Diclofenac sodium incorporated PLGA (50:50) microspheres: formulation considerations and in vitro/in vivo evaluation.

Recently, considerable interest has been focused on the use of biodegradable polymers for specialized applications such as controlled release of drug formulations; meanwhile, microsphere drug-delivery systems using various kinds of biodegradable polymers have been studied extensively during the past two decades. Poly (lactide-co-glycolide) (PLGA) polymers have been proven to be excellent drug carriers for microparticulate systems due to their advantages, e.g. biocompatibility and regulatory approval. The administration of nonsteroidal anti-inflammatory drugs (NSAIDs) into the intra-articular cavity in patients with chronic inflammatory disease is complicated due to the short duration of effect. In the present study, controlled-release parenteral formulations of diclofenac sodium (DS), a commonly used NSAID, were prepared for intra-articular administration, and evaluated in vitro for particle size, yield, drug loading, surface morphology and release characteristics. For in vivo studies, Technetium-99m labelled polyclonal human immunogammaglobulin (99m Tc-HIG) was used as the radiopharmaceutical to demonstrate arthritic lesions by gamma scintigraphy. Evaluation of arthritic lesions post-therapy in rabbits showed no significant difference in the group treated with PLGA (50:50) (mw 34000) DS microspheres compared to control groups.

Phase studies of ethoxylated surfactants-oil-water-undecylenic acid.

Two non-ionic surfactants (Simulsol OL 50 and Simulsol 98) separately or as 1:1 mixtures, together with corn oil-undecylenic acid and water formed various phases. Phase equilibrium studies were made. In all phase equilibrium diagrams investigated, both at 20 and 37 degrees C, lamellar and hexagonal liquid crystalline and oily isotropic phases were found, besides the emulsion system. Emulsions were composed of mixed lamellar and hexagonal liquid crystalline phases which formed at low concentrations of surfactant and oil and correspondingly high water concentrations.

Chitosan microspheres of diclofenac sodium, II: In vitro and in vivo evaluation.

A biodegradable diclofenac sodium (DS) microsphere system using chitosan has been characterized and evaluated in vitro and in vivo. The particle size distribution and drug content was determined. The release rate data were investigated by using zero-order, first-order, Hixson-Crowel and Higuchi kinetics. The optimum DS-Chitosan microsphere formulation, empty chitosan microspheres, sustained release commercial product and plain drug were evaluated for pharmacological activity. The ulcerogenic index in rabbits was also determined.

Studies on zinc sulphate microcapsules: (III) in vivo evaluation.

Zinc sulphate capsules and syrup were prepared as conventional dosage forms and in vivo experiments were performed for both on the conventional dosage forms as well as on microcapsules. Blood samples were taken from healthy volunteers at 1, 2, 3, 4 and 5 hours and AUC3 and AUC5 were calculated by trapezoidal rule. Relative bioavailability of zinc was calculated and the 5th hour relative bioavailability difference was found to be significant. The results show that zinc sulphate in microcapsule form was able to prolong the action.

The in vivo distribution of the 99mTc-labelled albumin and gelatin microspheres of a tuberculostatic agent, rifampicin.

The preparation of albumin and gelatin microspheres with a tuberculostatic agent, rifampicin, was studied, and its in vivo distribution was investigated by providing its accumulation in the target organ lungs. The purpose of the study is to improve the effectiveness by injecting the microspheres intravenously with much smaller doses than normally required with generalized systemic administration, whilst reducing the systemic side effects. The emulsion polymerization method is applied in microsphere preparation, and glutaraldehyde is employed for albumin and formaldehyde for gelatin microspheres as the cross-linking agents. Biodistribution was determined by intravenous administration of particles of 25 to 27 microns 99mTc-labelled microspheres to Swiss albino mice. The radioactivity of the lungs was compared with the radioactivity of the liver, spleen, kidney, stomach and heart at 10, 30 and 60 min, and 6 and 24 h post-injection. The percentage accumulated was higher in the lungs than in the other organs for both albumin and gelatin microspheres, whereas free rifampicin accumulated mainly in the liver. To support the data of the in vivo distribution studies, the microspheres were histopathologically investigated after the intravenous injection to Swiss albino mice. After the microscopic determination of the lungs and liver, the spherical microspheres were observed after 10,30 and 60 min, and 6 and 24 h post-injection.

