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Co-encapsulation of lyoprotectants improves the stability of protein-loaded PLGA nanoparticles upon lyophilization.

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      Abstract

      The purpose of this work was to evaluate the influence of the co-encapsulation of lyoprotectants with insulin into PLGA nanoparticles, on the stability of the protein and nanoparticles upon lyophilization. Different lyoprotectants were used, namely trehalose, glucose, sucrose, fructose and sorbitol at 10% (w/v). Insulin-loaded PLGA nanoparticles with co-encapsulated lyoprotectants achieved a mean particle size of 386-466nm, and a zeta potential ranging between -34 and -38mV, dependent on the lyoprotectant used. Formulations had association efficiencies and loading capacities of 85-91% and 10-12%, respectively. The lyophilization process increased the colloidal stability of nanoparticles, and maintained their spherical shape and smooth surface, particularly in presence of lyoprotectants. XRPD revealed that the lyophilizates of nanoparticles with co-encapsulated lyoprotectants were amorphous, whereas formulations with externally added lyoprotectants, except trehalose, showed crystallinity. FTIR assessment showed that co-encapsulating lyoprotectants better preserved insulin structure upon lyophilization with a spectral area overlap of 82-87%, compared to only 72% in lyoprotectant absence. These results were confirmed by circular dichroism spectroscopy. Surprisingly, the simultaneous co-encapsulation and addition of lyoprotectants was detrimental to protein stabilization. The insulin in vitro release studies demonstrated that formulations with co-encapsulated trehalose, glucose, sucrose, fructose and sorbitol achieved 83%, 69%, 70%, 77% and 74%, respectively after 48h. In contrast, formulations added with those lyoprotectants prior lyophilization showed a lower release rate not higher than 60% after 48h. This work gives rise to a different promising strategy of co-encapsulating lyoprotectants and therapeutic proteins, to better stabilize protein structure upon lyophilization.

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      Affiliations
      [1 ] UCIBIO, REQUIMTE, Department of Chemical Sciences-Applied Chemistry Lab, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-113 Porto, Portugal; CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde and Instituto Universitário de Ciências da Saúde, Rua Central de Gandra 1317, 4585-116 Gandra-PRD, Portugal. Electronic address: pedrofonte86@gmail.com.
      [2 ] Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal.
      [3 ] CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde and Instituto Universitário de Ciências da Saúde, Rua Central de Gandra 1317, 4585-116 Gandra-PRD, Portugal.
      [4 ] UCIBIO, REQUIMTE, Department of Chemical Sciences-Applied Chemistry Lab, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-113 Porto, Portugal.
      [5 ] Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
      [6 ] CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde and Instituto Universitário de Ciências da Saúde, Rua Central de Gandra 1317, 4585-116 Gandra-PRD, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal. Electronic address: bruno.sarmento@ineb.up.pt.
      Journal
      Int J Pharm
      International journal of pharmaceutics
      Elsevier BV
      1873-3476
      0378-5173
      Dec 30 2015
      : 496
      : 2
      26474964
      S0378-5173(15)30300-8
      10.1016/j.ijpharm.2015.10.032

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