Formulation parameters and release mechanism of theophylline loaded ethyl cellulose microspheres: effect of different dual surfactant ratios

Altering the combined hydrophilic-lipophilic balance (CHLB), by varying the ratio of dual surfactants, on formulation parameters and in vitro drug release of ethyl cellulose microspheres was examined.

Theophylline, a xanthine bronchodilator was used to model controlled release owing to its narrow therapeutic index. Microspheres were prepared using different ratios of dual surfactant in an emulsion-solvent evaporation process. Drug loading, encapsulation efficiency, particle size distribution, and geometric mean diameters were evaluated. Drug release was evaluated using several kinetic models including zero and first order, Higuchi square root, and Hixson-Crowell.

Microspheres presented as mostly spherical particles and diffusional drug release was affected by microsphere construction. For this novel, dual surfactant system the microsphere matrix is a hydrophobic polymer and the release rate may be modulated with variation in ratio of dual surfactants. Dissolution data followed the Higuchi model and supports the formation of a monolithic microsphere matrix that releases theophylline by Fickian diffusion.

Dual surfactants for preparation of microspheres are an inadequately studied research area that offers another means to modulate particle size and drug release. For the current study microspheres prepared with surfactant ratios of Span 65: Tween 40 between 3:1 and 2:1 provided the best control of size and drug release.     

Effect of the dispersion of Eudragit S100 powder on the properties of cellulose acetate butyrate microspheres containing theophylline made by the emulsion-solvent evaporation method

The dispersion/incorporation of Eudragit S100 powder as a filler in cellulose acetate butyrate (CAB-551-0.01) microsphere containing theophylline was investigated as a means of controlling drug release. Microspheres of CAB-551-0.01 of different polymer solution concentrations/viscosities were prepared (preparations Z(0), Z(A), Z(B) and Z(C)) and evaluated and compared to microspheres of a constant concentration of CAB-551-0.01 containing different amounts of Eudragit S100 powder as a filler (preparations X(A), X(B) and X(C)). The organic solvent acetonitrile used was capable of dissolving the matrix former CAB-551-0.01 only but not Eudragit S100 powder in the emulsion-solvent evaporation method. The CAB-551-0.01 concentration in Z(A), Z(B) and Z(C) was equal to the total polymer concentration (CAB-551-0.01 and Eudragit S100 powder) in X(A), X(B) and X(C), respectively. Scanning electron microscopy (SEM) was used to identify microspheres shape and morphology. In vitro dissolution studies were carried out on the microspheres at 37 degrees C (+/-0.5 degrees C) at two successive different pH media (1.2 +/- 0.2 for 2 h and 6.5 +/- 0.2 for 10 h). Z preparations exhibited low rates of drug release in the acidic and the slightly neutral media. On the other hand, X preparations showed an initial rapid release in the acidic medium followed by a decrease in the release rate at the early stage of dissolution in the slightly neutral pH which could be due to some relaxation and gelation of Eudragit S100 powder to form a gel network before it dissolves completely allowing the remained drug to be released.     

Cross-linked chitosan microspheres: preparation and evaluation as a matrix for the controlled release of pharmaceuticals.

Chitosan microspheres having good spherical geometry and a smooth surface were prepared by the glutaraldehyde cross-linking of an aqueous acetic acid dispersion of chitosan in paraffin oil using dioctyl sulphosuccinate as the stabilizing agent. Microspheres having different degrees of swelling were made by varying the cross-linking density. Microspheres were prepared by incorporating theophylline, aspirin or griseofulvin. Drug incorporation efficiencies exceeding 80% could be achieved for these drugs. In-vitro release studies of these drugs were carried out in simulated gastric and intestinal fluids at 37 degrees C. It was observed that the drug release rates were influenced by the cross-linking density, particle size and initial drug loading in the microspheres.     