In vitro and in vivo studies of ibuprofen-loaded biodegradable alginate beads.

The irritation effects of ibuprofen, a widely used non-steroidal anti-inflammatory drug (NSAID), were evaluated on mouse gastric and duodenal mucosa when suspended in 0.5% (w/v) sodiumcarboxymethylcellulose (NaCMC) solution and loaded in alginate beads. The ionotropic gelation method was used to prepare controlled release alginate beads of ibuprofen. The influence of various formulation factors on the encapsulation efficiency, as in vitro drug release and micromeritic properties, was investigated. Other variables included the alginate concentration, percentage drug loading and stirring speed during the microencapsulation process. Scanning electron micrographs of alginate beads loaded with ibuprofen showed rough surface morphology and particle sizes in the range of 1.15 +/- 0.4 - 3.15 +/- 0.6 mm. The yield of microspheres, as collected after drying, was generally 80-90%. Formulation code H showing t50% value of 3.5 h was chosen for in vivo trials because of the appropriate drug release properties. For in vivo trials, free ibuprofen (100 mg kg(-1)), blank and ibuprofen (100 mg kg(-1)) loaded alginate beads (formulation code H) were suspended in 0.5% (w/v) NaCMC solution and each group was given to six mice orally by gavage. NaCMC solution was used as a control in experimental studies. In vivo data showed that the administration of ibuprofen in alginate beads prevented the gastric lesions.

Chitosan: properties, preparations and application to microparticulate systems.

Chitosan, a hydrophilic biopolymer, is obtained industrially by hydrolysing the aminoacetyl groups of chitin. It is a natural, non-toxic, biodegradable polysaccharide available as solution, flake, fine powder, bead and fibre. The sources, biochemical aspects, structure and chemical modification, physico-chemical and functional properties, and applications of chitosan have been investigated extensively in the literature. In this paper, the attractive properties and broad applications of chitosan-based microparticles, their versatile properties, different preparation methods, and pharmaceutical and biopharmaceutical applications are reviewed.

Studies on zinc sulphate microcapsules (1): Microencapsulation and in vitro dissolution kinetics.

Microcapsules of zinc sulphate with core: wall ratios of 1:1 and 2:1 were prepared by the coacervation method, using ethylcellulose as the coating material. The prepared microcapsules were separated into batches of 250 and 500 micron in size by sieving. The effects of particle size, the amount of zinc sulphate, and the core: wall ratio on the dissolution kinetics were studied, and evaluated kinetically by the Rosin-Rammler-Sperling-Bennet-Weillbull (RRSBW) distribution.

Studies on zinc sulphate microcapsules (2): Application of factorial design.

In this study a 2(3) factorial design has been applied to the evaluation of dissolution characteristics of zinc sulphate microcapsules. The kinetic model according to the Rosin-Rimmler-Sperling-Bennet-Weillbull (RRSBW) distribution was applied for the parametric representation of the dissolution curves. The effect of three factors; core: wall ratio, amount of zinc sulphate and particle size of the microcapsules, on the dissolution rate of zinc sulphate were studied at two levels. The factorial design method proved to be useful for the examination of microcapsules.

Biodegradable bromocryptine mesylate microspheres prepared by a solvent evaporation technique. I: Evaluation of formulation variables on microspheres characteristics for brain delivery.

The aim of this study was to formulate biodegradable microspheres containing an anti-parkinsonian agent, bromocryptine mesylate, for brain delivery. The effect of formulation parameters (e.g. polymer, emulsifying agent type and concentration) on the characteristics of the microspheres produced, the efficiency of drug encapsulation, the particle size distribution and in vitro drug release rates from the bromocryptine mesylate microspheres were investigated using a 3(2) factorial design. Bromocryptine mesylate was encapsulated into biodegradable polymers using the following three different polymers; poly(L-lactide), poly(D,L-lactide) and poly(D,L-lactide-co-glycolide). The SEM photomicrographs showed that the morphology of the microspheres greatly depended on the polymer and emulsifying agent. The results indicate that, regardless of the polymer type, increase in emulsifying agent concentration from 0.25-0.75% w/v markedly decreases the particle size of the microspheres. Determination of particle size revealed that the use of 0.75% w/v of emulsifying agent concentration and a polymer solution concentration of 10% w/v resulted in optimum particle size. In order to prepare biodegradable microspheres with high drug content and small particle size, selection of polymer concentration as well as emulsifying agent concentration is critical. Polymer type has a less pronounced effect on the percentage encapsulation efficiency and particle size of microspheres than on the t(50%). The microspheres prepared by all three polymers, at a polymer concentration of 10% w/v and an emulsifying agent concentration of 0.75% w/v with NaCMC:SO (4:1, w/v) mixture was as the optimum formulation.

