Composite Sodium Alginate and Chitosan Based Wafers for Buccal Delivery of Macromolecules

Research Article

Austin J Anal Pharm Chem. 2014;1(5): 1022.

Composite Sodium Alginate and Chitosan Based Wafers for Buccal Delivery of Macromolecules

Boateng JS1* and Areago D1

1Department of Pharmaceutical, Chemical and Environmental Sciences, Faculty of Engineering and Science, University of Greenwich, UK

*Corresponding author: :Boateng JS, Department of Pharmaceutical, Chemical and Environmental Sciences, Faculty of Engineering and Science, University of Greenwich, UK.

Received: October 29, 2014; Accepted: November 06, 2014; Published: November 07, 2014


The objective of this study was to develop a composite buccal drug delivery wafer for protein drug delivery. The polymeric vehicle used in this study combined chitosan and sodium alginate with bovine serum albumin (BSA) as a model drug. The wafers were obtained by freeze-drying gels of the polymers in well plates. Prior to the lyophilisation process, differential scanning calorimetry was performed to establish a suitable freeze-drying cycle. Preliminary characterization experiments were undertaken to select the optimum composite gel containing sodium alginate and chitosan in a 4:1 ratio respectively for drug loading. A second series of characterisation tests were performed on the drug-loaded wafers prepared from gels containing 0.25 and 0.5 % w/w of BSA. The formulations were functionally characterised for swelling, mucoadhesive and drug dissolution properties. The morphology and crystallinity were investigated using a scanning electron microscope and X-ray diffractometer respectively. The results from drug dissolution studies over a two-hour period showed 66% and 31% cumulative drug release for the wafers obtained from gels containing 0.25 and 0.50 % w/w BSA respectively. These results show the feasibility of developing a sustained delivery system for macromolecules by combining chitosan and sodium alginate.

Keywords: Chitosan; Sodium alginate; Bovine serum albumin; Buccal delivery; Protein delivery


BSA (Bovine serum albumin); Ch (Chitosan); DSC (Differential scanning calorimetry); PAF (Peak adhesive force); PBS (Phosphate buffered saline); SA (Sodium alginate); SEM (Scanning electron microscopy); XRD (X-ray diffraction).


Mucosal drug delivery has gained interest for drug delivery involving the use of bioadhesive formulations to administer drugs via sites in the body such as buccal [1-4], nasal [5], wound surfaces [6-7] and vaginal [8] mucosa. The intimate contact between the bioadhesive dosage form and mucosa is facilitated by physico-chemical interactions which allow for an improvement of the drug's absorption and subsequent increase in its bioavailability [9]. The drug carrier system, typically a polymer hydrogel, adheres to the mucosa, via a process initiated by hydration and swelling which allows interpenetration between the bioadhesive polymeric chains and the mucin present on the mucosal membrane, resulting in the formation of weak bonds [10]. Mucosal surfaces are targeted as they present highly vascularised networks, which allow therapeutic delivery whilst avoiding pre systemic circulation (first pass metabolism). There are other benefits of mucosal drug delivery systems including increased patient compliance as there is no pain or risk of choking as for injections and tablets respectively. Drug levels remain steady therefore allowing better control; which in turn reduces the risk of toxicity, as well as complete utilization of the drug administered [11].

The lining of the oral cavity comprises the buccal (cheek muscle tissue), palatal, sublingual (floor of the mouth) and gingival areas. The sublingual and buccal areas are more useful for drug delivery as they are more permeable than any other areas of the mouth and represent roughly 60% of the total oral mucosa surface area. Despite having a smaller surface area of 100cm2 compared to the GIT and skin; which are 350,000cm2 and 20,000cm2 respectively, the oral mucosa is an area of significant interest [12]. The buccal mucosa is a highly adaptable area and considered useful for controlled drug release. One of its characteristics is that damaged tissue only requires a short period of time to heal in comparison to other areas [13].

