Microspheres containing lipid/chitosan nanoparticles complexes for pulmonary delivery of therapeutic proteins

Chitosan/tripolyphosphate nanoparticles have already been demonstrated to promote peptide absorption through several mucosal surfaces. We have recently developed a new drug delivery system consisting of complexes formed between preformed chitosan/tripolyphosphate nanoparticles and phospholipids, named as lipid/chitosan nanoparticles (L/CS-NP) complexes. The aim of this work was to microencapsulate these protein-loaded L/CS-NP complexes by spray-drying, using mannitol as excipient to produce microspheres with adequate properties for pulmonary delivery. Results show that the obtained microspheres are spherical and present appropriate aerodynamic characteristics for lung delivery (aerodynamic diameters around 2–3 μm and low apparent tap density of 0.4–0.5 g/cm³). The physicochemical properties of the L/CS-NP complexes are affected by the phospholipids composition. Phospholipids provide a controlled release of the encapsulated protein (insulin), which was successfully associated to the system (68%). The complexes can be easily recovered from the mannitol microspheres upon incubation in aqueous medium, maintaining their morphology and physicochemical characteristics. Therefore, this work demonstrates that protein-loaded L/CS-NP complexes can be efficiently microencapsulated, resulting in microspheres with adequate properties to provide a deep inhalation pattern. Furthermore, they are expected to release their payload (the complexes and, consequently, the encapsulated macromolecule) after contacting with the lung aqueous environment.     

Preparation of honokiol-loaded chitosan microparticles via spray-drying method intended for pulmonary delivery

It has been demonstrated that spray-drying is a powerful method to prepare dry powders for pulmonary delivery. This paper prepared dispersible dry powders based on chitosan and mannitol containing honokiol nanoparticles as model drug. The results showed that the prepared microparticles are almost spherical and have appropriate aerodynamic properties for pulmonary delivery (aerodynamic diameters was between 2.8–3.3 μm and tapped density ranging from 0.14–0.?18?g/cm³). Moreover, surface morphology and aerodynamic properties of the powders were strongly affected by the content of mannitol. Fourier transform infra-red (FTIR) spectrum of powders indicated that the honokiol nanoparticles were successfully incorporated into microparticles. In vitro drug release profile was also observed. The content of mannitol in powders significantly influenced the release rate of honokiol from matrices.     

Experimental pulmonary delivery of cyclosporin A by liposome aerosol

The utilization of CsA–liposome for aerosol delivery by jet nebulizers has potential advantages for clinical development including: aqueous compatibility, sustained pulmonary release to maintain therapeutic drug levels and facilitated delivery to alveolar macrophages and pulmonary lymphocytes. Inhalation of cyclosporin A (CsA)–dilauroylphosphatidylcholine (DLPC) liposome aerosols will theoretically result in localized and sustained delivery of therapeutic CsA concentrations within the lung as an alternative to local immunotherapy for pulmonary diseases. In the lung, targeted delivery of therapeutic CsA concentrations would require lower dosages than via conventional intravenous or oral routes of administration. Potential benefits from targeted lung delivery could include reduced systemic toxicity and prolonged immunosuppressive activity. Aerosol delivery systems have been developed to deposit drugs directly onto pulmonary surfaces at the sites of disease within the lung. A novel HPLC method for tissue analysis of CsA–liposomes is developed and utilized with a solid-phase extraction method to measure CsA recovered from Balb/c mouse lung tissues. A concentrated formulation containing 5 mg CsA–37.5 mg DLPC/ml was nebulized with an Aerotech II nebulizer generating an aerosol particle size distribution (mass median aerodynamic diameter (MMAD)) of 1.7 μm and geometric standard deviation (GSD) of 2.0. After a 15-min aerosol exposure, little of no CsA was detected in the blood, liver, kidney or spleen. The lung contained the highest organ CsA levels with high immunosuppressive activity demonstrating effective pulmonary targeting of the CsA–DLPC liposome aerosol. The results of this system will be utilized as the experimental basis for future pharmacokinetic, toxicological, immunosuppression and other biological studies.     

