Preparation and characterization of chitosan microparticles for oral sustained delivery of gliclazide: in vitro/in vivo evaluation

Chitosan microparticles were prepared with tripolyphosphate (TPP) by ionic cross‐linking with gliclazide (GLZ) as a model drug. The particle sizes of TPP‐chitosan microparticles ranged from 675–887 µm with loading efficiencies of greater than 94%. Chitosan concentration, TPP solution pH, and glutaraldehyde volume solution added to the TPP cross‐linking solution affected drug release characteristics. Pectin interactions with cationic chitosan on the surface of TPP/chitosan microparticles led to the formation of polyelectrolyte complex films that improved drug sustained release performance. In vivo testing of the GLZ‐chitosan microparticles in diabetic albino rabbits demonstrated a significant antidiabetic effect of GLZ/chitosan microparticles after 8 h that lasts for 18 h compared with GLZ powder that produced a maximal hypoglycemic effect at 4 h, suggesting that GLZ/chitosan microparticles represent an improved system for the long‐term delivery of GLZ. Drug Dev Res 72: 235–246, 2011. © 2010 Wiley‐Liss, Inc.     

Chitosan microparticle preparation for controlled drug release by response surface methodology

The objectives were to investigate the effects of formulation variables on the release of drug and to optimize the formulation of chitosan microparticles loaded with drug for controlled release using response surface methodology. Chitosan microparticles were prepared by dropping a chitosan solution into sodium tripolyphosphate (TPP) through ionic cross-linking. The release behaviour of felodipine as a model drug was affected by preparation variables. A central composite design was used to evaluate and optimize the effect of preparation variables, chitosan concentration (X1), the pH of the TPP solution (X2) and cross-linking time (X3) on the cumulative per cent drug release (Y) in 24 h. Chitosan concentration and cross-linking time affected negatively the release of felodipine, while the pH of the TPP did so positively and was the highest influential factor. The optimum rate of drug release, 100% in 24 h, was achieved at 1.8% chitosan concentration, a pH 8.7 for the TPP solution and 9.7 min cross-linking time.     

Chitosan microparticle preparation for controlled drug release by response surface methodology

The objectives were to investigate the effects of formulation variables on the release of drug and to optimize the formulation of chitosan microparticles loaded with drug for controlled release using response surface methodology. Chitosan microparticles were prepared by dropping a chitosan solution into sodium tripolyphosphate (TPP) through ionic cross-linking. The release behaviour of felodipine as a model drug was affected by preparation variables. A central composite design was used to evaluate and optimize the effect of preparation variables, chitosan concentration (X₁), the pH of the TPP solution (X₂) and cross-linking time (X₃) on the cumulative per cent drug release (Y) in 24 h. Chitosan concentration and cross-linking time affected negatively the release of felodipine, while the pH of the TPP did so positively and was the highest influential factor. The optimum rate of drug release, 100% in 24 h, was achieved at 1.8% chitosan concentration, a pH 8.7 for the TPP solution and 9.7 min cross-linking time.     

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.     

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.     

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.     

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

Objectives The objective of this study was to prepare gliclazide–chitosan microparticles with tripolyphosphate by ionic crosslinking. Methods Chitosan microparticles were produced by emulsification and ionotropic gelation. The effects of process variables including chitosan concentration, pH of tripolyphosphate solution, glutaraldehyde volume and release modifier agent such as pectin added to the tripolyphosphate crosslinking solution were evaluated. The microparticles were examined with scanning electron microscopy, infrared spectroscopy and differential scanning colorimetry. The serum glucose lowering effect of gliclazide microparticles was studied in streptozotocin‐diabetic rabbits compared with the effect of pure gliclazide powder and gliclazide commercial tablets. Key findings The particle sizes of tripolyphosphate–chitosan microparticles were over the range 675–887 µm and the loading efficiency of drug was greater than 94.0%. In‐vivo testing of the gliclazide–chitosan microparticles in diabetic rabbits demonstrated a significant antidiabetic effect of gliclazide–chitosan microparticles after 8 h that lasted for 18 h compared with gliclazide powder, which produced a maximum hypoglycaemic effect after 4 h. Conclusions The results suggests that gliclazide–chitosan microparticles are a valuable system for the sustained delivery of gliclazide.     