Chitosan microspheres of diclofenac sodium: I. application of factorial design and evaluation of release kinetics.

In this study microspheres of diclofenac sodium, an anti-inflammatory agent, were prepared by utilizing a natural polysaccharide, chitosan-H. The objective of this investigation was to sustain the action of diclofenac sodium and to show the effect of various conditions on release kinetics. For this reason factorial design experiments were performed. The independent variables in the 3(3) factorial design were chitosan-H concentration, tripolyphosphate concentration and stabilization time, and in the 3(2) factorial design were chitosan-H and tripolyphosphate concentrations. The dependent variables, t50% and the total drug content were investigated by the polynomial equations. The release profiles were evaluated kinetically and the best fit was obtained by the Higuchi equation.

Phenytoin sodium microcapsules: bench scale formulation, process characterization and release kinetics.

The objective of this investigation was to formulate and prepare sustained-action microcapsules of phenytoin sodium (diphenyl hydantoin sodium salt). Using ethylcellulose and methyl acrylic acid copolymers (Eudragit S-100 and L-100) as coating materials, microcapsules of phenytoin sodium were formulated by an organic phase separation and a granule coating method. The phase diagrams were used to study the phase separation in an ethylcellulose-petroleum ether-toluene system, and the effect of temperature and amount of petroleum ether on the ethylcellulose left in the organic solvent mixture was investigated. The phase diagrams showed that increase in temperature did not significantly affect the ethylcellulose residue, and 60 ml of nonsolvent was found adequate for microencapsulation. In vitro release of the formulated microcapsules and the commercially available preparations was performed in CO2-free distilled water using the USP XXIII rotating basket method, and the profiles were evaluated by Higuchi kinetics. Geometric mean diameters of the microparticles prepared by two different methods showed differences due to different core:wall ratios. A 4 x 5 factorial design was utilized and multiple regression was applied to the dependent variables (ethylcellulose content, percent dissolved) against the independent variables (amount of nonsolvent, temperature, core:wall ratio); the optimum phenytoin sodium-to-ethylcellulose ratio was 1:2.3. Utilizing second-order polynomial equations, response-surface graphs and contour plots pointed out the time necessary for 40%, 55%, and 70% release of phenytoin sodium. The desired release profiles were obtained with formulations E-5, ES-2 and ESL-2.

Cyclophosphamide loaded albumin microspheres II. Release characteristics.

The purpose of this investigation was to evaluate the release characteristics of cyclophosphamide (CP) from glutaraldehyde stabilized human serum albumin microspheres, and to study the effect of the extent of cross-linking, the amount of the stabilizing agent and the size of the microspheres on the in vitro release of CP. Microspheres were prepared by emulsion polymerization method using two different volumes (0.1 and 0.7 ml) of glutaraldehyde solution (25 per cent) and two different crosslinking durations (15 min and 1 h). The resulting mean particle size of the microspheres also varied between 2.5 microns and 3.7 microns. The total CP content in microspheres was analysed from the surface drug and the entrapped drug.

Naproxen incorporated lipid emulsions. I. Formulation and stability studies.