Chitosan/cyclodextrin nanoparticles as macromolecular drug delivery system

The aim of this study was to generate a new type of nanoparticles made of chitosan (CS) and carboxymethyl-β-cyclodextrin (CM-β-CD) and to evaluate their potential for the association and delivery of macromolecular drugs. CS and CM-β-CD or mixtures of CM-β-CD/tripolyphosphate (TPP) were processed to nanoparticles via the ionotropic gelation technique. The resulting nanoparticles were in the size range of 231–383 nm and showed a positive zeta potential ranging from +20.6 to +39.7 mV. These nanoparticles were stable in simulated intestinal fluid pH 6.8 at 37 °C for at least 4 h. Elemental analysis studies revealed the actual integration of CM-β-CD to CS nanoparticles. Insulin and heparin used as macromolecular model drugs, could be incorporated into the different nanocarriers with association efficiencies of 85.5–93.3 and 69.3–70.6%, respectively. The association of these compounds led to an increase of the size of the nanoparticles (366–613 nm), with no significant modification of their zeta potentials (+23.3 to +37.1 mV). The release profiles of the associated macromolecules were highly dependent on the type of molecule and its interaction with the nanomatrix: insulin was very fast released (84–97% insulin within 15 min) whereas heparin remained highly associated to the nanoparticles for several hours (8.3–9.1% heparin within 8 h). In summary, CS-CD (cyclodextrin) nanoparticles may be considered as nanocarriers for the fast or slow delivery of macromolecules.     

Different modalities of NaCl osmogen in biodegradable microspheres for bone deposition of risedronate sodium by alveolar targeting

Risedronate sodium was formulated into polylactide-co-glycolic acid microspheres for pulmonary delivery using the w/o/w double emulsion technique. Sodium chloride was used as osmogen in either the internal or external aqueous phase to surface-engineer the particles to achieve favorable properties. The prepared microspheres were characterized for the surface morphology, entrapment efficiency, in vitro release behavior, particle size, surface area, aerodynamic as well as powder flow properties. Furthermore, the safety of the drug and the selected formula were assessed by MTT viability test performed on Calu-3 cell line as well as histopathological lung tissue examination. A novel in vivo approach based on the radiolabeling of risedronate sodium with I¹²⁵ was developed in order to assess its deposition in the bones of male albino rats. The majority of the prepared microspheres exhibited high entrapment efficiency, sustained release profile up to 15 days, suitable geometric and aerodynamic particle sizes as well as good flow properties. The safety of the drug and the selected formula were proven by the high cell viability percentage of Calu-3 cells as well as the normal lung histology after intra-tracheal administration. The in vivo study showed high bone deposition for risedronate sodium following the pulmonary route, suggesting that it could be utilized as an alternative route of administration for delivery of bisphosphonates.     

Formulation and in vitro characterization of inhalable rifampicin-loaded PLGA microspheres for sustained lung delivery

The solvent evaporation method with premix membrane homogenization was applied, with class-3 ethyl acetate as organic solvent, to produce narrowly size-distributed rifampicin (RIF)-loaded poly(lactide-co-glycolide) (PLGA) microspheres for sustained lung delivery as aerosol. Microsphere formulations (simple or multiple emulsions, different PLGA and RIF concentrations) and process parameters (transmembrane pressure, SPG membrane pore diameter) were investigated as their effects on RIF content, microsphere size, aerodynamic properties of the freeze-dried powder and in vitro release profiles. Narrowly size distributed microspheres with diameters from 2 to 8 μm, satisfactory RIF contents (from 4.9 to 16.5%), 80% RIF release from 12h to 4 days, and adequate aerodynamic properties were prepared from a multiple emulsion and using SPG membrane pore diameter of 19.9 μm. The premix membrane homogenization appeared to be a rapid and efficient method to prepare monodisperse drug-loaded microspheres suitable for lung delivery as sustained-release microsphere aerosol.     

