL, Sorkin EM. Gabapentin. A review of its pharmacological properties and clinical potential in epilepsy. Drugs 1993; 46:409-427.
8. Dhuria SV, Hanson LR, Frey WH, 2nd. Intranasal delivery to the central nervous system: Mechanisms and experimental considerations. J Pharm Sci 2010; 99:1654-1673.
9. Gangurde PK, Ajitkumar BN, Kumar L. Lamotrigine Lipid Nanoparticles for Effective Treatment of Epilepsy: A Focus on Brain Targeting via Nasal Route. J Pharm Innov 2019; 14:91-111.
10. Crowe TP, Greenlee MHW, Kanthasamy AG, Hsu WH. Mechanism of intranasal drug delivery directly to the brain. Life Sci 2018; 195:44-52.
11. de Mendoza AE-H, Préat V, Mollinedo F, Blanco-Prieto MJ. In vitro and in vivo efficacy of edelfosine-loaded lipid nanoparticles against glioma. J Control Release 2011; 156:421-426.
12. Teaima MH, El-Nadi MT, Hamed RR, El-Nabarawi MA, Abdelmonem R. Lyophilized nasal ınserts of atomoxetine HCl solid lipid nanoparticles for brain targeting as a treatment of attention-deficit/hyperactivity disorder (ADHD): A pharmacokinetics study on rats. Pharmaceuticals (Basel) 2023; 16:326-354.
13. Khan A, Imam SS, Aqil M, Ahad A, Sultana Y, Ali A, et al. Brain targeting of temozolomide via the ıntranasal route using lipid-based nanoparticles: Brain pharmacokinetic and scintigraphic analyses. Mol Pharm 2016; 13:3773-3782.
14. Patel S, Chavhan S, Soni H, Babbar AK, Mathur R, Mishra AK, et al. Brain targeting of risperidone-loaded solid lipid nanoparticles by intranasal route. J Drug Target 2011; 19:468-474.
15. Battaglia L, Panciani PP, Muntoni E, Capucchio MT, Biasibetti E, De Bonis P, et al. Lipid nanoparticles for intranasal administration: Application to nose-to-brain delivery. Expert Opin Drug Deliv 2018; 15:369-378.
16. Correia AC, Moreira JN, Sousa Lobo JM, Silva AC. Design of experiment (DoE) as a quality by design (QbD) tool to optimise formulations of lipid nanoparticles for nose-to-brain drug delivery. Expert Opin Drug Deliv 2023;20:1731-1748.
17. Tapeinos C, Battaglini M, Ciofani G. Advances in the design of solid lipid nanoparticles and nanostructured lipid carriers for targeting brain diseases. J Control Release 2017; 264:306-332.
18. Cunha S, Costa CP, Moreira JN, Sousa Lobo JM, Silva AC. Using the quality by design (QbD) approach to optimize formulations of lipid nanoparticles and nanoemulsions: A review. Nanomedicine 2020; 28:102206.
19. Bastogne T. Quality-by-design of nanopharmaceuticals - a state of the art. Nanomedicine 2017; 13:2151-2157.
20. Yasir M, Chauhan I, Zafar A, Verma M, Noorulla KM, Tura AJ, et al. Buspirone loaded solid lipid nanoparticles for amplification of nose to brain efficacy: Formulation development, optimization by Box-Behnken design, characterization and biological evaluation. J Drug Deliv Sci Technol 2021; 61:102164.
21. Kamathe S, Patil P, Muchandi C. Solıd lıpıd nanopartıcles of gabapentın for partıal seızures. Indian Drugs 2023; 60:42.
22. Kumar S, Xu X, Gokhale R, Burgess DJ. Formulation parameters of crystalline nanosuspensions on spray drying processing: A DoE approach. Int J Pharm 2014; 464:34-45.
23. Panigrahi KC, Patra CN, Jena GK, Ghose D, Jena J, Panda SK, et al. Gelucire: A versatile polymer for modified release drug delivery system. Future J Pharm Sci 2018; 4:102-108.
24. Sistla R, Shastri N. Modulating drug release profiles by lipid semi solid matrix formulations for BCS class II drug--an in vitro and an in vivo study. Drug Deliv 2014; 22:418-426.
25. Russo S, Torrisi C, Cardullo N, Muccilli V, La Mantia A, Castelli F, et al. Ethyl protocatechuate encapsulation in solid lipid nanoparticles: Assessment of pharmacotechnical parameters and preliminary ın vitro evaluation for colorectal cancer treatment. Pharmaceutics 2023; 15:394-406.
26. Shah B, Khunt D, Bhatt H, Misra M, Padh H. Application of quality by design approach for intranasal delivery of rivastigmine loaded solid lipid nanoparticles: Effect on formulation and characterization parameters. Eur J Pharm Sci 2015; 78:54-66.
27. Abdulaal WH, Hosny KM, Alhakamy NA, Bakhaidar RB, Almuhanna Y, Sabei FY, et al. Fabrication, assessment, and optimization of alendronate sodium nanoemulsion-based injectable in-situ gel formulation for management of osteoporosis. Drug Deliv 2023; 30:2164094-2164102.
28. Piao HM, Balakrishnan P, Cho HJ, Kim H, Kim YS, Chung SJ, et al. Preparation and evaluation of fexofenadine microemulsions for intranasal delivery. Int J Pharm 2010; 395:309-316.
