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Enhanced Oral Absorption of Amisulpride Via a Nanostructured Lipid Carrier-Based Capsules: Development, Optimization Applying the Desirability Function Approach and In Vivo Pharmacokinetic Study

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A Correction to this article was published on 25 February 2019

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Abstract

Amisulpride (AMS), a second generation antipsychotic, suffers from low oral bioavailability (48%). This might be due to its pH-dependent solubility or being a substrate of P-glycoprotein efflux pump. Nanostructured lipid carriers (NLCs) were proposed in this study to enhance the oral absorption of AMS. AMS-NLCs were prepared by solvent evaporation technique according to (21.41.31) factorial design, whereas the type of solid lipid (tripalmitin or Gelucire® 43/1), lipid to drug ratio (7:1, 10:1, or 13:1) and type of external suspending medium (double distilled water, 0.5% TSP pH 12, 1% HPMC or 2.5% glycerin) were the independent variables. The average entrapment efficiency, particle size, polydispersity index, and zeta potential of the prepared formulations ranged from 29.01 to 69.06%, 184.9 to 708.75 nm, 0.21 to 0.59, and − 21 to − 33.55 mV, respectively. AMS-NLCs were optimized according to the desirability function to maximize the entrapment efficiency and minimize the particle size. Formulae G12, G10, and G7 with the highest desirability values of 0.915, 0.84, and 0.768, respectively, were chosen for further investigations. Novel AMS-NLCs capsules were prepared from the lyophilized formulations (TG7 and MG10) to enhance stability and increase patient compliance. The capsules were evaluated in terms of weight variation, content uniformity, and in vitro release pattern. The pharmacokinetics of AMS-NLCs capsules (formula TG7) were tested in rabbits compared to the commercial Amipride® tablets. The relative bioavailability of AMS-NLCs capsules was found to be 252.78%. In conclusion, the NLC-based capsules show potential to improve the oral bioavailability of AMS.

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Change history

  • 25 February 2019

    The second author’s name was incorrectly published as “Niha F. Younes”. The correct name is “Nihal Farid Younes” as shown above in the list of authors.

Abbreviations

AMS:

Amisulpride

ANOVA:

Analysis of variance

AUC(0-∞) :

Area under plasma concentration-time curve extrapolated to infinity

CNS:

Central nervous system

Cmax :

Peak plasma concentration

DF:

Desirability functions

DSC:

Differential scanning calorimetry

DLS:

Dynamic light scattering

DMSO:

Dimethyl sulfoxide

ESM:

External suspending medium

EE:

Entrapment efficiency

FT-IR:

Fourier-transform infrared

GIT:

Gastrointestinal tract

HPMC:

Hydroxypropyl methylcellulose

IS:

Internal standard

K :

Elimination rate constant

LC-MS/MS:

Liquid chromatography-tandem mass spectroscopy

MRM:

Multiple reaction monitoring

NLCs:

Nanostructured lipid carriers

PS:

Particle size

PDI:

Polydispersity index

TSP:

Tri-sodium ortho phosphate

TEM:

Transmission electron microscopy

T max :

Time to peak plasma concentration

XRD:

X-ray diffractometry

References

  1. Pringsheim T, Addington D. Canadian schizophrenia guidelines: introduction and guideline development process. 2017;30(2):279–93.

  2. Knapp M, Mangalore R, Simon J. The global costs of schizophrenia. p. 279–93.

  3. Komossa K, Rummel-kluge C, Hunger H, Schmid F. Europe PMC Funders Group Amisulpride versus other atypical antipsychotics for schizophrenia. 2014;1:1–106.

  4. Moffat AC, Osselton MD, Widdop B O. Clarke’s analysis of drugs and poisons. London: Pharmaceutical press; 2011.

  5. Sparshatt A, Taylor D, Patel MX, Kapur S. Amisulpride - dose, plasma concentration, occupancy and response: implications for therapeutic drug monitoring. Acta Psychiatr Scand. 2009;120:416–28.

