Delivery Of Gentamicin Research Articles

Discrepancies between predicted and observed rates of intravenous gentamicin delivery for neonates

This study aimed to investigate intravenous infusions as used in the neonatal intensive care setting, to determine the effect of gentamicin dose (mg), gentamicin concentrations (mg/ml), flow rate (ml/h) and flush volume (ml) upon the length of infusion time. Intravenous infusions were set up to simulate administration of gentamicin to neonates. Dextrose (10%, w/v) was administered as the primary intravenous fluid at 3.8 or 18.7 ml/h. Gentamicin doses (0.5 mg/0.2 ml, 2 mg/0.2 ml, 2.5 mg/1.0 ml, or 10 mg/1.0 ml) were delivered into the intravenous line at a T-connection using a Graseby pump over 35 min. This was followed by a saline flush of 1 or 2 ml over a further 35 min. At the end of each experiment a 2 ml 0.9% saline bolus was given. Analysis of gentamicin collected at 5-min intervals was by an HPLC method. The experiment demonstrated that under the infusion conditions neonates weighing 2.5 kg would receive only 80% of the drug at 60 min, increasing to 90-95% by 75 min. In extremely low birth weight neonates (0.5 kg), even lower percentage of gentamicin recovery occurred. At 60 min only 60% of the intended gentamicin dose had been delivered and this increased to only 70% by 75 min. The delivery of gentamicin administered by intravenous infusion is substantially extended in extremely low birth weight neonates. This appeared to be primarily due to the small volumes and low infusion rates used in these patients.

Bcl-2 Gene Therapy Prevents Aminoglycoside-Induced Degeneration of Auditory and Vestibular Hair Cells

To evaluate the protective effects of bcl-2, we have developed an in vivo model of gentamicin ototoxicity in C57BL/6 mice using intratympanic delivery of gentamicin. Hair cell survival was evaluated using myosin VIIa immunohistochemistry, cytocochleogram and auditory brainstem response (ABR) testing. At 10 days after gentamicin application, a consistent loss of outer hair cells was seen. Mice were pretreated with an adenovector expressing human bcl-2 (Ad.11D.bcl-2) or a control vector (Ad.11D). Seventy-two hours after vector delivery mice were treated with intratympanic gentamicin and evaluated at 10 days after ototoxin delivery. Pretreatment with Ad.11D.bcl-2 resulted in morphologic protection of hair cells and preservation of hearing thresholds measured by ABR.

In vitro gentamicin sustained and controlled release from chitosan cross-linked films

A novel wound dressing film was investigated for controlled and sustained delivery of gentamicin, while covering and protecting the wound. Chitosan was cross-linked with Hexamethylene 1,6-bis (aminocarboxysulfonate) to prepare the wound dressing films. Cross-linking reaction was required to control the water retention and release of encapsulated gentamicin. Cross-linked films swell less and became more hydrophilic than chitosan film itself. However, this behavior was inversely proportional to the degree of cross-linking. In vitro gentamicin release from the cross-linked films, at physiological conditions of pH and temperature, was studied for 2 weeks. The effects of gentamicin initial concentration and cross-linking ratio on the kinetics of gentamicin release were evaluated. Results showed that the diffusion rate was governed by initial concentration of gentamicin and degree of cross-linking, since higher gentamicin initial concentration and degree of cross-linking promoted the slower release, while lower gentamicin initial concentration and degree of cross-linking promoted the faster one.

State-of-the-art mechanisms of intracochlear drug delivery

Treatment of auditory and vestibular dysfunction has become increasingly dependent on inner ear drug delivery. Recent advances in molecular therapy and nanotechnology have pushed development of alternate delivery methodologies involving both transtympanic and direct intracochlear infusions. This review examines recent developments in the field relevant to both clinical and animal research environments. Transtympanic delivery of gentamicin and corticosteroids for the treatment of Meniere's disease and sudden sensorineural hearing loss continues to be clinically relevant, with understanding of pharmacokinetics becoming more closely studied. Stabilizing matrices placed on the round window membrane for sustained passive delivery of compounds offer more controlled dosing profiles than transtympanic injections. Nanoparticles are capable of traversing the round window membrane and cochlear membranous partitions, and may become useful gene delivery platforms. Cochlear and vestibular hair cell regeneration has been demonstrated by vector delivery to the inner ear, offering promise for future advanced therapies. Optimal methods of inner ear drug delivery will depend on toxicity, therapeutic dose range, and characteristics of the agent to be delivered. Advanced therapy development will likely require direct intracochlear delivery with detailed understanding of associated pharmacokinetics.

