Effect of ammonia on the anaerobic degradation of protein by a mesophilic and thermophilic biowaste population

The purpose of this study was to assess the effect of gastrointestinal proteins on the in vitro release of zidovudine (AZT) from ethylcellulose microspheres, and to investigate protein adsorption as a possible mechanism that mediates this effect. AZT release from ethylcellulose microspheres was tested in the presence of different gastrointestinal proteins, both dietary (casein and albumin) and endogenous (pepsin, pancreatin, and mucin) in simulated gastric fluid and/or simulated intestinal fluid. The resulting release profiles were compared with those produced in the corresponding release media without the presence of proteins. Protein adsorption on AZT-loaded ethylcellulose microspheres was studied for the five proteins under investigation. The amounts of adsorbed proteins were determined by fluorescent spectrometry after the protein solution was reacted with fluoraldehyde reagent. All of the investigated proteins were found to slow the release of AZT from ethylcellulose microspheres. At gastric pH, ovalbumin and casein had the maximum effect on AZT release. Mucin exerted a more pronounced effect at gastric pH compared with that at intestinal pH. The negative effect of pancreatin on AZT release increased when its concentration was increased. The five proteins were found to adsorb on AZT-loaded ethylcellulose microspheres with varying quantities. The observed protein adsorption is believed to cause blockage of the small pores and channels in the microsphere structure, and consequently slow the release of AZT.     

Effect of interparticulate interaction on release kinetics of microsphere ensembles

The release kinetics of microsphere ensembles is complicated by the mutual influence of the microspheres which are entrapped in small compartments such as body cavities. This work focused on the effect of interparticulate interaction on the release kinetics of microsphere ensembles with limited spreading. Experiments and finite element modeling were conducted to investigate diffusional drug release from a single sphere, a monolayer, and multiple layers of microspheres. Poly(methyl methacrylate-co-methacrylic acid) (P(MMA/MAA)) microspheres and azidothymidine (AZT) were used in the experiments. The order of the release rate of AZT from various microsphere populations was observed to be single sphere > monolayer > multiple layers. This evidenced the importance of interparticulate interaction. The finite element simulations elucidated the influence of various factors on the release kinetics of microsphere ensembles including the separation distance, location of the spheres, and the drug accumulation in the medium. Calibration of overall release kinetics for the neighboring effect was proposed on the basis of the spreading factor. Overall release profiles of microsphere ensembles were predicted using the release profiles of individual microspheres at various locations.     

The in vitro and in vivo indomethacin release from self-setting bioactive glass bone cement

The in vivo and in vitro drug release profiles from a self-setting bioactive CaO-SiO2-P2O5 glass bone cement containing indomethacin as a model drug were investigated. The cement containing 2% and 5% indomethacin (IMC) powder hardened within 5 min after mixing with ammonium phosphate buffer. After setting, in vitro drug release from drug-loaded cement pellets in a simulated body fluid (SBF) at pH 7.25 and 37 degrees C continued for two weeks. The hardened cement gradually formed low-crystallinity hydroxyapatite during the drug release test in SBF. An IMC-loaded cement device (2% and 5% drug) was implanted in the subcutaneous tissue on the back of rats. The in vivo IMC release from the cement increased and attained maximum levels (Cmax of 2% and 5% drug-loaded cements was 0.27 and 3.37 micrograms/ml, respectively) at Tmax, 3 and 0.5 d, respectively, upon subcutaneous (s.c.) administration in rats. This suggested that the s.c. administration of the cement provided IMC release for a much longer period than s.c. administration of the solution, and the plasma IMC concentration was dependent on the drug concentration in the cement. The plasma IMC concentration and the area under the curve from 2% and 5% IMC-loaded cements in rats were dependent on the concentration of IMC in the cements. The in vivo IMC concentration in plasma obtained by the deconvolution method was much lower than that delivered in SBF in vitro. Scanning electron microscopy and photomicrographs of cross sections showed that the bioactive bone cement had excellent biocompatibility with the surrounding soft tissues.     