Novel design of osmotic chitosan capsules characterized by asymmetric membrane structure for in situ formation of delivery orifice

In this study, chitosan capsules with asymmetric membrane to induce osmotic effects and in situ formation of the delivery orifice were optimally prepared and characterized. Chitosan capsules were formed on stainless steel mold pins by dipping the pins into a chitosan solution followed by forming asymmetric structure by dipping into a quenching solution containing tripolyphosphate (TPP) to cause an ionic cross-linking reaction between the outer layer of chitosan and TPP. Factors influencing the properties of the capsule membrane, such as the molecular weight of chitosan, the dipping solution and dipping time, and the quenching solution and time, were optimized to successfully produce osmotic chitosan capsules with asymmetric membrane using chitosans that possessed different viscosities. In situ formation of a delivery orifice on the asymmetric membrane of the chitosan capsule was proven by the observation of a jet stream of chlorophyll being released from the capsule. Drugs with different solubility were selected, and a linear correlation between drug solubility and the initial drug release rate calculated from the slope of the drug release profile was used to verify that the delivery orifices that were in situ formed on the asymmetric membrane of the chitosan capsules induced by osmotic effect was responsible for the drug release. Water permeability across the optimally produced asymmetric membrane of the capsule from chitosan of 500 cps (300-700 cps) quenched with TPP for 30 min (C500/TPP30) was determined to be 1.40 x 10(-6)cm(2)h(-1)atm(-1) at 37.0+/-0.5 degrees C. The encapsulation of poorly water-soluble drugs, felodipine (FE) and nifedipine (NF), in such an asymmetric chitosan capsule was capable of creating a sufficient osmotic effect to activate the release of the drug with the addition of SLS and HPMC. The multiple regression equations of maximal release percent at 24h for FE and NF confirmed that both sodium lauryl sulfate (SLS) and hydroxypropyl methylcellulose (HPMC) positively influenced this response factor, and the effect of SLS was greater than that of HPMC.     

Evaluation of ultrasonic atomization as a new approach to prepare ionically cross-linked chitosan microparticles

Ultrasonic atomization was evaluated as a new approach for the preparation of ionically cross-linked controlled-release chitosan microparticles loaded with theophylline as the model drug, using tripolyphosphate (TPP) as counter-ion. It was possible to nebulize both 2% and 3% (w/v) chitosan solutions as a function of their viscosity, usually not processed by employing the conventional nebulizer. The results of the chitosan molecular characterization using the SEC-MALS analysis revealed that ultrasonic atomization caused a certain depolymerization, probably due to the main chain scission of the 1,4-glycosidic bond; however, Fourier transform-infrared spectroscopy revealed the absence of other chemical modifications. The ultrasonic atomization allowed preparation of TPP cross-linked chitosan microparticles mostly ranging between 50 and 200 mum. As regards manufacturing parameters, the linking time and washing medium were found to affect the properties of the microparticles, while the stirring rate of the TPP solution did not show any influence. The evaluation of the formulation variables revealed that chitosan concentration strongly affected both the feasibility of the ultrasonic atomization and the drug release. All the microparticles showed an encapsulation efficiency of > 50 % and, after an initial burst effect, a controlled release of drug for 48 h. In conclusion, the ultrasonic atomization could be proposed as a robust and innovative single-step procedure with scale-up potential to successfully prepare ionically cross-linked chitosan microparticles.     

Controlled drug release properties of ionically cross-linked chitosan beads: the influence of anion structure

By adopting a novel chitosan cross-linked method, i.e. chitosan/gelatin droplet coagulated at low temperature and then cross-linked by anions (sulfate, citrate and tripolyphosphate (TPP)), the chitosan beads were prepared. Scanning electron microscopy (SEM) observation showed that sulfate/chitosan and citrate/chitosan beads usually had a spherical shape, smooth surface morphology and integral inside structure. Cross-sectional analysis indicated that the cross-linking process of sulfate and citrate to chitosan was much faster than that of TPP due to their smaller molecular size. But, once completely cross-linked, TPP/chitosan beads possessed much better mechanical strength and the force to break the beads was approximately ten times higher than that of sulfate/chitosan or citrate/chitosan beads. Release media pH and ionic strength seriously influenced the controlled drug release properties of the beads, which related to the strength of electrostatic interaction between anions and chitosan. Sulfate and citrate cross-linked chitosan beads swelled and even dissociated in simulated gastric fluid (SGF) and hence, model drug (riboflavin) released completely in 5 h; while in simulated intestinal fluid (SIF), beads remained in a shrinkage state and drug released slowly (release % usually <70% in 24 h). However, swelling and drug release of TPP/chitosan bead was usually insensitive to media pH. Chitosan beads, cross-linked by a combination of TPP and citrate (or sulfate) together, not only had a good shape, but also improved pH-responsive drug release properties. Salt weakened the interaction of citrate, especially sulfate with chitosan and accelerated beads swelling and hence drug release rate, but it was insensitive to that of TPP/chitosan. These results indicate that ionically cross-linked chitosan beads may be useful in stomach specific drug delivery.     