Effect of Drug Loading and Molecular Weight of Cellulose Acetate Propionate on the Release Characteristics of Theophylline Microspheres

Microspheres with 40, 50, and 60% drug loading of anhydrous theophylline core material were prepared by the emulsion-solvent evaporation method. Three different molecular weights of cellulose acetate propionate were used as encapsulating polymers. The geometric mean diameter of the microspheres increased with drug loading for all polymers. Dissolution rate for a given particle size fraction also increased with drug loading for all polymers. Higuchi/Baker-Lonsdale spherical matrix dissolution kinetics were followed by narrow particle size fractions of the microspheres. A linear relationship between the T-50% (time required for 50% of the drug to be released) and the square of microsphere diameter was observed with all three molecular weights of the encapsulants. The slowest drug release was obtained with the high molecular weight polymer, which also produced the smoothest microspheres.     

Preparation and investigation the release behaviour of wax microspheres loaded with salicylic acid

Salicylic acid-beeswax microspheres were prepared by melt dispersion technique. The effects of formulation parameters on the microscopic characteristic, drug loading and cumulative amount of released drug were investigated by experimental design. Results showed that all of the microparticles were spherical with porous surfaces. The average size of microspheres was 24-48 microm, the drug content was in the range of 22-45% and the encapsulation efficiency was 46-93%. Drug loading was influenced by emulsification speed as a main factor. All the microspheres had a burst release initially. The emulsifier concentration did not have a significant effect on drug release. The release behaviour of microspheres conformed best to Korsmeyer-Peppas semi-empirical model and the release of SA from beeswax microspheres was Fickian (n < 0.45).     

Evaluation of ibuprofen-loaded microspheres prepared from novel copolyesters

The utility of two novel linear random copolyesters to encapsulate and control the release of ibuprofen, via microspheres, was investigated. Various manufacturing parameters, including temperature, disperse phase volume and polymer:ibuprofen ratios were altered during the microsphere production. The effects of these changes on the morphological characteristics of the microspheres, yield, drug loading, encapsulation efficiency and drug release rates were examined. The diameter of the microspheres ranged from 36 to 89 microm and showed both smooth and ridged surfaces. Microsphere diameter was probably determined by the internal phase volume, while surface morphology was controlled by manufacturing temperature. Greater encapsulation efficiency was obtained by increasing the polymer:ibuprofen ratio and by reducing the internal phase volume. For all batches there was an initial burst drug release into phosphate buffer (pH 7.4) over the first 2-4h, which was followed by a much slower release rate over the remaining time period. Drug release rates during both these phases were dependent upon the amount and nature of the polymer in the microspheres, noting that the more hydrophilic polymer provided faster release rates. Ibuprofen solubility appeared to play a dominant role in controlling release, although both encapsulation efficiency and microsphere morphology were also contributing factors.     

Preparation and in vitro characterization of gelatin microspheres containing Levodopa for nasal administration

Transnasal absorption of pharmaceutical drugs has been recognized as an interesting alternative to the more conventional routes of administration. The aim of this paper was to develop a method of administrating L-dopa following the transnasal route. Gelatin microspheres were prepared by the w/o emulsification solvent extraction technique: the microspheres had a median particle size of 16.2 +/- 4.2 microm and were prepared using a stirring speed of 600 rpm for 5 min at 80 degrees C. The microspheres obtained were spherical and smooth-surfaced, and the microsphere size was inversely proportional to stirring speed (300-700 rpm) and to the percentage of the emulsifier (Tween 85, 1.4-2.7% v/v). L-dopa was incorporated into the microspheres with an efficiency of 65 +/- 6.7%. L-dopa was released from the microspheres, showing an initial fast release rate, followed by a second slower release rate.     