Liposomes as a carrier for gentamicin delivery: Development and evaluation of the physicochemical properties

The physicochemical properties of liposomal formulations containing gentamicin were investigated. A sustained release of gentamicin from liposomes was observed at both 4 °C and 37 °C in phosphate buffered saline. The distribution of the mean diameters of these liposomal formulations, evaluated by dynamic light scattering (DLS) over a 48 h time period, was bimodal with large polydispersity index values, i.e., ≥0.6. Incorporation of 5- or 16-doxylstearic acids (5- or 16-DSL) into the liposomes allowed the use of EPR spectroscopy to study the fluidity, order parameter, and phase behavior of the phospholipid bilayers in response to the compositions, temperature and time. While, our results revealed that gentamicin disturbs the packing and fluidizes the phospholipid chains, it did not seem to alter the nature of the microdomains at the polar interface of the bilayers. Simulation of the EPR spectra of 5-DSL containing liposomes revealed (1) the heterogeneous nature of the liposomal domains at the polar interfacial region, and (2) that encapsulation of gentamicin neither significantly alters the dynamic properties of the existing domains, nor induces the phase repartition of the liposomes within a 48 h time course.

Biodegradable gentamicin delivery systems for parenteral use for the treatment of intracellular bacterial infections

Gentamicin is an aminoglycoside with a wide spectrum of antibacterial activity. However, as a highly water-soluble drug, it penetrates cells poorly. This constitutes a particularly important drawback for treating intracellular bacterial infections. This major hurdle may be solved by the use of vectors to deliver and target bioactive agents to the intracellular sites of infection. Thus, in the case of antimicrobials, drug delivery systems may help to increase their therapeutic index in intracellular locations. The development and evolution of pharmaceutical forms of gentamicin for the parenteral treatment of intracellular pathogens is reviewed in this paper.

Adjunct collagen sponge-based local gentamicin delivery reduces the incidence of postoperative sternal wound infections,

Adjunct collagen sponge-based local gentamicin delivery reduces the incidence of postoperative sternal wound infections,

Local Antibiotic Delivery with OsteoSet??, DBX??, and Collagraft??

Biodegradable local antibiotic delivery systems have gained interest for prophylaxis and treatment of musculoskeletal infections. We studied the biodegradable materials Osteo- Set, DBX and Collagraft for local delivery of vancomycin and gentamicin in vitro. We determined the antimicrobial activity of vancomycin and gentamicin after mixing with each biodegradable material and determined the release of each antimicrobial from each material in an intermittent flow chamber. Antimicrobial activity was expressed as percent of antimicrobial loaded into each sample that was detected; antimicrobial release was expressed as concentration (microg/mL) after timed intervals of chamber flow, peak concentration, area under the curve and percent antimicrobial recovered. Activity of vancomycin after mixing with Osteo- Set, DBX and Collagraft was > 73%. Activity of gentamicin after mixing with DBX was 100%; after mixing with OsteoSet and Collagraft it was reduced to < 61%. AUC0-48hrs of vancomycin was 469, 426 and 432 microg x hr/mL, and the AUC0-48hrs of gentamicin was 368, 306 and 301 microg x hr/mL after release from OsteoSet, DBX, and Collagraft, respectively. Recovered percentages of vancomycin were 39%, 11% and 25%, and recovered percentages of gentamicin were 39%, 9% and 23% after release from OsteoSet, DBX, and Collagraft, respectively. OsteoSet, DBX and Collagraft may be suitable for local delivery of vancomycin and gentamicin.