Preparation of cross-linked chitosan microspheres by spray drying: effect of cross-linking agent on the properties of spray dried microspheres

Chitosan microspheres cross-linked with three different cross-linking agents viz, tripolyphosphate (TPP), formaldehyde (FA) and gluteraldehyde (GA) have been prepared by spray drying technique. The influence of these cross-linking agents on the properties of spray dried chitosan microspheres was extensively investigated. The particle size and encapsulation efficiencies of thus prepared chitosan microspheres ranged mainly between 4.1-4.7 microm and 95.12-99.17%, respectively. Surface morphology, % erosion, % water uptake and drug release properties of the spray dried chitosan microspheres was remarkably influenced by the type (chemical or ionic) and extent (1 or 2% w/w) of cross-linking agents. Spray dried chitosan microspheres cross-linked with TPP exhibited higher swelling capacity, % water uptake, % erosion and drug release rate at both the cross-linking extent (1 and 2% w/w) when compared to those cross-linked with FA and GA. The sphericity and surface smoothness of the spray dried chitosan microspheres was lost when the cross-linking extent was increased from 1 to 2% w/w. Release rate of the drug from spray dried chitosan microspheres decreased when the cross-linking extent was increased from 1 to 2% w/w. The physical state of the drug in chitosan-TPP, chitosan-FA and chitosan-GA matrices was confirmed by the X-ray diffraction (XRD) study and found that the drug remains in a crystalline state even after its encapsulation. Release of the drug from chitosan-TPP, chitosan-FA and chitosan-GA matrices followed Fick's law of diffusion.     

Preparation of cross-linked chitosan microspheres by spray drying: Effect of cross-linking agent on the properties of spray dried microspheres

Chitosan microspheres cross-linked with three different cross-linking agents viz, tripolyphosphate (TPP), formaldehyde (FA) and gluteraldehyde (GA) have been prepared by spray drying technique. The influence of these cross-linking agents on the properties of spray dried chitosan microspheres was extensively investigated. The particle size and encapsulation efficiencies of thus prepared chitosan microspheres ranged mainly between 4.1–4.7?µm and 95.12–99.17%, respectively. Surface morphology, % erosion, % water uptake and drug release properties of the spray dried chitosan microspheres was remarkably influenced by the type (chemical or ionic) and extent (1 or 2%?w/w) of cross-linking agents. Spray dried chitosan microspheres cross-linked with TPP exhibited higher swelling capacity, % water uptake, % erosion and drug release rate at both the cross-linking extent (1 and 2%?w/w) when compared to those cross-linked with FA and GA. The sphericity and surface smoothness of the spray dried chitosan microspheres was lost when the cross-linking extent was increased from 1 to 2%?w/w. Release rate of the drug from spray dried chitosan microspheres decreased when the cross-linking extent was increased from 1 to 2%?w/w. The physical state of the drug in chitosan-TPP, chitosan-FA and chitosan-GA matrices was confirmed by the X-ray diffraction (XRD) study and found that the drug remains in a crystalline state even after its encapsulation. Release of the drug from chitosan-TPP, chitosan-FA and chitosan-GA matrices followed Fick's law of diffusion.     

Development and in vitro evaluation of novel floating chitosan microcapsules for oral use: comparison with non-floating chitosan microspheres

