Nasal delivery of insulin using chitosan microspheres

Nasal delivery of insulin is an alternative route for administration of this drug. The objective of this study was preparation of chitosan microspheres for insulin nasal delivery. After preparation of insulin chitosan microspheres by emulsification-cross linking process, the effect of chitosan quantity (200–400?mg), cross-linker type (ascorbic acid or ascorbyl palmitate) and amount (70–140?mg) were studied on the morphology, particle size, loading efficiency, flow and release of insulin from the microspheres by a factorial design. Optimized formulation was administered nasally in four groups of diabetic rats and their serum insulin levels were analysed by the insulin enzyme immunoassay kit and the serum glucose by the glucose oxidase kits. Insulin loading in microspheres was between 4.7–6.4% w/w, preparation efficiency more than 65% and mean particle size was 20–45?µm. In most cases, drug released followed a Higuchi model. Ascorbic acid caused an increase in stability, particle size and T_50% while decreased the loading efficiency and production efficiency. Increasing the chitosan content, increased particle size, flow and insulin release rate form the microspheres. The increase of cross-linking percentage decreased the flow and size of the microspheres while increase of cross-linking percentage promoted the stability and decreased DE₈% of insulin. Microspheres containing 400?mg of chitosan and 70?mg ascorbyl palmitate caused a 67% reduction of blood glucose compared to i.v. route and absolute bioavaliability of insulin was 44%. The results showed that chitosan microspheres of insulin are absorbable from nasal route.     

Nasal Delivery of Insulin Using Novel Chitosan Based Formulations: A Comparative Study in Two Animal Models Between Simple Chitosan Formulations and Chitosan Nanoparticles

Purpose. To investigate whether the widely accepted advantages associated with the use of chitosan as a nasal drug delivery system, might be further improved by application of chitosan formulated as nanoparticles. Methods. Insulin-chitosan nanoparticles were prepared by the ionotropic gelation of chitosan glutamate and tripolyphosphate pentasodium and by simple complexation of insulin and chitosan. The nasal absorption of insulin after administration in chitosan nanoparticle formulations and in chitosan solution and powder formulations was evaluated in anaesthetised rats and/or in conscious sheep. Results. Insulin-chitosan nanoparticle formulations produced a pharmacological response in the two animal models, although in both cases the response in terms of lowering the blood glucose levels was less (to 52.9 or 59.7% of basal level in the rat, 72.6% in the sheep) than that of the nasal insulin chitosan solution formulation (40.1% in the rat, 53.0% in the sheep). The insulin-chitosan solution formulation was found to be significantly more effective than the complex and nanoparticle formulations. The hypoglycaemic response of the rat to the administration of post-loaded insulin-chitosan nanoparticles and insulin-loaded chitosan nanoparticles was comparable. As shown in the sheep model, the most effective chitosan formulation for nasal insulin absorption was a chitosan powder delivery system with a bioavailability of 17.0% as compared to 1.3% and 3.6% for the chitosan nanoparticles and chitosan solution formulations, respectively. Conclusion. It was shown conclusively that chitosan nanoparticles did not improve the absorption enhancing effect of chitosan in solution or powder form and that chitosan powder was the most effective formulation for nasal delivery of insulin in the sheep model.     

Chitosan Reduced Gold Nanoparticles as Novel Carriers for Transmucosal Delivery of Insulin

Purpose Colloidal metallic systems have been recently investigated in the area of nanomedicine. Gold nanoparticles have found themselves useful for diagnostic and drug delivery applications. Herein we have reported a novel method for synthesis of gold nanoparticles using a natural, biocompatible and biodegradable polymer; chitosan. Use of chitosan serves dual purpose by acting as a reducing agent in the synthesis of gold nanoparticles and also promotes the penetration and uptake of peptide hormone insulin across the mucosa. To demonstrate the use of chitosan reduced gold nanoparticles as carriers for drug delivery, we report herein the transmucosal delivery of insulin loaded gold nanoparticles. Materials and Methods Gold nanoparticles were prepared using different concentrations of chitosan (from 0.01% w/v up to 1% w/v). The gold nanoparticles were characterized for surface plasmon band, zeta potential, surface morphology, in vitro diffusion studies and fluorescence spectroscopy. The in vivo studies in diabetic male Wistar rats were carried out using insulin loaded chitosan reduced gold nanoparticles. Results Varying concentrations of chitosan used for the synthesis of gold nanoparticles demonstrated that the nanoparticles obtained at higher chitosan concentrations (>0.1% w/v) were stable showing no signs of aggregation. The nanoparticles also showed long term stability in terms of aggregation for about 6 months. Insulin loading of 53% was obtained and found to be stable after loading. Blood glucose lowering at the end of 2 h following administration of insulin loaded gold nanoparticles to diabetic rats was found to be 30.41 and 20.27% for oral (50 IU/kg) and nasal (10 IU/kg), respectively. Serum gold level studies have demonstrated significant improvement in the uptake of chitosan reduced gold nanoparticles. Conclusions The synthesis of gold nanoparticles using a biocompatible polymer, chitosan would improve its surface properties for binding of biomolecules. Our studies indicate that oral and nasal administration of insulin loaded chitosan reduced gold nanoparticles has led to improved pharmacodynamic activity. Thus, chitosan reduced gold nanoparticles loaded with insulin prove to be promising in controlling the postprandial hyperglycemia.     