Thiolated polymers--thiomers: synthesis and in vitro evaluation of chitosan-2-iminothiolane conjugates

The aim of this study was to improve the properties of chitosan as excipient in drug delivery systems by the covalent attachment of thiol moieties. This was achieved by the modification of chitosan with 2-iminothiolane. The resulting chitosan–4-thio-butyl-amidine conjugates (chitosan–TBA conjugates) displayed up to 408.9±49.8 μmol thiol groups per gram polymer. Because of the formation of disulfide bonds based on an oxidation process of the immobilized thiol groups under physiological conditions, chitosan–TBA conjugates exhibit in situ gelling properties. After less than 2 h, 1.5% (m/v) chitosan–TBA conjugate solutions of pH 5.5 formed covalently cross-linked gels. The viscosity increased in positive correlation with the amount of thiol groups immobilized on chitosan. In addition, also the mucoadhesive properties were strongly improved by the covalent attachment of thiol groups on chitosan. The adhesion time of tablets based on the unmodified polymer on freshly excised porcine intestinal mucosa spanned on a rotating cylinder in an artificial intestinal fluid was extended more than 140-fold by using the thiolated version. Drug release studies out of tablets comprising the chitosan–TBA conjugate demonstrated that an almost zero-order release kinetic was achieved for the model drug clotrimazole within the first 6 h. The modification of chitosan with 2-iminothiolane leads, therefore to thiolated polymers, which represent a promising tool for the development of in situ gelling and/or mucoadhesive drug delivery systems.     

Colon-specific delivery of mesalazine chitosan microspheres

Mesalazine (5-ASA) is a cyclo-oxygenase inhibitor and anti-inflammatory drug effective in Crohn's disease and ulcerative-colitis. As 5-ASA is rapidly absorbed from the small intestine and it is necessary to develop a colon-specific delivery system for it. Coated chitosan microspheres were used for this purpose by an emulsion-solvent evaporation technique based on a multiple w/o/w emulsion. Four hundred milligrams of chitosan solution (3%) in dilute acetic acid (0.5 M) containing 12% 5-ASA was dispersed into 2 ml solution of cellulose acetate butyrate (CAB) in methylene chloride. The primary induced w/o emulsion was dispersed into a 1% PVA aqueous solution to produce a w/o/w multiple emulsion and was stirred for approximately 2.5 h. The produced microspheres were separated, washed and dried. Release of 5-ASA from microspheres was studied in different pHs 1.2, 7.4, 6.8 and 6.8 in the presence of caecal contents of rat. The average size of microspheres was 200 microm. The highest yield efficiency (80%) was seen in medium molecular weight (MW) chitosan with a 1 : 2 core/coat ratio and the greatest loading efficiency (85%) related to the microspheres of the same type of chitosan but with a 1 : 1 core/coat ratio. Decreasing the coat content and increasing chitosan Mw increased the bioadhesion significantly (p < 0.05). Microspheres of chitosan with medium Mw and 1 : 1 core/coat that showed the greatest release of drug (near 80%) in the presence of caecal secretions with a zero-order mechanism, near zero per cent in pH 1.2 after 2 h, max 20% in pH 7.4 after 3 h and near 60% in pH 6.8 after 8 h seem suitable for site-specific delivery of 5-ASA in vitro.     

Nebulization performance of biodegradable sildenafil-loaded nanoparticles using the Aeroneb Pro: formulation aspects and nanoparticle stability to nebulization

Polymeric nanoparticles meet the increasing interest for drug delivery applications and hold great promise to improve controlled drug delivery to the lung. Here, we present a series of investigations that were carried out to understand the impact of formulation variables on the nebulization performance of novel biodegradable sildenafil-loaded nanoparticles designed for targeted aerosol therapy of life-threatening pulmonary arterial hypertension. Narrowly distributed poly(D,L-lactide-co-glycolide) nanoparticles (size: ～200 nm) were prepared by a solvent evaporation technique using poly(vinyl alcohol) (PVA) as stabilizer. The aerodynamic and output characteristics using the Aeroneb Pro nebulizer correlated well with the dynamic viscosity of the employed fluids for nebulization. The nebulization performance was mainly affected by the amount of employed stabilizer, rather than by the applied nanoparticle concentration. Nanoparticles revealed physical stability against forces generated during aerosolization, what is attributed to the adsorbed PVA layer around the nanoparticles. Sildenafil was successfully encapsulated into nanoparticles (encapsulation efficiency: ～80%). Size, size distribution and sildenafil content of nanoparticles were not affected by nebulization and the in vitro drug release profile demonstrated a sustained sildenafil release over ～120 min. The current study suggests that the prepared sildenafil-loaded nanoparticles are a promising pharmaceutical for the therapy of pulmonary arterial hypertension.     