29. Gupta A, Ciavarella AB, Sayeed VA, Khan MA, Faustino PJ. Development and application of a validated HPLC method for the analysis of dissolution samples of gabapentin drug products. J Pharm Biomed Anal 2008; 46:181-186.
30. Salama AH, Salama AAA, Elhabak M. Single step nanospray drying preparation technique of gabapentin-loaded nanoparticles-mediated brain delivery for effective treatment of PTZ-induced seizures. Int J Pharm 2021; 602:120604.
31. Castile J, Cheng YH, Simmons B, Perelman M, Smith A, Watts P. Development of in vitro models to demonstrate the ability of PecSys(R), an in situ nasal gelling technology, to reduce nasal run-off and drip. Drug Dev Ind Pharm 2013; 39:816-824.
32. Li X, Du L, Chen X, Ge P, Wang Y, Fu Y, et al. Nasal delivery of analgesic ketorolac tromethamine thermo- and ion-sensitive in situ hydrogels. Int J Pharm 2015; 489:252-260.
33. Morel S, Ugazio E, Cavalli R, Gasco MR. Thymopentin in solid lipid nanoparticles. Int J Pharm 1996; 132:259-261.
34. Gasco MR. Method for producing solid lipid microspheres having a narrow size distribution. Google Patents; 1993.
35. Hsu CH, Lin SY. Rapid examination of the kinetic process of intramolecular lactamization of gabapentin using DSC-FTIR. Thermochimica Acta 2009; 486:5-10.
36. Gamal A, Saeed H, El-Ela FIA, Salem HF. Improving the antitumor activity and bioavailability of sonidegib for the treatment of skin cancer. Pharmaceutics 2021; 13:1560-1575.
37. Rana SS, Bhatt S, Kumar M, Malik A, Sharma JB, Arora D, et al. Design and optimization of itraconazole loaded SLN for intranasal administration using central composite design. Nanosci Nanotechnol Asia 2020; 10:884-891.
38. Mallick A, Gupta A, Hussain A, Aparajay P, Singh S, Singh SK, et al. Intranasal delivery of gabapentin loaded optimized nanoemulsion for augmented permeation. J Drug Deliv Sci  Technol 2020; 56:101606.
39. Rimawi IB, Muqedi RH, Kanaze FI. Development of gabapentin expandable gastroretentive controlled drug delivery system. Sci Rep 2019; 9:11675-11686.
40. Swetha GA, Sachin HP, Choudhuri JR. Performance of an anticonvulsant drug, expired gabapentin, on zinc corrosion in an acidic environment. Emergent Mater 2023;6:721-740.
41. Alshawwa SZ, El-Masry TA, Elekhnawy E, Alotaibi HF, Sallam AS, Abdelkader DH. Fabrication of celecoxib PVP microparticles stabilized by gelucire 48/16 via electrospraying for enhanced anti-ınflammatory action. Pharmaceuticals (Basel) 2023; 16:258-275.
42. Agrawal M, Saraf S, Saraf S, Dubey SK, Puri A, Patel RJ, et al. Recent strategies and advances in the fabrication of nano lipid carriers and their application towards brain targeting. J Control Release 2020; 321:372-415.
43. Khan AR, Yang X, Fu M, Zhai G. Recent progress of drug nanoformulations targeting to brain. J Control Release 2018; 291:37-64.
44. Fukuda IM, Pinto CFF, Moreira CD, Saviano AM, Lourenço FR. Design of experiments (DoE) applied to pharmaceutical and analytical quality by design (QbD). Braz J Pharm Sci 2018; 54:1-15.
45. Rosa A, Nieddu M, Pitzanti G, Pireddu R, Lai F, Cardia MC. Impact of solid lipid nanoparticles on 3T3 fibroblasts viability and lipid profile: The effect of curcumin and resveratrol loading. J Appl Toxicol 2023; 43:272-286.
46. Bunjes H, Koch MH, Westesen K. Influence of emulsifiers on the crystallization of solid lipid nanoparticles. J Pharm Sci 2003; 92:1509-1520.
47. Duan Y, Dhar A, Patel C, Khimani M, Neogi S, Sharma P, et al. A brief review on solid lipid nanoparticles: part and parcel of contemporary drug delivery systems. RSC Adv 2020; 10:26777-26791.
48. Lai SK, Wang YY, Hanes J. Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues. Adv Drug Deliv Rev 2009; 61:158-171.
49. Wang Q, Gong T, Sun X, Zhang Z. Structural characterization of novel phospholipid lipid nanoparticles for controlled drug delivery. Colloids Surf B Biointerfaces 2011; 84:406-412.
50. Mirchandani Y, Patravale VB, S B. Solid lipid nanoparticles for hydrophilic drugs. J Control Release 2021; 335:457-464.
51. Öztürk AA, Aygül A, Şenel B. Influence of glyceryl behenate, tripalmitin and stearic acid on the properties of clarithromycin incorporated solid lipid nanoparticles (SLNs): Formulation, characterization, antibacterial activity and cytotoxicity. J Drug Deliv Sci Technol 2019; 54:101240.
52. Chen DB, Yang TZ, Lu WL, Zhang Q. In vitro and in vivo study of two types of long-circulating solid lipid nanoparticles containing paclitaxel. Chem Pharm Bull (Tokyo) 2001; 49:1444-1447.
53. Pardeshi CV, Belgamwar VS. Direct nose to brain drug delivery via integrated nerve pathways bypassing the blood-brain barrier: An excellent platform for brain targeting. Expert Opin Drug Deliv 2013; 10:957-972.