Diclofenac sodium loaded-cellulose acetate butyrate: Effect of processing variables on microparticles properties,drug release kinetics and ulcerogenic activity

The aim of this study was to develop and characterize diclofenac sodium loaded-cellulose acetate butyrate microparticles in order to obtain a controlled-release system. The influence of the type of polymer, the volume and composition of the internal phase, drug loading, surfactant concentration and additive added on microparticles characteristics (particle size, encapsulation efficiency, surface morphology and in vitro release profiles) was studied to optimize the microparticles system. The resultant microparticles were evaluated for the recovery, average particle size, drug loading and incorporation efficiency. The microparticles exhibited good flowing nature and compressibility index when compared to pure drug. Dissolution rate of diclofenac sodium in phosphate buffer (pH 6.8) increased with increases in initial drug loading, surfactant concentration and addition of alcohol as co-solvent but decreased with increases in the concentration of additives such as Gantrez® AN or Eudragit S100 in the internal phase. The dissolution data showed a Higuchi diffusion pattern for most of the formulations. About 56–81% reduction in ulcerogenic activity was observed with microparticles containing Eudragit S100 17–25%, based on total polymer concentration, when compared with pure diclofenac sodium.     

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     

Studies on the drug release properties of nano-encapsulated indomethacin microparticles

Indomethacin micro-crystals sized approximately 2 microm have been encapsulated with polyelectrolyte multi-layers for the purpose of controlled release. Charged linear poly (dimethyldiallyl ammonium chloride) (PDDA) and poly (styrene sulphonate) (PSS) were alternatively deposited on approximately 2 microm drug micro-crystals. The release of indomethacin from coated micro-crystals was measured in aqueous solutions of pH 1.4 and 6.8. The polyelectrolyte multi-layer capsule thickness was proved to control. The results provided a method of achieving prolonged drug release through self-assembly of polymeric shells on drug microcrystals.     

The effect of gamma-irradiation on drug release from bioerodible microparticles: a quantitative treatment

The two major objectives of this study were: (i) to monitor the effect of different gamma-irradiation doses (4-33 kGy) on the release kinetics from 5-fluorouracil (5-FU)-loaded poly(D,L-lactide-co-glycolide) (PLGA)-based microparticles, and (ii) to analyze the obtained experimental data with a new mathematical model giving insight into the occurring mass transport phenomena. Drug release was found to depend significantly on the applied gamma-irradiation dose. Interestingly, the obtained release profiles were all biphasic: a rapid initial drug release phase ("burst") was followed by a slower, approximately constant drug release phase. Surprisingly, only the initial rapid drug release was accelerated by gamma-irradiation; the subsequent zero-order phase was almost unaffected. Importantly, the new mathematical model which is based on Fick's second law of diffusion and which considers polymer degradation was applicable to all the investigated systems. In addition, the gamma-irradiation dose could be quantitatively related to the resulting drug release rate. In conclusion, diffusion seems to be the dominating release rate controlling mechanism in all cases, with a significant contribution of the polymer degradation process.     

Calcium pectinate gel beads for controlled release drug delivery: II. Effect of formulation and processing variables on drug release.

The effect of four formulation and processing variables, calcium concentration, drying condition, concentration of hardening agent and hardening time on the bead properties and the release characteristics of a model drug from calcium pectinate gel (CPG) beads were studied. A poorly soluble compound, indomethacin, was used as the model drug. The investigated variables affected the bead size, the entrapment efficiency and the release of indomethacin from CPG beads. Drug release was found to be a function of the formulation and processing variables. The slower drug release was achieved from the formulations with higher calcium concentration, higher concentration of hardening agent and longer hardening time. The drying condition, however, did not influence the drug release. The mechanism of indomethacin release from CPG beads followed the diffusion controlled model for an inert porous matrix. All drug release data fitted well to the Higuchi square root time expression.     

Calcium pectinate gel beads for controlled release drug delivery: II. Effect of form ulation and processing variables on drug release

The effect of four formulation and processing variables, calcium concentration, drying condition, concentration of hardening agent and hardening time on the bead properties and the release characteristics of a model drug from calcium pectinate gel (CPG) beads were studied. A poorly soluble compound, indomethacin, was used as the model drug. The investigated variables affected the bead size, the entrapment efficiency and the release of indomethacin from CPG beads. Drug release was found to be a function of the formulation and processing variables. The slower drug release was achieved from the formulations with higher calcium concentration, higher concentration of hardening agent and longer hardening time. The drying condition, however, did not influence the drug release. The mechanism of indomethacin release from CPG beads followed the diffusion controlled model for an inert porous matrix. All drug release data fitted well to the Higuchi square root time expression.     