In vitro evaluation of chondroitin sulphate-chitosan microspheres as carrier for the delivery of proteins

A novel formulation based on chondroitin sulphate/chitosan microspheres (CS/CH) has been investigated for oral delivery of macromolecules using ovalbumin as the model protein (OVA). The microspheres were prepared by a new emulsion-complex coacervation method. Physico-chemical properties of the polymers constituting microparticulate matrix were investigated by IR, DSC, TGA and X-ray diffraction analyses. In vitro tests were performed to evaluate the drug delivery system degradation and the protein release under conditions simulating the intestinal fluids. The ability of colonic enzymes to degrade the microparticulate systems was simulated employing the chondroitinase ABC enzyme. Results showed that the different CS/CH compositions influenced both microparticles stability and the protein release rate. Only the microspheres composed by 1:1 chondroitin sulphate–chitosan ratio achieved an OVA release profile suitable to a possible colon targeting. These microspheres released ～30% of ovalbumin encapsulated in 24 h in the different aqueous media tested, while they released 100% of protein in the presence of chondroitinase. The preliminary results demonstrated that chondroitin sulphate-chitosan microspheres can be a suitable delivery system for protein drug envisaged to oral administration.     

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.     

Pharmacoscintigraphic evaluation of polysorbate80-coated chitosan nanoparticles for brain targeting

Introduction

The blood-brain barrier (BBB) represents an insurmountable obstacle for delivery of a large number of drugs, including antibacterials, anticancer agents and neuropeptides. One approach to overcoming this barrier has been drug delivery to the brain using appropriately modified nanoparticles. Since polysorbate80 is known to facilitate uptake by brain endothelial cells, nanoparticles coated with polysorbate80 hold great promise for the transport of agents across the BBB. Since chitosan nanoparticles have extended circulation time in the blood and decreased uptake by the reticuloendothelial system, we decided to evaluate the efficiency of polysorbate80-coated chitosan nanoparticles as brain-delivery carriers.

Methods

Polysorbate80 (1% w/w)-coated, ultra-fine, crosslinked chitosan nanoparticles (10% crosslinking with glutaraldehyde) <100nm in diameter were prepared in the aqueous core of reverse micelles. After radiolabeling the nanoparticles with ^99mtechnetium (Tc), we studied their in vivo brain uptake profiles in Swiss Albino strain ‘A’ mice. The γ-scintigraphic technique was also employed to study the distribution of ^99mTc-labeled nanoparticles in the brain of New Zealand rabbits.

Results

Our studies revealed that the concentration of ^99mTc-labeled chitosan nanoparticles in the brain was increased nearly 5-fold when coated with polysorbate80 (1% w/w) compared with uncoated ^99mTc-labeled chitosan nanoparticles. The optimal composition of chitosan in polysorbate80 for the maximum delivery of nanoparticles to brain was found to be 1% w/w. Because of partial hydrophobicity rendered to the chitosan nanoparticles by coating with polysorbate80, blood kinetics data showed rapid clearance from blood of coated nanoparticles compared with uncoated nanoparticles. These results were further supported by the γ-scintigrams of New Zealand rabbits, which showed that ^99mTc-labeled chitosan nanoparticles coated with polysorbate80 (1% w/w) had a greater uptake by brain tissue than uncoated chitosan nanoparticles.

Conclusions

This study showed that chitosan nanoparticles coated with polysorbate80 have great potential as a drug delivery carrier to the brain. At a critical concentration of polysorbate80 (1% w/w) on the surface of chitosan nanoparticles, the translocation of nanoparticles from blood to brain was maximal.     

