Preparation Of Controlled Release Microcapsules For Colon Drug Delivery Based On Polyelectrolyte Complexes

The construction of drug carrier is the basis of dosage form, and it’s also the king process of designing drug delivery system. In this work, an orifice-polymerization/membrane emulsification method was used to prepare microcapsules formed by polyelectrolyte complexes (PEC). It confirmed that the microcapsules prepared could be a good candidate as a drug carrier for colon drug delivery. Based on the principle of structure deciding performance, the formation mechanism and the structure effecting on the performance of microcapsules were investigated. The results may provide a theoretical reference for application of novel sodium cellulose sulfate-chitosan/water soluble chitosan-sodium polyphosphate (NaCS-CS/WSC-PPS) polyelectrolyte complexes.NaCS-CS/WSC-PPS microcapsules were prepared using PEC that formed by NaCS, CS/WSC and PPS, in which PPS was used as a cross-linking agent. The microcapsules had a spherical shape and a typical wall-capsule/core structure. The formation mechanism analysis indicated that when the liquid drop of CS/WSC entered the aqueous solution of NaCS and PPS, NaCS could not penetrate into the core of the liquid drop but immediately formed a membrane on the surface; however, as a small molecular PPS could penetrate the PEC membrane into the CS/WSC-core to consolidate/crosslink, thus a typical wall-capsule/core structure was fabricated. It could be used as a potential carrier for drug delivery.5-Aminosalicylic acid (5-ASA) was chosen as a model drug with small molecular. NaCS-CS-PPS microcapsules loaded with5-ASA were prepared by orifice-polymerization method. The microcapsules prepared had a spherical shape and a double-walled capsule/core structure. It had an average diameter of1.90±0.09mm with loading efficiency of60.77±0.64%and encapsulation efficiency of90.03±0.95%.5-ASA entrapped in the capsule/core structure was in a crystal form. In simulated colonic fluid (SCF, pH6.4), the microcapsules had a favorable swelling/erosion property, and the drug was released sustainably and almost completely during12h. The kinetics model fitting results indicated that the drug was released under the mechanism of Anomalous (non-Fickian) transport, which means a combination of diffusion and macromolecular relaxation processes, and followed by the solubilization/erosion procedures of the system. It had a controlled release profile and could be used to encapsulate similar drugs. The optimal preparation conditions of drug-loaded microcapsules were pH values of inner water phase and outer water phase of4.25and6.0, concentrations of NaCS and PPS of1.4%(w/v) and0.5%(w/v), respectively.Lactoferrin (LF) was chosen as a model protein drug with macromolecular. NaCS-WSC-PPS microcapsules loaded with LF were prepared by orifice-polymerization method. The microcapsules prepared had a typical wall-capsule/core structure with a regular spherical shape and an average diameter of1.97±0.10mm. The formation mechanism analysis indicated that when the liquid drop of WSC containing LF entered the aqueous solution of NaCS and PPS, a PEC membrane was immediately formed on the surface to encapsulate the drug, meanwhile PPS could penetrate the membrane into the WSC-core to consolidate/crosslink so that a typical wall-capsule/core structure was formed. The primary structures and activities of the processed LF in the microcapsules were unchanged. The microcapsules had a relatively higher drug loading and encapsulation efficiency of45.6±0.6%and70.7±0.9%. With a trend of slow increasing, the drug was released sustainably and almost completely during12h under weak acidic conditions of SCF pH5.5and6.4; however, it showed an accelerating release behavior under neutral conditions (pH7.0). It can be inferred that the drug was released under the mechanism of non-Fickian/Anomalous transport, that is, a combination of diffusion/dissolution and macromolecular swelling/erosion processes.Degree of substitution (DS) of NaCS (DS:0.51and DS:0.66) had some effects on the performances of LF loaded NaCS-WSC-PPS microcapsules. NaCS (DS:0.51) with low DS but long molecular chains was helpful to form a membrane on the surface of WSC-core quickly and prevent PPS penetrating the membrane, hence the interior structure was a little looser and the size of drug-loaded microcapsules was a little bigger. Compared with the microcapsules with DS of0.66, the microcapsules (DS:0.51) had a lower drug loading and encapsulation efficiency but a higher erosion ratio; and the drug was released sustainably and completely during the12h study with a higher percentage of drug release in unit time (SCF, pH6.4). The kinetics model fitting studies showed that the drug release was under Anomalous (non-Fickian) transport in both of the microcapsules (DS:0.51and DS:0.66) which could be used as a controlled protein drug carrier with special release profiles.The micron-sized calcium alginate (CA)/NaCS-WSC microcapsules were prepared by membrane emulsification method using NaCS, sodium alginate (NaAlg) and WSC as raw materials. The CA/NaCS microspheres prepared had a good dispersivity and a spherical shape with an emulsifier volume ratio of7:3(Span80:Tween80) and a concentration of cross-linking agent of1.5%(w/v) calcium chloride and5%(w/v) sodium chloride. The CA/NaCS-WSC microcapsules had a spherical shape with an average diameter of62.36±13.87μn. A fluorescent ring could be seen obviously on the surface of CA/NaCS-WSC microcapsules when WSC labeled by fluorescein isothiocyanate (FITC). The formation mechanism studies showed that when the calcium chloride solution entered the emulsion of NaAlg/NaCS, Ca2+could diffuse into the droplets of NaAlg/NaCS quickly forming CA/NaCS microspheres; however, NaCS would be locked in the latticed structure of CA hydrogels, it would remove from the interior to the surface of CA hydrogels under the role of opposite electric attraction, meanwhile react with WSC forming a PEC film, thus a capsule/core structure of CA with a NaCS-WSC PEC film as the outer membrane was fabricated.In a word, when designing and operating at the optimum conditions, the PEC microcapsules prepared by orifice-polymerization/membrane emulsification method could be used as a novel micro-drug-carrier for colon drug delivery. The drug-loaded microcapsules had a relatively higher drug loading efficiency and a typical wall-capsule/core structure. It’s expected to be a promising carrier applied for designing oral colon-specific drug delivery system (OCDDS) with controlled release profiles.