Different active pharmaceutical ingredients with low molecular weights (small molecules) have been administered via the buccal route including analgesics such as fentanyl citrate, ACE inhibitors such as captopril and benzodiazepines such as midazolam [14]. However, the administration of macromolecules such as peptides and proteins are more challenging due to their large size and presence of charge [2, 15] and several approaches have been proposed to overcome these challenges. Ideal systems contain components such as permeation enhancers which can manipulate the site of absorption to enhance partitioning of the drug into the mucosal tissue or modification of the mucosal surface to increase solubility of the drug which increases the concentration gradient to enhance absorption [16]. Other studies have been reported which show that peptide drugs such as insulin can be transported across the mucosa through the use of enzyme inhibitors and bioadhesive polymers such as chitosan [17-20].

Sodium alginate, the salt form of alginic acid is a polysaccharide composed of 1-4 linked α-L-guluronic and β-D-mannuronic acid residues [21] and is widely used in pharmaceutical formulations due to its high bioadhesive nature, aqueous solubility and its good film forming properties [22]. Chitosan is a weak cationic polyaminosaccharide derived from deacetylation of the native polymer chitin [23], present in shellfish and discovered 200 years ago [24]. Chitosan is composed mainly of (1, 4) linked 2-amino-2- deoxy-β-D-glucan [25], and has been developed as a suitable matrix for the controlled release of protein or peptide drugs over the last two decades [26]. It has been reported that "pH sensitive hydrogels such as sodium alginate and chitosan are useful for protein delivery because of the immunogenicity of most synthetic polymers and the requirement for a harsher environment which may denature and inactivate the protein" [27]. Formulation of protein based systems using both alginate and chitosan as matrices can be achieved under relatively mild environments, therefore avoids potential damage to the proteins' native structure.

Formulations combining sodium alginate and chitosan have been reported including particulate systems (e.g. micro and nanoparticles) [28, 29] and tablets [30]. These formulations have mainly been used for small molecules or delivery via sites other than the buccal mucosa. To the best of our knowledge, no study has been reported of freeze-dried wafers combining both sodium alginate and chitosan for protein or peptide delivery via the buccal mucosa. Though similar studies have reported on buccal formulations for protein and peptide delivery, these have involved single polymers, mainly chitosan or its derivatives [4, 11, 15, 18, 19, 20]. Shaikh and co-workers reported that increasing the amount of chitosan in a composite mucoadhesive tablet formulation resulted in more controlled drug (itraconazole) release while an increase in sodium alginate resulted in improved adhesive properties of the tablet [30].

The aim of this study therefore, was to develop a lyophilised wafer as a controlled buccal delivery system for protein drugs using a combination of sodium alginate and chitosan as the polymeric matrices. Bovine serum albumin (BSA) was used as a model drug as it is a naturally occurring protein. The wafers have been characterised using various analytical techniques to evaluate the wafer's functional physical and mechanical properties.

Materials and Methods


Chitosan (medium molecular weight, 75-85% deacetylated), sodium alginate, bovine serum albumin (BSA), Bradford's reagent, mucin from porcine and gelatine were all purchased from Sigma- Aldrich, Gillingham, UK. Sodium di hydrogen orthophosphate dihydrate; acetic acid, sodium hydroxide pellets were all purchased from Fisher Scientific (UK).

Pre-formulation studies

Initial studies involved development of polymer gels to identify an optimum formulation for drug loading. Sodium alginate (SA) polymer gels were prepared at concentrations of 0.25% 0.5% and 1% w/w in distilled water with magnetic stirring at a temperature of 37°C. Chitosan (Ch) polymer gels were also prepared in the same way at the same concentrations but replacing distilled water with acetic acid solution (0.05 - 1% v/v). To obtain optimum amounts of both polymers in a composite gel (1% w/w solution), different ratios of each polymer were combined to give a total polymer weight of 0.5 g in 50ml of solution as shown in Table 1. The required amount of SA was dissolved in 25ml of distilled water (37°C) with stirring followed by the addition of 25ml of dilute acetic acid solution (0.05 - 1% v/v) after which the required amount of Ch was added. The pH of the final composite gels ranged between 4 and 5. Based on the previous criteria, the gel with SA: Ch ratio 4:1 was chosen as the ideal combination and loaded with two different concentrations of BSA (0.25 and 0.50% w/w). Different quantities (1-5 g) of the above gels were poured into separate wells of 24 well plates prior to freeze-drying to produce wafers with different thickness.