Nanocarriers with Gentamicin to Treat Intracellular Pathogens

Brucellosis is a worldwide zoonosis caused by different species of the genus Brucella. The intracellular localisation of this pathogen, particularly in macrophages, renders treatment difficult since most antibiotics known to be efficient in vitro do not actively pass through cellular membranes. As alternative to current treatment, polymeric drug delivery systems containing gentamicin have been developed. These particulate carriers target the drug into the mononuclear-phagocytic system, where the pathogen resides that will allow intracellular accumulation of the antibiotic after particle degradation. Besides, particle uptake may induce macrophage activation, increasing the production of reactive oxygen intermediates, involved in host defense against the intracellular pathogen. The aim of the present work was to study the suitability of polymeric nanoparticles for gentamicin entrapment in view to treat brucellosis. Different poly(lactide-co-glycolide) PLGA polymers were used to formulate the nanoparticles containing gentamicin by a water-oil-water solvent evaporation method. Furthermore, in vitro macrophage activation upon nanoparticles phagocytosis and in vivo distribution of the nanocarriers in the target organs for Brucella (liver and spleen) were also studied. The nanoparticle sizes were below 350 nm, the gentamicin encapsulation efficiency depended on the polymer type used for their preparation and the in vitro release of the antibiotic exhibited a continuos pattern (PLGA 502H). PLGA 502H nanoparticles were the most suitable due to the highest entrapment and the most sustained release. The nanoparticles were successfully phagocyted by a J774 murine monocytes cell line and biodistribution studies in mice after intravenous administration of the delivery systems revealed that the particles reached the target organs of Brucella (liver and spleen). All together, these results indicate that the nanocarriers described in this work may be suitable as gentamicin delivery system to control brucellosis.

Gentamicin negatively influenced osteogenic function in vitro

Local delivery of gentamicin is an accepted method of infection prophylaxis in the surgery of open fractures. However, the few reports of studies into the effect of locally applied gentamicin on osteoblasts used inadequate methods. In our study, we used the well-characterised C2C12 cell line with reproducible differentiation pathway into the osteoblast lineage. We investigated the viability, cell number, alkaline phosphatase activity, and the expression of osteogenic genes of C2C12 cells after exposure to gentamicin at concentrations of 12.5-800 microg/ml for 48 h. Exposure of C2C12 cells to gentamicin (12.5-800 mg/ml) for 48 h showed no significant changes in the cell number, but cell viability was decreased by one-third at the tested concentrations of 200-800 microg/ml. The alkaline phosphatase activity was significantly decreased by one-third to one-half at any tested concentration (12.5-800 microg/ml) of gentamicin. Any tested concentration of gentamicin up to 800 microg/ml for 48 h did not inhibit or decrease the osteogenic gene expression of osterix and alkaline phosphatase of the C2C12 cells. In conclusion, gentamicin at high concentrations as achieved by local application reduced cellular viability and alkaline phosphatase activity in vitro and therefore may be detrimental for bone healing and repair in vivo.

Gentamicin Causes Apoptosis at Low Concentrations in Renal LLC-PK 1 Cells Subjected to Electroporation