    CAS  PubMed  Google Scholar 

  6. Musenga A, Mandrioli R, Morganti E, Fanali S, Raggi MA. Enantioselective analysis of amisulpride in pharmaceutical formulations by means of capillary electrophoresis. J Pharm Biomed Anal. 2008;46(5):966–70.

    CAS  PubMed  Google Scholar 

  7. Moons T, De Roo M, Claes S, Dom G. Relationship between P-glycoprotein and second-generation antipsychotics. Pharmacogenomics. 2011;12(8):193–211.

    Google Scholar 

  8. Abraham J. Prolonged release formulation of amisulpride. WO2010023690A2.

  9. Besse J. Gastric-retained pharmaceutical composition and method for its use. Google Patents; 2001.

  10. Chai G-H, Xu Y, Chen S-Q, Cheng B, Hu F-Q, You J, et al. Transport mechanisms of solid lipid nanoparticles across Caco-2 cell monolayers and their related cytotoxicology. ACS Appl Mater Interfaces. American Chemical Society; 2016 Mar 9;8(9):5929–40.

  11. Porter CJ, Kaukonen AM, Taillardat-Bertschinger A, Boyd BJ, O’Connor JM, Edwards GA, et al. Use of in vitro lipid digestion data to explain the in vivo performance of triglyceride-based oral lipid formulations of poorly water-soluble drugs: studies with halofantrine. J Pharm Sci. 2004;93(5):1110–21.

    CAS  PubMed  Google Scholar 

  12. Pyo S-M, Müller RH, Keck CM. 4 - Encapsulation by nanostructured lipid carriers. In: Jafari SMBT-NT for the F and NI, editor. Nanoencapsulation Technologies for the Food and Nutraceutical Industries: Academic Press; 2017. p. 114–37.

  13. Selvamuthukumar S, Velmurugan R. Nanostructured lipid carriers: a potential drug carrier for cancer chemotherapy. Lipids Health Dis BioMed Central. 2012 Nov 20;11(159):1–8.

    Google Scholar 

  14. Nieto Montesinos R, Béduneau A, Pellequer Y, Lamprecht A. Delivery of P-glycoprotein substrates using chemosensitizers and nanotechnology for selective and efficient therapeutic outcomes. J Control Release. 2012;161(1):50–61.

    CAS  PubMed  Google Scholar 

  15. Akhtar N, Ahad A, Khan MF, Allaham A, Talegaonkar S. The ameliorated pharmacokinetics of VP-16 in Wistar rats: a possible role of P-glycoprotein inhibition by pharmaceutical excipients. Eur J Drug Metab Pharmacokinet. 2017;42(2):191–9.

    CAS  PubMed  Google Scholar 

  16. Dong X, Mattingly CA, Tseng MT, Cho MJ, Liu Y, Adams VR, et al. Doxorubicin and paclitaxel-loaded lipid-based nanoparticles overcome multidrug resistance by inhibiting P-glycoprotein and depleting ATP. Cancer Res. 2009/04/21. 2009 May 1;69(9):3918–26.

  17. Aboelwafa AA, Makhlouf AIA. In vivo evaluation and application of central composite design in the optimization of amisulpride self-emulsifying drug delivery system. Am J Drug Discov Dev. 2012;2(1).

  18. Gamal W, Fahmy RH, Mohamed MI. Development of novel amisulpride-loaded liquid self-nanoemulsifying drug delivery systems via dual tackling of its solubility and intestinal permeability. Drug Dev Ind Pharm. Taylor & Francis; 2017;43(9):1530–1538.

  19. Luo Y, Teng Z, Li Y, Wang Q. Solid lipid nanoparticles for oral drug delivery: chitosan coating improves stability, controlled delivery, mucoadhesion and cellular uptake. Carbohydr Polym. 2015;122:221–9.

    CAS  PubMed  Google Scholar 

  20. Ball RL, Bajaj P, Whitehead KA. Achieving long-term stability of lipid nanoparticles: examining the effect of pH , temperature , and lyophilization. Int J Nanomedicine. 2017;12:305–15.

