Slow Release Phase Research Articles

Usefulness of microspheres composed of gelatin with various cross-linking density

The release rate of insulin, as a model peptide, from gelatin microspheres (GM) prepared with gelatin having various cross-linking densities in vitro was examined. The release of insulin from GM showed the burst effect, followed by a slow release phase regardless of the cross-linking density of gelatin. The total amount of insulin released in 2 weeks decreased with increasing cross-linking density of gelatin. The release rate of insulin within 6h was well correlated with the cross-linking density of gelatin. The remaining amounts of both insulin and GM after injection of insulin incorporated in GM to mice femoral muscle tissue were also examined in vivo. Both insulin and GM rapidly disappeared from the injection site within 1 day, and thereafter slowly disappeared over 14 days. The time courses of the remaining amounts were fairly similar to each other. Furthermore, the remaining amount of insulin 1 day after administration was well correlated with the cross-linking density of gelatin. These data suggest that insulin was released from GM with the degradation of GM in mice muscular tissue and that the release rate of insulin can be controlled by modifying the cross-linking density of gelatin. In conclusion, the control of the release rate of insulin from GM can be achieved under both in vitro and in vivo conditions by gelatin through the alteration of cross-linking conditions.

Usefulness of microspheres composed of gelatin with various cross-linking density.

The release rate of insulin, as a model peptide, from gelatin microspheres (GM) prepared with gelatin having various cross-linking densities in vitro was examined. The release of insulin from GM showed the burst effect, followed by a slow release phase regardless of the cross-linking density of gelatin. The total amount of insulin released in 2 weeks decreased with increasing cross-linking density of gelatin. The release rate of insulin within 6 h was well correlated with the cross-linking density of gelatin. The remaining amounts of both insulin and GM after injection of insulin incorporated in GM to mice femoral muscle tissue were also examined in vivo. Both insulin and GM rapidly disappeared from the injection site within 1 day, and thereafter slowly disappeared over 14 days. The time courses of the remaining amounts were fairly similar to each other. Furthermore, the remaining amount of insulin 1 day after administration was well correlated with the cross-linking density of gelatin. These data suggest that insulin was released from GM with the degradation of GM in mice muscular tissue and that the release rate of insulin can be controlled by modifying the cross-linking density of gelatin. In conclusion, the control of the release rate of insulin from GM can be achieved under both in vitro and in vivo conditions by gelatin through the alteration of cross-linking conditions.

Optimizing formulation factors in preparing chitosan microparticles by spray-drying method

The chitosan only, chitosan/Pluronic F68, chitosan/gelatin, chitosan/Pluronic F68/gelatin microparticles and betamethasone-loaded chitosan/Pluronic F68/ gelatin microparticles were successfully prepared by a spray-drying method. Microparticle characteristics (yield rate, zeta potential, particle size and tap density), loading efficiencies, microparticle morphology and in-vitro release properties were investigated. By properly choosing excipient type, concentration and varying the spray-drying parameters, a high degree of control was achieved over the physical properties of the dry chitosan powders. SEM micrograph shows that the particle sizes of the varied chitosan composed microparticles ranged from 2.12–5.67 μm and the external surfaces appeal-smooth. Using betamethasone as model drug, the spray-drying is a promising way to produce good spherical and smooth surface microparticles with a narrow particle size range for controlled delivery of betamethasone. The positively charged betamethasone-loaded microparticles entrapped in the chitosan/Pluronic F68/gelatin microparticles with trapping efficiencies up to 94.5%, yield rate 42.5% and mean particle size 5.64 μm varied between 4.32–6.20 μm and tap densities 0.128 g/cm3. The pH of particle was increased with increasing betamethasone-loaded amount, but both zeta potential and tap density of the particles decreased with increasing betamethasone-loaded amount. The betamethasone release rates from chitosan/Pluronic F68/gelatin microparticles were influenced by the drug/polymer ratio in the manner that an increase in the release% and burst release% was observed when the drug loading was decreased. The in vitro release of betamethasone showed a dose-dependent burst followed by a slower release phase that was proportional to the drug concentration in the concentration range between 14–44%w/w.

