Volume Of External Aqueous Phase Research Articles

Effect of Processing Parameters on Release Profiles of Donepezil Hydrochloride-Loaded Microparticles

The purpose of this study was to examine the effect of processing parameters on drug release profiles of microparticles. Double emulsion solvent evaporation technique was utilized to encapsulate donepezil hydrochloride which is a hydrophilic drug. The processing parameters examined were polymer amount, stirring time and volume of external aqueous phase. The morphology of microparticles was observed under light microscope and scanning electron microscope. After that, in vitro drug release testing was conducted in simulated salivary fluid (pH6.75) and simulated gastric fluid (pH1.2). The results showed that these three parameters were the significant parameter affecting drug release profiles of the microparticles.

ENCAPSULATION AND RELEASE PROFILE OF PROTEIN CAGE FROM A POLYMERIC MATRIX

Protein cages have been widely investigated as molecular drug carrier. E2 protein from Bacillus stearothermophillus forms a dodecahedral cage structure of approximately 24 nm in diameter. To formulate a sustainable release profile, E2 protein was further encapsulated into poly(lactide-co-glycolide) (PLGA) microparticles to form a composite structure using water-in-oil-in-water (W/O/W) double emulsion method. The influence of fabrication parameters on microparticle morphology and E2 protein release profile were investigated. The microparticle size increased when the stirring speed of the second emulsification decreased. Decrease in the volume of external aqueous phase led to the reduction of microparticle size without affecting its porosity. The higher ionic concentration of external aqueous phase in the presence of surfactant resulted in microparticles with closed pores on surface. Increase in polymer concentration also led to the formation of less porous microparticles. The E2 protein was not dissociated upon encapsulation into PLGA microparticles based on the unchanged particle size of E2 protein. E2 protein release was studied in phosphate-buffered saline solution at 37°C. The initial burst and release rate were lowered as the surfactant concentration in external water phase during the fabrication process was increased from 0.1% to 1% (w/v). After 14-day incubation, no observable polymer degradation was found while the surface of microparticles appeared to be smoother than before incubation.

BIODEGRADABLE SOLID LIPID MICROPARTICLES LOADED WITH DILTIAZEM HYDROCHLORIDE FOR ORAL DELIVERY: PREPARATION AND IN-VITRO/IN-VIVO EVALUATION

Diltiazem, a benzodiazepine, voltage sensitive ca2+ channel blocker with a high therapeutic potential but with a very short biological half life was encapsulated within microparticles. The encapsulation efficiency of prepared SLM reached 70.48±1.67% w/w. Further, the particle size (99.52±1.06μm), surface morphology (spherical) and drug loading efficiency (17.62±2.14%w/w) were investigated. Various formulation and process parameters like drug polymer ratio (3:1), nature and concentration of emulsion stabilizer in the external aqueous i.e. aqueous PVA solution (0.1%), phase viscosity of external aqueous phase (0.5%), volume of external aqueous phase and stirring rate (1000 rpm for 2 h) were optimized. The in-vitro release of diltiazem from the microparticles as observed with the initial burst release of 17% followed by the slow release to avoid dose dumping. The analytical methodology employed for characterization included UV and IR Spectroscopy, DSC, physicochemical stability studies which proves that the prepared solid lipid microparticles appear to have promising abilities for oral administration of diltiazem hydrochloride with improved half life, improved bioavailability and minimized local and systemic GI disturbances.

Physico-chemical properties investigation of cisplatin loaded polybutyladipate (PBA) nanoparticles prepared by w/o/w