BACKGROUND: Intravenous lipid emulsions stabilized with phospholipids have been an attractive alternative as vehicles for drug delivery, particularly for the parenteral administration of drugs with solubility problems. METHODS: Naproxen (a poorly aqueous soluble non-steroidal anti-inflammatory agent) emulsions were formulated with different types of emulsifiers (soybean lecithin, synperonic PEF-127 and a 50:50 mixture of these). The stability of the various emulsion systems was evaluated at different temperatures (4, 25 and 40 degrees C) for a period of 6 months by measuring changes in pH, droplet size, viscosity and percentage oil separation. The percentage of naproxen incorporation and the degree of haemolysis induced by the different types of emulsion systems was also determined. RESULTS: The emulsifier type showed a pronounced effect on the physicochemical properties of the emulsion systems, whereas storage temperature and time did not. Irrespective of emulsifier type, storage temperature and time, the percentage incorporation of naproxen in emulsions was between 80 and 100%. The degree of haemolysis induced by other emulsion components (dimethylsulfoxide (DMSO) and naproxen solution in DMSO) was about 10 times higher than that induced by emulsion systems. CONCLUSION: Choice of emulsifier is the most important factor in the stability of the naproxen emulsions.

In-vitro studies of enteric coated diclofenac sodium-carboxymethylcellulose microspheres.

MIcrospheres containing diclofenac sodium (DS) were prepared using carboxymethylcellulose (CMC) as the main support material (1.0, 2.0, 3.0% (w/v)) and aluminum chloride as the crosslinker. Drug to polymer ratios of 1:1, 1:2 and 1:4 were used to obtain a range of microspheres. The microspheres were then coated with an enteric coating material, Eudragit S-100, efficiency, % yield value, particle sizes an in-vitro dissolution behaviour were investigated. The surface of the enteric coated microspheres seemed to be all covered with Eudragit S-100 from scanning electron microscopy observation. It was also observed that increasing the CMC concentration led to an increase in the encapsulation efficiency, % yield value and particle size and decreased the release rate. Eudragit S-100 coating did not significantly alter the size but the release rate was significantly lower even when the lower concentration solution was used.

Factorial design-based optimization of the formulation of isosorbide-5-mononitrate microcapsules.

Sustained action Isosorbide-5-mononitrate (IS-5-MN) microcapsules are prepared in order to overcome the tolerance developed in conventional preparations and to increase patient compliance. For this purpose, factorial design experiments are performed and microcapsules of IS-5-MN are formulated by the organic phase separation method using ethylcellulose with two different viscosities (10 and 45 cp) as coating material. The independent variables in the 2 x 3 x 3 factorial design are core: wall ratio, particle size and pH of the medium. The dependent variable, t50 percent is investigated by the second-order polynomial equation to establish the correlation between independent variables. By using the calculated equations, the response-surface graphs, from which various levels of independent variables could be predicted, are obtained. The in vitro release profiles of the formulated microcapsules and the commercially available preparations are obtained by using the rotating basket method. In vitro release is evaluated by zero-order, first-order, Hixson-Crowell and Higuchi release kinetics. The t50 percent values obtained from the Higuchi equation are used as response in the 2 x 3 x 3 factorial design experiments.

Formulation and release of dihydralazine sulphate from tabletted microcapsules.

One of the principal uses suggested for the microencapsulation of pharmaceuticals has been the preparation of the sustained release dosage form. The finished microcapsules have usually been presented in the form of suspensions or gels, but in order to obtain greater sustained release effect a non-disintegrating tablet would be a better formulation. Dihydralazine sulphate (Nepresol) is a dihydralazine-1,4-phthalazine derivative and used as an antihypertensive drug. This work was planned to prepare sustained action preparations of dihydralazine sulphate by microencapsulation and by tabletted microcapsules. Microcapsules were prepared from the microcapsule fractions using biconvex punches with 0.81 cm diameter fitted into a single punch by hand compressor. Avicel PH 101 and lactose were used as disintegrating materials in tablets having 2 kg hardness. Dissolution from both suspended microcapsules and the tablets was studied using the USP XX basket method. A study of in vitro release for both the free and tabletted microcapsules showed basically the same pattern but the time for the release was extended in the case of the tabletted preparations. Dissolution of dihydralazine sulphate was found to be governed by the core: wall ratio, microcapsule size, and the amount and kind of disintegrating agents. Dissolution kinetics were studied and evaluated.

Formulation and in vitro/in vivo evaluation of terbutaline sulphate incorporated in PLGA (25/75) and L-PLA microspheres.