Gentamicin accumulates in the lysosomes of kidney proximal tubular cells and causes apoptosis at clinically relevant doses. Gentamicin-induced apoptosis can be reproduced with cultured renal cells, but only at high extracellular concentrations (1 to 3 mM; 0.4 to 1.2 g/liter) because of its low level of uptake. We recently showed that gentamicin-induced apoptosis in LLC-PK1 cells involves a rapid (2-h) permeabilization of lysosomes and activation of the mitochondrial pathway of apoptosis (10 h). We now examine whether the delivery of gentamicin to the cytosol by electroporation would sensitize LLC-PK1 cells to apoptosis. Cells were subjected to eight pulses (1 ms) at 800 V/cm (square waves) in the presence of gentamicin (3 microM to 3 mM; 1.2 mg/liter to 1.2 g/liter); returned to gentamicin-free medium; and examined at 8 h for their Bax (a marker of mitochondrial pathway activation) contents by Western blotting and competitive reverse transcriptase PCR and at 24 h for apoptosis by 4',6'-diamidino-2'-phenylindole staining (confirmed by electron microscopy) and for necrosis (by determination of lactate dehydrogenase release). Nonelectroporated cells were incubated with gentamicin for 8 and 24 h. Significant increases in Bax levels (8 h) and apoptosis (24 h) were detected with 0.03 mM (13.2 mg/liter) gentamicin in electroporated cells compared with those achieved with 2 mM (928 mg/liter) in incubated cells. The increase in the Bax level was not associated with an increase in the level of its mRNA but was associated with the accumulation of ubiquitinated forms (probably as a result of impairment of its degradation by the proteasome). Assay of cell-associated gentamicin showed a marked, immediate, but transient accumulation in electroporated cells, whereas a slow, steady uptake was detected in incubated cells. The data indicate that cytosolic gentamicin triggers apoptosis. Sequestration of gentamicin in lysosomes would, to some extent, protect against apoptosis.

Lung accumulation of niosome-entrapped gentamicin sulfate follows intravenous and intratracheal administration in rats

The organ distribution pattern of gentamicin from niosomes (25 mg/ml) w as studied in albino rats (n = 30) in comparison with free drug solution to determine the potential of the delivery system for site-specific delivery of gentamicin and also to find out the effective route of administration of this delivery system. The comparative AUC study (t = 0 to 24 h) indicated higher organ to serum AUC ratio in the case of niosomes (208.85 in the case of lung!serum. 5.10 liver/serum and 17.78 kidney!serum) against those obtained following the administration of free drug solution (25.51 in the case of lung/serum, 5.9 liver/serum and 58.1 kidney/serum). After intratracheal administration, the lung to serum concentration ratio in the case of niosome was 483.68 as against 18.23 for free drug solution which amounts to a 27-time increase in drug accumulation capacity of gentamicin sulfate niosomes to free drug solution in lungs. A significant difference in total drug concentration in lung, liver, kidney and blood serum was found between gentamicin loaded niosomes and free gentamicin solutions (P

META-ANALYSIS OF INTRATYMPANIC GENTAMICIN

To the Editor: We appreciate Dr. Longridge's letter to the editor in the May 2005 issue regarding our recent publication “Intratympanic Gentamicin Therapy for Ménière's Disease: A Meta-analysis” (1). In his letter, Dr. Longridge questioned the inclusion of patients undergoing different dosing regimens of gentamicin (daily, twice daily, and weekly administration) in the titration group. In particular, he notes that symptoms of inner ear disturbance typically have a delay in presentation, making comparisons between results from papers utilizing different dosing regimens difficult. We agree with Dr. Longridge's assessment of the limitations of the inclusion criteria of our study. However, this is a recognized limitation of a meta-analysis in an area where there is no standardized or clearly superior method of treatment. Our paper was prepared in an effort to sift through the multiple methods of gentamicin delivery in the literature to determine if one method was clearly superior. The method of titration to inner ear symptoms, regardless of dosing regimens, showed the most benefit, which was the conclusion from this method of analysis. It certainly is possible that unnecessary over treatment by the short interval dosing regimens could occur if one doesn't allow time for the effect to become evident. However, were this to have been the case then one would also have expected to see a higher rate of unwanted side effects such as hearing loss which was not seen when studied as a group. As in all clinical trials, in order to definitively determine which method is superior, a prospective, randomized study comparing two or more regimens would be informative. We also agree with Dr. Longridge that the AAO-HNS criteria are not perfect. He points out that frequency of attacks taken in isolation from severity of attacks provides an incomplete picture of the patient's outcome. Similarly, patients may experience much less frequent and less severe attacks following gentamicin treatment yet remain constantly off balanced and incapacitated. Having quality of life measures incorporated into the AAO-HNS criteria might be an additional benefit when looking at outcomes of any treatment (2). Yours sincerely, Jeffrey P. Harris, M.D., Ph.D. Stanley Chia, M.D. Anthony Gamst, Ph.D. John P. Anderson, Ph.D. University of California San Diego La Jolla, California, U.S.A.

