Elsevier

Il Farmaco

Volume 60, Issues 11–12, November–December 2005, Pages 919-924
Il Farmaco

Original article
Nasal administration of heparin-loaded microspheres based on poly(lactic acid)

https://doi.org/10.1016/j.farmac.2005.08.004Get rights and content

Abstract

In this study, heparin-loaded microspheres having smooth surface and small particle size were designed in order to provide the absorption of heparin through nasal mucosa. For this purpose, microspheres at different polymer/drug ratios (1:10, 1:2.5 and 1:1) and at different concentrations of polyvinyl alcohol, emulsifying agent (1.5% and 2.5% w/v) were prepared by solvent evaporation method with poly(lactic acid). The microspheres were for evaluated shape and surface properties, particle size, production yield, encapsulation efficiency and in vitro drug release. Based on the in vitro data, selected microspheres were applied by nasal route to Wistar albino rats. According to in vivo studies, heparin-loaded microspheres may be used by nasal route as an alternative to parenteral route.

Introduction

Heparin is one of the most potent anticoagulant widely used for the treatment and prevention of deep vein thrombosis [1]. The mean half-life observed in practically human cases amounts to approximately 1.5 h [2]. Heparin is degraded to ineffective fragments after oral ingestion [3] and while subcutaneous administration is efficacious, it is uncomfortable and associated with poor patient compliance [4].

In recent years, the nasal cavity has been widely investigated as a potential site for non-invasive drug delivery. As a site for drug delivery, nasal cavity possesses many advantages such as a large surface area for absorption with a highly vascularized subepithelial layer. In addition, blood is drained directly from the nose into the systemic circulation, thereby avoiding first-pass metabolism by the liver [5].

Microspheres of different materials have been evaluated in vivo as nasal drug delivery system [6]. Among the biodegradable polymers, poly(lactic acid) (PLA), a polyester, is the most widely used material for preparing microspheres because of its biodegradability and low toxicity [7].

In the literature, heparin implants have been prepared with PLA [8], ethylene-vinyl acetate [9] and poly(d,l-lactic-co-glycolic acid) (PLGA) [10], [11], [12] for local treatment; heparin-loaded microparticles prepared using biodegradable (poly-ε-caprolactone, PLA, PLGA) and nonbiodegradable (Eudragit RS and RL) polymers have been evaluated after oral administration in rabbits [13], [14], [15]; conjugates of heparin with deoxycholic acid have been synthesized in order to enhance heparin absorption from the gastrointestinal tract [16]. Yang et al. [17] has reported that low-molecular-weight heparin with cyclodextrins can be used nasal delivery. There were no data on heparin microspheres applied via nasal route in the literature.

In this study, heparin-loaded microspheres were prepared with PLA using solvent evaporation method. The surface morphology of microspheres was evaluated. The influence of drug-polymer ratio and emulsifying agent concentration on the formation of microspheres, drug loading capacity and particle size were also investigated. The formulations were characterized by in vitro release study and the formulations providing suitable highest drug release were selected for in vivo study via nasal route. After nasal administration of these formulations to rats, the time course of the anticoagulant activity was investigated by means of aPTT and compared with heparin solution.

Section snippets

Materials

PLA was purchased from Boehringer Ingelheim (Resomer L104). Polyvinyl alcohol (PVA) (Mw: 13,000–23,000, 88% hydrolyzed) was obtained from E. Merck. Heparin (195.3 IU/mg) was supplied by Mustafa Nevzat Pharmaceutical Company, Istanbul, Turkey. Sodium azide, methylene chloride, sodium hydroxide, hydrochloric acid, sodium chloride were from E. Merck. Azure A was from Eastman and methylcellulose was from Sigma.

Preparation of heparin microspheres

Heparin-loaded microspheres (12 formulations) were prepared with single and double

Results and discussion

The scanning electron microphotograph results exhibited good spherical shape and smooth surface for all microsphere formulations (S1–S6 and D1–D6). Fig. 1 shows typical scanning electron microphotographs of heparin-loaded microspheres prepared using single and double emulsion technique.

Thermal analyses of blank and heparin-loaded microspheres were performed by differential scanning calorimetry (DSC). The values of the glass transition (Tg), crystallization (Tc) and melting (Mp) of the polymer

Acknowledgements

This work was supported by the Research Fund of Istanbul University. Project number: T-953/06112000.

Authors wish to thank Mustafa Nevzat Pharmaceutical Company for kindly supplying heparin.

In vitro part of this study was presented at the Fourth World Meeting on Pharmaceutics, Biopharmaceutics, Pharmaceutical Technology, April 8–11, 2002, Florence, Italy.

In vivo part of this study was resented at the Fifth International Conference and Workshop on Cell Culture and In vitro Models of Drug

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