Terbutaline sulphate (TBS) is widely used in the treatment of bronchial asthma, chronic bronchitis and emphysema. Because of its short biological half life and dosing schedule, a long acting TBS formulation is required to improve patient compliance. The objective of this study was to develop a TBS containing biodegradable microsphere formulation. Poly(D,L-lactide-co-glycolide) (PLGA) and poly(L-lactic acid) (L-PLA) were chosen as matrix materials. A solvent evaporation method was used for preparation of microspheres. Surface morphology, particle size distribution and encapsulation efficiency were investigated. In vitro release studies were performed in pH 7.4 phosphate buffer. In vitro distribution of microspheres were studied in the Swiss albino male mice. All microspheres were spherical in shape and had a porous surface with mean diameters of 9-21 microm. The encapsulation efficiency was influenced by the polymer type, but not the molecular weight. About 90% of the initial amount was trapped in PLGA microspheres, and the remainder was on the surface. In the case of L-PLA, 50% of the total drug was associated with the surface of microspheres. The In vitro release pattern was biphasic characterized by an initial burst phase followed by a slower phase. The L-PLA microspheres released approximately 92% of the initial payload in 72 h. On the other hand, TBS release was increased with an increase in the molecular weight of PLGA. Biodistribution of L-PLA microspheres was characterized by an initially high uptake (35%) by the lungs. All these results suggest that L-PLA and PLGA microspheres have the potential to be used for passive lung targeting.

In vitro/in vivo evaluation of the efficiency of teicoplanin-loaded biodegradable microparticles formulated for implantation to infected bone defects.

Chronic osteomyelitis is still the cause of many problems in orthopaedics in terms of therapy and infection persistence. Four-to-six week systemic antibiotic therapy is required along with bone and soft tissue debridement in the therapy of chronic osteomyelitis. Prolonged-release local antibiotic therapy has been taken into consideration due to the side effects encountered in long-term high dose antibiotic use and the duration of hospitalization of the patients. Although local antibiotic therapy has been achieved by bone cement, a second surgical operation is needed for the removal of the system. On the other hand, heat generation during cement curing limits the use of heat-sensitive active ingredients. The most frequent osteomyelitis inducing micro-organism is gram (+) Staphylococcus aureus. In this study, teicoplanin, a glycopeptide antibiotic, active on gram (+) bacteria, was incorporated in a synthetic polymer in order to prepare a microsphere formulation for implantation to bone defects. Particle size, surface characteristics, loading capacity and in vitro release characteristics of the microspheres were determined as well as stability assessment of teicoplanin under accelerated conditions. In vivo studies were performed on rabbits and the microparticles were implanted intra-articularly to the lateral condylus of the femur. Antibiotic presence was detected by a microbiological assay from synovial fluid sample aspirated throughout 5 weeks. In the light of these evaluations, microspheres prepared from PLGA (75:25) (Mw 136,000) polymer were determined to be effective, and promising for obtaining prolonged local antibiotic release.

In vitro and in vivo evaluation of diclofenac sodium loaded albumin microspheres.

The use of polymeric carriers in formulations of therapeutic drug delivery systems has gained widespread application, due to their advantage of being biodegradable and biocompatible. Among the microparticulate systems, microspheres have a special importance since it is possible to target drugs and provide controlled release. Diclofenac sodium (DS), is a potent drug in the NSAID group having non-steroidal, anti-inflammatory properties, and is widely used in the treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. In this present study, it was aimed to prepare microsphere formulations of DS using a natural biodegradable polymer as a carrier for intraarticular administration to extend the duration period of the dosage form in the knee joint. Microsphere formulations of DS which were prepared were evaluated in vitro for particle size, yield value, encapsulation efficiency, surface morphology, and in vitro drug release. Two appropriate formulations were selected for in vivo trials. For the in vivo studies, Technetium-99m labelled polyclonal human immunogammaglobulin (99mTc-HIG) was used as the radiopharmaceutical to demonstrate arthritic lesions by gamma scintigraphy. After the induction of arthritis in knee joints of rabbits, the radio-labelled microspheres loaded with DS were injected directly into the articular cavity and at specific time points gamma scintigrams were obtained to find the residence time of the microspheres in knee joints in order to determine the most suitable formulation.