The effect of surface charge on the disposition of liposome-encapsulated gentamicin to the rat liver, brain, lungs and kidneys after intraperitoneal administration

The disposition of gentamicin to the normal rat brain, lung, kidney and liver was studied at intervals of 1, 2, 4, 6 and 8 h after intraperitoneal injection of gentamicin encapsulated in positive, negative and neutral liposomes. Compared with the control, which was treated with free gentamicin, liposomes were associated with higher concentrations of gentamicin in the brain and liver, while concentrations were lower in the kidney. The average concentrations of gentamicin in the liver and the brain were highest with positive liposomes, while, gentamicin concentrations in the kidneys and lungs were not influenced by surface charge of the liposomes. These observations have important implications on the selective delivery of gentamicin to tissues and on the intraperitoneal route of administration.

Liposome-mediated gentamicin delivery: development and activity against resistant strains of Pseudomonas aeruginosa isolated from cystic fibrosis patients

Chronic pulmonary infection by Pseudomonas aeruginosa in cystic fibrosis patients is virtually impossible to eradicate by means of existing free antibiotics. We sought to assess the antibacterial activities of liposomal gentamicin against clinical isolates of P. aeruginosa. Gentamicin was encapsulated into liposomes with different lipid compositions (1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-distearoyl-sn-glycero-3-phosphocholine) and cholesterol in the molar ratio of 2:1 by sonication. The in vitro stability of liposome-encapsulated gentamicin was studied over a 48 h period at 4 and 37 degrees C in PBS and at 37 degrees C in pooled plasma. The MICs of free and liposomal gentamicin for clinical isolates of P. aeruginosa were assessed by broth dilution. The encapsulation efficiency of all liposomal preparations was 4%-5.18% of the initial amount of the drug in solution. The liposomes retained 60%-70% of the encapsulated gentamicin for 48 h when they were incubated in normal human pooled plasma or PBS at 4 or 37 degrees C. The MICs of liposomal gentamicin for all clinical isolates of P. aeruginosa were lower than the MICs of free gentamicin. Importantly, liposomal gentamicin altered the susceptibilities of these clinical isolates from gentamicin resistant to either intermediate or susceptible. Taken together, these data indicate that liposomal gentamicin formulations could be more effective than the free drug in controlling pulmonary infections due to P. aeruginosa.

Delivery of gentamicin to the rabbit eye by drug-loaded hydrogel iontophoresis.

To assess the corneal iontophoretic delivery of gentamicin by drug-loaded hydrogel probe, and to determine the resultant ocular disposition and elimination of the drug from the cornea and anterior chamber. Corneal iontophoresis of gentamicin sulfate was studied in healthy white rabbits by using drug-loaded disposable hydroxyethyl methacrylate (HEMA) hydrogel disk probes and a portable mini-ion device designed in the authors' laboratory. The iontophoretic treatment was performed with a current intensity of 1 mA for 60 seconds only. Three control groups were used: mock iontophoresis (no current) for 60 seconds, topical eye drops of fortified gentamicin (1.4%) every 5 minutes for 1 hour, and subconjunctival injection of 0.25 mL of 40 mg/mL gentamicin solution. The animals in the iontophoretic experimental groups were killed at predetermined time points. The gentamicin concentrations in the cornea and aqueous humor were assayed with a fluorescence polarization immunoassay. Analysis of the gentamicin eye pharmacokinetics was performed with a modeling approach. Peak gentamicin concentrations in the cornea (363.1 +/- 127.3 microg/g) and in the aqueous humor (29.4 +/- 17.4 microg/mL) were reached at 0 and 2 hours after the iontophoretic treatment, respectively. The peak gentamicin concentrations after a single iontophoresis treatment were 12 to 15 times higher than those obtained after gentamicin injection or after topical eye drop instillation, and much higher than in mock iontophoresis. The concentration versus time profile of gentamicin in the cornea and the anterior chamber after iontophoresis was appropriately described by applying a two-compartment pharmacokinetic model. A short iontophoretic treatment using gentamicin-loaded hydrogels has potential clinical value in increasing drug penetration to the anterior segments of the eye and maintaining therapeutic drug levels in the cornea for more than 8 hours.

