| Oral colon-specific drug delivery system is a novel drug delivery system, which targets drug to the colon for treatment of local or systemic disorders with proper methods. With colon-specific drug delivery system, drug could act directly on the lesion site, reduce side effect induced by drug release in the upper gastrointestinal tract, and enable biomacromolecules to be used for oral administration. Carriers play the key role in the oral colon-specific drug delivery systems. They have decisive effect on the release, as well as the target sites of active components. Among various carriers, natural polysaccharides are investigated more frequently for oral colon-specific delivery systems, owing to their good biocompatibility and biodegradability. Chitosan and sodium cellulose sulfate (NaCS) are both derivatives of natural polysaccharides with abundant resources. The combination of the two polymers could form polyelectrolyte complex (PEC) insoluble in water. It was reported that chitosan/NaCS PEC had great potential for colon-specific drug delivery systems. This work will focus on the mechanical and swelling properties, biodegradation and drug permeation of chitosan/NaCS complex film. In addition, we explored the preparation of microspheres based on chitosan and NaCS and its application in the delivery of proteinic drugs.Considering the problems in the measurement of NaCS properties, gel permeation chromatograph, BaSO4 turbidimetry and enzymatic degradation were employed to determine the molecular weight, structure and degradation properties of NaCS, as well as the influence of the preparation conditions. The results showed that increasing the reaction time would lead to lower molecular weight. Meanwhile, the polydispersity changed with the reaction time. With the increase of the reaction time, the polydispersity increased and obtained the maximum (5.16) at 6 h. However, further increase would cause a sharp decrease of polydispersity. When it came to the substitution degree of NaCS, it increased with increase of reaction time gradually, and kept about 0.5 from 6 h. In addition, the degradation of NaCS by cellulose decreased with the increase of the preparation time of NaCS. The results showed that the preparation conditions have great influence on the properties and application of NaCS.Effects of the weight of chitosan to NaCS on the morphology, the mechanical (strength and brittleness) and swelling properties of the complex film were studied. Obviously, chitosan/NaCS complex films were porous membrane. When chitosan/ NaCS ratio was 1:2, the complex film was smooth, with diverse, irregular pores. It was confirmed by mechanical and swelling studies that the optimum chitosan/NaCS ratio was about 1:2. The mechanical and swelling properties of chitosan/NaCS films could be controlled by adjusting chitosan Mw, and the Mw and substitution degree of NaCS. Higher elongation at break of the complex films would be obtained with chitosan of higher Mw. Meanwhile, the increase of the Mw and substitution degree of NaCS would cause the decrease of the swelling ratios. In addition, pH of the solution has great influence on the swelling ratios of chitosan/NaCS films.The biodegradation characteristics of chitosan, NaCS and chitosan/NaCS PEC films were investigated with main gastrointestinal enzymes, including pepsin, trypsin, lipase,α-amylase, and cellulase. The results showed that pepsin, amylase, trypsin and lipase have the appreciable hydrolytic activity to chitosan, but can not degrade NaCS. However, cellulase showed high cellulosic activity and low chitosanolytic activity. For the hydrolysis of chitosan/NaCS films, the degradation rates were greatly influenced by the molecular weights of chitosan and NaCS. Furthermore, in order to study biodegradation behaviors of chitosan/NaCS complex in gastrointestinal tract, the simulated gastric fluids (SGF), simulated intestinal fluids (SIF) and simulated colonic fluids (SCF) were prepared by adding enzymes to the solutions, respectively, with pH 1.5,7.4 and 6.4. In vitro tests showed that different formulations caused diverse disintegration time of the films through the gastrointestinal tract. For example, when the Mw of chitosan and NaCS were 563.3 and 169.7 kDa, respectively, the complex film would disintegrate after treatment in SGF for 3 h. However, when the Mw of chitosan and NaCS were 563.3 and 710.8 kDa, respectively, the complex film would keep intact after treatment in SGF for 3 h and SIF for 6 h. The results indicated the PEC based on chitosan and NaCS showed good potential for the gastrointestinal delivery systems.In order to assess the controlled drug release behavior of films composed of chitosan and sodium cellulose sulfate (NaCS), the permeability of drugs across chitosan/NaCS films were measured. The permeability experiments were conducted with three substances, including paracetamol,5-aminosalicylic acid (5-ASA) and protein mixture from Escherichia coli. The results showed that the permeability of chitosan/NaCS films was closely related to the swelling properties. In addition, both the permeability and swelling properties of chitosan/NaCS films were markedly influenced by the weight ratio of chitosan to NaCS, the molecular weight (Mw) of chitosan and NaCS as well as pH values. Furthermore, the permeability of paracetamol across the film was conducted in simulated gastrointestinal solutions for in vitro tests. The results showed that the films have the gastro-, intestine-and colon-targeted drug release properties, respectively, when they were exposed to the simulated gastrointestinal fluids in sequence.Chitosan/NaCS was found to have great potential in the delivery of protein in ourwork. So double-walled microspheres based on chitosan, NaCS and sodium tripolyphosphate (TPP) were prepared by dipping method. It was found by fourier transform infrared spectroscopy (FTIR) that the shell of the microspheres was composed of chitosan, NaCS and TPP, while the inner layer was based on chitosan and TPP. The concentration of TPP and the reaction time had marked influence on the morphology of the double-walled microspheres. When the concentration of TPP was low, the surface of the microspheres seemed smooth. Nevertherless, higher concentration of TPP and increase of the reaction time would cause shrinkage of the surface of the microspheres. When the reaction time was 10 min, smooth microspheres would be obtained.Furthermore, encapsulation efficiency (EE) and loading efficiency (LE) and the release behavior of the microspheres were investigated with bovine serum albumin (BSA) as the model drug. The concentration of TPP had great influence on EE and LE. Without addition of TPP, rather high EE (99.8%±0.1%) and LE (37.5%±1.9%) could be achieved. However, quite low LE (4.5%±2.7%) would be got with chitosan/TPP microspheres. As for chitosan/NaCS/TPP double-walled microspheres, high EE (above 79%) and LE (above 18%) could also be obtained. In order to assess in vitro release of BSA from chitosan/NaCS/TPP double-walled microspheres, the environment of SGF, SIF and SCF were simulated with solutions of pH 2.0,7.4 and 6.4, respectively. Two-step swelling performance was observed with concentration of TPP≥1.0%(w/v). However, the release of BSA from the microspheres was not in conformance with the swelling studies. It should be noted that almost no BSA released when the microspheres with 1.5% TPP was at pH 2.0 and 6.4. Less than 25% BSA was released even after treatment in the solution of pH7.4 for 4 h. Addition of cellulose to the solution of pH 6.4 would cause marked increase of BSA from the microsphers, from 1.9% to over 50% after 120 min.To prepare uniform double-walled microspheres, microfluid control was employed. Chitosan microspheres with diameter 100-200μm and distribution efficiency≤6% could be obtained with 2% (w/v) chitosan and liquid paraffin (5% Span 80). This work will be useful for the development of chitosan/NaCS complex in the technology of pharmaceutics. |
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