cis-Diamminedichloroplatinum(II) (cisplatin) is used against different kinds of cancers. Unfortunately, because of the severe side-effects like nephrotoxicity, ototoxicity, etc., they are administered in small doses at low concentrations. The purpose of this work is to improve injectional controlled release (ICR) of cisplatin that releases drug in the extended temporal periods. In order to access this aim, biodegradable polymeric nanoparticles containing cisplatin as anticancer drug of various ranges from 71 to 661nm were prepared by a w/o/w double emulsion solvent evaporation technique. Influences of process parameters such as solvent removal technique, type and concentration of polymer, volume of oil phase, volume of external aqueous phase, concentration of stabilizer, drug concentration in the internal and external aqueous phases and power of sonication on morphology, characteristics of the nanoparticles and release profile were investigated. Morphology of the nanoparticles was studied by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) and the images indicated that spherical shape of the nanoparticles can be tailored to rod-like shape by changing the reaction parameters. Size of the nanoparticles decreased as polymer concentration decreases. Volume of oil phase, power of sonication and drug concentration in the internal water phase affected the size of nanoparticles. Drug release profiles indicate that polymer concentration in the oil phase and stabilizer concentration in the external water phase have critical role in the drug release process from the nanoparticles. The in-vitro release of the encapsulated drug was observed by using the diffusion models of release from a sphere carrier and the release pattern was shown to be a complex process.

Development of enteric submicron particles formulation of α-amylase for oral delivery

Enteric submicron particles (SPs) formulations of α-amylase were prepared by w/o/w emulsion solvent evaporation using hydroxypropyl methylcellulose phthalate (HPMCP) and Eudragit L 100, to avoid gastric inactivation of α-amylase. Smaller internal and external aqueous phase volume provided maximum encapsulation efficiency (71.92–73.40%), least particle size (546.4–595.4 nm) and 23–26% loss of enzyme activity. Release studies in 0.1 N HCl confirmed the gastro-resistance of formulations. The anionic SPs aggregated in 0.1 N HCl (i.e. gastric pH 1.2), due to protonation of carboxylic groups of enteric polymer. The aggregates being < 500 µm size would not impede gastric emptying. However, at pH >5.0 (duodenal pH), SPs showed de-aggregation due to restoration of surface charge. HPMCP and Eudragit L 100 SPs facilitated almost complete release of α-amylase within 30 min at pH 6.0 and 6.8, respectively, following Higuchi kinetics. PXRD and DSC indicated amorphous character and scanning electron microscope showed spherical shape of SPs. In simulated gastro-intestinal pH condition, HPMCP and Eudragit L 100 SPs showed good digestion of cooked rice and could serve as potential carrier for oral enzyme delivery. Stability studies indicated the formulations as quite stable to ensure 2 years shelf life at room temperature.

In vitro release characteristics and cellular uptake of poly(D,L-lactic-co-glycolic acid) nanoparticles for topical delivery of antisense oligodeoxynucleotides

The efficacy of antisense oligodeoxynucleotides (AsODNs) is compromised by their poor stability in biological fluids and the inefficient cellular uptake due to their size and negative charge. Since chemical modifications of these molecules have resulted in a number of non-antisense activities, incorporation into particulate delivery systems has offered a promising alternative. The aim of this study was to evaluate various poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles for AsODN entrapment and delivery. PLGA nanoparticles were prepared using the double emulsion solvent evaporation method. The influence of formulation parameters such as PLGA concentration and volume ratio of internal aqueous phase volume (Va1) to organic phase volume (Vo) to external aqueous phase volume (Va2) on particle size, polydispersity index (PDI) and zeta potential (ZP) was investigated using a full factorial study. The particle size increased with increasing PLGA concentrations and volume ratios, with an interaction detectable between the two factors. AsODN entrapment efficiencies ranged between 49.97% and 54.95% with no significant difference between various formulations. By fitting the in vitro release profiles to a dual first order release model it was shown that the AsODN release occurred via two processes: a diffusion controlled process in the early phase (25 to 32% within one day) and a PLGA degradation process in the latter (39 to 70% after 14 days). Cellular uptake studies using primary corneal epithelial cells suggested active transport of nanoparticles via endocytosis. PLGA nanoparticles therefore show potential to successfully entrap AsODNs, transport them into cells and release them over time due to polymer erosion.