5-Fluorouracil-loaded chitosan coated polylactic acid microspheres as biodegradable drug carriers for cerebral tumours

The development of injectable microspheres for anticancer drug delivery into the brain is a major challenge. The possibility of entrapping 5-fluorouracil (5-FU) in chitosan coated monodisperse biodegradable microspheres with a mean diameter of 10-25um was demonstrated. An emulsion of 5-FU (in water) and polylactic acid (PLA) dissolved in acetone-dichloromethane mixture was poured into an aqueous solution of chitosan (or poly-vinyl alcohol) with stirring using a high-speed homogenizer, for the formation of microspheres. 5-FU recovery in microspheres ranged from 44-66% depending on the polymer and emulsification systems used for the preparation. Scanning electron microscopy revealed that the chitosan coated microspheres had less surface micropores compared to PVA based preparations. The drug release behaviour from microspheres suspended in phosphate buffered saline exhibited a biphasic pattern. The amount of drug release was much higher initially (25%),followed by a constant slow release profile for a 30 days period of study. This chitosan coated PLA/PLGA microsphere formulation may have potential for the targeted delivery of 5-FU to treat cerebral tumours.     

Hydrophilic versus hydrophobic porogens for engineering of poly(lactide-co-glycolide) microparticles containing risedronate sodium

Objective: The aim of this study was to investigate the effect of two mechanistically different porogens, namely: the hydrophilic hydroxy-propyl-β-cyclodextrin and the hydrophobic porogens (mineral oil and corn oil) in producing open/closed pored engineered polylactide-co-glycolic-acid microspheres suitable for pulmonary delivery of risedronate sodium (RS).

Materials and methods: Surface morphology of the microspheres was studied and they were characterized for entrapment efficiency (%EE), particle size, and porosity as well as aerodynamic and flow properties. Selected formulae were investigated for in vitro drug release and deposition behavior using next generation impactor. Furthermore, the safety of the free drug and the selected prepared systems was assessed by MTT viability test performed on Calu-3 cell line.

Results and discussion: The current work revealed that HP-β-CD produced open-pored microspheres, while oils produced closed pored microspheres. Modulation of preparation parameters generated porous RS microspheres with high %EE, sustained drug release profile up to 15 days, suitable geometric and aerodynamic particle sizes and excellent flow properties. The safety of HP-β-CD systems was higher than the systems utilizing oil as porogen.

Conclusion: Porogen type affected the behavior of the microspheres as demonstrated by the various characterization experiments, with microspheres prepared using HP-β-CD being superior to those prepared using oils as porogens.     

Effervescent dry powder for respiratory drug delivery.

The objective of this work was to develop a new type of respiratory drug delivery carrier particle that incorporates an active release mechanism. Spray drying was used to manufacture inhalable powders containing polybutylcyanoacrylate nanoparticles and ciprofloxacin as model substances for pulmonary delivery. The carrier particles incorporated effervescent technology, thereby adding an active release mechanism to their pulmonary route of administration. Effervescent activity of the carrier particles was observed when the carrier particles were exposed to humidity. Gas bubbles caused by the effervescent reaction were visualized by confocal laser scanning microscopy. The images showed that nanoparticles were distributed throughout the gas bubble. For the effervescent formulation the average mass median aerodynamic diameter (MMAD) was 2.17 microm+/-0.42, fine particle fraction (FPF(<=5.6 microm)) was 46.47%+/-15 and the GSD was 2.00+/-0.06. The results also showed that the effervescent carrier particles released 56+/-8% ciprofloxacin into solution compared with 32+/-3% when lactose carrier particles were used. The mean nanoparticle size did not significantly change upon release when the nanoparticles were incorporated into an effervescent formulation. However, the mean size significantly increased upon release when only lactose was used as carrier particle matrix. In conclusion, effervescent carrier particles can be synthesized with an adequate particle size for deep lung deposition. This opens the door for future research to explore this technology for delivery of a large range of substances to the lungs with possible improved release compared to conventional carrier particles.     