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.     

Mathematical modeling of drug release from bioerodible microparticles: effect of gamma-irradiation.

Bioerodible polymers used in controlled drug delivery systems, such as poly(lactic-co-glycolic acid) (PLGA) undergo radiolytic degradation during gamma-irradiation. In spite of the considerable practical importance, yet only little knowledge is available on the consequences of this sterilization method on the resulting drug release patterns in a quantitative way. The major objectives of the present study were: (i) to monitor the effects of different gamma-irradiation doses on the physicochemical properties of drug-free and drug-loaded, PLGA-based microparticles; (ii) to analyze the obtained experimental results using adequate mathematical models; (iii) to get further insight into the occurring physical and chemical phenomena; and (iv) to relate the applied gamma-irradiation dose in a quantitative way to the resulting drug release rate. 5-Fluorouracil-loaded, PLGA-based microparticles were prepared with an oil-in-water solvent extraction method and exposed to gamma-irradiation doses ranging from 0 to 33 kGy. Size exclusion chromatography, differential scanning calorimetry, scanning electron microscopy, particle size analysis, determination of the actual drug loading and in vitro drug release kinetics were used to study the effects of the gamma-irradiation dose on the physicochemical properties of the microparticles. Two mathematical models-a simplified and a more comprehensive one-were used to analyze the experimental results. The simplified model considers drug diffusion based on Fick's second law for spherical geometry and a Higuchi-like pseudo-steady-state approach. The complex model combines Monte Carlo simulations (describing polymer erosion) with partial differential equations quantifying drug diffusion with time-, position- and direction-dependent diffusivities. Interestingly, exponential relationships between the gamma-irradiation dose and the initial drug diffusivity within the microparticles could be established. Based on this knowledge both models were used to predict the resulting drug release kinetics as a function of the gamma-irradiation dose. Importantly, the theoretical predictions were confirmed by experimental results.     

Ivermectin-loaded microparticles for parenteral sustained release: in vitro characterization and effect of some formulation variables

Ivermectin (IVM) is a BCS II drug with potent antiparasitic activity in veterinary applications. In this study, poly(lactide-co-glycolide) (PLGA) and poly(DL-lactide) (PLA) Ivermectin-loaded microparticles were prepared by the simple emulsion (O/W) solvent evaporation method in order to obtain sustained release formulations for parenteral applications. The effects of polymer end-groups (ester or free acid) and the addition of the hydrophilic polyvinylpyrrolidone polymer (PVP) in in vitro drug release profiles were also studied. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analysis showed that IVM was present in an amorphous state or as a molecular dispersion within the polymers or theirs mixtures with PVP and that a PVP-drug complex was formed. Drug entrapment efficiency in the microparticles (>90%) was independent of the polymer composition, the end groups and the presence of PVP. However, microscopic (SEM) observations showed that the addition of PVP led to more porous microparticles accompanied by the increased rates of drug release.     

Solid lipid microparticles: formulation, preparation, characterisation, drug release and applications

This review details the properties of solid lipid microparticles (SLMs): a promising drug carrier system that has been until now rather unexploited. First, the advantages of SLMs compared with other drug carrier systems are listed. Then an overview of SLM manufacturing compounds and techniques is presented. A detailed discussion of the characteristics of SLMs follows, and includes the determination of particle size distribution, the determination of SLM morphology, the solid-state analysis, the determination of SLM drug loading and the factors influencing it. The in vitro drug release studies that have been carried out so far and the parameters affecting them are also described. Some preliminary in vivo aspects (in vivo drug release studies, biocompatibility studies and in vivo fate) are also considered.     

Solid lipid microparticles: formulation,preparation, characterisation,drug release and applications

This review details the properties of solid lipid microparticles (SLMs): a promising drug carrier system that has been until now rather unexploited. First, the advantages of SLMs compared with other drug carrier systems are listed. Then an overview of SLM manufacturing compounds and techniques is presented. A detailed discussion of the characteristics of SLMs follows, and includes the determination of particle size distribution, the determination of SLM morphology, the solid-state analysis, the determination of SLM drug loading and the factors influencing it. The invitro drug release studies that have been carried out so far and the parameters affecting them are also described. Some preliminary invivo aspects (invivo drug release studies, b-iocompatibility studies and invivo fate) are also considered.     