Enteric Microsphere Formulations of Papain for Oral Delivery

Enteric microspheres formulations of papain were prepared by w/o/w emulsion solvent evaporation using hydroxypropyl methylcellulose phthalate (HPMCP), Eudragit L 100 and Eudragit S 100, to avoid gastric inactivation of papain. Smaller internal and external aqueous phase volume provided maximum encapsulation efficiency (74.49-79.76%), least particle size (52.4-60.2 µm) and 21-26% loss of enzyme activity. Release studies in 0.1 N HCl confirmed the gastro-resistance of formulations. The anionic microspheres, zeta potential between -18.21 and -20.06 mV, aggregated in 0.1 N HCl (i.e., gastric pH 1.2), due to protonation of carboxylic groups of enteric polymer and loss of surface charge with subsequent change in zeta potential. The aggregates being <500 µm size would not impede gastric emptying. However, at pH>5.0 (duodenal pH) the microspheres showed de-aggregation due to restoration of surface charge. HPMCP and Eudragit L 100 microspheres facilitated almost complete release of papain within an hour at pH 6.0 and 6.8, respectively while Eudragit S 100 microspheres released 84.56% papain at pH 7.4, following Higuchi kinetics. FTIR spectroscopy revealed entrapment of enzyme; PXRD & DSC indicated amorphous character and SEM showed spherical shape of microspheres. In simulated gastro-intestinal pH condition, HPMCP, Eudragit L 100 and Eudragit S 100 microspheres showed good digestion of paneer and milk protein. Thus, enteric microspheres formulations could serve as potential carrier for oral enzyme delivery. Stability studies indicated the formulations with around 5% overage would ensure 2 years shelf life at room temperature.

Optimized Formulation of High-Payload PLGA Nanoparticles Containing Insulin–Lauryl Sulfate Complex

A novel poly(lactic acid-co-glycolic acid) nanoparticle loaded with insulin–lauryl sulfate complex was prepared by spontaneous emulsion solvent diffusion method. The effects of key parameters such as agitation speed, poly(vinyl alcohol) concentration, solvent composition, polymer concentration, and the volume of external aqueous phase on the properties of the nanoparticles were investigated. To enhance the drug recovery and drug content simultaneously, a response surface methodology with five-level, two-factor central composite design was employed. The weight ratio of polymer to drug and volume ratio of external aqueous phase to solvent phase were selected as controlled factors on account of their interactions found in the monofactorial investigations. The experimental datum allowed the development of quadratic models (p < .05) describing the inter-relationships between the dependent and independent variables. By solving the regression equation, and graphic analyzing the response surface contour and plots, the optimum values of the two factors were determined as 20/1 and 10/1. The optimized conditions led to 89.6% of drug recovery and 4.57% of drug content during nanoparticle preparation.

Poly (ε-caprolactone) microparticles containing Levobunolol HCl prepared by a multiple emulsion (W/O/W) solvent evaporation technique: Effects of some formulation parameters on microparticle characteristics

The aim of this study was to prepare poly (ε-caprolactone) (PCL) microparticles of Levobunolol HC1 (L-HC1) for use as an anti-glaucomatous drug to the eye. The double emulsion (W/O/W) solvent evaporation technique was used for encapsulating L-HC1 as a hydrophilic drug. The study examined the impact of different factors including the pH and volume of the external aqueous phase, the concentration of polyvinylalcohol (PVA) and pluronic® F68 (PF68) used as stabilizers and drug/polymer ratios on the characteristics of the microparticles. Scanning electron microscopy (SEM) and differential scanning calorimetry (DSC) were used to identify the physical state of the drug and polymer. The zeta potential of the particles was also identified. Entrapment efficiency was found to be highest with a 0.5% PVA concentration and 100 mL volume of external aqueous phase at pH 12. The high efficiency was due to a reduction in the degree of drug ionization. The microparticles were spherical and appropriately sized for ophthalmic application. Drug release from the microparticles appears to consist of two components, with an initial rapid release followed by a slower stage. Drug release was slower when the microparticle was incorporated into the thermally reversible gel (Pluronic® F127) in comparison to drug release from the free drug incorporated into the gel and drug release from the free microparticle.

