Polyelectrolyte complex of carboxymethyl starch and chitosan as drug carrier for oral administration
Introduction
Since carboxymethyl starch (CMS) was proposed (Mulhbacher, Mateescu, & Calinescu, 2004) as an excipient for controlled drug release from oral solid dosage forms (tablet), several studies have been undertaken in order to investigate the properties and the efficiency of this excipient. The influence of the degree of substitution (DS), of the degree of protonation, and of the formulated drug type and loading on release kinetics of small molecules from CMS matrices has been recently studied (Assaad and Mateescu, 2010, Assaad et al., 2008, Ispas-Szabo et al., 2007, Lemieux et al., 2009). Moreover, the effects of certain formulation parameters, such as compression force and NaCl electrolyte particle size, on drug release rate have been investigated (Brouillet et al., 2008, Nabais et al., 2007). CMS has also been suggested for the formulation of large size bioactive agents, such as pancreatic enzymes (α-amylase, lipase and trypsin) (Massicotte, Baille, & Mateescu, 2008), Escherichia coli, filamentous surface proteins of Escherichia coli (F4 fimbriae) and Lactobacillus rhamnosus probiotic (Calinescu and Mateescu, 2008, Calinescu et al., 2005, Calinescu et al., 2007). These studies have shown that CMS can reduce the damaging effect of the acidity of gastric medium on bioactive agents and affords a controlled drug release in intestinal medium. In simulated gastric fluid (SGF, pH 1.2), the CMS in the outer layer of tablet is protonated, making the matrix compact. At higher pH (simulated intestinal fluid, SIF, pH 6.8), the carboxyl groups are deprotonated and ionized, thus favoring hydration, swelling and finally solubilisation of tablet. The solubility of CMS in neutral medium (SIF) and its digestion by pancreatic α-amylase can be limiting factors to effect a sustained drug release (Assaad and Mateescu, 2010, Calinescu and Mateescu, 2008). With the aim to ensure a longer time of drug release and targeting to the colon, chitosan dry powder has been used as a coexcipient in such formulations (Calinescu and Mateescu, 2008, Leonida and Mateescu, 2006). Chitosan has been shown to interact with unmodified starch via intermolecular hydrogen bonds, leading to the formation of chitosan–starch complex (Xu, Kim, Hanna, & Nag, 2005).
There is a recent growing interest for polyelectrolyte complexes of chitosan due to its cationic character and biocompatibility (Chen & Fan, 2007): some of them have been proposed for delivery of bioactive agents, such as chitosan–xanthan complexes (Chitoxan TM) for controlled drug delivery (Chellat et al., 2000); chitosan–carboxymethyl konjac glucomannan and chitosan–heparin for delivery of albumin (Du et al., 2005, Liu et al., 2007); chitosan–dextran sulfate and chitosan–alginate for oral delivery of insulin (Sarmento et al., 2006); chitosan–polyaspartate for delivery of 5-fluorouracil (Zheng et al., 2007). A number of polyelectrolyte complexes of chitosan and polyuronans have been prepared and spray-dried as microspheres (Muzzarelli, Stanic, Gobbi, Tosi, & Muzzarelli, 2004).
The objectives of the present study are (i) to prepare CMS–chitosan polyelectrolyte complex (PEC) and to investigate its performance in drug delivery; (ii) to evaluate the influence of chitosan molecular weight on drug release rate; (iii) to compare the drug dissolution from tablets based on anionic water-soluble excipient (CMS) alone, on cationic water-insoluble excipient (chitosan) alone, on physical mixture powder of these two excipients, or on PEC; and (iv) to compare the dissolution profiles of drugs with different charges and solubilities.
Section snippets
Materials
High amylose corn starch (Hylon VII) was obtained from National Starch (Bridgewater, NJ, USA) and crab shell chitosans were from Marinard Biotech (Rivière-au-Renard, QC, Canada). Acetaminophen was from Sigma-Aldrich (St-Louis, MO, USA). Metformin (1,1-dimethylbiguanide hydrochloride) was from MP Biomedicals (Solon, OH, USA). Aspirin (acetylsalicylic acid) and monochloroacetic acid were from Fisher Scientific (Fair Lawn, NJ, USA). The other chemicals were of reagent grade and used without
Characterization of the excipients
The degree of substitution of carboxymethyl starch (CMS) determined by the back-titration method was about 0.14, representing the average number of carboxymethyl groups per glucose unit. The degrees of deacetylation of chitosans determined by acid-base titration were about 80% and the approximate molecular weights determined by Mark–Houwink–Sakurada method were about 400 kDa for chitosan-400 and 700 kDa for chitosan-700.