Development and internal validation of an in vitro-in vivo correlation for a hydrophilic metoprolol tartrate extended release tablet formulation

PURPOSE: To develop and validate internally an in vitro-in vivo correlation (IVIVC) for a hydrophilic matrix extended release metoprolol tablet. METHODS: In vitro dissolution of the metoprolol tablets was examined using the following methods: Apparatus II, pH 1.2 & 6.8 at 50 rpm and Apparatus I, pH 6.8, at 100 and 150 rpm. Seven healthy subjects received three metoprolol formulations (100 mg): slow, moderate, fast releasing and an oral solution (50 mg). Serial blood samples were collected over 48 hours and analyzed by a validated HPLC assay using fluorescence detection. The f2 metric (similarity factor) was used to analyze the dissolution data. Correlation models were developed using pooled fraction dissolved (FRD) and fraction absorbed (FRA) data from various combinations of the formulations. Predicted metoprolol concentrations were obtained by convolution of the in vivo dissolution rates. Prediction errors were estimated for Cmax and AUC to determine the validity of the correlation. RESULTS: Apparatus I operated at 150 rpm, and pH of 6.8 was found to be the most discriminating dissolution method. There was a significant linear relationship between FRD and FRA when using either two or three of the formulations. An average percent prediction error for Cmax and AUC for all formulations of less than 10% was found for all IVIVC models. CONCLUSIONS: The relatively low prediction errors for Cmax and AUC observed strongly suggest that the metoprolol IVIVC models are valid. The average percent prediction error of less than 10% indicates that the correlation is predictive and allows the associated dissolution data to be used as a surrogate for bioavailability studies.     

Vascular Parkinson syndromes: a controversial concept]

Development of a Sustained-Release Biodegradable Polymer Delivery System for Site-Specific Delivery of Oligonucleotides: Characterization of P(LA-GA) Copolymer Microspheres In Vitro Antisense oligodeoxynucleotides (ODNs) can selectively inhibit individual gene expression provided they gain access to and remain stable at the target site for a sufficient period of time. Biodegradable sustained-release delivery systems may facilitate site-specific delivery and also prevent degradation of ODNs by nucleases whilst delivering the nucleic acid in a controlled manner to the desired site of action. In this study, we have characterized biodegradable poly (lactide-co-glycolide) (P(LA-GA)) 50:50 microspheres for the potential delivery of antisense oligonucleotides in vivo. Phosphodiester (PO) oligonucleotides complementary to either c-myc proto-oncogene or the tat gene in HIV-RNA were adequately incorporated within P(LA-GA) microspheres with entrapment efficiencies up to 60% depending on particles size. In vitro release profiles of antisense nucleic acids from 10-20 microm size microspheres over 56 days in physiological buffer were triphasic. Profiles were characterised by an initial burst effect during the first 48 hours (phase 1) of release followed by a more sustained release (phase 2) with an additional increased release (phase 3) being observed after 25 days which corresponded with bulk degradation of the copolymer matrix. The release profiles were influenced by microsphere size, copolymer molecular weight, ODN loading, ODN length and by the pH of release medium used. The serum stability of PO ODNs was significantly improved when entrapped within P(LA-GA) microspheres and the hybridization capability, as assessed by duplex melting (Tm) measurements, of released ODN was not impaired by the double-emulsion microsphere fabrication procedure used. Thus, P(LA-GA) microspheres appear to be promising candidates for improving site-specific delivery profiles for ODNs and are worthy of further evaluation in vivo.     