Formulation optimization of double emulsification method for preparation of enzyme-loaded Eudragit S100 microspheres

The present study aimed to develop an oral sustained release microparticulate system for acid labile enzyme-Serratiopeptidase. A 32 full factorial experiment was designed to study the effects of the external aqueous phase volume and stabilizer (Tween® 80) concentration on the entrapment and size of Eudragit S100 microspheres prepared by a modified double emulsion solvent evaporation technique. The results of analysis of variance tests for both effects indicated that the test is significant. The effect of external aqueous phase volume was found to be higher on the entrapment efficiency of microspheres (SSY1 = 1362.63; SSY2 = 250.13), whereas Tween® 80 produced a significant effect on size of microspheres (SSY1 = 944.01; SSY2 = 737.26). Scanning electron microscopy of microspheres demonstrated smooth surface spherical particles. The effect of formulation variables on the integrity of enzyme was confirmed by in vitro proteolytic activity. Microspheres having maximum drug encapsulation (81.32 ± 3.97) released 4–5% enzyme at pH 1.2 in 2 h. The release of enzyme from microspheres followed Higuchi kinetics (R2 = 0.987). In phosphate buffer, microspheres showed an initial burst release of 25.65 ± 2.35% in 1 h with an additional 62.96 ± 4.09% release in the next 5 h. Thus, formulation optimization represents an economical approach for successful preparation of Eudragit S100 microspheres involving fewest numbers of experiments.

Eudragit S100 entrapped insulin microspheres for oral delivery

The purpose of this research was to investigate whether Eudragit S100 microspheres have the potential to serve as an oral carrier for peptide drugs like insulin. Microspheres were prepared using water-in oil-in water emulsion solvent evaporation technique with polysorbate 20 as a dispersing agent in the internal aqueous phase and polyvinyl alcohol (PVA)/polyvinyl pyrrolidone as a stabilizer in the external aqueous phase. The use of smaller internal aqueous-phase volume (50 microL) and external aqueous-phase volume (25 mL) containing PVA in the manufacturing process resulted in maximum encapsulation efficiency (81.8% +/- 0.9%). PVA-stabilized microspheres having maximum drug encapsulation released 2.5% insulin at pH 1.0 in 2 hours. In phosphate buffer (pH 7.4), microspheres showed an initial burst release of 22% in 1 hour with an additional 28% release in the next 5 hours. The smaller the volumes of internal and external aqueous phase, the lower the initial burst release. The release of drug from microspheres followed Higuchi kinetics. Scanning electron microscopy of PVA-stabilized microspheres demonstrated spherical particles with smooth surface, and laser diffractometry revealed a mean particle size of 32.51 +/- 20 microm. Oral administration of PVA stabilized microspheres in normal albino rabbits (equivalent to 6.6 IU insulin/kg of animal weight) demonstrated a 24% reduction in blood glucose level, with maximum plasma glucose reduction of 76 +/- 3.0% in 2 hours and effect continuing up to 6 hours. The area under the percentage glucose reduction-time curve was 93.75%. Thus, our results indicate that Eudragit S100 microspheres on oral administration can protect insulin from proteolytic degradation in the gastrointestinal tract and produce hypoglycemic effect.

Improvement of the encapsulation efficiency of oligonucleotide-containing biodegradable microspheres

The objective of this study was to encapsulate an oligonucleotide drug within poly(lactide) microparticles with high encapsulation efficiencies at high theoretical drug loadings by the solvent evaporation method. With the conventional W/O/W method, the encapsulation efficiency decreased with increasing internal water content, increasing stirring time prior to filtration of the microparticles and increasing drug loading. The encapsulation was improved by replacing methylene chloride with ethyl acetate, by using micronized drug powder instead of an internal aqueous phase or by adding electrolytes or nonelectrolytes to the external phase. With ethyl acetate, a pre-emulsification step into a smaller volume of external aqueous phase was necessary in order to avoid premature polymer precipitation and to obtain microparticles. The addition of salts (NaCl or MgCl 2) or sorbitol to the external aqueous phase significantly improved the encapsulation efficiency, even at high theoretical drug loadings. The microparticles had a denser structure with a smooth, pore-free surface.