QbD driven targeted pulmonary delivery of dexamethasone-loaded chitosan microspheres: Biodistribution and pharmacokinetic study

Inhaling drugs, on the other hand, is limited mainly by the natural mechanisms of the respiratory system, which push drug particles out of the lungs or make them inefficient once they are there. Because of this, many ways have been found to work around the problems with drug transport through the lungs. Researchers have made polymeric microparticles (MP) and nanoparticles as a possible way to get drugs into the lungs. They showed that the drug could be trapped in large amounts and retained in the lungs for a long time, with as little contact as possible with the bloodstream. MP were formulated in this study to get dexamethasone (DMC) into the pulmonary area. The Box-Behnken design optimized microspheres preparation to meet the pulmonary delivery prerequisites. Optimized formulation was figured out based on the desirability approach. The mass median aerodynamic diameter (MMAD) of the optimized formula (O-DMC-MP) was 8.46 ± 1.45 µm, and the fine particle fraction (FPF) was 77.69 ± 1.26%. This showed that it made suitable drug delivery system, which could make it possible for MP to settle deeply in the lung space after being breathed in. With the first burst of drug release, it was seen that drug release could last up to 16 h. Also, there was no clear sign that the optimized formulation was toxic to the alveoli basal epithelial cells in the lungs, as supported by cytotoxic studies in HUVEC, A549, and H1299 cell lines. Most importantly, loading DMC inside MP cuts the amount of drug into the bloodstream compared to plain DMC, as evident from biodistribution studies. Stability tests have shown that the product can stay the same over time at both the storage conditions. Using chitosan DMC-MP can be a better therapeutic formulation to treat acute respiratory distress syndrome (ARDS).     

Evaluation of microcrystalline chitosans for gastro-retentive drug delivery

In vivo absorption studies were carried out in human volunteers to evaluate whether microcrystalline chitosan (MCCh) granules would be gastro-retentive. Furosemide, which is site-specifically absorbed from the upper gastrointestinal tract, was used as model drug. The rate of release of furosemide in vitro could be prolonged by increasing the molecular weight (M_w) or amount of MCCh (150 to 240 kDa; 80 to 95%) in the granules, and also by addition of acidic excipients to the formulations. No marked changes in the in vivo absorption rate (t_max) were noted, but the amounts of furosemide absorbed (AUC_0–∞ and C_max) decreased as the in vitro release rate decreased, although this was not statistically significant in the case of AUC. The highest AUC_0–∞ (3050 μg l⁻¹ h) for furosemide (40 mg) was achieved with granules containing 80% MCCh of 150 kDa M_w. With MCCh of 240 kDa M_w AUC_0–∞ was 1890 μg l⁻¹ h. This kind of pharmacokinetic profile of furosemide suggests that the gastric retention time of the granules is too short in relation to the release rate, and a large amount of the drug passes its “absorption window” before being released. The in vivo study produced no evidence that the chitosan formulations studied can be used as mucoadhesive gastro-retentive drug delivery systems. The results of in vitro mucoadhesion studies did not predict the results of in vivo studies.     

Controlled release pulmonary administration of curcumin using swellable biocompatible microparticles

This study involves a promising approach to achieve sustained pulmonary drug delivery. Dry powder particulate carriers were engineered to allow simultaneous aerosol lung delivery, evasion of macrophage uptake, and sustained drug release through a controlled polymeric architecture. Chitosan grafted with PEG was synthesized and characterized (FTIR, EA, DSC and 2D-XRD). Then, a series of respirable amphiphilic hydrogel microparticles were developed via spray drying of curcumin-loaded PLGA nanoparticles with chitosan-grafted-PEG or chitosan. The nanoparticles and microparticles were fully characterized using an array of physicochemical analytical methods including particle size, surface morphology, dynamic swelling, density, moisture content and biodegradation rates. The PLGA nanoparticles and the hydrogel microspheres encapsulating the curcumin-loaded PLGA nanoparticles showed average size of 221-243 nm and 3.1-3.9 μm, respectively. The developed carriers attained high swelling within a few minutes and showed low moisture content as dry powders (0.9-1.8%), desirable biodegradation rates, high drug loading (up to 97%), and good sustained release. An aerosolization study was conducted using a next generation impactor, and promising aerosolization characteristics were shown. In vitro macrophage uptake studies, cytotoxicity and in vitro TNF-α assays were performed for the investigated particles. These assays revealed promising biointeractions for the respirable/swellable nano-micro particles developed in this study as potential carriers for sustained pulmonary drug delivery.     