An investigation into the suitability of amidated pectin hydrogel beads as a delivery matrix for chloroquine

The aim of the present study was to delay the release of chloroquine to distal parts of the gastrointestinal tract by using a multiparticulate hydrogel formulation. Amidated pectin chloroquine beads (PC) with varying pectin-to-chloroquine ratios (PC) w/w loadings of 4:1, 2:1, and 1:1 in the dried beads were prepared by the gelation of drug-loaded pectin solutions in the presence of calcium. In vitro release studies of chloroquine from pectin-chloroquine hydrogel beads and chloroquine diphosphate powder were carried out in simulated gastric and intestinal fluids. The total release of the entrapped chloroquine from the hydrogel beads was achieved between 4 and 7 h in simulated intestinal fluid, but total release was not achieved in simulated gastric fluid. However, total release from chloroquine diphosphate powder was achieved by 1.5 and 2 h in gastric and intestinal fluids, respectively. The plasma pharmacokinetics of chloroquine from pectin hydrogel beads and chloroquine diphosphate solution following single or repeated dosing were compared in male Sprague-Dawley rats over a period of 60 h. Oral administration of the hyrogel beads to rats produced maximum plasma concentrations by 7 h, but highest plasma concentrations following chloroquine solution administration were observed by 2 h. The dissolution data and appearance of significant plasma concentrations of chloroquine 2 to 4 h after oral administration suggests release in duodenum, jejunum, or ileum.     

Characterization of poly(glycolide-co-D,L-lactide)/poly(D,L-lactide) microspheres for controlled release of GM-CSF

PURPOSE: This study describes the preparation and characterization of a controlled release formulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) encapsulated in poly(glycolide-co-D,L-lactide) (PLGA) and poly(D,L-lactide) (PLA) microspheres. METHODS: GM-CSF was encapsulated in PLGA/PLA microspheres by a novel silicone oil based phase separation process. Several different blends of PLGA and low molecular weight PLA were used to prepare the microspheres. The microspheres and the encapsulated GM-CSF were extensively characterized both in vitro and in vivo. RESULTS: Steady release of GM-CSF was achieved over a period of about one week without significant "burst" of protein from the microspheres. Analysis of microsphere degradation kinetics by gel permeation chromatography (GPC) indicated that low molecular weight PLA enhanced the degradation of the PLGA and thereby affected release kinetics. GM-CSF released from the microspheres was found to be biologically active and physically intact by bioassay and chromatographic analysis. Analysis of serum from mice receiving huGM-CSF indicated that the GM-CSF was biologically active and that a concentration of greater than 10 ng/mL was maintained for a period lasting at least nine days. MuGM-CSF was not detected following in vivo administration of muGM-CSF microspheres. The tissues of mice receiving muGM-CSF microspheres were characterized by infiltration of neutrophils, and macrophages which were in significant excess of those found in mice administered with placebo controls (i.e. microspheres without GM-CSF). CONCLUSIONS: This study demonstrates the influence of formulation parameters on the encapsulation of GM-CSF in PLGA/PLA microspheres and its controlled release in biologically active form. The intense local tissue reaction in mice to muGM-CSF microspheres demonstrates the importance of the mode of delivery on the pharmacologic activity of GM-CSF.     

131I therapy for pediatric thyroid cancer

Azido-3'-deoxy-thymidine (AZT) is a drug extensively used in the treatment of AIDS. AZT was incubated in vitro either with the pituitary-hypothalamus complex (PHc) or the intact pituitary (PI) of male rats. The PHc is comprised of the hypothalamus and the attached pituitary gland. After a preincubation period, the PHc or PI was incubated for 1 or 2 h with Krebs-Ringer bicarbonate buffer or either of two different concentrations of AZT (1 and 10 microM). In the control incubations, the PHc released less prolactin (PRL) and more follicle-stimulating hormone (FSH) and luteinizing hormone (LH) than the PI, indicating that hypothalamic control of the pituitary was exerted in vitro, presumably by diffusion of releasing and inhibiting hormones from the neurohypophysis to the anterior lobe of the hypophysis. Both concentrations of AZT evoked a significant increase in release of PRL and a decreased release of LH and FSH from the PHc. In the case of LH, the higher concentration of AZT partially suppressed LH release within 1 h. The other effects were not dose-related and were observed after incubating the tissue with AZT for 2 h. However, incubation of the PI with AZT failed to alter anterior pituitary hormone release, illustrating that the site of action of AZT is in the hypothalamus. We hypothesize that AZT blocks DNA synthesis resulting in suppression of synthesis and consequent release of hypothalamic hormones that control release of pituitary hormones in vitro. The results raise the possibility that AZT may alter hypothalamic-pituitary function in vivo.     

