Mucoadhesive microspheres for nasal administration of an antiemetic drug, metoclopramide: in-vitro/ex-vivo studies

Microparticulate delivery systems designed for the nasal administration of an antiemetic drug, metoclopramide hydrochloride, were prepared. Microspheres composed of sodium alginate, chitosan hydrochloride, or both, were obtained using a spray-drying method; some batches of drug-free microparticles were prepared as a comparison. The morphology, in-vitro swelling behaviour, mucoadhesive properties and drug release from microparticles were evaluated. Ex-vivo drug permeation tests were carried out using sheep nasal mucosa; permeation test of the drug solution was performed as comparison. During ex-vivo permeation tests, transmission electron microscopy (TEM) analyses were carried out on the nasal mucosa to study the morphological changes of epithelial cells and tight junctions, while the change in microsphere morphology was examined using photostereo microscopy (PM). Spray-dried microparticles had a mean diameter (d(vs)) in the range of about 3-10 microm. They showed good in-vitro mucoadhesive properties. In-vitro release profiles and swelling behaviour depended on their composition: the drug release occurred in 1-3 h. Ex-vivo studies showed that drug permeation through the mucosa from microparticles based on chitosan was higher than from those consisting of alginate alone. This can be related to the penetration enhancing properties of chitosan. Complexation of chitosan with alginate led to a control of the drug release. Microscopy observation of microspheres during the permeation tests revealed that microparticles swelled and gelled, maintaining their shape. TEM analyses of the mucosa after exposure to the microparticles consisting of alginate/chitosan showed opened tight junctions. This preliminary study shows that alginate/chitosan spray-dried microspheres have promising properties for use as mucoadhesive nasal carriers of an antiemetic drug.     

Chitosan and poly(methyl vinyl ether-co-maleic anhydride) microparticles as nasal sustained delivery systems.

An original dosage form for nasal delivery based on the encapsulation of hydrophilic drug in chitosan-poly(methyl vinyl ether-co-maleic anhydride) (CH-PVM/MA) microparticles prepared by spray-drying technique was developed. Microparticles were characterized in terms of morphology, size, swelling properties, encapsulation efficiency and drug release. The physical state of the drug and the polymer was determined by scanning electron microscopy (SEM) and infrared spectroscopy (IR). Propranolol hydrochloride (PH) was a beta-blocker, used for the treatment of hypertension and was chosen as a model of hydrophilic drug. SEM studies showed spherical particles with smooth surfaces for chitosan hydrochloride (CH-HCl), whereas rather gross surface defects resulted from the incorporation of poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA). In vitro release studies revealed a sustained release of propranolol HCl from microparticles and in particular chitosan hydrochloride provided the lowest release of drug.     

Chitosan and poly(methyl vinyl ether-co-maleic anhydride) microparticles as nasal sustained delivery systems

An original dosage form for nasal delivery based on the encapsulation of hydrophilic drug in chitosan-poly(methyl vinyl ether-co-maleic anhydride) (CH-PVM/MA) microparticles prepared by spray-drying technique was developed. Microparticles were characterized in terms of morphology, size, swelling properties, encapsulation efficiency and drug release. The physical state of the drug and the polymer was determined by scanning electron microscopy (SEM) and infrared spectroscopy (IR). Propranolol hydrochloride (PH) was a β-blocker, used for the treatment of hypertension and was chosen as a model of hydrophilic drug. SEM studies showed spherical particles with smooth surfaces for chitosan hydrochloride (CH-HCl), whereas rather gross surface defects resulted from the incorporation of poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA). In vitro release studies revealed a sustained release of propranolol HCl from microparticles and in particular chitosan hydrochloride provided the lowest release of drug.     

Controlled release study of 5-fluorouracil-loaded chitosan/polyethylene glycol microparticles

The aim of this research is to reduce the frequency of taking therapeutic drugs. Thus, anti-cancer drug [5-fluorourical (5-FU)] loaded chitosan/polyethylene glycol microparticles were prepared by a phase-inversion technique with tripolyphosphate (TPP) used as a cross-linking agent. The relationships between 5-FU release behavior/encapsulation efficiencies and chitosan concentrations, TPP concentrations, as well as cross-linking time were studied to identify better/superior conditions (3.5 wt% chitosan, 3 wt% TPP, and cross-linking time?=?4?h) for preparing 5-FU-loaded microparticles. Furthermore, in order to ascertain the influence of their physical properties on 5-FU release performance, 5-FU-loaded microparticles were evaluated by swelling tests and scanning electron microscopy.     