Micromeritics and release behaviours of cellulose acetate butyrate microspheres containing theophylline prepared by emulsion solvent evaporation and emulsion non-solvent addition method

The present research work compares the effect of microsphere preparation technique on micromeritics and release behaviors of theophylline microspheres. Microspheres were prepared by oil-in oil (O₁/O₂) emulsion solvent evaporation method (ESE) using different ratios of anhydrous theophylline to cellulose acetate butyrate (CAB). Cyclohexane was used as non-solvent to modify the ESE technique (MESE method) and the effect of non-solvent volume on properties of microspheres was investigated. The obtained microspheres were analyzed in terms of drug content, particle size and encapsulation efficiency. The morphology of microsphere was studied using scanning electron microscope. The solid state of microspheres, theophylline and CAB were investigated using X-ray, FT-IR and DSC. The drug content of microspheres prepared by MESE method was significantly lower (15.54% ± 0.46) than microspheres prepared by ESE method (41.08 ± 0.40%). The results showed that as the amount of cyclohexane was increased from 2 mL to 6 mL the drug content of microspheres was increased from 15.54% to 28.71%. Higher encapsulation efficiencies were obtained for microspheres prepared by ESE method (95.87%) in comparison with MESE method (64.71%). Mean particle size of microsphere prepared by ESE method was not remarkably affected by drug to polymer ratio, whereas in MSES method when the volume of cyclohexane was increased the mean particle size of microsphere was significantly decreased. The ratio of drug to polymer significantly changed the rate of drug release from microspheres and the highest drug release was obtained for the microsphere with high drug to polymer ratio. The amount of cyclohexane did not significantly change the drug release. Although, x-ray showed a small change in crystallinity of theophylline in microspheres, DSC results proved that theophylline in microspheres is in amorphous state. No major chemical interaction between the drug and polymer was reported during the encapsulation process.     

Solvent, emulsifier and drug concentration factors in poly(D,L-lactic acid) microspheres containing hexamethylmelamine.

Biodegradable poly(D,L-lactic acid) (PLA) microspheres containing hexamethylmelamine (HMM) were developed for potential use in chemoembolization and intraperitoneal implantation. The emulsion-solvent-evaporation/extraction method was used to prepare 15 formulations with different drug/polymer ratios, solvent compositions and emulsifer concentrations in the continuous aqueous phase. A central composite experimental design was used, with five levels of the three different factors. All formulations resulted in the formation of discrete matrix microspheres containing crystalline drug. The mean particle sizes of the microsphere formulations ranged from 62-348 microm and the effect of the independent variables on microsphere size was satisfactorily predicted using response surface methodology. For theoretical drug loads of 5-40%, efficiency of entrapment ranged from 75-107% and porosities of the microspheres were between 0-6.5%. The rate of drug release from the microspheres depended on drug loading and particle size. Microspheres with 22.5% or greater theoretical drug content released drug rapidly, with almost complete release occurring in 70 h or less. Formulations with drug loading of 5% and 9.57%, however, released drug very slowly, with less than 50% released in 40 days. Release kinetics of narrow sieve cuts of microspheres with high drug load (35.4%) followed square root of time profiles.     

Bimodal release of theophylline from "seed-matrix" beads made of acrylic polymers

The purpose of this research was to design a "seed-matrix" structure for an in vitro bimodal theophylline release profile and to investigate the mechanism and kinetics of drug release as well as the influence of various factors on the properties of the theophylline-containing microspheres. "Seed" microspheres with high theophylline content were prepared from Eudragit L100 and Eudragit S100, copolymers of methyl methacrylate and methacrylic acid, by the solvent removal process. The seed-matrix beads were subsequently prepared by incorporation of the seed microspheres into Eudragit RL100, a copolymer of acrylic and methacrylic acid esters with a low content of quaternary ammonium group. Increasing the size of encapsulated drug particles and the rate of agitation during the preparation, or decreasing the amount of surfactants led to an increase in the size of the microspheres produced. Scanning electron microscopy revealed porous morphology of the microspheres. The release rate of theophylline was enhanced as the content of methacrylic acid in the copolymer increased and the size of the microspheres decreased. The kinetics of drug release from the microspheres was controlled by swelling at the early stage and by diffusion in the later stage. The drug was released from the matrix of the seed-matrix beads at pH 1.2 and from both the matrix and the seeds at pH 6.8. A bimodal release profile of theophylline was obtained from the seed-matrix beads made of acrylic polymers.     