The characteristics of betamethasone-loaded chitosan microparticles by spray-drying method

Betamethasone (BTM)-loaded microparticles prepared by a spray drying method using chitosan (CTS) as raw material, type-A gelatin and ethylene oxide-propylene oxide block copolymer (Pluronic F68) as modifiers. The BTM-loaded in varied chitosan/Pluronic F68/gelatin microparticle formulations was investigated. By properly choosing excipient type and concentration a high degree of control was achieved over the physical properties of the BTM-loaded microparticles. Microparticle characteristics (zeta potential, tap density, particle size and yield), loading efficiencies, microparticle morphology and in-vitro release properties were examined. Surface morphological characteristics and surface charges of prepared microparticles were observed by using scanning electron microscopy (SEM) and microelectrophoresis. A SEM micrograph shows that the particle sizes of the varied chitosan composed microparticles ranged from 1.1-4.7 μ m and the external surfaces appear smooth. The BTM-loaded microparticles entrapped in the chitosan/Pluronic F68/gelatin microparticles with trapping efficiencies up to 93%, collected yield rate 44%, and mean particle size varied between 1-3 μ m, positive surface charge (20-40 mv), and tap densities (0.04-0.40 g/cm3) were obtained. The collected BTM yield and size of particle was increased with increasing BTM-loaded amount but both zeta potential and tap density of the particles decreased with increasing BTM-loaded amount. The in vitro release of BTM showed a dose-dependent burst followed by a slower release phase that was proportional to the drug concentration in the concentration range between 5-30%w/w. The in vitro drug release from the chitosan/Pluronic F68/gelatin 1/0.1/0.4 microspheres had a prolong release pattern. These formulation factors were correlated to particulate characteristics for optimizing BTM microspheres in pulmonary delivery.

Sustained release of 5-fluorouracil from polymeric nanoparticles.

The use of biodegradable nanoparticles loaded with 5-fluorouracil was investigated as a potential means to sustain the release of this drug. Nanoparticles prepared from four biodegradable polymers were loaded with 5-fluorouracil using three loading concentrations of drug and three different concentrations of added polymer. Washing particles using a centrifugation/re-suspension with ultrasound protocol was found to dislodge the majority of drug, resulting in an over-estimation of incorporation efficiency and low levels of strongly entrapped drug. Increasing the initial 5-fluorouracil concentration before polymer/monomer addition increased the drug loading in both washed and unwashed particles. Increasing the amount of polymer used to make nanoparticles did not increase loadings, but did produce increased amounts of unusable polymer waste. Drug release from nanoparticles was evaluated using a Franz cell diffusion apparatus, which showed an initial burst effect followed by a slower release phase over 24 h. Indeed, nanoparticles prepared from poly(lactide-co-glycolide) released 66% of their 5-fluorouracil payload over this period. It was concluded that 5-fluorouracil-loaded nanoparticles could be readily included into a hydrogel-based delivery system to provide sustained drug release for trans-epithelial drug-delivery applications.

Distinct contributions of glutamate and dopamine receptors to temporal aspects of rodent working memory using a clinically relevant task.