Design and development of gliclazide-loaded chitosan for oral sustained drug delivery: in vitro/in vivo evaluation

Gliclazide (GLZ)/Chitosan microparticles were prepared with tripolyphosphate (TPP) by ionic cross-linking. The particle sizes of TPP-chitosan microparticles were in the range 675-887 μm and the loading efficiencies of drug was more than 94.0%. Chitosan concentration, TPP solution pH and glutaraldehyde volume added to the TPP cross-linking solution had an effect on the drug release characteristics. The microparticles were examined with scanning electron microscopy and infrared spectroscopy. Furthermore, pectin can interact with cationic chitosan on the surface of these TPP/chitosan microparticles to form a polyelectrolyte complex film for the improvement of the drug sustained-release performances. In vivo testing of the GLZ-chitosan microparticles in diabetic albino rabbits demonstrated significant antidiabetic effect of GLZ/chitosan microparticles after 8 h which lasts for 18 h, compared with GLZ powder which produced maximum hypoglycaemic effect after 4 h, suggesting that GLZ/chitosan microparticles are a valuable system for the long-term delivery of GLZ.     

Supercritical fluid assisted impregnation of indomethacin into chitosan thermosets for controlled release applications

Supercritical carbon dioxide (sc-CO(2)) was used to impregnate indomethacin (a non-steroidal anti-inflammatory drug) into chitosan thermosets for the preparation of controlled release formulations. The products were analyzed by a range of methods including powder X-ray diffraction (XRD) and scanning electron microscopy (SEM). The effects of the experimental temperature and pressure of the sc-CO(2) on the thermal behavior of chitosan-indomethacin drug composites (DCs) was investigated via differential scanning calorimeter (DSC). The interaction of chitosan and indomethacin after impregnation was then studied by Fourier transform infrared (FTIR) and Raman spectroscopy, respectively. Our results suggest that the supercritical fluid impregnation process results in indomethacin being amorphously dispersed within the chitosan matrix. FTIR data suggest that the aliphatic carbonyl group of indomethacin interacts with the NH(2) group of the chitosan backbone. In vitro dissolution studies (via UV-vis spectroscopy) reveal that the dissolution rate of indomethacin substantially increases after processing in sc-CO(2), particularly, under the experimental conditions 20.7 MPa and 70 degrees C.     

Sustained release of antineoplastic drugs from chitosan-reinforced alginate microparticle drug delivery systems

Alginate based microparticle drug delivery systems were prepared for the sustained release of antineoplastic drugs. Two drugs, 5-fluorouracil (5-FU) and tegafur, were encapsulated into the microparticles. The drug loaded microparticles were fabricated using a very convenient method under very mild conditions, i.e., directly shredding the drug loaded beads into microparticles in a commercial food processor. The mean sizes of the obtained microparticles were between 100 and 200 μm. To effectively sustain the drug release, alginate microparticles were reinforced by chitosan during gelation. The drug release from the chitosan-reinforced alginate microparticles was obviously slower than that from the unreinforced microparticles. The effect of the reinforcement conditions on the drug release property of the microparticles was studied, and the optimized concentration of chitosan solution for reinforcement was identified. The effects of drug feeding concentration and pH value of the release medium on the drug release were investigated.     

Preparation and characterization of chitosan microparticles intended for controlled drug delivery

Chitosan microparticles were prepared with tripolyphosphate (TPP) by ionic crosslinking. The particle sizes of TPP-chitosan microparticles were in range from 500 to 710 microm and encapsulation efficiencies of drug were more than 90%. The morphologies of TPP-chitosan microparticles were examined with scanning electron microscopy. As pH of TPP solution decreased and molecular weight (MW) of chitosan increased, microparticles had more spherical shape and smooth surface. Release behaviors of felodipine as a model drug were affected by various preparation processes. Chitosan microparticles prepared with lower pH or higher concentration of TPP solution resulted in slower felodipine release from microparticles. With decreasing MW and concentration of chitosan solution, release behavior was increased. The release of drug from TPP-chitosan microparticles decreased when cross-linking time increased. These results indicate that TPP-chitosan microparticles may become a potential delivery system to control the release of drug.     