Preparation and characterization of Mitomycin-C loaded chitosan-coated alginate microspheres for chemoembolization

Mitomycin-C loaded and chitosan-coated alginate microspheres were prepared for use in chemoembolization studies. In this respect, first alginate microspheres were prepared by using a spraying method using an extrusion device with a small orifice and following suspension cross-linking in an oil phase. Chitosan-coating onto the alginate microspheres was achieved by polyionic complex formation between alginate and chitosan. CaCl(2) was used as a cross-linker for alginate microspheres. The obtained chitosan-coated alginate microspheres were spherical shaped and approximately 100-400 microm average size. The microspheres were evaluated based on their swellability and the swelling ratio was changed between 50-280%. CaCl(2) concentration, stirring rate, chitosan molecular weight, chitosan concentration and time for coating with chitosan were selected as the effective parameters on microsphere size and swelling ratio. Equilibrium swellings were achieved in approximately 30 min. On the other hand, chitosan molecular weight, chitosan concentration and time for coating with chitosan were found as the most effective parameters on both drug loading ratio and release studies. Maximum drug loading ratio of 65% was achieved with high molecular weight (HMW) chitosan, highest chitosan concentration (i.e. 1.0% v/v) and shortest time for coating with chitosan (i.e. 1 h) values.     

Sophoridine-loaded PLGA microspheres for lung targeting: preparation,in vitro,and in vivo evaluation

Lung-targeting sophoridine-loaded poly(lactide-co-glycolide) (PLGA) microspheres were constructed by a simple oil-in-oil emulsion-solvent evaporation method. The obtained microspheres were systematically studied on their morphology, size distribution, drug loading, encapsulation efficiency, in vitro release profile, and biodistribution in rats. The drug-loaded microparticles showed as tiny spheres under SEM and had an average size of 17?μm with 90% of the microspheres ranging from 12 to 24?μm. The drug loading and encapsulation efficiency were 65% and 6.5%, respectively. The in vitro drug release behavior of microspheres exhibited an initial burst of 16.6% at 4?h and a sustained-release period of 14 days. Drug concentration in lung tissue of rats was 220.10?μg/g for microspheres and 6.77?μg/g for solution after intraveneous injection for 30?min, respectively. And the microsphere formulation showed a significantly higher drug level in lung tissue than in other major organs and blood samples for 12 days. These results demonstrated that the obtained PLGA microspheres could potentially improve the treatment efficacy of sophoridine against lung cancer.     

Preparation and characterization of biodegradable or enteric-coated microspheres containing the protease inhibitor camostat

We have produced biodegradable or enteric-coated microspheres containing camostat mesylate, a protease inhibitor, using a water-oil-water emulsion solvent evaporation method. The characteristics of the microspheres were determined. When polylactic acid, a biodegradable polymer, was used as a wall material, the optimized microsphere obtained showed a loading efficiency of almost 95% and had a mean diameter of 30 microm. This microsphere showed a sustained-release profile, with nearly 25% of drug being released at seven days in a dissolution test. When hypromellose acetate succinate (AS-HG type, with a high content of succinyl group) was used as an enteric wall material, optimized microspheres showed a loading efficiency of almost 80%. In this case, pH 3.0 citrate buffer was used as an internal aqueous phase, and citrate buffer containing 0.5% polyvinylalcohol was used as the external aqueous phase. These microspheres showed a rapid release profile in pH 6.8 buffer, whereas the release was extremely slow in pH 1.2 buffer. Hypromellose acetate succinate microspheres were also prepared containing 10% (w/w) N-benzoyl-dl-arg-4-nitroanilide as a model substrate for trypsin, with or without 5% (w/w) camostat. These microspheres were incubated in pH 6 or 7 buffer containing trypsin at 37 degrees C. When camostat was included in the microspheres, the substrate was protected from attack by trypsin, while in the absence of camostat, the released substrate was immediately attacked by trypsin to produce the degradation product N-benzoyl-dl-arginine.     