Nasal delivery of insulin using chitosan microspheres

Nasal delivery of insulin is an alternative route for administration of this drug. The objective of this study was preparation of chitosan microspheres for insulin nasal delivery. After preparation of insulin chitosan microspheres by emulsification-cross linking process, the effect of chitosan quantity (200-400mg), cross-linker type (ascorbic acid or ascorbyl palmitate) and amount (70-140 mg) were studied on the morphology, particle size, loading efficiency, flow and release of insulin from the microspheres by a factorial design. Optimized formulation was administered nasally in four groups of diabetic rats and their serum insulin levels were analysed by the insulin enzyme immunoassay kit and the serum glucose by the glucose oxidase kits. Insulin loading in microspheres was between 4.7-6.4% w/w, preparation efficiency more than 65% and mean particle size was 20-45 microm. In most cases, drug released followed a Higuchi model. Ascorbic acid caused an increase in stability, particle size and T50%, while decreased the loading efficiency and production efficiency. Increasing the chitosan content, increased particle size, flow and insulin release rate form the microspheres. The increase of cross-linking percentage decreased the flow and size of the microspheres while increase of cross-linking percentage promoted the stability and decreased DE8% of insulin. Microspheres containing 400mg of chitosan and 70mg ascorbyl palmitate caused a 67% reduction of blood glucose compared to i.v. route and absolute bioavaliability of insulin was 44%. The results showed that chitosan microspheres of insulin are absorbable from nasal route.     

Intranasal delivery of tapentadol hydrochloride–loaded chitosan nanoparticles: formulation,characterisation and its in vivo evaluation

The aim of the present investigation was to formulate tapentadol hydrochloride–loaded chitosan nanoparticles (CS-NPs) for nose to brain delivery. Chitosan nanoparticles were prepared using ionotropic gelation technique. Optimisation of the formulation and process parameters was done using Box–Behnken Design. The entrapment efficiency, drug loading, Z-average size and zeta potential of the optimised batch were 63.49?±?1.61%, 17.25?±?1.38%w/w, 201.2?±?1.5?nm and +49.3?mV, respectively. In-vitro release study showed 84.04?±?1.53% drug release after 28?h, while ex vivo studies indicated higher permeation of CS-NPs through nasal mucosa. The nanoparticles exhibited good mucoadhesiveness, haemocompatibility and safety as evidenced by histopathology. The results of the pharmacodynamic study revealed prolongation of the analgesic activity. The intranasal instillation of CS-NPs resulted in the higher concentrations in brain compared to the drug solution and intravenous administration of CS-NPs. In a nutshell, intranasal administration of tapentadol hydrochloride–loaded CS-NPs is a promising approach for effective pain management.     

Nasal absorption enhancement of insulin using PEG-grafted chitosan nanoparticles.

The objective of this work was to explore the potential of polyethylene glycol-grafted chitosan (PEG-g-chitosan) nanoparticles as a system for improving the systemic absorption of insulin following nasal administration. Insulin-loaded PEG-g-chitosan nanoparticles were prepared by the ionotropic gelation of PEG-g-chitosan solution using tripolyphosphate ions as the crosslinking agent. The nanoparticles were in the size range 150-300 nm, had a positive electrical charge (+16 to +30 mV) and were associated with insulin (loading efficiency 20-39%). The physicochemical properties of nanoparticles were affected by the composition of the copolymer. In vitro insulin release studies showed an initial burst followed by a slow release of insulin. Intranasal administration of PEG-g-chitosan nanoparticles in rabbits enhanced the absorption of insulin by the nasal mucosa to a greater extent than a suspension of insulin-PEG-g-chitosan and control insulin solution. PEG-g-chitosan nanoparticles are promising vehicles for insulin transport through the nasal mucosa.     

