Elsevier

Biomaterials

Volume 22, Issue 21, November 2001, Pages 2857-2865
Biomaterials

Amoxicillin-loaded polyethylcyanoacrylate nanoparticles: Influence of PEG coating on the particle size, drug release rate and phagocytic uptake

https://doi.org/10.1016/S0142-9612(01)00030-8Get rights and content

Abstract

Polyethyleneglycol (PEG)-coated polyethylcyanoacrylate (PECA) nanoparticles loaded with amoxicillin were prepared and the influence of the PEG coating on the particle size, zeta potential, drug release rate and phagocytic uptake by murine macrophages was studied. Experimental results show that this colloidal drug delivery system could be useful for intravenous or oral administration. The profile of amoxicillin release from PECA nanoparticles system was studied under various conditions similar to those of some corporeal fluids. In all these experiments, amoxicillin release in the free form was studied by HPLC analysis. Experimental results showed that at pH 7.4 drug release rises when molecular weight of PEG added to polymerization medium increases; in human plasma on the contrary drug release is reduced as molecular weight of PEG rises. Phagocytosis was evaluated by incubating amoxicillin-loaded PECA nanoparticles with murine macrophages and determining the amount of phagocytized nanoparticles by dosing the amoxicillin present inside the macrophages. The results of this study showed significative differences between nanoparticles prepared in the presence or in the absence of PEG and demonstrated that the PEG coating reduces the macrophages uptake. These results suggest that nanoparticles prepared in the presence of PEG are stealth carriers, which could be an injectable colloidal system able to avoid MPS recognition after intravenous injection. Experimental data of drug release at pH 1.1 and in the presence of urease, taking into account the mucoadhesive properties of polyalkylcyanoacrylate nanoparticles and the activity of the amoxicillin versus Helicobacter pylori, suggest moreover that the colloidal drug delivery system obtained in our laboratory could be useful for the treatment of diseases caused by H. pylori by peroral administration.

Introduction

It is well known that changing appropriately some physicochemical properties of polymeric nanoparticles, such as size and surface characteristics, it is possible to modulate their biodistribution parameters.

In the design of a colloidal drug delivery system, which can give a large biodistribution of the drug and can allow the reaching of particular sites, different from reticuloendothelial cells, it is necessary to avoid the removal of drug-loaded nanoparticles from blood by endocytic uptake of Kupfer cells or other phagocytic cell populations within the mononuclear phagocyte system (MPS) [1].

In case of polymeric drug carriers, constituted by polyalkylcyanoacrylate nanoparticles, to prevent this uptake it has been suggested to prepare very small nanoparticles [2], [3] or modify the surface of particulate carrier by more hydrophilic polymers avoiding opsonins adsorption on particles surface that makes them recognizable to the macrophages of the MPS [4], [5]. Polyethyleneglycol (PEG) is one of the most investigated hydrophilic polymers, able to modify the surface of particulate carriers [6], [7], [8]. PEG is fixed on particle surface by adsorption or covalent binding [9].

The results of recent studies show that nanoparticles prepared by emulsion polymerization of alkylcyanoacrylate in the presence of PEG represent potential stealth rapidly biodegradable carriers, possibly able to avoid MPS recognition in vivo [10], [11], [12], [13], [14].

The first purpose of this work was to prepare amoxicillin-loaded polyethylcyanoacrylate (PECA) nanoparticles in the presence and in the absence of PEG and to study the influence of PEG coating at different molecular weights on the particle size, zeta potential, loading capacity, rate of amoxicillin release from nanoparticles in some simulated biological fluids and phagocytic uptake, in view of a possible use of this colloidal carrier for controlled intravenous drug delivery and targeting.

Polyalkylcyanoacrylate nanoparticles have been also studied as oral drug carriers to overcome problems of administration of drugs that are unstable in the gastrointestinal tract or are inadequately adsorbed [15], [16], [17].

For example, the treatment of H. pylori infection in peptic ulcer disease usually requires a triple therapy that includes antibiotic, antibacterial and proton pump inhibitors. Unfortunately, infact, when administred in vivo, no single antibiotic is effective in eradication of H. pylori [18], [19].

The failure of a single antibiotic therapy could be due to poor stability of the drug in the acidic pH of the stomach, poor permeability of the antibiotics across the mucus layer, or due to the availability of sub-therapeutic antibiotic concentrations at the infection site after oral administration in a conventional capsule or tablet dosage form.

To overcome some of these problems, the preparation of an antibiotic delivery system which is able to localize the drug at infection site to achieve bactericidal concentrations, would be desirable [20], [21].

Taking into account the mucoadhesive properties of polyalkylcyanoacrylate nanoparticles [22] and the activity of the amoxicillin versus H. pylori [23], [24], the second purpose of this work was to study the colloidal drug delivery system obtained in our laboratory in order to evaluate its eventual peroral administration for the treatment of diseases caused by H. pylori.

Section snippets

Chemicals

Ethyl-2-cyanoacrylate (ECA) used as the monomer for polymerization, was obtained from Sigma Chemical Company (St. Louis, MO, USA).

PEG 600, 2000 and 4000 and Pluronic F68 were obtained from Fluka (Buchs, Switzerland).

Amoxicillin and urease type III from beans (16.0 U/g solid) were obtained from Sigma Chemical Company (St. Louis, MO, USA).

Water (HPLC grade) was used. All other chemicals were of analytical grade.

Preparation of amoxicillin-loaded nanoparticles

Amoxicillin-loaded nanoparticles were easily prepared by emulsion polymerization of

Results and discussion

Amoxicillin loaded PECA nanoparticles show a drug encapsulation capacity and a particle size distribution that can be successfully exploited for the formulation of colloidal pharmaceutical systems.

PECA nanoparticles were easily prepared by emulsion polymerization of ethylcyanoacrylate, using Pluronic F68 as surfactant, in the absence and in the presence of PEG at different molecular weights. Amoxicillin was solubilized in the polymerization medium, which is composed of aqueous solution

Conclusions

The present paper describes the experimental conditions for preparing amoxicillin loaded polyethylcyanoacrylate (PECA) nanoparticles in the presence and in the absence of polyethyleneglycol (PEG) at different molecular weights. It was observed that the PEG added in polymerization medium during the nanoparticle preparation, influences particle size, zeta potential, drug loading capacity, drug release rate and phagocytic uptake from murine macrophages.

Drug release studies at pH 7.4 and in human

Acknowledgments

This paper was financially supported by MURST grants.

References (30)

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