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Multiple Lipid Nanoparticles (MLN), a New Generation of Lipid Nanoparticles for Drug Delivery Systems: Lamivudine-MLN Experimental Design

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Abstract

Purpose

An optimized methodology for the development of a new generation of lipid nanoparticles, the multiple lipid nanoparticles (MLN) is described. MLN have characteristics between nanostructured lipid carriers (NLC) and multiple emulsions (W/O/W), but without the outer aqueous phase.

Methods

The production is based on a hot homogenization method combined with high shear and ultrasonication. The antiretroviral agent lamivudine (3TC), was loaded in the MLN. For comparison purposes, NLC-3TC formulation was also developed and physico-chemically characterized by the same parameters as MLN-3TC. The development and optimization of MLN and NLC formulations were supported by a Quality by Design (QbD) approach.

Results

The MLN-3TC formulation exhibited a size of about 450 nm, polydispersity <0.3 and negative zeta potential > −20 mV. Furthermore, the morphology assessed by TEM showed a structure with multiples aqueous vacuoles. MLN-3TC was physically stable for at least 45 days, had low cytotoxicity and drug release studies showed a sustained and controlled release of 3TC under gastric and plasma-simulated conditions (at pH 7.4 for about 45 h).

Conclusions

The optimized formulations present suitable profiles for oral administration. Overall, the results reveal that MLN present higher loading capacity and storage stability than NLC.

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Abbreviations

3TC:

Lamivudine

ANOVA:

Analysis of variance

AP:

Aqueous phase

BCS:

Biopharmaceutical classification system

DLS:

Dynamic light scattering

DMSO:

Dimethyl sulfoxide

DOE:

Design of experiments

EE:

Entrapment efficiency

EPC:

Egg phosphatidylcholine

FBS:

Fetal bovine serum

FMEA:

Failure modes and effects analysis

HIV:

Human immunodeficiency virus

HLB:

Hydrophilic-lipophilic balance

IC50 :

Half maximal inhibitory concentration

LC:

Loading capacity

LL:

Liquid lipid

LNP:

Lipid nanoparticles

MLN:

Multiple lipid nanoparticles

MLP:

Multiple lipid particles

MTT:

Methylthiazoletetrazolium

NLC:

Nanostructured lipid carriers

NPs:

Nanoparticles

NRTI:

Reverse transcriptase inhibitors

PDI:

Polydispersity index

QbD:

Quality by design

RS:

Response surface

RT:

Room temperature

SL:

Solid lipid

SLN:

Solid lipid nanoparticles

TEM:

Transmission electron microscopy

W/O/W:

Water/oil/water

Zeta:

Zeta potential

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Acknowledgments and Disclosures

Cavalcanti and Soares-Sobrinho thank the Facepe (1316–4.03/12) and CNPq (482,954/2013–2) for financial support. Lima thanks Operação NORTE-01-0145-FEDER-000011. Nunes thanks FCT for her Investigator grant (IF/00293/2015). The authors are also grateful to Dr. Rui Fernandes (Histology and Electron Microscopy Service – Instituto de Biologia Molecular e Celular [HEMS-I3S], University of Porto). This work received financial support from the European Union (FEDER funds) and National Funds (FCT/MEC, Fundação para a Ciência e Tecnologia and Ministério da Educação e Ciência) under the Partnership Agreement PT2020 UID/MULTI/04378/2013.

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Authors and Affiliations

  1. UCIBIO/REQUIMTE, Department of Chemistry, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal

    Suellen M. T. Cavalcanti, Cláudia Nunes, Sofia A. C. Lima & Salette Reis

  2. Core of Medicine and Corelated Quality Control – NCQMC Department of Pharmaceutical Sciences,, Federal University of Pernambuco, Rua Arthur de Sá, s/n, Cidade Universitária, Recife, PE, 50740-521, Brazil

    Suellen M. T. Cavalcanti & José L. Soares-Sobrinho

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  1. Suellen M. T. Cavalcanti
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  2. Cláudia Nunes
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  3. Sofia A. C. Lima
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Correspondence to Cláudia Nunes.

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Cavalcanti, S.M.T., Nunes, C., Lima, S.A.C. et al. Multiple Lipid Nanoparticles (MLN), a New Generation of Lipid Nanoparticles for Drug Delivery Systems: Lamivudine-MLN Experimental Design. Pharm Res 34, 1204–1216 (2017). https://doi.org/10.1007/s11095-017-2136-0

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  • DOI: https://doi.org/10.1007/s11095-017-2136-0

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