Purpose: The aim of this study is to develop, characterize and optimize composite lyophilized wafers, comprising metolose (MET), carrageenan (CAR) and low molecular weight chitosan (CS) loaded with 75 mg of aspirin, for potential delivery via the oral (buccal mucosa and GIT) route in geriatric patients with dysphagia to target deep vein thrombosis
Methods: Lyophilized drug loaded wafers were formulated by freeze-drying process. They were prepared based on the optimized blank formulations and from a further study performed to improve the drug loading capacity. The composite wafers were prepared by combining 2.5% w/v MET with CAR (MET:CAR) ratio 1:1 and 3:1, 4.0% w/v MET with CS (MET:CS) ratio 1:3 and 4.0% w/v carrageenan with CS (CAR:CS) ratio 1:1 and 1:3 (Table 1). Functional characterization tests [resistance to compressive deformation, mucoadhesion, swelling capacity (in phosphate buffered saline - PBS, and simulated saliva – SS, at pH of 6.8) and porosity (%)] were performed in order to select the optimized aspirin drug loaded wafer for advanced analytical characterization. Scanning electron microscopy (SEM) was employed to assess the surface morphology, X-ray diffraction (XRD) to investigate the physical form (crystalline/amorphous) and differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) to investigate the thermal properties of the wafers and the starting materials. Finally, in vitro dissolution studies were carried out to investigate the release profile of aspirin within 2 hours.
Results: The freeze-drying method can be used to obtain wafers of different sizes and shapes that can be easily loaded with the drug. Table 1 summarises the key functional physical properties investigated. The composite wafers obtained from 2.5% w/v MET:CAR ratio 1:1, 3:1, 4.0% w/v MET:CS ratio 3:1 and 4.0% w/v CAR:CS ratio 1:1 and 1:3 gels were elegant in appearance and non-brittle in nature and therefore suitable for potential GIT and buccal mucosa delivery. The MET content in the MET:CAR formulations influenced the wafer structure by increasing significantly (p < 0.05) the resistance to compression and making them more rigid when the MET content was higher. The swelling results from table 1 showed that % swelling capacity was higher in PBS than in SS due to the differences in ionic strength of the media . The wafers with higher resistance to compression, swelled less due to collapsed pores and the peak adhesive force (PAF) decreased due to reduced polymer-drug interaction, resulting from the collapse pores. The wafers prepared form 4.0% w/v CAR:CS gels, ratios 1:1 and 3:1, showed similar results as the 2.5% w/v MET:CAR ratios 1:1 and 3:1, however, the resistance to compression increased significantly (p < 0.05) with increased CS content resulting in a decreased swelling capacity (%) and increase in the mucoadhesion profile, which can be attributed to the fact that increasing amount of CS in CAR:CS formulations forms a gel like structure upon hydration and helps more intimate contact with the substrate. SEM showed a porous internal morphology as a result of ice nucleation formed during freeze-drying and XRD showed that the drug loaded wafers were crystalline in nature due to the high aspirin loading. The porosity results (Table 1) show that when the MET content increased in the 2.5% w/v MET:CAR ratio 1:1 and 3:1 formulations, the porosity % also increased. However, with the 4.0% w/v CAR:CS formulations, porosity % of the wafers decreased with increase in CS content from 69 ± 9 for CAR:CS 1:1 to 58 ± 7 for CAR:CS 1:3. Figure 1 shows the drug dissolution profiles of aspirin loaded wafers in PBS and SS at pH 6.8. For the 4.0% w/v CAR:CS 1:1 the release of the drug was 64.8 % within 20 minutes and for CAR:CS 1:3 the release was of 90.5% within the same time period in PBS. The release from 4.0% w/v MET:CS was of 100.0 % within 20 minutes in PBS. The % release in SS was observed to be lower than in PBS with only 20.0% released for 4.0% w/v CAR:CS 1:3 in the first 20 minutes. PBS showed higher release than SS which is related to the effect of SS on the initial swelling of the polymer matrix and subsequent drug diffusion as well as matrix erosion. This could be attributed to the difference in osmotic pressure and ionic strength as SS contains more sodium, chloride and sulfate ions than PBS.
Conclusion: Lyophilized 2.5% w/v MET: CAR 1:1 and 3:1, 4.0% w/v CAR: CS 1:1 and 3:1 as well as 4.0% MET: CS 1:3 seems to be very promising systems for the administration of low dose aspirin for older patients with dysphagia and other age related problems to target deep vein thrombosis