雌二醇鼻用壳聚糖纳米粒的制备及体外性质的考察

目的 研究雌二醇壳聚糖纳米粒的理化性质及鼻黏膜吸收动力学。方法 以三聚磷酸钠( TPP) 为交联剂,用生物降解聚合物材料壳聚糖(CS) 制成纳米粒,通过离子凝胶化法制备雌二醇（E2）壳聚糖纳米粒,分别用动态光散射法仪测定了纳米粒的粒径,高速离心法测定其包封率,透析袋法对其体外释放过程进行了研究,采用大鼠在体灌流模型,考察了质量浓度分别为3.86、7.20、24.75、32.74、51.62 mg&;#8226;L^-1的雌二醇壳聚糖纳米粒的鼻黏膜吸收动力学。结果 当m (CS) : m (TPP)在3:1～7:1之间时,可以形成壳聚糖纳米粒,5:1时得到得纳米粒最佳,平均粒径为(279.1±7.2) nm。随着E2质量浓度的增加,包封率有降低的趋势;E2在前2 h内发生突释现象,12 h释放量达80%以上。在循环液体积为5 mL、流速为2.5 mL&;#8226;min^-1下,不同质量浓度的雌二醇壳聚糖纳米粒鼻黏膜吸收速度常数不同,且随药液质量浓度的增加而增大。结论 通过离子凝胶化法制备的壳聚糖纳米粒外观呈半透明状,粒径较为均一,有一定的缓释效果,鼻黏膜吸收具有浓度依赖性,一定质量浓度条件下的吸收动力学过程为符合零级动力学。     

Nanoparticles of quaternized chitosan derivatives as a carrier for colon delivery of insulin: ex vivo and in vivo studies

The aim of the present study was to develop insulin nanoparticulate systems by using chitosan (CS), triethylchitosan (TEC) and dimethyl-ethylchitosan (DMEC, a new quaternized derivative of chitosan) for colon delivery. The nanoparticles were prepared by the polyelectrolyte complexation (PEC) method. Particle size distribution, zeta potential and polydispersity index of the nanoparticles were determined using dynamic light scattering technique. Transmission electron microscopy (TEM) was also used to observe the morphology of the nanoparticles. It was found that the nanoparticles carried positive charges and showed a size distribution in the range of 170-270 nm with spherical morphology and smooth surface structure. The amount of insulin loaded into the nanoparticles was determined by measuring the association efficiency and also the content of insulin in the nanoparticles. Insulin loading was found to be more than 80% for all of the nanoparticles. In vitro release studies showed a small burst effect at the beginning and then a sustained release characteristic for 5h. Ex vivo investigations revealed better insulin transport across the colon membrane of rats for nanoparticles made with quaternized derivatives than those made of chitosan. In vivo studies in rats have showed enhanced colon absorption of insulin by using these nanoparticles compared to free insulin in diabetic rats. The insulin absorption from the rat's colon was evaluated by its hypoglycemic effect.     

Biodegradable Nanoparticles Containing Doxorubicin-PLGA Conjugate for Sustained Release