Calcium alginate microparticles for oral administration: II effect of form ulation factors on drug release and drug entrapment efficiency

The release rate of nicardipine HCl from various alginate microparticles was investigated. Manugel A7B618 which has a high guluronic acid content of 70% and a low polymerization degree of 60-400 was used as alginate. A 23 factorial design was utilized for the preparation of the alginate microparticles. The effect of drug:polymer weight ratio, CaCl2 concentration and curing time on parameters such as the time for 50% of the drug to be released (t50%) and the drug entrapment efficiency were evaluated with analysis of variance. The mean particle sizes and the swelling ratios of the microparticles were determined. The in vitro release studies were carried out with a flow-through cell apparatus at different media (pH 1.2, 2.5, 4.5, 7, 7.5 buffer solutions). Drug:polymer weight ratio and the concentration of the crosslinking agent were the influential factors on the release of NC from the alginate microparticles. The release of nicardipine was extended with alginate microparticles prepared in aratio of 1:1 (drug:polymer weight ratio). The release of drug from alginate microparticles took place by both diffusion through the swollen matrix and relaxation of the polymer at pH: 1.2-4.5. However, the release was due to diffusion and erosion mechanisms at pH 7-7.5.     

Effect of formulation variables on in vitro drug release and micromeritic properties of modified release ibuprofen microspheres

Modified release microspheres of the non-steroidal anti-inflammatory drug, ibuprofen, were formulated and prepared using the emulsion solvent diffusion technique. The contribution of various dispersed phase and continuous phase formulation factors on in vitro drug release and micromeritic characteristics of microspheres was examined. The results demonstrated that the use of Eudragit RS 100 and Eudragit RL 100 as embedding polymers modified the drug release properties as a function of polymer type and concentration. Eudragit RS 100 retarded ibuprofen release from the microspheres to a greater extent than Eudragit RL 100. The drug/polymer concentration of the dispersed phase influenced the particle size and drug release properties of the formed microspheres. It was found that the presence of emulsifier was essential for microsphere formation. Increasing the concentration of emulsifier, sucrose fatty acid ester F-70, decreased the particle size which contributed to increased drug release properties. Scanning electron microscopy revealed profound distortion in both the shape and surface morphology of the microspheres with the use of magnesium stearate as added emulsifier. The application of an additional Eudragit RS 100 coat onto formed microspheres using fluid bed technology was successful and modulated the drug release properties of the coated microspheres.     

Synthesis of lidocaine-loaded PLGA microparticles by flow focusing. Effects on drug loading and release properties

In the present work, two methods for the preparation of lidocaine-loaded PLGA microparticles are compared. The differences between the polymeric particles obtained by solvent evaporation (SEVM) or flow focusing (FF) were studied by means of scanning electron microscopy and surface thermodynamics determinations. A detailed investigation of the capabilities of the polymer particles to load this drug is described. The physical state of the drug in the polymeric particles and the existence of interactions between both entities were studied by differential scanning calorimetry. The main factors determining the lidocaine incorporation and the release kinetics were the synthesis procedure followed, the amount of drug dissolved in the organic phase during the synthesis routine, the type of polymer (molecular weight and end chemical groups) and the size and the hydrophobic/hydrophilic properties of the particles. The FF technology allowed higher drug incorporations and slower release kinetics. The release studies showed a biphasic profile probably due to diffusion-cum-degradation mediated processes.     

Effect of formulation variables on in vitro drug release and micromeritic properties of modified release ibuprofen microspheres.

Modified release microspheres of the non-steroidal anti-inflammatory drug, ibuprofen, were formulated and prepared using the emulsion solvent diffusion technique. The contribution of various dispersed phase and continuous phase formulation factors on in vitro drug release and micromeritic characteristics of microspheres was examined. The results demonstrated that the use of Eudragit RS 100 and Eudragit RL 100 as embedding polymers modified the drug release properties as a function of polymer type and concentration. Eudragit RS 100 retarded ibuprofen release from the microspheres to a greater extent than Eudragit RL 100. The drug/polymer concentration of the dispersed phase influenced the particle size and drug release properties of the formed microspheres. It was found that the presence of emulsifier was essential for microsphere formation. Increasing the concentration of emulsifier, sucrose fatty acid ester F-70, decreased the particle size which contributed to increased drug release properties. Scanning electron microscopy revealed profound distortion in both the shape and surface morphology of the microspheres with the use of magnesium stearate as added emulsifier. The application of an additional Eudragit RS 100 coat onto formed microspheres using fluid bed technology was successful and modulated the drug release properties of the coated microspheres.     