Threaded implant design criteria

The in vivo performance of multiparticulate sustained-release diltiazem preparations [HER-SR(A,B,C)] coated with water-insoluble polymer (ethylcellulose), to control the in vitro dissolution rate, was evaluated in dogs. With a decrease in dissolution rate, HER-SR maintained sustained-release characteristics, although the bioavailability decreased slightly. The bioavailability of HER-SR(A,B,C) was comparable with that of a conventional diltiazem tablet (HER). Plasma diltiazem concentrations for the HER-SR preparations were analyzed with a two-fraction absorption model and the pharmacokinetic characteristics were discussed. From the results, it was considered that HER-SR(B) preparation had desirable pharmacokinetic characteristics as sustained-release diltiazem preparations. The absorption site of the slow-release component of HER-SR(B) in the gastrointestinal tract was examined. Almost all of the component had reached the colon within 5 h of administration, the diltiazem content remaining in the component being approximately 60% of the initial amount. Thus, it was shown that the HER-SR(B) preparation had particular absorption characteristics that resulted in the colon being the part of the gastrointestinal tract most receptive to its release. In vivo release profiles of diltiazem from the HER-SR(B) preparation were calculated by the Wagner-Nelson method, and in vitro and in vivo release profiles of HER-SR(B) were further analyzed with a two-fraction release equation. A close correlation of in vitro and in vivo release profiles of HER-SR(B) was found.     

In vivo characterization of sustained-release formulations of human growth hormone

Long-acting formulations of recombinant human growth hormone (rhGH) were prepared by stabilizing and encapsulating the protein into three different injectable, biodegradable microsphere formulations composed of polymers of lactic and glycolic acid. The formulations were compared in juvenile rhesus monkeys by measuring the serum levels of rhGH and two proteins induced by hGH, insulin-like growth factor-I and IGF binding protein-3 (IGFBP-3) after single s.c. administration. All three formulations, which differed principally in the composition of the polymer, provided sustained elevated levels of all three proteins for several weeks, and the rate of release of rhGH differed among the formulations consistent with the molecular weight of the polymer used. All three formulations induced a higher level of insulin-like growth factor-I and insulin-like growth factor binding protein than was induced by daily injections of the same amount of rhGH in solution. After three monthly injections of one of the formulations, both the rhGH and IGF-I levels remained elevated for nearly 90 days. Immunogenicity of the rhGH released from this formulation, as assessed by the incidence of seroconversion to hGH and the titer of anti-hGH antibody in both the rhesus monkeys and transgenic mice expressing rhGH, was no greater than that of the unencapsulated protein. In addition, the microsphere injection sites appeared normal by macroscopic evaluation between 1 to 2 mo after microsphere administration and by microscopic evaluation between 2 to 3 mo. These results show that serum levels of a therapeutic protein can be sustained for an extended period when encapsulated into different formulations of injectable, biodegradable microspheres.     