    CAS  PubMed  Google Scholar 

  21. Yang S, Liu C, Liu W, Yu H, Zheng H, Zhou W, et al. Preparation and characterization of nanoliposomes entrapping medium-chain fatty acids and vitamin C by lyophilization. Int J Mol Sci. Molecular Diversity Preservation International (MDPI); 2013;14(10):19763–73.

  22. Niu L, Panyam J. Freeze concentration-induced PLGA and polystyrene nanoparticle aggregation: imaging and rational design of lyoprotection. J Control Release. 2017;248:125–32.

    CAS  PubMed  Google Scholar 

  23. Mesa L, Martínez Y, Barrio E, González E. Desirability function for optimization of dilute acid pretreatment of sugarcane straw for ethanol production and preliminary economic analysis based in three fermentation configurations. Appl Energy. 2017;198:299–311.

    CAS  Google Scholar 

  24. Şimşek B, Uygunoğlu T, Korucu H, Kocakerim MM. Analysis of the effects of dioctyl terephthalate obtained from polyethylene terephthalate wastes on concrete mortar: a response surface methodology based desirability function approach application. J Clean Prod. 2018;170:437–45.

    Google Scholar 

  25. Andalib S, Varshosaz J, Hassanzadeh F, Sadeghi H. Optimization of LDL targeted nanostructured lipid carriers of 5-FU by a full factorial design. Adv Biomed Res. Medknow Publications & Media Pvt Ltd; 2012;1:45.

  26. Varshosaz J, Minayian M, Moazen E. Enhancement of oral bioavailability of pentoxifylline by solid lipid nanoparticles. J Liposome Res [Internet]. Taylor & Francis; 2010;20(2):115–23. Available from: https://doi.org/10.3109/08982100903161456.

  27. Silva AC, Kumar A, Wild W, Ferreira D, Santos D, Forbes B. Long-term stability, biocompatibility and oral delivery potential of risperidone-loaded solid lipid nanoparticles. Int J Pharm. 2012;436(1):798–805.

    CAS  PubMed  Google Scholar 

  28. Jain NK, Ram A. Development and characterization of nanostructured lipid carriers of oral hypoglycemic agent: selection of surfactants. Int J Pharm Sci Rev Res. 2011;7:125–30.

    CAS  Google Scholar 

  29. Ganesan V, Muthukumarappan K, Rosentrater KA. Effect of moisture content and soluble level on the physical, chemical, and flow properties of distillers dried grains with Solubles (DDGS). Cereal Chem. 2008;85(4):464–70.

    CAS  Google Scholar 

  30. European pharmacopoeia: Council of Europe. pth Editio. 2010.

  31. Rohrs BR, Amidon GE, Meury RH, Secreast PJ, King HM, Skoug CJ. Particle size limits to meet USP content uniformity criteria for tablets and capsules. J Pharm Sci [Internet]. John Wiley & Sons, Ltd; 2006;95(5):1049–59. Available from: https://doi.org/10.1002/jps.20587.

  32. Saffari M, Ebrahimi A, Langrish T. European Journal of Pharmaceutical Sciences A novel formulation for solubility and content uniformity enhancement of poorly water-soluble drugs using highly-porous mannitol. PHASCI [Internet]. Elsevier B.V.; 2016;83:52–61. Available from: https://doi.org/10.1016/j.ejps.2015.12.016

  33. Palaparthy R, Banfield C, Alvarez P, Yan L, Smith B, Johnson J. Relative bioavailability, food effect, and safety of the single-dose pharmacokinetics of omecamtiv mecarbil following administration of different modified-release formulations in healthy subjects. Int J Clin Pharmacol Ther. 2016

  34. Pouton CW, Porter CJH. Formulation of lipid-based delivery systems for oral administration: materials , methods and strategies. 2008;60:625–37.

  35. Youshia J, Kamel AO, El Shamy A, Mansour S. Design of cationic nanostructured heterolipid matrices for ocular delivery of methazolamide. Int J Nanomedicine. 2012/05/17. Dove Medical Press; 2012;7:2483–96.