5-Fluorouracil-loaded chitosan coated polylactic acid microspheres as biodegradable drug carriers for cerebral tumours

The development of injectable microspheres for anticancer drug delivery into the brain is a major challenge. The possibility of entrapping 5-fluorouracil (5-FU) in chitosan coated monodisperse biodegradable microspheres with a mean diameter of 10-25 um was demonstrated. An emulsion of 5-FU (in water) and polylactic acid (PLA) dissolved in acetone-dichloromethane mixture was poured into an aqueous solution of chitosan (or poly-vinyl alcohol) with stirring using a high-speed homogenizer, for the formation of microspheres. 5-FU recovery in microspheres ranged from 44-66% depending on the polymer and emulsification systems used for the preparation. Scanning electron microscopy revealed that the chitosan coated microspheres had less surface micropores compared to PVA based preparations. The drug release behaviour from microspheres suspended in phosphate buffered saline exhibited a biphasic pattern. The amount of drug release was much higher initially (approximately 25%), followed by a constant slow release profile for a 30 days period of study. This chitosan coated PLA/PLGA microsphere formulation may have potential for the targeted delivery of 5-FU to treat cerebral tumours.     

Influence of the co-encapsulation of different excipients on the properties of polyester microparticle-based vaccine against brucellosis

The nasal cavity possesses many advantages as a site for drug delivery, such as; ease of administration, applicability for long-term treatments and a large surface area for absorption. One important limiting factor for nasal drug delivery is the limited time available for absorption within the nasal cavity due to mucociliary clearance. Several drug delivery systems including different kinds of microspheres have been tried for encapsulation of drugs and increasing the residence time in nasal cavity. In this study the clearance rate of three kinds of microspheres (Alginate, PLGA, and Sephadex) was determined by gamma-scintigraphy with lactose powder being used as negative control.

^99mTc labeled microspheres were prepared using technetium pertechnetate in the presence of a potent reducing agent, stannus chloride. The labeling procedure was set in a manner that each 3–5 mg of microspheres contained 2 MBq of radioactivity. Labeling efficiency was calculated by paper chromatography using acetone as a mobile phase. Each delivery system containing 2 MBq of activity was administered into right nostril of four healthy volunteers and 1 min static views were repeated each half an hour until 4 h. Clearance rates were compared using two regions of interest (ROIs); the initial site of deposition of particles, and all of the nasopharynx region. The clearance rate of each one of microspheres was calculated after applying the physical decay corrections.

The mean labeling efficiencies for Alginate, PLGA, and Sephadex microspheres were calculated as 60%, 59%, and 74%, respectively. The cleared percent of formulations from nasopharynx region after 4 h was determined as follows: PLGA microspheres 48.5 ± 8.2%; Alginate microspheres 45.0 ± 0.8%; Sephadex microspheres 63.1 ± 3.4%; lactose powder 74.5 ± 4.9%. Alginate and PLGA microspheres showed the lowest clearance rate compared to lactose powder (P < 0.0001 and P < 0.001, respectively), followed by Sephadex microspheres (P < 0.01). The clearance profiles of formulations from deposition ROI and nasopharynx ROI were identical.

This study shows that Alginate and PLGA microspheres have the highest mucoadhesion properties and are suitable nasal delivery systems. Futhermore, this study proves that limiting step for the nasal clearance of nasally administered particulate systems is their dislocation from the initial site of deposition, and their following interactions with mucus layer in the rest of the nasal passage does not significantly affect the clearance time.