Purpose. Doxorubicin was chemically conjugated to a terminal end group of poly(D,L-lactic-co-glycolic acid) [PLGA] and the doxorubicin-PLGA conjugate was formulated into nanoparticles to sustain the release of doxorubicin. Methods. A hydroxyl terminal group of PLGA was activated by p-nitrophenyl chloroformate and reacted with a primary amine group of doxorubicin for conjugation. The conjugates were fabricated into ca. 300 nm size nanoparticles by a spontaneous emulsion-solvent diffusion method. The amount of released doxorubicin and its PLGA oligomer conjugates was quantitated as a function of time. The cytotoxicity of the released species was determined using a HepG2 cell line. Results. Loading efficiency and loading percentage of doxorubicin-PLGA conjugate within the nanoparticles were 96.6% and 3.45 (w/w) %, respectively while those for unconjugated doxorubicin were 6.7% and 0.26 (w/w) %, respectively. Both formulation parameters increased dramatically due to the hydrophobically modified doxorubicin by the conjugation of PLGA. The nanoparticles consisting of the conjugate exhibited sustained release over 25 days, whereas those containing unconjugated free doxorubicin showed rapid doxorubicin release in 5 days. A mixture of doxorubicin and its PLGA oligomer conjugates released from the nanoparticles had comparable IC₅₀ value in a HepG2 cell line compared to that of free doxorubicin. Sustained drug release was attributed to the chemical degradation of conjugated PLGA backbone, which permitted water solubilization and subsequent release of doxorubicin conjugated PLGA oligomers into the medium. Conclusions. The conjugation approach of doxorubicin to PLGA was potentially useful for nanoparticle formulations that require high drug loading and sustained release. The doxorubicin-PLGA oligomer conjugate released in the medium demonstrated a slightly lower cytotoxic activity than free doxorubicin in a HepG2 cell line.     

依托泊苷壳聚糖胶束的制备及壳聚糖促进依托泊苷肠吸收作用的研究

目的 制备依托泊苷壳聚糖胶束,并研究壳聚糖对依托泊苷肠吸收的促进作用。方法 用透析法制备依托泊苷壳聚糖胶束,建立依托泊苷HPLC含量测定方法,测定了其包封率与载药量;采用大鼠在体肠循环实验,研究不同剂量壳聚糖对依托泊苷全肠段和各个肠段吸收的影响。结果 壳聚糖胶束平均粒径为139.5 nm,多分散系数为0.569;依托泊苷标准曲线为A=8 436.8C-4 963.8,r=1.000 0,日内、日间精密度符合要求;包封率为（47.3±2.84）%,载药量为（1.10±1.27）%;随着壳聚糖浓度的增加,依托泊苷在全肠段的单位面积吸收量有不同程度的增加;壳聚糖对依托泊苷的吸收促进作用存在着肠道特异性,作用大小顺序：回肠 >空肠 >十二指肠。结论 在十二指肠、空肠和回肠,壳聚糖都不同程度促进了药物的吸收,且在空肠和回肠有显著性的影响。     

Immunoadjuvant potential of cross-linked dextran microspheres mixed with chitosan nanospheres encapsulated with tetanus toxoid

Context: Nasal mucosa is a desirable route for mucosal vaccine delivery. Mucosal co-administration of chitosan nanoparticles with absorption enhancers such as cross-linked dextran microspheres (CDM, Sephadex^®) is a promising antigen delivery system.

Objective: In the current study, the chitosan nanospheres loaded with tetanus toxoid (CHT:TT NPs) was prepared and characterized. The immune responses against tetanus toxoid after nasal administration of CHT:TT NPs alone or mixed with CDM were also determined.

Materials and methods: Chitosan nanospheres were prepared by ionic gelation method. Particle size, releasing profile and antigen stability were evaluated by dynamic light scattering, diffusion chamber and SDS-PAGE methods, respectively. Rabbits were nasally immunized with different formulations loaded with 40 Lf TT. After three times immunizations with 2 weeks intervals, sera IgG titres and nasal lavage sIgA titres were determined.

Results: Mean size of CHT NPs and CHT:TT NPs were 205?±?42?nm and 432?±?85?nm, respectively. The release profile showed that 42.4?±?10.5% of TT was released after 30?min and reached to a steady state after 1.5?h. Stability of encapsulated TT in nanospheres was confirmed by SDS-PAGE. The antibody titres showed that CHT:TT NPs-induced antibody titres were higher than TT solution. CHT NPs mixed with CDM induced the systemic IgG and nasal lavage sIgA titres higher than intranasal administration of TT solution (p?Discussion and conclusion: As the results indicated, these CHT:TT NPs when co-administered with CDM were able to induce more immune responses and have the potential to be used in mucosal immunization.     