Microspheres for colonic delivery of ketoprofen-hydroxypropyl-β-cyclodextrin complex

A new multiparticulate system, with the potential for site-specific delivery to the colon, has been developed using ketoprofen as model drug. The system simultaneously exploits cyclodextrin complexation, to improve drug solubility, and vectorization in microspheres (MS) based on Ca-pectinate and chitosan. The effect of complexation with hydroxypropyl-β-cyclodextrin (HPβCyd) and of chitosan presence on drug entrapment efficiency and release properties, as well on the drug permeation rate across Caco-2 cells has been investigated. Solid-state interactions between the components have been investigated by FTIR spectroscopy, differential scanning calorimetry and X-ray powder diffractometry. The morphology of MS was examined by scanning electron microscopy. Release studies revealed a different behaviour for MS containing drug alone or as complex: drug alone was released faster than in the presence of cyclodextrin from MS without chitosan, due to a reservoir effect. The opposite was found for MS containing chitosan, due to a competition effect between polymer and drug for the cyclodextrin. Cytotoxicity tests demonstrated the safety of these formulations. Permeation studies showed an increased permeation of the drug formulated as MS, particularly marked when it was used as complex, thus revealing an enhancing power of both cyclodextrin and chitosan with a synergistic effect in improving drug permeation.     

Preparation and characterization of 2-hydroxyethyl starch microparticles for co-delivery of multiple bioactive agents

The present study reports the generation of 2-hydroxyethyl starch microparticles for co-delivery and controlled release of multiple agents. The obtained microparticles are characterized by using Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction analysis, energy-dispersive X-ray spectroscopy, and scanning electron microscopy. By using ofloxacin and ketoprofen as drug models, the release sustainability of the microparticles is examined at pH 1.2, 5.4, and 6.8 at 37 °C, with Fickian diffusion being found to be the major mechanism controlling the kinetics of drug release. Upon being loaded with the drug models, the microparticles show high efficiency in acting against Escherichia coli and Bacillus cereus. The results suggest that our reported microparticles warrant further development for applications in which co-administration of multiple bioactive agents is required.     

Calcium alginate microparticles for oral administration: I: effect of sodium alginate type on drug release and drug entrapment efficiency

The natural polymers alginate and chitosan were used for the preparation of controlled release nicardipine HCl gel microparticles. The effect of the mannuronic/guluronic acid content and the alginate viscosity on the prolonged action of the microparticles, which were prepared with different types of alginates, were investigated. The mean particle sizes and the swelling ratios of the microparticles were also determined. The in vitro release studies were carried out with a flow-through cell apparatus in different media (pH 1.2, 2.5, 4.5, 7 and 7.5 buffer solutions). The release of nicardipine was extended with the alginate gel microparticles prepared with guluronic acid rich alginate. After the determination of the most appropriate alginate type, the effect of alginatechitosan complex formation was studied on the release pattern of drug incorporated. It was observed that the alginate-chitosan complex formation reduced the erosion of the alginate-chitosan matrix at pH 7-7.5. The release of drug from the chitosan-alginate gel microparticles took place by both diffusion through the swollen matrix and relaxation of the polymer at pH 1.2-4.5     

Preparation and characterization of drug‐loaded chitosan–tripolyphosphate microspheres by spray drying

The present study reports on the preparation of chitosan–tripolyphosphate (TPP) microspheres by the spray‐drying method using acetaminophen as a model drug substance. Chitosan–TPP microspheres were spherical and had a smooth surface. Perfectly spherical chitosan–TPP microparticles loaded with acetaminophen were obtained in the size range of 3.1–10.1 µm. Spray‐dried chitosan–TPP microspheres were positively charged (zeta potential ranged from +18.4 to +31.8). The encapsulation efficiency of these microspheres was in the range of 48.9–99.5%. The swelling capacity of chitosan–TPP microspheres increased with increases in the molecular weight of chitosan and decreases with increasing volume of 1% wt/vol TPP solution used for the cross‐linking reaction. The effect of chitosan concentration, drug loading, volume of TPP solution used for cross‐linking, and chitosan molecular weight on surface morphology and drug release rate was extensively investigated. Microparticles with spherical shape and slower release rates were obtained from chitosan–TPP microspheres prepared using a higher concentration of chitosan, higher volume of TPP solution, a higher molecular weight chitosan and/or a higher drug loading. Most importantly, the drug release rate was mainly controlled by the chitosan–TPP matrix density and, thus, by the degree of swelling of the hydrogel matrix. Drug release from chitosan–TPP microspheres occurred via diffusion as the best fit for drug release was obtained using the Higuchi equation. Drug Dev. Res. 64:114–128, 2005. © 2005 Wiley‐Liss, Inc.     