  36. Tsai M-J, Wu P-C, Huang Y-B, Chang J-S, Lin C-L, Tsai Y-H, et al. Baicalein loaded in tocol nanostructured lipid carriers (tocol NLCs) for enhanced stability and brain targeting. Int J Pharm. 2012;423(2):461–70.

    CAS  PubMed  Google Scholar 

  37. Urbán-Morlán Z, Ganem-Rondero A, Melgoza-Contreras LM, Escobar-Chávez JJ, Nava-Arzaluz MG, Quintanar-Guerrero D. Preparation and characterization of solid lipid nanoparticles containing cyclosporine by the emulsification-diffusion method. Int J Nanomedicine. 2010;5:611–20.

    PubMed  PubMed Central  Google Scholar 

  38. Hao J, Fang X, Zhou Y, Wang J, Guo F, Li F, et al. Development and optimization of solid lipid nanoparticle formulation for ophthalmic delivery of chloramphenicol using a Box-Behnken design. Int J Nanomedicine. 2011/04/06. Dove Medical Press; 2011;6:683–92.

  39. Jana U, Mohanty AK, Pal SLAL, Manna PK, Mohanta GP. Preparation and in vitro characterization of felodipine loaded Eudragit ® RS100 nanoparticles. Int J Pharm Pharm Sci. 2014;6(4):4–7.

    Google Scholar 

  40. Development of surfactant free nanoparticles by a single emulsion high pressure homogenization technique and effect of formulation parameters on the drug entrapment and release. Int J Pharm. 2013;3(4):843–52.

  41. Murshed SMS, Estellé P. A state of the art review on viscosity of nanofluids. Renew Sust Energ Rev. 2017;76:1134–52.

    CAS  Google Scholar 

  42. Yehia SA, Elshafeey AH, Elsayed I. Biodegradable donepezil lipospheres for depot injection: optimization and in-vivo evaluation. J Pharm Pharmacol. Wiley/Blackwell (10.1111); 2012 May 2;64(10):1425–37.

  43. Masarudin MJ, Cutts SM, Evison BJ, Phillips DR, Pigram PJ. Factors determining the stability, size distribution, and cellular accumulation of small, monodisperse chitosan nanoparticles as candidate vectors for anticancer drug delivery: application to the passive encapsulation of [(14)C]-doxorubicin. Nanotechnol Sci Appl. Dove Medical Press; 2015;8:67–80.

  44. Yang C-R, Zhao X-L, Hu H-Y, Li K-X, Sun X, Li L, et al. Preparation, optimization and characteristic of huperzine a loaded nanostructured lipid carriers. Chem Pharm Bull. 2010;58(5):656–61.

    CAS  PubMed  Google Scholar 

  45. Chen C-C, Tsai T-H, Huang Z-R, Fang J-Y. Effects of lipophilic emulsifiers on the oral administration of lovastatin from nanostructured lipid carriers: physicochemical characterization and pharmacokinetics. Eur J Pharm Biopharm. 2010;74(3):474–82.

    CAS  PubMed  Google Scholar 

  46. Wehrung D, Geldenhuys WJ, Oyewumi MO. Effects of gelucire content on stability, macrophage interaction and blood circulation of nanoparticles engineered from nanoemulsions. Colloids Surfaces B Biointerfaces. Elsevier B.V.; 2012;94:259–65.

  47. Elmowafy M, Ibrahim HM, Ahmed MA, Shalaby K, Salama A, Hefesha H. Atorvastatin-loaded nanostructured lipid carriers (NLCs): strategy to overcome oral delivery drawbacks. Drug Deliv. 2017;24(1):932–41.

    CAS  PubMed  Google Scholar 

  48. Date AA, Vador N, Jagtap A, Nagarsenker MS. Lipid nanocarriers (GeluPearl) containing amphiphilic lipid Gelucire 50/13 as a novel stabilizer: fabrication, characterization and evaluation for oral drug delivery. Nanotechnology. 2011;22(27):275102.