Understanding the mechanistic basis of working memory, the capacity to hold representation "on line," is important for delineating the processes involved in higher cognitive functions and the pathophysiology of thought disorders. We compared the contribution of glutamate and dopamine receptor subtypes to temporal aspects of working memory using a modified rodent spatial working memory task that incorporates important elements of clinical working memory tasks. A discrete paired-trial variable-delay T-maze task was used. Initial characterization studies indicated that performance on this task is stable at seconds-long retention intervals, is sensitive to retention interval and proactive interference, and is dependent on the integrity of the medial prefrontal cortex. Consistent with clinical findings, low dose amphetamine (0.25 mg/kg) produced a delay-dependent improvement in performance, while higher doses impaired performance at all retention intervals. D1 receptor blockade produced the predicted dose- and delay-dependent impairment. D2 receptor blockade had no effect. Activation of metabotropic glutamate 2/3 (mGluR2/3) receptors, which in the prefrontal cortex inhibits the slow asynchronous phase of glutamate release, also produced a delay-dependent impairment. Low doses of an AMPA/kainate antagonist had effects similar to the mGluR2/3 agonist. In contrast, NMDA receptor antagonist-induced impairment was memory load-insensitive, resulting in chance-level performance at all retention intervals. These findings suggest that activation of NMDA receptors is necessary for the formation of mnemonic encoding while modulatory components involving slow asynchronous release of glutamate and phasic release of dopamine contribute to the active maintenance of information during the delay period.

In vitro evaluation of sol–gel processed spray dried silica gel microspheres as carrier in controlled drug delivery

The objective of this study was to evaluate sol–gel-derived spray dried silica gel microspheres as carrier material for dexmedetomidine HCl and toremifene citrate. The drug was dissolved in sol–gel processed silica sol before spray drying with Büchi laboratory scale equipment. Microspheres with a low specific surface area were spherical by shape with a smooth surface without pores on the external surface. The particle size distribution was quite narrow. The in vitro release of toremifene citrate and dexmedetomidine HCl showed a dose-dependent burst followed by a slower release phase, that was proportional to the drug concentration in the concentration range between 3.9 and 15.4 wt.%. The release period for toremifene citrate was approximately 10 days and for dexmedetomidine HCl between 7 and 50 days depending on drug concentration. Spray drying is a promising way to produce spherical silica gel particles with a narrow particle size range for controlled delivery of toremifene citrate and dexmedetomidine HCl.

Hot-Melt Coating Technology. I. Influence of Compritol® 888 Ato and Granule Size on Theophylline Release

The aim of this work was to study the influence of theophylline granule size and the percentage of Compritol® 888 Ato on in vitro drug release from granules and tablets. The granules were coated in a fluidized bed apparatus. The dissolution profiles of these granules differed from those of granules coated with classical agents, and there were also differences between the various sieve fractions studied. Drug release was characterized by a rapid-release phase, followed by a slow-release phase. Results indicate that theophylline release can be controlled by controlling granule size. Inspection of the appearance of the tablets at the end of the dissolution test revealed that all tablets containing Compritol 888 Ato remained intact. This indicated that the Compritol 888 Ato used in the tablet formulation created an inert matrix through which the drug diffused. It was found that the Higuchi relationship of linear square root of time was the best model to describe the release kinetics of the drug from tablets. This also confirmed that a matrix diffusion-controlled mechanism was operative. Given the difference between the dissolution profiles of the granules and the tablets, it was concluded that this matrix is formed during compression.

Luminal dissociation of Ca2+ from the phosphorylated Ca2+-ATPase is sequential and gated by Mg2+

Transport of Ca2+ across the membrane by the Ca2+-ATPase of skeletal muscle sarcoplasmic reticulum involves the transfer of two Ca2+ ions from a pair of cytoplasmic sites to a pair of luminal sites, driven by phosphorylation of the ATPase. The ATPase is inhibited by Mg2+ at alkaline pH values. Inhibition follows from a decrease in the rate of release of Ca2+ from the phosphorylated ATPase. Phosphorylation-induced release of Ca2+ from the ATPase is biphasic at alkaline pH, which is consistent with sequential release of Ca2+ from the phosphorylated ATPase; the rates of both components decrease with increasing Mg concentration. The effect of Mg2+ on the slow phase of release follows from the binding of Mg2+ at the empty outer luminal site, vacated by the release of the first Ca2+ ion. The effect of Mg2+ on the rate of release of the first Ca2+ ion could follow from binding to a gating site also affecting the binding of Ca2+ to the cytoplasmic sites.