Chitosan microspheres of aceclofenac: In vitro and in vivo evaluation

The objective of this investigation was to achieve controlled drug release of Aceclofenac (ACE) microspheres and to minimize local side-effects in the gastrointestinal tract (GIT). Sustained release chitosan microspheres containing ACE were prepared using double-emulsion solvent evaporation method (O/W/O). Chitosan microspheres were prepared by varying drug to polymer ratio (1:3, 1:4, 1:5 and 1:6). Microspheres were characterized for morphology, swelling behavior, mucoadhesive properties, FTIR and DSC study, drug loading efficiency, in vitro release, release kinetics, and in vivo study was performed on rat model. ACE-loaded microspheres were successfully prepared having production yield, 57–70% w/w. Drug encapsulation efficiency was ranging from 53–72% w/w, Scanning electron microscopy (SEM) revealed particle size of microspheres was between 39 and 55 μm. FTIR spectra and DSC thermograms demonstrated no interaction between drug and polymer. The in vitro release profiles of drug from chitosan microspheres showed sustained-release pattern of the drug in phosphate buffer, pH 6.8. In vitro release data showed correlation (r² > 0.98), good fit with Higuchi/Korsmeyer-Peppas models, and exhibited Fickian diffusion. ACE microspheres demonstrated controlled delivery of aceclofenac and apparently, no G.I.T. erosion was noticed.     

Uptake and Transport of PEG-Graft-Trimethyl-Chitosan Copolymer–Insulin Nanocomplexes by Epithelial Cells

Purpose The effect of chitosan and polyethylene glycol (PEG)ylated trimethyl chitosan copolymer structure on the uptake and transport of insulin nanocomplexes was evaluated and transport mechanisms were investigated. Methods Insulin nanocomplexes were prepared from chitosan and its copolymers by self-assembly. Complex uptake in Caco-2 cells was quantified by measuring the cell-associated fluorescence and cellular localization was visualized by confocal laser scanning microscopy (CLSM) using tetra-methyl-rhodamine isothiocyanate-labeled insulin. The transport of selected insulin complexes through Caco-2 monolayers was then investigated and compared with in vivo uptake by nasal epithelium in diabetic rats. Results All complexes were 200–400 nm in diameter, positively charged, and displayed an insulin loading efficiency of approximately 90%. In vitro release of insulin from the complexes was dependent on the medium pH. Insulin uptake was enhanced by nanocomplex formation, and was dependent on incubation time, temperature, and concentration. Complex uptake in Caco-2 cells was inhibited by 25.2 ± 1.3%, 13.0 ± 1.0%, and 16.6 ± 0.7% in the presence of cytochalasin D, sodium azide, and 2,4-dinitrophenol, respectively. The uptake mechanism was assumed to be adsorptive endocytosis. Additionally, cell uptake efficiency was shown to be influenced by a combination of polymer molecular weight, viscosity, and positive charge density. However, none of the nanocomplexes displayed improved transport properties when compared to insulin transport data after 2 h incubation with Caco-2 monolayers. This result was further confirmed with animal experiments. Conclusions Small, stable insulin nanocomplexes were formed using PEGylated trimethyl chitosan copolymers, which significantly enhanced the uptake of insulin in Caco-2 cells by adsorptive endocytosis. However, nanocomplexation did not seem to enhance transcellular insulin transport across cell monolayers, which is in line with animal data in rats. This implies that PEGylated trimethyl chitosan complexes with insulin need further optimization and the Caco-2 cell line is a predictable in vitro cell culture model for drug absorption.     

Nasal insulin delivery in the chitosan solution: in vitro and in vivo studies

The effects of chitosan concentrations, osmolarity, medium and absorption enhancers in the chitosan solution on nasal insulin delivery were studied in vitro and in vivo. The penetration of insulin through the mucosa of rabbit nasal septum was investigated by measuring the transmucosal flux in vitro, while the nasal absorption of insulin in vivo was assessed by the efficiency in lowering the blood glucose levels in normal rats. It was demonstrated that increasing concentrations of chitosan up to 1.5% (w/v) caused an increase in the permeability of insulin across the nasal mucosa. Insulin given intranasally in hypo- or hyperosmotic formulation showed a higher hypoglycemic effect than insulin delivered in isoosmotic formulation. Insulin formulation in chitosan solution prepared with deionized water brought to a higher relative pharmacological bioavailability (Fr) value than that prepared with 50 mM pH 7.4 phosphate buffer. A formulation containing both 1% chitosan and 0.1% ethylenediaminetetraacetic acid (EDTA), 5% polysorbate 80 (Tween 80) or 1.2% beta-cyclodextrin (beta-CD) did not lead to a higher Fr than insulin formulated with 1% chitosan alone. The formulation containing both 5% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and 1% chitosan was more effective at reducing blood glucose levels than the formulation containing 5% HP-beta-CD or 1% chitosan alone. The studies indicated that chitosan concentrations, osmolarity, medium and absorption enhancers in chitosan solution have significant effect on the insulin nasal delivery. The results of in vitro experiments were in good agreement with that of in vivo studies.     