Floating (F) microcapsules containing melatonin (MT) were prepared by the ionic interaction of chitosan and a negatively charged surfactant, sodium dioctyl sulfosuccinate (DOS). The DOS/chitosan complex formation was confirmed employing infrared spectroscopy, differential scanning calorimetry (DSC), solubility and X-ray diffraction analysis. The characteristics of the F microcapsules generated compared with the conventional non-floating (NF) microspheres manufactured from chitosan and sodium tripolyphosphate (TPP) were also investigated. The effect of various factors (crosslinking time, DOS and chitosan concentrations, as well as drug/polymer ratio) on microcapsule properties were evaluated. The use of DOS solution in coagulation of chitosan produced well-formed microcapsules with round hollow core and 31.2-59.74% incorporation efficiencies. Chitosan concentration and drug/polymer ratio had a remarkable effect on drug entrapment in DOS/chitosan microcapsules. The dissolution profiles of most of microcapsules showed near zero order kinetics in simulated gastric fluid (S.G.F: pH 1.2). Moreover, release of the drug from these microcapsules was greatly retarded with release lasting for several hours (t(50%) (S.G.F.): 1.75-6.7 h, depending on processing factors), compared with NF microspheres where drug release was almost instant. Most of the hollow microcapsules developed tended to float over simulated biofluids for more than 12 h. Swelling studies conducted on various drug-free formulations, clearly indicated that DOS/chitosan microcapsules showed less swelling and no dissolution in S.G.F. for more than 3 days, whereas, TPP/chitosan microspheres were markedly swollen and lost their integrity in S.G.F. within 5 h. Therefore, data obtained suggest that the F hollow microcapsules produced would be an interesting gastroretentive controlled-release delivery system for drugs.     

Ca-alginate microspheres encapsulated in chitosan beads

Chitosan beads (CBs) incorporating Ca-alginate microspheres (CAMs), containing a drug, were prepared as an oral sustained delivery system. Stable and monodisperse Ca-alginate microspheres loaded with drug were obtained by a membrane emulsification method. The Ca-alginate microspheres were encapsulated in chitosan beads by the ionotropic gelation method with a polyelectrolyte complex reaction between two oppositely charged polyions. The surface and internal characteristics of the beads were improved by ionic cross-linking in tripolyphosphate (TPP) solution adjusted to pH 5.0. The release experiments were performed using lidocaine·HCl (cationic drug) and sodium salicylate (anionic drug) as model drugs. Initial release of drugs depended on the degree of swelling. Ca-alginate microspheres encapsulated in chitosan beads were superior to both drug-loaded CBs and CAMs beads for sustained release because they had a three-layer composition; a calcium alginate core bounded by an inter-phasic chitosan-alginate membrane, which itself was surrounded by a layer of chitosan-TPP.     

Ca-alginate microspheres encapsulated in chitosan beads

Chitosan beads (CBs) incorporating Ca-alginate microspheres (CAMs), containing a drug, were prepared as an oral sustained delivery system. Stable and monodisperse Ca-alginate microspheres loaded with drug were obtained by a membrane emulsification method. The Ca-alginate microspheres were encapsulated in chitosan beads by the ionotropic gelation method with a polyelectrolyte complex reaction between two oppositely charged polyions. The surface and internal characteristics of the beads were improved by ionic cross-linking in tripolyphosphate (TPP) solution adjusted to pH 5.0. The release experiments were performed using lidocaine.HCl (cationic drug) and sodium salicylate (anionic drug) as model drugs. Initial release of drugs depended on the degree of swelling. Ca-alginate microspheres encapsulated in chitosan beads were superior to both drug-loaded CBs and CAMs beads for sustained release because they had a three-layer composition; a calcium alginate core bounded by an inter-phasic chitosan-alginate membrane, which itself was surrounded by a layer of chitosan-TPP.     

Design and characterisation of doxorubicin-releasing chitosan microspheres for anti-cancer chemoembolisation

The aims of this study were to design and characterise doxorubicin-loaded chitosan microspheres for anti-cancer chemoembolisation. Doxorubicin-loaded chitosan microspheres were prepared by emulsification and cross-linking methods. Doxorubicin–chitosan solution was initially complexed with tripolyphosphate (TPP) to improve drug loading capabilities. Doxorubicin-loaded chitosan microspheres were highly spherical and had approximately diameters of 130–160?µm in size. Drug loading amount and loading efficiency were in the range 3.7–4.0% and 68.5–85.8%, respectively, and affected by TPP concentration, drug levels and cross-linking time. Doxorubicin release was affected by TPP complexation, cross-linking time and release medium. Especially, lysozyme in release media considerably increased drug release. Synergistic anti-cancer activities of doxorubicin-releasing chitosan microspheres were confirmed to VX2 cells in the rabbit auricle model compared with blank microspheres. Doxorubicin-loaded chitosan microspheres can efficiently be prepared by TPP gelation and cross-linking method and developed as multifunctional anti-cancer embolic material.     

