Elsevier

Journal of Controlled Release

Volume 93, Issue 3, 12 December 2003, Pages 293-300
Journal of Controlled Release

Oral colon-specific drug delivery for bee venom peptide: development of a coated calcium alginate gel beads-entrapped liposome

https://doi.org/10.1016/j.jconrel.2003.08.019Get rights and content

Abstract

Colon-specific drug delivery systems (CDDSs) can be used to improve the bioavailability of protein and peptide drugs through the oral route. A novel formulation for oral administration using coated calcium alginate gel beads-entrapped liposome and bee venom peptide as a model drug has been investigated for colon-specific drug delivery in vitro. Drug release studies under conditions mimicking stomach to colon transit have shown that the drug was protected from being released completely in the physiological environment of the stomach and small intestine. The release rate of bee venom from the coated calcium alginate gel beads-entrapped liposome was dependent on the concentration of calcium and sodium alginate, the amount of bee venom in the liposome, as well as the coating. Furthermore, a human γ-scintigraphy technique was used in vivo to determine drug delivery more precisely. The colonic arrival time of the tablets was found to be 4–5 h. The results clearly demonstrated that the coated calcium alginate gel beads-entrapped liposome is a potential system for colon-specific drug delivery.

Introduction

Many protein and peptide drugs cannot be administered through the oral route because of their degradation by the digestive enzymes of the stomach and the small intestine. The oral route is by far the most popular route for drug administration, and a number of studies have been carried out in attempts to deliver peptide and protein drugs effectively into the circulation. Problems such as acid-catalyzed degradation in the stomach, proteolytic breakdown in the gastrointestinal tract, poor permeability across the gastrointestinal mucosa and first-pass metabolism during transfer across the absorption barrier and in the liver must be overcome for the efficient delivery of drugs into the bloodstream. Delivery of drugs to the systemic circulation through colonic absorption represents a novel mode of introducing peptide and protein drug molecules and drugs that absorb poorly from the upper gastrointestinal tract (GIT), as the colon lacks various digestive enzymes that are present in the upper GIT. Colonic drug delivery is also useful for systemic absorption of drugs, especially protein and peptide drugs, because of the less hostile environment prevailing in the colon compared with the stomach and small intestine. The different approaches for targeting orally administered drugs to the colon include coating with pH-dependent polymers, design of timed-release dosage forms and the utilisation of carriers that are degraded exclusively by colonic bacteria [1], [2]. The poor site-specificity of pH-dependent systems, because of large variations in the pH of the gastrointestinal tract, has been very well established [3], [4]. The site-specificity of timed-release dosage forms is considered poor because of large variations in gastric emptying times [5] and in passage across the ileocaecal junction [6].

Alginate is a natural polyacid, and has a unique property of gel formation in the presence of multivalent cations, such as calcium ions in aqueous media, which takes place mainly at junctions in the G–G sequence rich chain region know as the “egg box junctions”. Therefore, alginate is used as an immobilization matrix for cells and enzymes as well as pharmaceutical and food adjuvants [7], [8], [9]. When an aqueous solution of sodium alginate is added dropwise to an aqueous solution of calcium chloride, a spherical gel with regular shape and size is obtained. The spherical gel is termed an “alginate bead”. Alginate beads have the advantages of being nontoxic orally and having high biocompatibility. Another advantageous property is their ability of reswell. This property is susceptible to the pH of an environment, so acid-sensitive drugs incorporated into the beads would be protected from gastric juice [10]. Because of this, many results have been reported concerning the use of alginate beads as a drug-controlled release formulation [11], [12], [13], [14]. However, the porosity of alginate beads results in a very low efficiency of incorporation with drugs that have a low molecular weight and are water-soluble drugs, and they result in a fast release of incorporated drugs. On the other hand, liposomes also provide protection of the entrapped peptides from enzymatic degradation [15], [16] and disrupt the mucosal membrane to increase absorption of peptides [17].

Bee venom is a typical representative of biologically active peptide drugs with high therapeutic potential, but it has great disadvantages of a relatively short plasma half-life after intravenous infusion administration and failing to know exact dose after the conventional therapy of stings by bees. Our previous work showed that bee venom became inactive in pepsin and trypsin after 5 min in vitro and the bioavailability was only 5.22% after a single oral dose of bee venom in vivo (data not shown). Therefore, to obtain a long-term and constant therapeutic effect, an oral release system is needed. Whereas the development of controlled delivery systems has focused on entrapping the macromolecule protein inside the polymer matrix [12], the aim of this study was to evaluate a new colon-specific drug delivery system (CDDS). Instead of entrapping the drug inside the matrix during fabrication of the calcium alginate gel beads, we propose coating the alginate beads and entrapping a peptide-loaded liposome with Eudragit S100. In this experiment, we prepared the calcium alginate gel beads containing liposome-loaded bee venom and investigated the factors that influenced the release of the model peptide, bee venom, which exhibited antitumor activity in vitro and in vivo [18].

When applied to the assessment of oral drug delivery, γ-scintigraphy can be used to take a time-lapse photographic sequence of images. In this paper, γ-scintigraphy was used to show the passage of the dosage form through the gut and to track the times at which it left the stomach and arrived at the colon.

Section snippets

Materials and methods

Alginate, obtained from brown algae (Laminaria hyperborea), was purchased from the Beijing Chemical (China). Lyophilized bee venom, l-α-phosphatidylcholine from soybean and Lowry Reagent, modified for use in the determination of total protein concentration, were purchased from the Sigma (St. Louis, MO, USA). Eudragit S100 (methacrylic acid copolymer B) was donated by the Rohm (Germany). 99mTc-MIBI was purchased from the Beijing Institute of Atomic Energy (China). All other chemicals were of

Effect on the characterization of the calcium alginate gel beads

As shown in Table 1, the results demonstrated that the sodium alginate concentration, calcium chloride concentration and the ratio of liposome/sodium alginate affected the beads' characteristics and the percentage of the release of bee venom. The results prove that on increasing the sodium alginate concentration used for the beads, the reswelling time and the diameter of the dried gel beads increased for a given calcium chloride concentration. Similarly, on increasing the calcium chloride

Conclusions

Bee venom is a small molecular weight peptide. The release of liposome entrapped bee venom is strongly influenced by the swelling and erosion of the alginate gel matrix. The characterization of calcium alginate gel beads has a significant dependence on the sodium alginate concentration, calcium chloride concentration and the ratio of liposome/sodium alginate. In addition, the drug release also depends on the coating membrane. Using gamma scintigraphy, the present study proved that coated

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