Luminal dissociation of Ca2+ from the phosphorylated Ca2+-ATPase is sequential and gated by Mg2+

Transport of Ca2+ across the membrane by the Ca2+-ATPase of skeletal muscle sarcoplasmic reticulum involves the transfer of two Ca2+ ions from a pair of cytoplasmic sites to a pair of luminal sites, driven by phosphorylation of the ATPase. The ATPase is inhibited by Mg2+ at alkaline pH values. Inhibition follows from a decrease in the rate of release of Ca2+ from the phosphorylated ATPase. Phosphorylation-induced release of Ca2+ from the ATPase is biphasic at alkaline pH, which is consistent with sequential release of Ca2+ from the phosphorylated ATPase; the rates of both components decrease with increasing Mg concentration. The effect of Mg2+ on the slow phase of release follows from the binding of Mg2+ at the empty outer luminal site, vacated by the release of the first Ca2+ ion. The effect of Mg2+ on the rate of release of the first Ca2+ ion could follow from binding to a gating site also affecting the binding of Ca2+ to the cytoplasmic sites.

Preparation and characterization of ofloxacin microspheres for the eradication of bone associated bacterial biofilm

Biodegradable polymers for localized delivery of antibiotics have emerged as an important approach to treating orthopaedic infections. In chronic forms of osteomyelitis which arethought tobeassociated with bacterial biofilm, localized delivery of a suitable antibiotic is desirable. This paper describes the formulation and in vitro evaluation of biodegradable ofloxacin microspheres for the eradication of bone associated bacterial biofilm infections. Ofloxacin microspheres were formulated using poly(glycolic acid-co-dl-lactic acid) (PGLA) by the emulsion solvent evaporation technique. The effects of process parameters such as phase volume, poly(vinyl alcohol) (PVA) concentration, and viscosity grade of the polymer during preparation on encapsulation efficiency (EEF) and in vitro release profiles were investigated. An increase in the phase volume or volume fraction from 21 to 35% at a constant internal phase volume resulted in an increase in EEF from 34 to 74%. Increasing PVA concentration from 0.25 to 2.5% w/v at a constant phase volume or volume fraction did not have an effect on the EEF. Ofloxacin release from the microsopheres was biphasic with an initial burst release followed by a slow release phase. An optimum slowing down of release was observed when the phase volume was 29%. Above and below this phase volume, release of ofloxacin was higher. The higher the viscosity grade of the polymer used for the preparation of microspheres, the higher the PVA concentration needed to prepare microspheres with slower release. The study indicates that various rates of ofloxacin release is possible by varying formulation conditions. This should provide a means for formulating sustained release microspheres of antibiotics for the treatment of biofilm infections associated with the bone.

Release of Chemicals from Contaminated Soils

At sites that contain contaminated soils, there can be questions about the magnitude of risk posed by the chemicals in the soils and about the cleanup levels that should be achieved. Knowledge about the rate of release of chemicals is important to answers to such questions. This article: (1) describes a laboratory protocol to obtain rate of release information for chemicals in soils, and (2) provides estimates of the rate of release of individual polyaromatic hydrocarbon (PAH) compounds from several manufactured gas plant (MGP) site soils. The data were analyzed using an empirical two-site model. Different fractions of PAH were released rapidly from these soils. For one soil, this fraction was less than 20%, for others, the fraction ranged from 36 to 85%. The first-order rate constant (k2) of PAH released during the slow phase of chemical release ranged from 0.0001 to 0.01 per hour.

Termination of cytosolic Ca2+ signals: Ca2+ reuptake into intracellular stores is regulated by the free Ca2+ concentration in the store lumen.