    PubMed  Google Scholar 

  49. Fatouh AM, Elshafeey AH, Abdelbary A. Intranasal agomelatine solid lipid nanoparticles to enhance brain delivery: formulation, optimization and in vivo pharmacokinetics. Drug Des Devel Ther. 2017;11:1815–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Date AA, Vador N, Jagtap A, Nagarsenker MS. Lipid nanocarriers (GeluPearl) containing amphiphilic lipid Gelucire 50/13 as a novel stabilizer: fabrication, characterization and evaluation for oral drug delivery. Nanotechnology. 2011;22(27).

  51. Das S, Ng WK, Tan RBH. Are nanostructured lipid carriers (NLCs) better than solid lipid nanoparticles (SLNs): development, characterizations and comparative evaluations of clotrimazole-loaded SLNs and NLCs? Eur J Pharm Sci. 2012;47(1):139–51.

    CAS  PubMed  Google Scholar 

  52. Shamma RN, Elsayed I. Transfersomal lyophilized gel of buspirone HCl: formulation, evaluation and statistical optimization. J Liposome Res Taylor & Francis. 2013;23(3):244–54.

    CAS  Google Scholar 

  53. Govender T, Stolnik S, Garnett MC, Illum L, Davis SS. PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug. J Control Release. 1999;57(2):171–85.

    CAS  PubMed  Google Scholar 

  54. Kovačević AB, Müller RH, Savić SD, Vuleta GM, Keck CM. Solid lipid nanoparticles (SLN) stabilized with polyhydroxy surfactants: preparation, characterization and physical stability investigation. Colloids Surfaces A Physicochem Eng Asp. 2014;444:15–25.

    Google Scholar 

  55. Chen C, Han D, Cai C, Tang X. An overview of liposome lyophilization and its future potential. J Control Release. 2010;142(3):299–311.

    CAS  PubMed  Google Scholar 

  56. Thorat AA, Dalvi SV. Liquid antisolvent precipitation and stabilization of nanoparticles of poorly water soluble drugs in aqueous suspensions: recent developments and future perspective. Chem Eng J. 2012;181–182:1–34.

    Google Scholar 

  57. Singh G, Pai RS, VKD. Optimization of pellets containing solid dispersion prepared by extrusion/spheronization using central composite design and desirability function. J Young Pharm. 2012;4(3):146–56.

    PubMed  PubMed Central  Google Scholar 

  58. Shahgaldian P, Gualbert J, Aïssa K, Coleman AW. A study of the freeze-drying conditions of calixarene based solid lipid nanoparticles. Eur J Pharm Biopharm 2003;55(2):181–184.

  59. Abdelbary G, Makhlouf A. Adoption of polymeric micelles to enhance the oral bioavailability of dexibuprofen: formulation, in-vitro evaluation and in-vivo pharmacokinetic study in healthy human volunteers. Pharm Dev Technol. 2014;19(6).

  60. El-Mahrouk GM, Aboul-Einien MH, Makhlouf AI. Design, optimization, and evaluation of a novel metronidazole-loaded gastro-retentive pH-sensitive hydrogel. AAPS PharmSciTech. 2016;17(6):1285–97.

    CAS  PubMed  Google Scholar 

  61. Nabi-Meibodi M, Vatanara A, Najafabadi AR, Rouini MR, Ramezani V, Gilani K, et al. The effective encapsulation of a hydrophobic lipid-insoluble drug in solid lipid nanoparticles using a modified double emulsion solvent evaporation method. Colloids Surfaces B Biointerfaces. 2013;112:408–14.

    CAS  PubMed  Google Scholar 

  62. Abdelbary G, Fahmy RH. Diazepam-loaded solid lipid nanoparticles: design and characterization. AAPS PharmSciTech Springer US. 2009;10(1):211–9.

    CAS  Google Scholar 

  63. Patil-Gadhe A, Pokharkar V. Montelukast-loaded nanostructured lipid carriers: part I Oral bioavailability improvement. Eur J Pharm Biopharm. 2014;88(1):160–8.

    CAS  PubMed  Google Scholar 

  64. Negi JS, Singh S. Spectroscopic investigation on the inclusion complex formation between amisulpride and γ-cyclodextrin. Carbohydr Polym. 2013;92(2):1835–43.