Evaluation of chitosan–anionic polymers based tablets for extended-release of highly water-soluble drugs

The objective of this study is to develop chitosan–anionic polymers based extended-release tablets and test the feasibility of using this system for the sustained release of highly water-soluble drugs with high drug loading. Here, the combination of sodium valproate (VPS) and valproic acid (VPA) were chosen as the model drugs. Anionic polymers studied include xanthan gum (XG), carrageenan (CG), sodium carboxymethyl cellulose (CMC-Na) and sodium alginate (SA). The tablets were prepared by wet granulation method. In vitro drug release was carried out under simulated gastrointestinal condition. Drug release mechanism was studied. Compared with single polymers, chitosan–anionic polymers based system caused a further slowdown of drug release rate. Among them, CS–xanthan gum matrix system exhibited the best extended-release behavior and could extend drug release for up to 24 h. Differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) studies demonstrated that polyelectrolyte complexes (PECs) were formed on the tablet surface, which played an important role on retarding erosion and swelling of the matrix in the later stage. In conclusion, this study demonstrated that it is possible to develop highly water-soluble drugs loaded extended-release tablets using chitosan–anionic polymers based system.     

Preparation, characterization and in vitro cytotoxicity of indomethacin-loaded PLLA/PLGA microparticles using supercritical CO(2) technique.

In this work, indomethacin-loaded poly(l-lactic acid)/poly(lactide-co-glycolide) (IDMC-PLLA/PLGA) microparticles were prepared using solution-enhanced dispersion by supercritical fluids (SEDS) technique in an effort to obtain alternative IDMC formulation for drug delivery system. Surface morphology, particle size and particle size distribution, drug encapsulation efficiency, drug release kinetics, in vitro cytotoxicity and the cellular uptake of drug-loaded microparticles were investigated. The drug-loaded microparticles exhibited sphere-like shape and small particle size with narrow particle size distribution. IDMC was amorphously dispersed within the PLLA/PLGA matrix after the SEDS process. In vitro release studies revealed that the drug-loaded microparticles substantially enhanced the dissolution rate of IDMC compared to the free IDMC, and demonstrated a biphasic drug release profile. In vitro cytotoxicity assays indicated that drug-loaded microparticles possessed longer sustained inhibition activity on proliferation of the non-small-cell lung cancer A549 cell lines than did free IDMC. Fluorescence microscopy and transmission electron microscopy identified the phagocytosis of drug-loaded microparticles into the A549 cells and characteristic morphology of cell apoptosis such as the nuclear aberrations, condensation of chromatin, and swelling damage in mitochondria. These results collectively suggested that IDMC-PLLA/PLGA microparticles prepared using SEDS would have potentials in anti-tumor applications as a controlled drug release dosage form without harmful organic solvent residue.     

Controlled release of dexamethasone from poly(vinyl alcohol) hydrogel

This study investigated a chemically crosslinked poly(vinyl alcohol) (PVA) hydrogel controlled drug delivery system to deliver the anti-inflammatory drug dexamethasone (DEX). The PVA hydrogels, with different crosslinking densities, were characterized by swelling studies, electron scanning microscopy, viscosity, Fourier transform infrared spectroscopy (FTIR) and in vitro release assessment. Increasing crosslinking density slowed and decreased swelling and water absorption. FTIR analysis suggested DEX has possible interactions with the crosslinker and the PVA polymer. In vitro release of DEX from PVA hydrogels was sustained for 33 days and appeared to fit the Higuchi and Korsmeyer–Peppas models. This work indicates the likelihood of PVA hydrogel as a controlled drug release system for DEX for anti-inflammatory uses.     

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.     

Intranasal Delivery of Chitosan Nanoparticles for Migraine Therapy

Objective

The objective of the research was to formulate and evaluate sumatriptan succinate-loaded chitosan nanoparticles for migraine therapy in order to improve its therapeutic effect and reduce dosing frequency.

Material and Methods

The Taguchi method design of experiments (L9 orthogonal array) was applied to obtain the optimized formulation. The sumatriptan succinate-loaded chitosan nanoparticles (CNPs) were prepared by ionic gelation of chitosan with tripolyphosphate anions (TPP) and Tween 80 as surfactant.