The mechanism by which agonist-evoked cytosolic Ca2+ signals are terminated has been investigated. We measured the Ca2+ concentration inside the endoplasmic reticulum store of pancreatic acinar cells and monitored the cytoplasmic Ca2+ concentration by whole-cell patch-clamp recording of the Ca2+-sensitive currents. When the cytosolic Ca2+ concentration was clamped at the resting level by a high concentration of a selective Ca2+ buffer, acetylcholine evoked the usual depletion of intracellular Ca2+ stores, but without increasing the Ca2+-sensitive currents. Removal of acetylcholine allowed thapsigargin-sensitive Ca2+ reuptake into the stores, and this process stopped when the stores had been loaded to the pre-stimulation level. The apparent rate of Ca2+ reuptake decreased steeply with an increase in the Ca2+ concentration in the store lumen and it is this negative feedback on the Ca2+ pump that controls the Ca2+ store content. In the absence of a cytoplasmic Ca2+ clamp, acetylcholine removal resulted in a rapid return of the elevated cytoplasmic Ca2+ concentration to the pre-stimulation resting level, which was attained long before the endoplasmic reticulum Ca2+ store had been completely refilled. We conclude that control of Ca2+ reuptake by the Ca2+ concentration inside the intracellular store allows precise Ca2+ signal termination without interfering with store refilling.

Influence of the preparation methods on the drug release behaviour of loperamide-loaded nanoparticles

Polylactide (PLA) or poly(lactide-coglycolide) (PLGA) nanoparticles containing loperamide (LPM) were prepared by an incorporation or adsorption method with the objective of developing nanoparticles with a rapid drug release. The use of polymers such as PLA with lower molecular weights and the addition of sorhitan fatty acid esters (SFAE) for the incorporation led to an almost complete entrapment of LPM in nanoparticles. Preparation of PLA nanoparticles by adsorption was performed by addition of LPM methanol solution before, during and after evaporation of dichloromethane from the system. The adsorption of LPM onto the nanoparticles with low molecular weight PLA (m.w. 2000) showed an isotherm with a good correlation to the Langmuir equation. A high amount of LPM can be entrapped or adsorbed in nanoparticles only with low molecular weights of PLA or PLGA. In the incorporation method, the addition of SFAEs increased drug entrapment. However, in the adsorption method they had no effect on nanoparticle drug adsorption. The drug-release profiles from both nanoparticles, prepared by the adsorption and incorporation methods, were biphasic with an initial rapid release and a second slower release phase, although their initial extents of release were different. The release rates wcrc almost the same for both the adsorption and incorporation method without SFAEs. The addition of SFAEs to the adsorption system increased the extent of drug release from nanoparticles. In conclusion, a rapid loperamide release from nanoparticles can be achicved hy use of PLA or PLGA with low molecular weights and in the adsorption method by the addition of SFAEs.

Kinetics of nucleoside triphosphate cleavage and phosphate release steps by associated rabbit skeletal actomyosin, measured using a novel fluorescent probe for phosphate.

We have measured the kinetics of inorganic phosphate (Pi) release during a single turnover of actomyosin nucleoside triphosphate (NTP) hydrolysis using a double-mixing stopped-flow spectrofluorometer, at very low ionic strength to increase the affinity of myosin-ATP and myosin-ADP-Pi to actin. Myosin subfragment 1 and a series of nucleoside triphosphates were mixed and incubated for approximately 1-10 s to allow NTP to bind to myosin and generate a steady state mixture of myosin-NTP and myosin-NDP-Pi. The steady state intermediates were then mixed with actin. The kinetics of Pi release were measured using a fluorescent probe for Pi, based on a phosphate binding protein [Brune et al. (1994) Biochemistry 33, 8262-8271]. These data are correlated with quenched-flow data, where the extent of the rapid burst of hydrolysis during the first turnover of ATP hydrolysis was followed by chemical quenching of the reaction mix at various times after rapidly mixing ATP and myosin subfragment 1. From the double-mixing actomyosin measurements, the kinetics of Pi release are biphasic. The fast phase corresponds to Pi release from the associated actomyosin-ADP-Pi complex. The slow phase measures the rate of the cleavage step on associated actomyosin. At saturating actin, there is a correlation between the amplitude of the fast phase and the size of the Pi burst observed by quenched flow in the absence of actin: the size of this phase corresponds to the amount of myosin-ADP-Pi formed during the first mix. For ATP at 20 degrees C the rate of the Pi release step is 75 (+/-5) s-1, 25-fold larger than the cleavage step, which is the rate-limiting step of actomyosin ATP hydrolysis at saturating actin. The rate constant of Pi release varies only slightly with nucleoside structure. The rate constant of the slow phase of the Pi release (measuring cleavage) is highly dependent upon the structure of the NTP substrate.