    CAS  PubMed  Google Scholar 

  65. Kushwaha AK, Vuddanda PR, Karunanidhi P, Singh SK, Singh S. Development and evaluation of solid lipid nanoparticles of raloxifene hydrochloride for enhanced bioavailability. 2013;2013:1–9.

  66. Cavatur RK, Vemuri NM, Pyne A, Chrzan Z, Toledo-Velasquez D, Suryanarayanan R. Crystallization behavior of mannitol in frozen aqueous solutions. Pharm Res. 2002;19(6):894–900.

    CAS  PubMed  Google Scholar 

  67. Motwani SK, Chopra S, Talegaonkar S, Kohli K, Ahmad FJ, Khar RK. Chitosan–sodium alginate nanoparticles as submicroscopic reservoirs for ocular delivery: formulation, optimisation and in vitro characterisation. Eur J Pharm Biopharm. 2008;68(3):513–25.

    CAS  PubMed  Google Scholar 

  68. Trivedi P, Verma AML, Garud N. Preparation and characterization of aceclofenac microspheres. Asian J Pharm. 2008;(April):110–5.

  69. Chronopoulou L, Massimi M, Giardi MF, Cametti C, Devirgiliis LC, Dentini M, et al. Chitosan-coated PLGA nanoparticles: a sustained drug release strategy for cell cultures. Colloids Surfaces B Biointerfaces. 2013;103:310–7.

    CAS  PubMed  Google Scholar 

  70. Rajan M, Raj V. Encapsulation, characterisation and in-vitro release of anti-tuberculosis drug using chitosan – poly ethylene glycol nanoparticles. Int J Pharm Pharm Sci. 2012;4(4):255–9.

    CAS  Google Scholar 

  71. Olivares-Morales A, Kamiyama Y, Darwich AS, Aarons L, Rostami-Hodjegan A. Analysis of the impact of controlled release formulations on oral drug absorption, gut wall metabolism and relative bioavailability of CYP3A substrates using a physiologically-based pharmacokinetic model. Eur J Pharm Sci. 2015;67:32–44.

    CAS  PubMed  Google Scholar 

  72. Zhang H, Yao M, Morrison RA, Chong S. Commonly used surfactant, Tween 80, improves absorption of P-glycoprotein substrate, digoxin, in rats. Arch Pharm Res 2003;26(9):768–772.

  73. Lo Y-L, Huang J-D. Effects of sodium deoxycholate and sodium caprate on the transport of epirubicin in human intestinal epithelial Caco-2 cell layers and everted gut sacs of rats. Biochem Pharmacol. 2000;59(6):665–72.

    CAS  PubMed  Google Scholar 

  74. Dhumal RS, Biradar SV, Aher S, Paradkar AR. Cefuroxime axetil solid dispersion with polyglycolized glycerides for improved stability and bioavailability. J Pharm Pharmacol. 2009;61(6):743–51.

    CAS  PubMed  Google Scholar 

  75. Shimpi SL, Chauhan B, Mahadik KR, Paradkar A. Stabilization and improved in vivo performance of amorphous etoricoxib using Gelucire 50/13. Pharm Res. 2005;22(10):1727–34.

    CAS  PubMed  Google Scholar 

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  1. Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El Aini, Cairo, 12411, Egypt

    Abd El-Halim I. El Assasy, Niha F. Younes & Amal I. A. Makhlouf

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  3. Amal I. A. Makhlouf
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Correspondence to Amal I. A. Makhlouf.

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The study protocol was approved by the institutional review board; Research Ethics Committee-Faculty of Pharmacy, Cairo University (REC-FOPCU), Egypt, Serial No. (PI 1308).

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El Assasy, A.EH.I., Younes, N.F. & Makhlouf, A.I.A. Enhanced Oral Absorption of Amisulpride Via a Nanostructured Lipid Carrier-Based Capsules: Development, Optimization Applying the Desirability Function Approach and In Vivo Pharmacokinetic Study. AAPS PharmSciTech 20, 82 (2019). https://doi.org/10.1208/s12249-018-1283-x

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