Investigation on process parameters involved in preparation of poly- dl-lactide-poly(ethylene glycol) microspheres containing Leptospira Interrogans antigens

Block copolymer, poly- dl-lactide-poly(ethylene glycol) (PELA) with 11.5% of poly(ethylene glycol) (PEG) content was prepared by bulk ring-opening polymerization using stannous chloride as initiator. PELA microspheres with entrapped Leptospira Interrogans antigens, outer membrane protein (OMP) were elaborated by solvent extraction method based on the formation of multiple w/o/w emulsion, and the resulting microspheres were characterized with respect to particle size, OMP entrapment and morphology characteristics. The purpose of the present study is to perform the optimization of preparative parameters for OMP-loaded PELA micropsheres to control particle size and improve the OMP encapsulation efficiency. Of all the parameters investigated, the polymer concentration of organic phase and the external aqueous phase volume play major roles on particle size, while the organic phase volume, internal aqueous phase volume and the addition of surfactant into the internal aqueous phase display considerable effects on OMP loading efficiency. A small volume of internal aqueous phase and intermediate volumes of organic phase and external aqueous phase were favorable to achieve micropsheres with a size of 1–2 μm and high antigen encapsulation efficiency (70–80%). In vitro OMP release profiles from PELA microspheres consist of a small burst release followed by a gradual release phase. The OMP release rate shows some relations with the porous and water-swollen inner structure of the microspheres matrix. The presence of surfactant in microspheres accelerates OMP release, but the OMP entrapment within microspheres shows limited effects on the release profile.

Transport of Te 4+ through liquid surfactant membrane using D2EHPA as the carrier

A preliminary study of Te 4+ transport through liquid surfactant membrane using di(2-ethylhexyl)phosphoric acid (D2EHPA) as the carrier and kerosene as the diluent has been made in a batch extractor. Extraction rate is studied as a function of stripping phase acid concentration, ratio of emulsion volume to external aqueous phase volume, Biot number, etc. A diffusion controlled, film model is proposed for the above system which adequately describes the permeation mechanism of the metal through the membrane. The model takes into account both the continuous phase and membrane phase resistances in the form of a Biot number. The computed results are found to be in good agreement with the experimental data. The continuous phase resistance is found to be the controlling factor for tellurium extraction under the present experimental conditions.

The preparation and characterization of poly(lactide-co-glycolide) microparticles. II. The entrapment of a model protein using a (water-in-oil)-in-water emulsion solvent evaporation technique.

Poly(lactide-co-glycolide) (PLG) microparticles with entrapped antigens have recently been investigated as controlled-release vaccines. This paper describes the preparation of PLG microparticles with an entrapped model antigen, ovalbumin (OVA), using a (water-in-oil)-in-water emulsion solvent evaporation technique. In a series of experiments, the effects of process parameters on particle size and OVA entrapment were investigated. It was found that smooth, spherical microparticles 1-2 microns in diameter containing up to 10% (w/w) OVA could be produced using a small volume of external aqueous phase containing a high concentration of emulsion stabilizer and a 1:5 antigen:polymer ratio. PAGE analysis, isoelectric focusing, and Western blotting of OVA released from the microparticles in vitro confirmed that the molecular weight and antigenicity of the protein remained largely unaltered by the entrapment procedure.

2-Thiouracil for Congestive Heart Failure

Serratiopeptidase-loaded poly (D,L-lactic-co-glycolic acid) (PLGA) microspheres were prepared using the modified double emulsion method. The effect of polymer concentration and external aqueous phase volume on microsphere size and entrapment efficiency was studied by 3² full factorial experiments. The results of analysis of variance test for measured responses indicated the test9s significance (<i>P</i> &lt; 0.05). The contribution of PLGA concentration on microsphere size and percentage yield was found to be higher than that of external aqueous phase volume, which produced a significant effect on entrapment efficiency. Microspheres demonstrated spherical particles in the size range of 19.08–41.14 μm and entrapment efficiency between 15.37 and 79.86%. The formulation using a medium level of polymer and a low level of external aqueous phase (PLGA: 300 mg; EAP: 100 mL) showed maximum entrapment (75.86 ± 2.31%). The in vitro release profile of all formulations demonstrated a similar sustained release showing an initial burst followed by diffusion. The bioactivity of the peptide remained intact after microencapsulation as assayed by in vitro proteolytic activity. Response surface graphs are presented to examine the effects of independent variables on the responses studied. In conclusion, controlled-release serratiopeptidase-loaded PLGA microspheres demonstrating maximum entrapment were successfully prepared by an experimental design methodology with a minimum number of runs, representing an economical approach.