Amphiphilic Block Copolymer Microspheres Derived from Castor Oil, Poly(ε-carpolactone), and Poly(ethylene glycol): Preparation, Characterization and Application in Naltrexone Drug Delivery.

Maria Nerantzaki,Eirini Skoufa,Kyriakos-Vasileios Adam,Apostolos Avgeropoulos,Dimitrios Bikiaris,Stavroula Nanaki,Margaritis Kostoglou

doi:10.3390/ma11101996

Abstract

In the present study, the newly synthesized castor oil-derived thioether-containing ω-hydroxyacid (TEHA) block copolymers with polycaprolactone (TEHA-b-PCL), with methoxypoly(ethylene glycol) (mPEG), (TEHA-b-mPEG) and with poly(ethylene glycol) (PEG) (TEHA-b-PEG-b-TEHA), were investigated as polymeric carriers for fabrication of naltrexone (NLX)-loaded microspheres by the single emulsion solvent evaporation technique. These microspheres are appropriate for the long-term treatment of opioid/alcohol dependence. Physical properties of the obtained microspheres were characterized in terms of size, morphology, drug loading capacity, and drug release. A scanning electron microscopy study revealed that the desired NLX-loaded uniform microspheres with a mean particle size of 5–10 µm were obtained in all cases. The maximum percentage encapsulation efficiency was found to be about 25.9% for the microspheres obtained from the TEHA-b-PEG-b-TEHA copolymer. Differential scanning calorimetry and X-ray diffractometry analysis confirmed the drug entrapment within microspheres in the amorphous state. In vitro dissolution studies revealed that all NLX-loaded formulations had a similar drug release profile: An initial burst release after 24 h, followed by a sustained and slower drug release for up to 50 days. The analysis of the release kinetic data, which were fitted into the Korsmeyer–Peppas release model, indicated that diffusion is the main release mechanism of NLX from TEHA-b-PCL and TEHA-b-mPEG microspheres, while microspheres obtained from TEHA-b-PEG-b-TEHA exhibited a drug release closer to an erosion process.

Highlights

Since the pioneering studies by Bader et al in 1984 on the use of polymeric micelles in the form of microspheres for solubilizing anti-cancer drugs, amphiphilic copolymers, which can be Materials 2018, 11, 1996; doi:10.3390/ma11101996 www.mdpi.com/journal/materialsMaterials 2018, 11, 1996 either block copolymers (ABCs) or graft copolymers, have been used extensively in pharmaceutical applications ranging from sustained-release technologies to gene delivery [1]
In addition to the total conversion of the double bonds, new 1 H chemical shifts of protons attached to the carboxylic and hydroxyl groups were detected in the spectrum of thioether-containing ω-hydroxyacid (TEHA) at 2.34 ppm and 3.72 ppm, respectively (Figure 1, H1, H4 ), while the methylene protons linked to sulfur appeared as two triple peaks at
This study confirmed that the castor oil derived copolymers: TEHA-b-PCL, TEHA-b-methoxypoly(ethylene glycol) (mPEG), and TEHA-b-poly(ethylene glycol) (PEG)-b-TEHA, which could be obtained using a one-pot synthetic procedure involving TEHA, ε-CL, mPEG, and PEG, could be efficiently used for the preparation of amphiphilc block copolymer microspheres

Summary

Introduction

Since the pioneering studies by Bader et al in 1984 on the use of polymeric micelles in the form of microspheres for solubilizing anti-cancer drugs, amphiphilic copolymers, which can be Materials 2018, 11, 1996; doi:10.3390/ma11101996 www.mdpi.com/journal/materialsMaterials 2018, 11, 1996 either block copolymers (ABCs) or graft copolymers, have been used extensively in pharmaceutical applications ranging from sustained-release technologies to gene delivery [1]. The utility of ABCs for delivery of therapeutic agents results from their unique self-assembly property in aqueous media Such copolymers are made up of two segments of different chemical nature, both hydrophilic and hydrophobic components [2]. The hydrophobic segment forms the core of the micelle, whereas the hydrophilic segment surrounds this core as a hydrated outer shell This core–shell structure enables polymer microspheres, such as microspheres and nanoparticles, to have potential as vehicles for drug delivery because upon micellization, the hydrophobic core regions serve as reservoirs for hydrophobic drugs, which may be loaded by chemical, physical, or electrostatic means, depending on the specific functionalities of the core-forming block and the solubilizate [3]. The injectable sustained-release formulations address issues of daily oral NLX non-compliance, they still depend on patient compliance with treatment for subsequent treatments over 4 to 6 months. Concerning the sustained-release NLX implants, an early phase (up to 12 months post-implant) of inflammation, foreign body reaction, and fibrosis has been reported, while high cost of the implant limits its use [10]

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