Nasal delivery of insulin using bioadhesive chitosan gels

Recently nasal delivery of insulin has gained considerable attention. Some limitations of this route include rapid mucociliary clearance of the drug from the site of deposition resulting in short time span available for absorption and low permeability of the nasal membrane for peptides. The objective of the present study was development of a chitosan bioadhesive gel for nasal delivery of insulin. A nasal perfusion test was used to study the toxicity of 4 absorption enhancers: saponin, sodium deoxycholate, ethylendiamine tetra-Acetic Acid (EDTA) and lecithin. The gels contained 4000 Iu/dl insulin, 2 or 4% of low and medium molecular weight of chitosan, and lecithin or EDTA. Drug release was studied by a membraneless diffusion method and bioadhesion by a modified tensiometry test. The optimized gel was administered nasally in diabetic rats. The serum insulin levels were analyzed by an insulin enzyme immunoassay kit and serum glucose by glucose oxidase method kits. Formulations containing 2% of low molecular weight of chitosan with EDTA had higher release percentage and dissolution efficiency (DE)_2.5%, lower T_50% (Time required to release 50% of the drug), mean dissolution time, and bioadhesion than gels containing 4% of medium molecular weight of chitosan with lecithin. Insulin was released by a zero-order kinetic from the gels. The gel of 2% medium molecular weight of chitosan with EDTA caused increase in insulin absorption and reduction the glucose level by as much as 46% of the intravenous route. Considering our in vitro and in vivo studies, the proposed gel formulation could be a useful preparation for controlled delivery of insulin through the nasal route.     

Plasmid DNA loaded chitosan nanoparticles for nasal mucosal immunization against hepatitis B

This work investigates the preparation and in vivo efficacy of plasmid DNA loaded chitosan nanoparticles for nasal mucosal immunization against hepatitis B. Chitosan pDNA nanoparticles were prepared using a complex coacervation process. Prepared nanoparticles were characterized for size, shape, surface charge, plasmid loading and ability of nanoparticles to protect DNA against nuclease digestion and for their transfection efficacy. Nasal administration of nanoparticles resulted in serum anti-HBsAg titre that was less compared to that elicited by naked DNA and alum adsorbed HBsAg, but the mice were seroprotective within 2 weeks and the immunoglobulin level was above the clinically protective level. However, intramuscular administration of naked DNA and alum adsorbed HBsAg did not elicit sIgA titre in mucosal secretions that was induced by nasal immunization with chitosan nanoparticles. Similarly, cellular responses (cytokine levels) were poor in case of alum adsorbed HBsAg. Chitosan nanoparticles thus produced humoral (both systemic and mucosal) and cellular immune responses upon nasal administration. The study signifies the potential of chitosan nanoparticles as DNA vaccine carrier and adjuvant for effective immunization through non-invasive nasal route.     

Intestinal Absorption of Octreotide Using Trimethyl Chitosan Chloride: Studies in Pigs

Purpose. To investigate the enhancing effect of trimethyl chitosan chloride (TMC) on the enteral absorption of octreotide and to delineate the required doses of both TMC and peptide in vivo in juvenile pigs. Methods. Six female pigs (body weight, 25 kg) were operated to induce a stoma at the beginning of their jejunum and to insert an in-dwelling fistula for intrajejunal (IJ) administration of the formulations. A silicone cannula was inserted at the jugular vein for blood sampling. One week after surgery the pigs received IJ octreotide solution administrations with or without TMC at pH 7.4 or chitosan HCl at pH 5.5. For determining bioavailability (F) values, the pigs also received an octreotide solution intravenously (IV). Blood samples were taken from the cannulated jugular vein and subsequently analyzed by radioimmunoassay. Results. Intrajejunal administration of 10 mg octreotide without any polymer (control solution) resulted in F values of 1.7 ± 1.1% (mean ± SE). Chitosan HCl 1.5% (w/v) at pH 5.5 led to a 3-fold increase in F compared to the control (non-polymer containing) formulations. Co-administration of octreotide with 5 and 10% (w/v) TMC at pH 7.4 resulted in 7.7- and 14.5-fold increase of octreotide absorption, respectively (F of 13.9 ± 1.3% and 24.8 ± 1.8%). IJ administration of 5 mg octreotide solutions resulted in low F values of 0.5 ± 0.6%, whereas co-administration with 5% (w/v) TMC increased the intestinal octreotide bioavailability to 8.2 ± 1.5%. Conclusions. Cationic polymers of the chitosan type are able to enhance the intestinal absorption of the peptide drug octreotide in pigs. In this respect, TMC at neutral pH values of 7.4 appears to be more potent than chitosan HCl at a weak acidic pH of 5.5.     