Anti-inflammatory effect and low ulcerogenic activity of etodolac,a cyclooxygenase-2 selective non-steroidal anti-inflammatory drug,on adjuvant-induced arthritis in rats

Adjuvant arthritic rats are known to be more susceptible to gastric damage induced by non-steroidal anti-inflammatory drugs (NSAIDs) than are normal rats. We compared the relative gastric safety profile of etodolac with those of meloxicam, diclofenac sodium and indometacin in adjuvant arthritic rats and normal rats or mice. As a measure of the safety profiles of NSAIDs, we used the safety index, the ratio of the dose that elicits gastric mucosal lesions to the effective dose as an anti-inflammatory or analgesic compound. The anti-inflammatory or analgesic effects of NSAIDs were assessed by paw swelling in adjuvant arthritic rats, and either carrageenin-induced paw edema or brewer's yeast-induced hyperalgesia, as well as acetic acid-induced writhing, in normal rats or mice. In addition, we also investigated the effects of these NSAIDs on human COX-1 and COX-2 activity. Etodolac and other NSAIDs inhibited paw swelling and caused gastric mucosal lesions in adjuvant arthritic rats in a dose-dependent manner. Etodolac showed the highest UD(50) value and safety index among these NSAIDs in arthritic rats. In normal rats, etodolac also showed the highest UD(50) value and safety index, except when its effects were assessed by acetic acid-induced writhing. Etodolac and meloxicam showed selectivity for human COX-2 over COX-1. In contrast, diclofenac sodium and indometacin were selective for COX-1. These results suggest that etodolac, a COX-2 selective NSAID, has anti-inflammatory effects with a better safety profile for the stomach than do non-selective NSAIDs, including diclofenac sodium and indometacin, in adjuvant arthritic as well as normal rats.     

Effects of the type of release medium on drug release from PLGA-based microparticles: experiment and theory

The major objectives of the present study were: (i) to prepare 5-fluorouracil (5-FU)-loaded, poly(lactic-co-glycolic acid) (PLGA)-based microparticles, which can be used for the treatment of brain tumors, (ii) to study the effects of the type of release medium on the resulting drug release kinetics, and (iii) to get further insight into the underlying drug release mechanisms. Spherical microparticles were prepared by a solvent extraction method and characterized using different techniques, including size exclusion chromatography (SEC), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and particle size analysis before and upon exposure to various release media. Interestingly, very different drug release patterns (including mono-, bi- and tri-phasic ones) were observed, depending on the pH, osmolarity and temperature of the release medium. An adequate mathematical theory was used to quantitatively describe the experimentally measured 5-FU release patterns. The model considers the limited solubility of the drug, polymer degradation as well as drug diffusion and allowed to determine system and release medium specific parameters, such as the diffusion coefficient of the drug. In particular, the pH and temperature of the release medium were found to be of major importance for the resulting release patterns. Based on the obtained knowledge the selection of an appropriate release medium for in vitro tests simulating in vivo conditions can be facilitated, and "stress tests" can be developed allowing to get rapid feedback on the release characteristics of a specific batch.     

Alginate-magnesium aluminum silicate films: effect of plasticizers on film properties, drug permeation and drug release from coated tablets

The effect of hydrophilic plasticizers, namely glycerin and polyethylene glycol 400 (PEG400), on physicochemical properties of sodium alginate-magnesium aluminum silicate (SA-MAS) microcomposite films was characterized and application of the films for controlling drug release from tablets was evaluated as well. The plasticizers could possibly interact with SA or MAS by formation of hydrogen bonding, as revealed using FTIR spectroscopy. PXRD studies presented that glycerin or PEG400 could intercalate into the silicate layers of MAS and higher crystallinity of the films with PEG400 was obtained. This led to a different thermal behavior of the films. Glycerin gave more flexibility of the films than PEG400. Incorporation of plasticizers into the films did not affect water uptake in acid medium, but increasing an erosion of the films because of the leaching of the plasticizers. Water vapor permeability of the films decreased with increasing amount of plasticizers in the range of 10-30% (w/w). Diffusion coefficient (D) of acetaminophen (ACT) across the films in acid medium increased with addition of the plasticizers because the leaching of plasticizers could reduce tortuosity of aqueous pore channels of the films. The tablets coated with plasticized films had a quite smooth surface without defect as shown by SEM. The ACT release profiles from the coated tablets showed a zero-order release kinetic with drug diffusion mechanism across in situ insoluble composite films in acid medium, and coating film swelling and erosion mechanism in pH 6.8 phosphate buffer. Moreover, neither the release rate nor the release pattern of the ACT coated tablets was obviously changed. The findings show that glycerin or PEG400 could improve physicochemical properties of the SA-MAS films and the plasticized films could control the drug release from tablets in gastro-intestinal condition.