Prolonged release of tegafur from S/O/W multiple emulsion

To develop a prolonged and sustained release preparation, we prepared an albumin microsphere-in-oil-in-water emulsion (S/O/W) and examined sustained release from it in comparison with other control preparations such as water-in-oil (W/O) emulsions and microspheres in vitro and in vivo, respectively. Tegafur was used as a model drug. A microsphere-in-oil emulsion was prepared by adding albumin microspheres to soybean oil containing 20% Span 80. To prepare an S/O/W emulsion, the microsphere-in-oil emulsion was added into an aqueous solution of hydroxypropyl methylcellulose containing Pluronic F68. The mean particle size of the albumin microspheres was 3 microns, and the ratio of entrapment of tegafur into albumin microspheres was about 25%. In an in vitro release test, the t75 of the S/O/W emulsion was fourfold greater and in an in vivo release test the mean residence time of tegafur from the S/O/W emulsion was more than twofold that from a W/O emulsion or microsphere system. The mean residence time of 5-fluorouracil (5-FU) from an S/O/W emulsion was also greater than with other dosage forms. These results suggest the possible usefulness of an S/O/W emulsion for the sustained and prolonged release of tegafur.     

Analysis of commercial mini-bus accidents

The major challenge in liquid sustained-release oral suspensions is to minimize drug diffusion into the suspending medium and to retain the original properties of the microparticles during storage. Diclofenac wax microspheres prepared by the hydrophobic congealable disperse phase method were formulated as a sustained release suspension and stored at three different temperatures (25, 37 and 45 degrees C) for 3 months, to evaluate the physical and chemical stability of the suspended microspheres. Suspensions of microspheres stored at ambient temperatures were both physically and chemically stable, but at higher temperatures, up to 45 degrees C, there was a decrease in drug release due to scaling and melting on the microsphere surface as observed by scanning electron microscopy. However, on prolonged storage, up to 90 days, especially at 45 degrees C, temperature became a dominant factor causing an increase in drug release. The suspension of diclofenac microspheres was chemically stable for 3 months, while the plain drug suspension exhibited slight degradation.     

In vitro-in vivo relationships for oral extended-release drug products

It is of interest to predict the in vivo behavior of an oral extended-release drug product based on its in vitro dissolution profile. In some cases a suitable convolution-based prediction model can be found. We present a methodology for developing statistical models of in vitro-in vivo relationships under the framework of the mixed-effects nonlinear model and discuss methods for assessing the validity and strength of the relationship. These methods are illustrated and contrasted with a level A in vitro-in vivo correlation using data from a study involving four different formulations of an oral extended-release drug product.     

In vitro/in vivo correlation of the bioadhesive properties of a buccal bioadhesive miconazole slow-release tablet

An in vitro-in vivo correlation study was performed on the bioadhesive properties of three buccal formulations based on modified starch (drum-dried waxy maize)/polyacrylic acid mixtures. Mixtures containing 10 mg miconazole nitrate, characterized by a different in vitro detachment force and work of adhesion, were evaluated for their bioadhesive properties in human volunteers. The results obtained showed that no significant difference could be seen among the formulations in vivo. The in vitro method showed no significant influence of miconazole nitrate on the bioadhesion properties of the polymers, while the in vivo adhesion time of the pure polymer mixtures was significantly higher than for the polymers containing miconazole. The results from the in vitro method thus did not correlate well with the in vivo data. The in vitro method provided information only on the initial bioadhesion and no correlation could be made with the residence time of the tablet in the oral cavity.     

Controlled delivery of therapeutics from microporous membranes. II. In vitro degradation and release of heparin-loaded poly(D,L-lactide-co-glycolide)

In vitro degradation and release of five types of heparin/surfactant-loaded poly(D,L-lactide-co-glycolide 50:50) (PLG) microspheres alone and also incorporated within microporous polyurethane tubes were studied over a 3-month period. Degradation was studied with scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), gel permeation chromatography (GPC) and differential scanning calorimetry (DSC). Heparin release was characterized using a modified Azure A assay. SEM suggests that microspheres may be entrapped within polyurethane fibrils of the polyurethane tubes, thereby reducing contact with their hydrated environment. FTIR transmittance spectra confirm microsphere incorporation within the polyurethane tubes and PLG ester hydrolysis occurring over the 3-month period. A correlation was observed between decreasing molecular weights and glass transition temperatures (Tg). The microspheres alone exhibited a change in Tg but not when incorporated within the microporous tubes. Release profiles revealed a burst effect occurring during the first 4h and total release of the heparin from the microspheres by 12 weeks.     

