Composite microparticle drug delivery systems based on chitosan, alginate and pectin with improved pH-sensitive drug release property

https://doi.org/10.1016/j.colsurfb.2008.10.013Get rights and content

Abstract

Composite microparticle drug delivery systems based on chitosan, alginate and pectin with improved pH sensitivity were developed for oral delivery of protein drugs, using bovine serum albumin (BSA) as a model drug. The composite drug-loaded microparticles with a mean particle size less than 200 μm were prepared by a convenient shredding method. Since the microparticles were formed by tripolyphosphate cross-linking, electrostatic complexation by alginate and/or pectin, as well as ionotropic gelation with calcium ions, the microparticles exhibited an improved pH-sensitive drug release property. The in vitro drug release behaviors of the microparticles were studied in simulated gastric (pH 1.2 and pH 5.0), intestinal (pH 7.4) and colonic (pH 6.0 and pH 6.8 with enzyme) media. For the composite microparticles with suitable compositions, the releases of BSA at pH 1.2 and pH 5.0 could be effectively sustained, while the releases at pH 7.4, pH 6.8 and pH 6.0 increased significantly, especially in the presence of pectinase. These results clearly suggested that the microparticles had potential for site-specific protein drug delivery through oral administration.

Introduction

Oral drug administration is one of the most preferred routes for its convenience and no cross-infection [1]. However, the gastrointestinal condition is not suitable for protein drug delivery. The instability of protein is one of the major reasons by which protein drugs are administered traditionally through injection rather than taken orally [1], [2]. To protect the protein drugs from the harsh environment in the stomach before they can be absorbed in the intestine, pH-sensitive polysaccharides like chitosan and alginate have attracted increasing attention due to their favorable properties including biocompatibility, biodegradability, pH sensitivity, and mucoadhesive property [2], [3], [4]. Chitosan with amino groups is soluble at low pH and insoluble at high pH, whereas alginate with carboxyl groups has the property of shrinking at low pH and getting dissolved at high pH. Upon mixing, the ammonium groups of chitosan and the carboxylate groups of alginate ionically interact to form the polyelectrolyte complex [2]. Complexation of chitosan with alginate reduces the porosity of gels and decreases the leakage of the encapsulated drugs. The solubility of chitosan at low pH is reduced by the alginate network since alginate is insoluble under low pH conditions, and the possible dissolution of alginate at high pH is reduced by chitosan which is stable at high pH ranges [2]. Pectin is another important polysaccharide widely explored as the matrix for drug delivery. Pectin is able to resist protease and amylase which are active in the upper gastrointestinal tract, whereas can be digested by pectinase in the colon [5], [6], [7]. This makes pectin an ideal drug carrier for colon-specific drug delivery, which is known to have the advantage to achieve higher biological availability because the pH in colon is neutral and peptidase activity is relatively lower [1].

For designing oral dosage forms, the pH environment of gastrointestinal tract varying from acidic in the stomach to slightly alkaline in the intestine must be considered [1], [2], [3]. However, most literatures were focused on the drug carriers responding to a relatively large pH difference between 1.2 and 7.4, and did not report their drug release behaviors at pH values slightly lower than 7.4 [8], [9], [10], [11]. As we know, many factors may affect gastric pH although most commonly the gastric pH is lower than pH 3 under the fasted state, after ingestion of a meal the gastric acidity can vary over a wide range and be typically higher than pH 3. Other influences on gastric pH include pathophysiological conditions and individual variations [6], [11]. Therefore, it is important to explore the drug release behavior at the pH higher than 3 and lower than 7.4. To this end, in this study we fabricated a class of new pH-sensitive microparticles drug delivery systems based on chitosan, alginate and pectin with significant differences in release rates when pH varies from acidic (pH 1.2 and pH 5.0) in the stomach to slightly alkaline (pH 7.4) in the intestine, and evaluated their potential as ‘intelligent’ drug delivery carriers.

Polymeric micro- and nanoparticles are of especial interest for oral drug delivery because their small size and large surface area favor their absorption compared to larger carriers [12]. In this investigation, we used a very convenient method, i.e. directly shredding the drug-loaded beads in a commercial food processor to obtain microparticles with particle sizes in the range of 100–200 μm before freeze drying. Compared with other conventional methods for fabrication of microparticles based on natural polymers, the method we used is very rapid, convenient, and solvent free.

Section snippets

Materials

Sodium alginate (viscosity  0.02 Pa s in 1% aqueous solution at 20 °C, Mw = 2.85 × 105 g/mol determined by multiangle laser light scattering) was supplied by Sinopharm Chemical Reagent Co. Ltd. (Shanghai, China). Chitosan (Mw=8.66 × 104 g/mol determined by multiangle laser light scattering, degree of deacetylation  90%), pectin (P9135, Mw = 1.18 × 105 g/mol determined by multiangle laser light scattering), bovine serum albumin (BSA) and pectinase from Aspergillus niger were obtained from Sigma. Calcium chloride

Preparation and characterizations of microparticles

In this study, the composite microparticle drug delivery systems were prepared using chitosan, alginate and pectin. Since BSA is electrically negative and chitosan is electrically positive in particular pH range, polyelectrolyte complexes could be formed between BSA and chitosan via electrostatic interactions during the microparticle preparation. To achieve a high encapsulation efficiency, BSA was mixed with chitosan first and then reinforced by complexation between chitosan and

Conclusions

Using a convenient shredding method, composite microparticle drug delivery systems based on chitosan, alginate and pectin with improved pH sensitivity were prepared for oral delivery of protein drugs. The in vitro drug release study shows that the microparticles have a high pH sensitivity, i.e. the BSA releases at pH 1.2 and pH 5.0 are slow, while the release at pH 7.4 is much faster. Besides the pH sensitivity, the microparticle drug delivery systems also exhibit enzyme-controlled drug release

Acknowledgements

Financial supports from National Natural Science Foundation of China (20774070) and Ministry of Education of China (Cultivation Fund of Key Scientific and Technical Innovation Project 707043) are gratefully acknowledged. Financial support from Ministry of Science and Technology of China (973 Programme 2005CB623903) is also appreciated.

References (22)

  • L.S. Liu et al.

    Biomaterials

    (2003)
  • M. George et al.

    J. Control. Release

    (2006)
  • S.A. Agnihotri et al.

    J. Control. Release

    (2004)
  • M.J. Fernández-Hervás et al.

    Int. J. Pharm.

    (1998)
  • K. Itoh et al.

    Int. J. Pharm.

    (2007)
  • R. Semdé et al.

    Int. J. Pharm.

    (2000)
  • R. Rastogi et al.

    Int. J. Pharm.

    (2007)
  • M. George et al.

    Int. J. Pharm.

    (2007)
  • F. Siepmann et al.

    Eur. J. Pharm. Biopharm.

    (2008)
  • S.C. Chen et al.

    J. Control. Release

    (2004)
  • A. des Rieux et al.

    J. Control. Release

    (2006)
  • Cited by (170)

    • Formulation, characterization and in vitro digestion of polysaccharide reinforced Ca-alginate microbeads encapsulating citrus medics L. phenolics

      2021, LWT
      Citation Excerpt :

      However, a substantial increase in swelling (525.31%) was found in the end of 960th min. Yu et al., 2009 also demonstrated that pectin highly influences the swelling under gastric HCl environment (pH-1.2). In contrast, dried pectin hydrogel particles were studied in a related analysis and found to have substantial swelling in simulated gastric medium, as well as loss of sphericity anYud full dissolution after 4 h in simulated intestinal medium (Popov et al., 2017).

    View all citing articles on Scopus
    View full text