Controlled release of U-86983 from double-layer biodegradable matrices: effect of additives on release mechanism and kinetics

Effects of additives on the drug release kinetics from biodegradable matrices is an important determinant in designing a drug delivery system. These experiments introduced the influence of an array of additives on the drug release from double-layered poly(lactic-co-glycolic acid) (PLGA) matrices. Various additives such as l-tartaric acid dimethyl ester (DMT), Pluronic® F127 (F127); 2-hydroxypropyl derivative of β-cyclodextrin (HPB), methyl derivative of β-cyclodextrin (MMB) and Beeswax (Wax), differing in molecular size, hydrophilicity and steric configuration were selected for this study. An antiproliferative 2-aminochromone, U-86983 (U-86, Pharmacia and Upjohn), was used as a model agent because of our interest in investigating local drug delivery systems for the inhibition of restenosis. The in vitro release of U-86 from PLGA matrices without additive showed a typical biphasic release kinetics, i.e. a slow diffusion release (Phase I) followed by a fast erosion-mediated release (Phase II). The water-soluble additives in PLGA matrices changed the biphasic release pattern to a near monophasic profile by increasing the release rate of the Phase I. Increasing the ratio of additives to PLGA in matrices causes a significant increase in the U-86 release rates. The high molecular weight water-soluble additive, Pluronic® F127, resulted in a matrix showing perfect zero-order release kinetics. The water-soluble cyclodextrin derivative, HPB, gave the highest release rate among all the matrices formulated. A hydrophobic additive, Beeswax, however showed biphasic release kinetics comparable to PLGA control matrices, but delayed the onset of the Phase II by 4 days. The U-86 release profiles were in good agreement with the mass loss profiles of these matrices except for the matrices with F127 and HPB additives. The morphologic evaluation of matrices using scanning electron microscopy indicates that the water-soluble additives are leachable and thus generate a highly porous structure in the matrices. The matrix pore configuration (e.g. interconnected or closed) created with different additives determined the mechanism of drug release kinetics from the various matrix formulations. In conclusion, the feasibility of modulating release rates and kinetics of an agent from PLGA monolithic matrices by utilizing various types of additives is demonstrated. Water-solubility, molecular size and steric configuration of the additives are the important determinants in generating various types of pore structures in polymer matrix which in turn affect the release mechanism and release kinetics.

In vitro evaluation of Poly( d, l-lactide-co-glycolide) polymer-based implants containing the α-melanocyte stimulating hormone analog, Melanotan-I

The release of the melanotropic peptide, Melanotan-I (MT-I), from biodegradable implants of poly( d, l lactide-co-glycolide) (PLGA) copolymer was studied. The implants were prepared by a melt-extrusion method. The in vitro release of MT-I exhibited a triphasic profile with an initial rapid release followed by a secondary phase of slow release, then a tertiary phase of rapid release due to erosion of the polymer. The initial rapid release observed with PLGA (50:50 molar ratio of lactic/glycolic acid) polymers was less than 5% of the drug load and the tertiary phase commenced after about 3 weeks. The factors controlling the drug release are degradation and erosion of the polymer which may, in turn, be controlled by the physical properties of the polymer such as molecular weight and viscosity. The influence of viscosity (0.2–1.08 dl/g) of the polymer, on the release kinetics of MT-I were analyzed and the polymer having a viscosity of 0.6 dl/g was selected for preparing a 1-month implant system. Molecular weight distribution analysis indicated a biphasic rate of molecular weight reduction and within 12 days, the molecular weight had decreased to 50% of the initial value. The release rate was examined at different drug loading levels and in the presence of some hydrophilic additives. The effect of gamma radiation on the release kinetics of the peptide was analyzed to determine the optimal radiation sterilization dose for the PLGA implants. There was no significant difference in the total duration of MT-I release between the implants exposed to no radiation and the 2.5 Mrad dose selected.