Development and in vitro/in vivo evaluation of Zn-pectinate microparticles reinforced with chitosan for the colonic delivery of progesterone

The colon is a promising target for drug delivery owing to its long transit time of up to 78?h, which is likely to increase the time available for drug absorption. Progesterone has a short elimination half-life and undergoes extensive first-pass metabolism, which results in very low oral bioavailability (～25%). To overcome these shortcomings, we developed an oral multiparticulate system for the colonic delivery of progesterone. Zn-pectinate/chitosan microparticles were prepared by ionotropic gelation and characterized for their size, shape, weight, drug entrapment efficiency, mucoadhesion and swelling behavior. The effect of cross-linking pH, cross-linking time and chitosan concentration on progesterone release were also studied. Spherical microparticles having a diameter of 580–720?µm were obtained. Drug entrapment efficiency of ～75–100% was obtained depending on the microparticle composition. Microparticle mucoadhesive properties were dependent on the pectin concentration, as well as the cross-linking pH. Progesterone release in simulated gastric fluids was minimal (3–9%), followed by burst release at pH 6.8 and a sustained phase at pH 7.4. The in vivo study revealed that the microparticles significantly increased progesterone residence time in the plasma and increased its relative bioavailability to ～168%, compared to the drug alone. This study confirms the potential of Zn-pectinate/chitosan microparticles as a colon-specific drug delivery system able to enhance the oral bioavailability of progesterone or similar drugs.     

Stomach-specific anti-H. pylori therapy. I: Preparation and characterization of tetracyline-loaded chitosan microspheres

The main objective of the study was to develop a stomach-specific drug delivery system to increase the efficacy of tetracycline against Helicobacter pylori. Chitosan microspheres were prepared by ionic cross-linking and precipitation with sodium sulfate. Two different methods were used for drug loading. In method I, tetracycline was mixed with chitosan solution before the simultaneous cross-linking and precipitation. In method II, the drug was incubated with pre-formed microspheres for 48 h. The cumulative amount of tetracycline that was released from chitosan microspheres and the stability of the drug was examined in different pH medium at 37 degrees C. Microspheres with a spherical shape and an average diameter of 2.0-3.0 microm were formed. When the drug was added to the polymer solution before cross-linking and precipitation only 8% (w/w) was optimally incorporated in the final microsphere formulation. When the drug was incubated with the pre-formed microspheres, on the other hand, a maximum of 69% (w/w) could be loaded. Thirty percent of tetracycline either in solution or when released from microspheres was found to degrade at pH 1.2 in 12 h. The preliminary results from this study suggest that chitosan microspheres can be used to incorporate antibiotic drugs and may be effective when administered locally in the stomach against H. pylori.     

Preparation and in vitro evaluation of chitosan microgranules with clotrimazole

Mucoadhesive polymers have gained much attention due to the possibility to overcome physiological barriers in long-term drug delivery. Chitosan is a biocompatible and non-toxic chitin derivative, which due to its mucoadhesive properties enables to obtain prolonged drug delivery. The aim of this study was to formulate and in vitro evaluate chitosan microgranules with clotrimazole. Microgranules were prepared by the wet-granulation method using pentabasic tripolyphosphate (TPP) as an ion cross-linker. It was shown that crosslinked chitosan significantly prolonged the release of clotrimazole. Microgranules in formulation F4 (with chitosan:clotrimazole:TPP ratio 5:1:1) not only maintained regular surface morphology, but also ensured prolonged release of clotrimazole over the period of 6 h. The obtained results indicate that chitosan is a suitable polymer for developing a sustained-release dosage form of clotrimazole for local delivery.     

Biopolymeric microparticles combined with lyophilized monophase dispersions for controlled flutamide release

Despite its short half-life, no controlled release formula of flutamide (FLT) was prepared until now. Therefore, 15 chitosan microparticle formulations were prepared for oral prolonged delivery of FLT via ionotropic gelation and emulsification-ionic gelation techniques then characterized for various parameters. FLT was successfully encapsulated into microparticles with loading capacity up to 39.98% and entrapment efficiency up to 97.16% using emulsification technique. Differential scanning calorimetry indicated that FLT was retained in a crystalline form in the microparticles prepared using ionotropic gelation whereas its crystallinity was significantly reduced using emulsification technique. Relationship between formulation variables and release behavior of FLT was explored. Chitosan microparticles prepared by ionotropic gelation showed a slower FLT release with a T(25%) of 7.9h whereas microparticles prepared by emulsification-ionic gelation under the same conditions showed a quick release profile with a T(25%) of 0.3h. Using 3 different hydrophilic carriers, immediate release FLT dispersions were prepared via lyophilization of monophase solution technique then combined with prolonged release chitosan microparticles to develop 6 controlled release formulae of FLT. A wide range of FLT release profiles were generated providing a prolonged release of drug after a suitable initial burst release.