Development of drug-loaded chitosan–vanillin nanoparticles and its cytotoxicity against HT-29 cells

Chitosan as a natural polysaccharide derived from chitin of arthropods like shrimp and crab, attracts much interest due to its inherent properties, especially for application in biomedical materials. Presently, biodegradable and biocompatible chitosan nanoparticles are attractive for drug delivery. However, some physicochemical characteristics of chitosan nanoparticles still need to be further improved in practice. In this work, chitosan nanoparticles were produced by crosslinking chitosan with 3-methoxy-4-hydroxybenzaldehyde (vanillin) through a Schiff reaction. Chitosan nanoparticles were 200–250?nm in diameter with smooth surface and were negatively charged with a zeta potential of???17.4?mV in neutral solution. Efficient drug loading and drug encapsulation were achieved using 5-fluorouracil as a model of hydrophilic drug. Drug release from the nanoparticles was constant and controllable. The in vitro cytotoxicity against HT-29 cells and cellular uptake of the chitosan nanoparticles were evaluated by methyl thiazolyl tetrazolium method, confocal laser scanning microscope and flow cytometer, respectively. The results indicate that the chitosan nanoparticles crosslinked with vanillin are a promising vehicle for the delivery of anticancer drugs.     

Chitosan-based hydrogels for nasal drug delivery: from inserts to nanoparticles

Importance of the field: Chitosan represents a multifunctional polymer, featuring both mucoadhesive and permeation-enhancing properties and therefore is a widely studied excipient for mucosal drug delivery. As regards nasal administration, chitosans have been used for the preparation of gels, solid inserts, powders and nanoparticles in which a three-dimensional network can be recognized.

Areas covered in this review: This review provides a discussion of the different nasal dosage forms based on chitosan hydrogels. In the first section intranasal delivery is discuss as a useful tool for non-invasive administration of drugs intended for local or systemic treatments. Then chitosan-based hydrogels are described with a focus on their mucoadhesive and permeation-enhancing ability as well as their capacity of controlled drug release. Finally, a detailed discussion regarding several examples of the different nasal dosage forms is reported, including considerations on in vitro, ex vivo and in vivo studies.

What the reader will gain: Summary and discussion of recent data on the different pharmaceutical forms based on chitosan hydrogels could be of interest to researchers dealing with nasal drug delivery.

Take home message: The aim of this review is to stimulate further investigations in order to achieve the collection of harmonized data and concrete clinical perspectives.     

Mutual Inhibition of the Insulin Absorption-Enhancing Properties of Dodecylmaltoside and Dimethyl-β-cyclodextrin Following Nasal Administration

Purpose. To determine if a nasal insulin formulation containing two distinct absorption–enhancing agents exhibits an additive or synergistic increase in the rate of systemic insulin absorption. Methods. The pharmacokinetics and pharmacodynamics of insulin absorption were measured in hyperglycemic anesthetized rats following nasal insulin administration with formulations containing two different types of absorption–promoting agents, dimethyl––cyclodextrin (DMBCD) and dodecylmaltoside (DDM). Results. When either DDM (0.1–0.5%) or DMBCD (1.0–5.0%) was added to the nasal insulin formulation, a significant and rapid increase in plasma insulin levels was observed, with a concomitant decrease in blood glucose concentration. A combined preparation containing 0.25% DDM (0.005 M) and 2.5% DMBCD (0.019M), however, failed to cause an increase in plasma insulin levels or a decrease in blood glucose concentration. Increasing concentrations of DDM added to an insulin formulation with a fixed DMBCD concentration caused a decrease, rather than an increase, in systemic absorption of insulin. Conclusions. Mixing DMBCD and DDM resulted in mutual inhibition of their ability to enhance systemic absorption of insulin following nasal delivery. The results are consistent with the formation of an inclusion complex between DDM and DMBCD which lacks the ability to enhance nasal insulin absorption.