Controlled release of thyrotropin releasing hormone from microspheres: evaluation of release profiles and pharmacokinetics after subcutaneous administration

The drug-release kinetics of thyrotropin releasing hormone (TRH) containing copoly(dl-lactic/glycolic acid) (PLGA) microspheres were evaluated both in vitro and in vivo. The drug was encapsulated in PLGA using an in-water drying method through a water in oil in water emulsion. The drug release from the PLGA microspheres in vitro correlated well with that in vivo, and pseudo-zero-order release kinetics were observed. The pharmacokinetics of TRH following administration of this controlled-release parenteral dosage form have been also examined in rats. Following a transient increase in the plasma level due to an initial burst, steady-state plasma levels were observed. The duration of drug release estimated from the plasma level was comparable with the results in the in vitro and in vivo release studies. The steady-state plasma levels correlated well with the levels predicted from the pharmacokinetic parameters following a single subcutaneous or intravenous injection of TRH solution. The results of this study confirm the previously reported in vivo sustained release of TRH achieved with this drug-delivery system.     

Perception of two-tone complexes by the goldfish (Carassius auratus)

Smooth, highly spherical, crosslinked chitosan microspheres in the size range of 45-300 microns loaded with progesterone were prepared by glutaraldehyde crosslinking of an aqueous acetic acid dispersion of chitosan containing progesterone in a non-aqueous dispersion medium consisting of liquid paraffin and petroleum ether stabilized using sorbitan sesquioleate. In vitro release of the drug into phosphate buffer at 37 degrees C was determined as a function of crosslinking density of the microspheres and particle size. The extent of drug release had a remarkable dependence on the crosslinking density of the microspheres, the highly crosslinked spheres releasing only around 35% of the incorporated steroid in 40 days compared to 70% from spheres lightly crosslinked. Determination of the in vivo bioavailability of the steroid from microsphere formulation by intramuscular injection in rabbits showed that a plasma concentration of 1 to 2 ng/ml was maintained up to 5 months without a high 'burst effect'. Data obtained suggest that the crosslinked chitosan microspheres would be an interesting system for long term delivery of steroids.     

New approaches for encapsulation of peptides into poly(lactic/glycolic acid) microspheres

The aim of the work was to develop small microspheres made from a biodegradable polymer, poly(lactide-co-glycolide), in order to entrap small peptides. Microspheres prepared by a water-in-oil-in-water emulsion solvent evaporation technique displayed a mean diameter below than 10 microns and showed high encapsulation efficiency of a 33 amino acid peptide (V3 BRU). In vitro release kinetics studies showed that such microparticles could be employed for both oral immunization and controlled release. The encapsulation of a seven aminoacid peptide in the same conditions, led to a very low encapsulation efficiency. In order to increase the entrapment efficiency, two strategies were adopted: taking into account the solubility of pBC 264 at different pH, a pH gradient was created to prevent the leakage of the encapsulated peptide into the outer aqueous phase. The inner aqueous phase was maintained at basic pH where the peptide was soluble, while the external aqueous phase was acidic: ovalbumin was added during preparation to stabilize the inner emulsion. These two strategies allowed to increase significantly the encapsulation rate of pBC 264. Nevertheless, the in vitro release kinetics of the peptide were strongly influenced by the presence of ovalbumin which seems to form pores in the microsphere structure (80% of the total peptide content was released after 30 minutes). By contrast, when ovalbumin was replaced by Pluronic F 68 microspheres did not have pores, thus the release profile and the extent of the burst were much smaller. When microspheres were stereotactically implanted in the rat brain, in vivo release profiles were in good agreement with the release observed in vitro. In conclusion, these microspheres are well suited for the slow delivery of neuropeptides in the brain, a feature expected to facilitate the study of long term effects of these compounds.     