Results

The CNPs had a mean size of 306.8 ± 3.9 nm, a zeta potential of +28.79 mV, and entrapment efficiency of 75.4 ± 1.1%. The in vitro drug release of chitosan nanoparticles was evaluated in phosphate buffer saline pH 5.5 using goat nasal mucosa and found to be 76.7 ± 1.3% within 28 hours.

Discussion

The release of the drug from the nanoparticles was anomalous, showing non-Fickian diffusion indicating that drug release is controlled by more than one process i.e. the superposition of both phenomena, a diffusion-controlled as well as a swelling-controlled release. This is clearly due to the characteristics of chitosan which easily dissolves at low pH, thus a nasal pH range of 5.5 ± 0.5 supports it very well. The mechanism of pH-sensitive swelling involves protonation of the amine groups of chitosan at low pH. This protonation leads to chain repulsion, diffusion of protons and counter ions together with water inside the gel, and the dissociation of secondary interactions.

Conclusion

The results suggest that sumatriptan succinate-loaded chitosan nanoparticles are the most suitable mode of drug delivery for promising therapeutic action.     

Calcium alginate microparticles for oral administration: I: Effect of sodium alginate type on drug release and drug entrapment efficiency.

The natural polymers alginate and chitosan were used for the preparation of controlled release nicardipine HCl gel microparticles. The effect of the mannuronic/guluronic acid content and the alginate viscosity on the prolonged action of the microparticles, which were prepared with different types of alginates, were investigated. The mean particle sizes and the swelling ratios of the microparticles were also determined. The in vitro release studies were carried out with a flow-through cell apparatus in different media (pH 1.2, 2.5, 4.5, 7 and 7.5 buffer solutions). The release of nicardipine was extended with the alginate gel microparticles prepared with guluronic acid rich alginate. After the determination of the most appropriate alginate type, the effect of alginate-chitosan complex formation was studied on the release pattern of drug incorporated. It was observed that the alginate-chitosan complex formation reduced the erosion of the alginate-chitosan matrix at pH 7-7.5. The release of drug from the chitosan-alginate gel microparticles took place by both diffusion through the swollen matrix and relaxation of the polymer at pH 1.2-4.5.     

Structure and release behavior of PMMA/silica composite drug delivery system

The preparation, characterization, and in vitro release of aspirin from polymethylmethacrylate (PMMA)/silica composites prepared via a sol-gel route are reported. The in vitro drug release test revealed that the release rate of aspirin in PBS increased with the silica content in the composites; on the contrary, the increase of the content of 3-(trimethoxysilyl) propyl methacrylate (MSMA), a coupling agent, decreased the drug release rate. The drug release rate/composite structure relationship was studied using Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and swelling ratio (SR) measurement. The results indicated that the interface between polymer matrix and inorganic fillers has significant influence on the drug release behavior of the composite materials. In addition, models of mass transfer based on Fickian diffusion law at constant temperature and pressure were employed to analyze the results of the in vitro drug release experiments. The drug release behaviors of the composite samples fitted well with the Fickian diffusion model. The values of k, which is in direct proportion to drug release rate, increased with the increasing content of silica while decreased with that of MSMA in the composite samples.     

Freeze dried chitosan/ poly-(glutamic acid) microparticles for intestinal delivery of lansoprazole

Lansoprazole sodium is a proton pump inhibitor used in treating gastroesophageal reflux disease (GERD). It is highly acid-labile and presents many formulation challenges. Therefore, this drug needs to be protected from the harsh environment in the stomach. In order to achieve this, a pH-sensitive microparticle system composed of chitosan and γ- poly-(glutamic acid) was prepared and loaded with Lansoprazole. The prepared microparticles were not stable in gastric pH. To overcome this problem microparticles were freez-dried and filled in an enteric-coated capsule. Upon oral administration, the enteric-coated capsule remained intact in the acidic environment of the stomach, but dissolved rapidly in the distal segment of the GIT. Consequently, all the microparticles loaded in the capsule were brought into the intestine, thus enhancing the intestinal absorption of drug. Drug encapsulation efficiency of formulation F3 was found to be 82.82 % and in vitro release of prepared formulation F3 was found to be 94% after 8 h of dissolution in 7.4 pH phosphate buffer. FTIR and DSC studies showed no interaction between the drug and polymer. The formulation showed good swelling property. SEM photographs showed that microparticles are spherical and lies in size range of 300-400 μm. From the above, it can be concluded that the prepared chitosan/ γ-poly-(glutamic acid) microparticles can be used as carriers for the intestinal delivery of acid liable drugs such as lansoprazole.