The scanning electron microscopy micrographs showed that chitosan particles
Conclusion
The CMS–chitosan polyelectrolyte complex (PEC) showed a polymorphism with a lower order degree than those of carboxymethyl starch (CMS) and of chitosan-700. The fluid (SGF or SIF) diffusion and the swelling were lower with PEC tablets than with those based on CMS:chitosan-700 powder mixture. The PEC provided a controlled release of acetaminophen and a markedly slower sustained release of aspirin than that provided by CMS or chitosan-700, making this excipient favorable to colon targeting.
Acknowledgements
Support from NSERC (Natural Sciences and Engineering Research Council) of Canada granted to MAM and XXZ, from CRIP-FQRNT (Swine Infectious Disease Research Centre – Quebec Nature and Technology Research Fund), and graduate studentships from FQRNT and from MITACS (Canada) awarded to E. Assaad, are gratefully acknowledged.
References (45)
- et al.
The influence of protonation ratio on properties of carboxymethyl starch excipient at various substitution degrees: Structural insights and drug release kinetics
International Journal of Pharmaceutics
(2010) - et al.
High-amylose sodium carboxymethyl starch matrices for oral, sustained drug-release: Formulation aspects and in vitro drug-release evaluation
International Journal of Pharmaceutics
(2008) - et al.
Carboxymethyl high amylose starch: Chitosan self-stabilized matrix for probiotic colon delivery
European Journal of Pharmaceutics and Biopharmaceutics
(2008) - et al.
Carboxymethyl high amylose starch (CM-HAS) as excipients for Escherichia coli oral formulations
European Journal of Pharmaceutics and Biopharmaceutics
(2005) - et al.
Carboxymethyl high amylose starch for F4 fimbriae gastro-resistant oral formulation
International Journal of Pharmaceutics
(2007) - et al.
Effect of N-acylation on structure and properties of chitosan fibers
Carbohydrate Polymers
(2007) Calculation of Mark–Houwink–Sakurada (MHS) equation viscometric constants for chitosan in any solvent-temperature system using experimental reported viscometric constants data
Carbohydrate Polymers
(2007)- et al.
Characterization of a crosslinked high amylose starch excipient
International Journal of Biological Macromolecules
(1999) - et al.
Carboxymethyl high amylose starch as excipient for controlled drug release: Mechanistic study and the influence of degree of substitution
International Journal of Pharmaceutics
(2009) - et al.
Carboxylated high amylose starch as pharmaceutical excipients: Structural insights and formulation of pancreatic enzymes
International Journal of Pharmaceutics
(2008)
Characterisation of ferulic acid incorporated starch–chitosan blend films
Food Hydrocolloids
Cross-linked high amylose starch derivatives as matrices for controlled release of high drug loadings
Journal of Controlled Release
Spray-drying of solutions containing chitosan together with polyuronans, and characterization of the microspheres
Carbohydrate Polymers
High-amylose carboxymethyl starch matrices for oral sustained drug-release: In vitro and in vivo evaluation
European Journal of Pharmaceutics and Biopharmaceutics
Determination of the viscometric constants for chitosan
International Journal of Biological Macromolecules
Glass transition temperature of chitosan and miscibility of chitosan/poly(N-vinyl pyrrolidone) blends
Polymer
NMR spectroscopy and imaging studies of pharmaceutical tablets made of starch
Carbohydrate Polymers
Determination of the Mark–Houwink equation for chitosans with different degree of deacetylation
International of Journal of Biological Macromolecules
Biopolymer chitosan/montmorillonite nanocomposites: Preparation and characterization
Polymer Degradation and Stability
Chitosan–starch composite film: Preparation and characterization
Industrial Crops and Products
Nanoparticles based on the complex of chitosan and polyaspartic acid sodium salt: Preparation, characterization and the use for 5-fluorouracil delivery
European Journal of Pharmaceutics and Biopharmaceutics
Cited by (79)
Carboxymethyl Starch Films as Enteric Coatings: Processing and Mechanistic Insights
2024, Journal of Pharmaceutical SciencesComplexation behavior of carboxymethyl short-chain amylose and quaternized chitosan
2022, International Journal of Biological MacromoleculesCytocompatible drug delivery hydrogels based on carboxymethylagarose/chitosan pH-responsive polyelectrolyte complexes
2022, International Journal of Biological MacromoleculesCarboxymethylated polysaccharides in drug delivery
2022, Tailor-Made Polysaccharides in Drug DeliveryDevelopments on carboxymethyl starch-based smart systems as promising drug carriers: A review
2021, Carbohydrate PolymersChitosan-based polyelectrolyte complexes in biomedical applications
2021, Tailor-Made and Functionalized Biopolymer Systems: For Drug Delivery and Biomedical Applications