Preparation and testing of cyclosporine microsphere and solution formulations in the treatment of polyarthritis in rats

We prepared a microencapsulated sustained-release formulation of cyclosporine A (CsA) and compared its efficacy to the solution formulation of cyclosporine A (Sandimmune, Sandoz) in an attempt to improve the treatment of rheumatoid arthritis. Microspheres containing cyclosporine were prepared with poly(lactic co-glycolic acid) (PLGA), a polymer in the submicron particle range of 0.22-0.8 micron. Studies were carried out to determine uptake rates and mechanisms of lymphocyte inhibition mediated by macrophages containing CsA microspheres in vitro. The results of these studies were used to establish whether lower doses of the microencapsulated cyclosporine could be used in in vivo studies in the polyarthritic rat model for rheumatoid arthritis. In vitro dissolution testing revealed that CsA was released extremely slowly from microspheres for up to 48 hr (0.002%). Radiolabeled 3H CsA was incorporated into some PLGA microspheres or the microspheres were labeled using a 99mTc radioligand when needed, and radiolabeling efficiency was consistently above 50%. Uptake studies at various microsphere-to-macrophage ratios (1:1, 1:5, 1:10) were carried out using 99mTc radiolabeled microspheres and macrophages obtained from normal and polyarthritic rats. Normal macrophages behaved significantly differently from arthritic macrophages throughout the study. Arthritic macrophages cause increased amounts of CsA to be released (68% of the dose) into the culture medium past 24 hr compared to normal macrophages (48% of the dose). This factor may account for the significantly increased inhibition (68.2%) of mixed lymphocyte culture proliferation in the presence of arthritic macrophages containing CsA-loaded PLGA microspheres over normal macrophages (48.2%) that were pre-exposed to the same microsphere dose. The equivalent quantity of CsA as that contained in the microspheres when placed in solution or the same quantity of blank PLGA microspheres caused decreased levels of lymphocyte inhibition when compared to the effects of CsA microspheres in macrophages of normal cells, but significantly decreased levels of inhibition in arthritic cells. From the in vivo studies, it is evident that CsA microspheres, even at low dose levels, were highly effective in inhibiting polyarthritis in rats.     

Role of nitric oxide in angiotensin IV-induced increases in cerebral blood flow

Whether a rapid elevation of serum gliclazide concentration in human subjects can be achieved through an acceleration of dissolution of gliclazide from a formulation was examined. A soft gelatin capsule containing PEG 400, PEG 4000, Tween 20 and glycerin was prepared as a formulation that may accelerate dissolution of gliclazide. The in vitro dissolution of gliclazide at pH 7.2 was identical for the soft capsule and conventional tablets, Diamicron and Diberin. However, at pH 1, 2 and 4.0 the dissolution from the soft capsule was more rapid compared to the tablets. When bioavailability parameters were compared following oral administration of the soft capsule and Diamicron to 16 healthy Korean male subjects, the parameters representing the amount of adsorption (i.e. the area under the serum gliclazide concentration vs. time curve up to 24 h, AUC24, and the peak serum concentration Cmax) were not statistically different for both formulations. However, the time required to reach the peak (Tmax) was significantly shorter for the soft capsule than for the Diamicron. Our results, therefore, indicate that a rapid elevation of serum gliclazide concentration following oral administration of a formulation can be achieved by accelerating the in vitro dissolution of gliclazide from the formulation into the acidic buffers. Thus, the rate of gastrointestinal absorption of gliclazide appears to be dependent on its in vivo dissolution rate in gastric fluid. A soft capsule containing a PEG 400 suspension of gliclazide appears to be an appropriate formulation for accelerating the dissolution.