Screening of Lipid Carriers and Characterization of Drug-Polymer-Lipid Interactions for the Rational Design of Polymer-Lipid Hybrid Nanoparticles (PLN)
- 721 Downloads
The thermodynamics and solid state properties of components and their interactions in a formulation for polymer-lipid hybrid nanoparticles (PLN) were characterized for screening lead lipid carriers and rational design of PLN.
Verapamil HCl (VRP) was chosen as a model drug and dextran sulfate sodium (DS) as a counter-ionic polymer. Solubility parameters of VRP, VRP-DS complex, and various lipids were calculated and partition of VRP and VRP-DS in lipids was determined. Thermodynamics of VRP binding to DS was determined by isothermal titration calorimetry (ITC). The solid state properties of individual components and their interactions were characterized using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD).
Dodecanoic acid (DA) was identified as the best lipid carrier among all lipids tested based on the solubility parameters and partition coefficients. VRP-DS complexation was a thermodynamically favorable process. Maximum binding capacity of DS and the highest drug loading capacity of DA were obtained at an equal ionic molar ratio of DS to VRP. In the PLN formulation, DA remained its crystal structure but had a slightly lower melting point, while VRP-DS complex was in an amorphous form.
Drug loading efficiency and capacity of a lipid matrix depend on the VRP-DS binding and the interactions of the complex with the lipid. A combined analysis of solubility parameters and partition coefficients is useful for screening lipid candidates for PLN preparation.
Key wordsdrug-polymer complex isothermal titration calorimetry partition coefficient polymer-lipid hybrid nanoparticles (PLN) solid lipid nanoparticles solubility parameters
distilled and deionized
dextran sulfate sodium salt
differential scanning calorimetry
isothermal titration calorimetry
polymer-lipid hybrid nanoparticles
powder X-ray diffraction
solid lipid nanoparticles
- VRP-DS complex
the complex of verapamil HCl and dextran sulfate sodium salt
This work was supported by the Canadian Institute of Health Research. The authors would like to thank Dr. Sr. Petrov, Department of Chemistry, University of Toronto, for his comments on the PXRD patterns; Dr. T.V. Chalikian and Dr. Lakshmi P. Kotra for kind permission on use of ITC and a freeze drier, respectively. In addition, the discussion with Ho-lun Wong about SLN, Jubo Liu about solubility parameters and Ms. Feixue Han for help with ITC data fitting; the kind donations of free samples from Gattefossé Inc. (Canada), and the Ontario Graduate Scholarship in Science and Technology (OGSST) to Y. Li are also gratefully acknowledged.
- 3.R. H. Müller, W. Mehnert, J. S. Lucks, C. Schwarz, A. zur Muhlen, H. Weyhers, C. Freitas, and D. Ruhl. Solid lipid nanoparticles (SLN)–an alternative colloidal carrier system for controlled drug delivery. Eur. Pharm. Biopharm. 41:62–69 (1995).Google Scholar
- 12.H. L. Wong, A. M. Rauth, R. Bendayan, and X. Y. Wu. A new solid lipid nanoparticle formulation increases cytotoxicity of doxorubicin against multidrug-resistant human breast cancer cells. Pharm. Res. In press.Google Scholar
- 13.H. L. Wong. Ph.D. dissertation, University of Toronto, Canada, 2006.Google Scholar
- 22.J. Barra, P. Bustamante, and E. Doelker. Use of the solubility parameter and surface energy concepts in the formulation of solid dosage forms. S.T.P. Pharm. Sci. 9:293–305 (1999).Google Scholar
- 23.J. L. Garson. The influence of polarity on the solubility parameter concept. J. Paint Technol. 38:43–57 (1966).Google Scholar
- 25.D. W. Van Krevelen. Cohesive properties and solubility. In D.V. Van Krevelen. (ed.), Properties of Polymers: Their Correlation with Chemical Structure; Their Numerical Estimation and Prediction from Additive Group Contribution. Elsevier, New York, 1990, pp. 189–224.Google Scholar
- 27.C. M. Hansen. The three dimensional solubility parameters—key to paint component affinities. 1. Solvents, plasticizers, polymers and resins. J. Paint Technol. 39:104–117 (1967).Google Scholar