Mucoadhesive properties of carbopol or chitosan-coated liposomes and their effectiveness in the oral administration of calcitonin to rats

https://doi.org/10.1016/S0168-3659(02)00411-XGet rights and content

Abstract

Mucoadhesive liposomes were prepared by coating multilamellar liposomes with Carbopol (CP) in a similar manner to that used in the preparation of chitosan-coated liposomes (CS–Lip) previously reported [Takeuchi et al., Chem. Pharm. Bull. 42 (1994) 1954–1956; Pharm. Res. 13 (1996) 896–901]. The positively charged liposomes containing dipalmitoylphosphatidylcholine (DPPC) and stearylamine at an optimum formulation ratio (40:1) could be coated with CP without aggregation of the liposomal particles during the coating process. The mucoadhesive properties of both the resultant polymer-coated liposomes (CP–Lip and CS–Lip) and the positively or negatively charged noncoated liposomes (Non-Lip) were evaluated using the rat intestine. The order was CS–Lip⩾ CP–Lip>positively charged Non-Lip>negatively charged Non-Lip. The adhesive property of CP–Lip decreased on increasing pH of the dispersing medium from pH 5.0 to 7.4, probably owing to the electric repulsion between CP–Lip and the mucus layer. The effectiveness of the liposomal formulations in oral administration of calcitonin was evaluated by measuring the change in the blood calcium concentration of rats. Administration of CP–Lip and CS–Lip containing calcitonin showed an enhanced and prolonged reduction in blood calcium concentration. The overall pharmacological effect of CP– and CS–Lips evaluated by means of the area under the plasma calcium concentration curve was 2.4 and 2.8 times higher than that of negatively and positively charged Non-Lips, respectively.

Introduction

There is a need to develop a dosage form suitable for oral administration of peptide drugs such as insulin because oral administration of these drugs may improve patient compliance. As orally administered peptide drugs are very poorly absorbed, partly because of enzymatic degradation in the gastrointestinal tract, the use of carrier systems is preferable. Liposomes are a suitable vehicle for the peptide drugs, and many studies have been carried out to investigate aspects such as drug encapsulation, absorption in vivo etc. [1].

Considering the poor absorption of peptide drugs owing to their high molecular weight and hydrophilicity, the residence time of the drug carrier systems in the gastrointestinal tract is an important factor controlling the bioavailability of a drug. Recently, the mucoadhesive function has received much attention for prolonging the residence time of dosage forms at the absorption site [2]. Mucoadhesive particulate systems have been prepared by coating microspheres of poly(hydroxyethylmethacrylate) with mucoadhesive polymers using laboratory-scale equipment [3], [4]. Pimienta et al. [5] investigated the bioadhesion of hydroxypropylmethacrylate nanoparticles or isohexylcyanoacrylate nanocapsules coated with poloxamers and poloxamine to rat ileal segments in vitro using labeled compounds. We have also prepared liposomal mucoadhesive systems by coating the surface of liposomes with several mucoadhesive polymers, including chitosan, and demonstrated the enhanced enteral absorption of insulin with the chitosan-coated liposomes which showed the highest degree of mucoadhesion in our in vitro adhesion test [6], [7]. The feasibility of chitosan coating for nanospheres of lactide–glycolide co-polymer (PLGA) and their mucoadhesive properties has also been confirmed [8].

In this paper, the effectiveness of mucoadhesive liposomes as an oral dosage form for peptide drugs was investigated using calcitonin as a model peptide drug. Carbopol-coated liposomes were prepared, as well as chitosan-coated ones, because Carbopol has been shown to be a useful mucoadhesive polymer [9], [10]. The mucoadhesive properties of these liposomes and their pharmacological effectiveness in the oral administration of drugs to rats were compared under similar conditions.

Section snippets

Materials

l-α-Dipalmitoylphosphatidylcholine (DPPC, Nippon Oil and Fats), dicetylphosphate (DCP, Sigma), stearylamine (SA, Tokyo Kasei) and Carbopol 971-P (CP, BFGoodrich) were used as received. Chitosan (CS), which is a deacetylated chitin, poly(N-deacetylglucosamine) and industrially prepared by hydrolyzing the aminoacetyl groups of chitin in aqueous alkaline solution, was a gift from Katakurachikkarin (Japan). The molecular weight and the percentage deacetylation of CS used (CS-15) were ∼150 000 and

Preparation of Carbopol-coated liposomes

In previous papers, we have reported the preparation of Chitosan-coated liposomes (CS–Lip), in which the chitosan covers the surface of the liposomes by forming the ion-complex with DCP in the liposomal formulation. Here, we intended to prepare Carbopol-coated liposomes (CP–Lip) in a similar manner with the ion complex formation of CP with positively charged ions on the surface of the liposomes. The cationic liposomes were prepared by incorporating various amounts of SA into DPPC liposomes. The

Conclusion

Mucoadhesive liposomes can be prepared by coating positively charged liposomes with Carbopol (CP–Lip). The mucoadhesive properties of CP–Lip were comparable with that of chitosan-coated liposomes (CS–Lip). Both CP–Lip and CS–Lip improved the enteral absorption of a model peptide drug, calcitonin, in rats, owing to their mucoadhesive properties. Studies on the factors controlling the mucoadhesive properties of the polymer-coated liposomes, such as particle size and the type of core particles,

Acknowledgements

Part of this study was supported by a Grant-in-Aid for Scientific Research (C-12672091, B-14370731) from the Ministry of Education, Science, Sports and Culture, Japan. We are also grateful to Katakura-Chikkarin, Japan and Asahi Chemical, Japan for the gifts of chitosan and elcatonin, respectively.

References (17)

There are more references available in the full text version of this article.

Cited by (270)

  • Advanced delivery systems for peptide antibiotics

    2023, Advanced Drug Delivery Reviews
  • Colonic delivery of surface charge decorated nanocarrier for IBD therapy

    2022, Journal of Drug Delivery Science and Technology
View all citing articles on Scopus
View full text