Effect of temperature-increase rate on drug release characteristics of dextran microspheres prepared by emulsion solvent evaporation process

Microspheres containing theophylline (TH) were prepared from a hydrophobic dextran derivative by an emulsion solvent evaporation process using an acetone/liquid paraffin system. The effects of solvent evaporation rate on particle properties and drug release characteristic of the microspheres were evaluated. The solvent evaporation rate was controlled by the rate of increase in temperature of the water bath, ranging 7.5-30 degrees C/h. Drug release from the microspheres was examined using JPXIV 2nd fluid (pH 6.8) containing 0.1% Tween 80, and was found to be greatly affected by the solvent evaporation rate. The percentage of drug released until 8h varied; from 28% to 84% for 30 and 7.5 degrees C, respectively. Differential scanning calorimetry and powder X-ray diffraction studies revealed that TH partially interacted with the polymer and drug crystallinity was maintained intact in the microspheres. According to scanning electron microscopy observations, all microspheres showed a well-formed spherical particle with a solid interior. The appearances of the microspheres were, however, extremely different. Microspheres prepared at 30 degrees C/h had a very smooth surface, while those prepared at 7.5-15 degrees C/h had a rough surface with large craters. These findings demonstrated that the surface morphology and drug release characteristic were controlled by the rate of increase of temperature.     

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.     

Development and Evaluation of Sustained-Release Ibuprofen–Wax Microspheres. II. In Vitro Dissolution Studies

A modified USP paddle method using minibaskets was used to study the effects of various formulations on in vitro dissolution of ibuprofen microspheres. Formulations containing waxes such as paraffin or ceresine wax without modifiers exhibited very slow dissolution profiles and incomplete release, which did not improve with increased drug loading or the preparation of smaller microspheres. The addition of modifiers such as stearyl alcohol and glyceryl mono-stearate greatly increased the dissolution rate, with 20% (w/w) near the optimum for predictable dissolution. Higher drug loading and decreased microsphere size increased the dissolution rate from microspheres containing modifier. Optimum formulations contained ceresine wax or microcrystalline wax and stearyl alcohol as a modifier, with a drug content of 17%. An increase in the encapsulation dispersant concentration had little effect on the dissolution profiles. The dissolution data from narrow size fractions of microspheres indicated spherical matrix drug release kinetics; the 50% dissolution time decreased with the square of the microsphere diameter. With appropriate modifiers, wax microsphere formulations of drugs with solubility characteristics similar to those of ibuprofen can offer a starting basis for predictable sustained release dosage forms.     

Application of Eudragit P-4135F for the delivery of ellagic acid to the rat lower small intestine

Based on the assumption that the delivery of ellagic acid to its site of action would show an antiinflammatory activity in inflammatory bowel disease (IBD), we have prepared microspheres using a new pH-sensitive polymer, Eudragit P-4135F (P-4135F), to deliver ellagic acid to the lower small intestine in rats. The microspheres were spherical in shape and the mean diameters were approximately 100-150 microm. The amount of ellagic acid released from the microspheres decreased by increasing the formulated amount of P-4135F. The release characteristics of ellagic acid were pH-dependent. By considering the factors loading efficiency and microsphere particle size distribution, ellagic acid-2 microspheres (P-4135F/ellagic acid = 1.65) were selected for further investigation. In a dissolution study, more than 95% ellagic acid was released within 0.5 h in pH 7.4 and 8.0 buffers. The release percent of ellagic acid was less than 40% in pH 6.8 and 7.0 and was less than 10% in pH 5.6 and 5.9. To observe the dissolution sites of the microspheres in the rat small intestine fluorescein was formulated in the microspheres as a tracer drug along with ellagic acid (50 mg kg(-1)). After intraduodenal administration of fluorescein-labelled microspheres to rats, the plasma fluorescein level started to increase at 0.5 h, by which time the microspheres had reached the middle part of the ileum. Microspheres started to dissolve within 1.0 h and the peak plasma fluorescein concentration was observed at 3.0 h, when the majority of the administered microspheres were dissolved in the terminal ileum. These results suggested that P-4135F microspheres could deliver ellagic acid to the lower part of the small intestine, and that the released ellagic acid would be distributed into the caecum and the ascending colon.     