Mechanisms responsible for quantal Ca2+ release from inositol trisphosphate-sensitive calcium stores.

Activation of cells by hormones, growth factors or neurotransmitters leads to an increased production of inositol trisphosphate (InsP3) and, after activation of the InsP3 receptor (InsP3R), to Ca2+ release from intracellular Ca2+ stores. The release of intracellular Ca2+ is characterised by a graded response when submaximal doses of agonists are used. The basic phenomenon, called "quantal Ca2+ release", is that even the maintained presence of a submaximal dose of agonist or of InsP3 for long time periods (up to 20 min) provokes only a partial release of Ca2+. This partial, or quantal, release phenomenon is due to the fact that the initially very rapid InsP3-induced Ca2+ release eventually develops into a much slower release phase. Physiologically, quantal release allows the Ca2+ stores to function as increment detectors and to induce local Ca2+ responses. The basic mechanism for quantal release of Ca2+ is presently not known. Possible mechanisms to explain the quantal behaviour of InsP3- induced Ca2+ release include the presence of InsP3Rs with varying sensitivities for InsP3, heterogeneous InsP3R distribution, intrinsic inactivation of the InsP3Rs, and regulation of the InsP3Rs by Ca2+ store content. This article reviews critically the evidence for the various mechanisms and evaluates their functional importance. A Ca2+-mediated conformational change of the InsP3R is most likely the key feature of the mechanism for quantal Ca2+ release, but the exact mode of operation remains unclear. It should also be pointed out that in intact cells more than one mechanism can be involved.

Release control of albumin from polylactic acid microspheres

This paper reports how poly(DL-lactide) microspheres of different molecular weight and BSA content were manufactured in order to evaluate the influence of these two variables on the protein release profile, using a composite central rotational design. The microspheres were prepared by a double emulsion method using different w/o phase ratios. The BSA encapsulated was about 80% of the theoretical amount incorporated. The resulting microspheres proved porous except for three batches. The release of BSA from microspheres presented two phases, first a high burst effect ranging from 37.3 to 75% of the protein incorporated, and a second slower one. Analysis of the release results clearly shows a positive linear dependence of the slope of the slow release phase on the molecular weight of polymer, due most likely to the formation of hydrogen bridges between the terminal -OH groups of the polymer chains and the solitary pairs of donor atoms of the protein. Non-porous microspheres with a lesser burst effect were obtained by decreasing the w/o ratio of the first emulsion during the preparation process.

The effect of particle microstructure on the somatostatin release from poly(lactide) microspheres prepared by a W/O/W solvent evaporation method

Somatostatin acetate-containing poly(lactide) microspheres were prepared by a W/O/W multiple emulsion solvent evaporation method. The resulting microspheres were characterized with respect to encapsulation efficiency, drug release and morphological properties (scanning electron microscopy). The addition of various buffers (pH 2.2, 3.0, 4.0 or 5.0) or salts (NaCl or CaCl 2) to the internal aqueous and/or external aqueous phase affected the osmotic pressure gradient between the two aqueous phases and the solvent/ water flux during the microsphere formation. Addition to the internal aqueous phase promoted the influx of water from the external aqueous phase. This resulted in more porous microspheres. Reversing the osmotic pressure gradient by adding salts to the external aqueous medium resulted in the formation of a dense and homogeneous polymer matrix. Intermediate structures were obtained through variations in the salt concentration gradient. The drug release profiles consisted of a rapid drug release phase followed by a slow release phase. The initial peptide release from the microspheres could be controlled through changes in the microstructure of the microspheres, with the peptide being released faster from the more porous microspheres. Lower encapsulation efficiencies were obtained with the more porous microspheres.