In vitro evaluation of gentamicin released from microparticles

In this study, the preparation, characterization and drug release behaviour of gentamicin (GM)-loaded poly(D,L-lactide-co-glycolide) microspheres are described. The microspheres were produced using a double emulsion solvent evaporation technique. All the microspheres preparation resulted in spherical shape and the mean diameter was 3 microm (for empty microspheres) and between 5 and 9 microm for microparticles loaded with GM. The encapsulation efficiency (EE) ranged from 3.4 to 90% depending on the formulation. Increasing the volume of the external aqueous phase, increased the EE. Encapsulation also depended on the pH value of the internal aqueous phase, the highest value was achieved when maintained the internal aqueous phase at pH 6, where GM was more soluble. Moreover, increasing nominal GM loading yielded lower encapsulation efficiencies. The release profiles of GM from microparticles resulted in biphasic patterns. After an initial burst, a continuous drug release was observed for up to 4 weeks. Finally, the formulations with higher loading released the drug faster.     

Studies on the poly(lactic-co-glycolic) acid microspheres of cisplatin for lung-targeting

Lung-targeting cisplatin-loaded poly(lactic-co-glycolic) acid microspheres (CDDP-PLGA-MS) were prepared by a solvent evaporation method. The uniform design was used to optimize the technology of preparation, the appearance and size distribution were examined by scanning electron microscope, and the aspects such as in vitro release characteristics, stability, drug loading, loading efficiency, pharmacokinetics and tissue distribution in rabbit were studied. The experimental results showed that the microspheres were globular in appearance and dispersed well. The average particle size was 12.8 microm with 98% of the microspheres being in the range of 5-30 microm. The drug loading and loading efficiency were 17.68 and 53.2%, respectively. The in vitro release behavior could be expressed by the following equation: 1-Q=0.424e(-0.360t)+0.474e(-0.001t). After i.v. administration (15 min), the drug concentration of microspheres group in lung in rabbits was 212 microg/g, while that of controlled group was 1.37 microg/g. CDDP-PLGA-MS showed a combination of lung-targeting and sustained drug release in experiments on rabbits.     

In vitro and in vivo evaluation of insulin microspheres containing protease inhibitor

The aim of this study was to investigate the applicability of microspheres containing protease inhibitor for oral delivery of insulin (CAS 9004-10-8). Microspheres of insulin were prepared by water-in-oil-in-oil (w/o1/o2) double emulsion solvent evaporation method. Formulations with different drug/polymer ratios were prepared and characterized by drug loading, loading efficiency, yield, particle size, scanning electron microscopy (SEM), Fourier Transform Infrared spectroscopy (FTIR). The in vitro release studies were performed in pH 1.2 and 7.4. In vivo studies on rats were conducted in order to investigate the bioavailability and performance of oral microspheres. The best polymer to drug ratio in microspheres was 15.6:1 (F2 formulation). The loading efficiency was 77.36%, production yield was 54.55% and mean particle size was 222.4 microm. SEM studies showed that the microspheres were spherical and porous in nature. Data obtained from in vitro release were fitted to various kinetic models and high correlation was obtained in the first order model. The results of enzymatic degradation indicated that insulin could be protected from trypsinic degradation in the microspheres. Our results indicate that the microspheres containing aprotinin (CAS 9087-70-1) have the advantage of high loading efficiency, pH responsive and prolonged release carrying insulin to the optimum site of absorption as well as the enhanced insulin absorption and biological response.