Iontophoresis–gentamicin delivery into the rabbit cornea, using a hydrogel delivery probe

Purpose. To evaluate the efficacy of penetration of gentamicin into the cornea of rabbits using iontophoresis with a hydrogel–gentamicin containing probe. Methods. Eight of 10 groups (groups 3–10) of 6 rabbits (one eye per rabbit), underwent corneal iontophoresis using soft stable hydroxyethyl methacrylate hydrogel discs (80% water content) loaded with gentamicin sulphate which were mounted on an iontophoresis probe. The studied current intensities were 0, 0·1, 0·3 and 0·6 mAmp, and the durations of iontophoresis were 10 and 60 sec. Two control groups received 1·4% topical drops of gentamicin every 5 min for 1 hr (group 1) or sub-conjunctival injection of 10 mg gentamicin (group 2). Following sacrifice, aqueous humour was taken, corneas were excised, and gentamicin concentration was determined in aqueous humour and cornea samples. Results. Post-iontophoresis, the concentration of gentamicin in the corneas ranged from high (88·60±38·64 μg ml −1) to very low (0·10±0·89 μg ml −1). Both the control groups and those rabbits treated with current intensity of 0·1 mAmp or greater obtained therapeutic gentamicin levels in the corneas. Use of iontophoresis for 60 sec or current intensity greater than 0·1 mAmp obtained corneal gentamicin levels not different from sub-conjunctival injection. Application of current intensity of 0·1 mAmp or greater gave corneal gentamicin concentrations comparable to topical application of the drug, except when 0·6 mAmp were used for 60 sec ( p=0·05). Increasing current intensity or duration of iontophoresis significantly increased ( p=0·001 for both) gentamicin penetration into the cornea. Current intensity had more influence (Beta 2=0·40) than duration (Beta 2=0·13) on drug penetration. A significant interaction was found between the duration of iontophoresis and the current intensity. Very small or no concentrations of the drug were discovered in the anterior chambers of rabbits. Conclusions. Iontophoresis using hydrogel–gentamicin probe may deliver therapeutic concentrations of gentamicin into the cornea.

Collagen/PLGA Microparticle Composites for Local Controlled Delivery of Gentamicin

To preserve the positive effect of collagen on tissue regeneration and to locally deliver low molecular weight compounds for an extended time period, a composite for parenteral application was devised based on a collagen sponge with gentamicin‐loaded PLGA microparticles incorporated. Antibiotic liberation from the particles was sustained over 1 week by blending two PLGA polymers. Homogenous incorporation of the microspheres in the porous carrier could be realized by lyophilization of a particle suspension in the aqueous collagen preparation. Particle loss upon incubation was reduced with higher collagen concentration enabling local particle retention after application. Lower freezing rate and longer exposure of the PLGA microparticles to the acidic collagen dispersion at temperatures below the glass transition temperature resulted in an increase of the gentamicin burst. The final implant containing both nonencapsulated gentamicin and an equivalent amount incorporated in the microparticles reflected the microbiological demands and exhibited liberation of a high gentamicin dose initially and subsequently extended antibiotic liberation for about one week. © 2003 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2145–2151, 2003

Long-term bactericidal properties of a gentamicin-coated antimicrobial external fixation pin sleeve.

External fixation is a versatile method of fracture treatment. However, pin-track infections remain a major complication. Despite the routine use of antibiotics, pin-track infections occur in 57% to 75% of cases1,2. One factor contributing to the high prevalence of infection is the access that the pin track provides to bacteria and the ability of bacteria to colonize the metal surface of the pin or wire. The OrthoGuard AB antimicrobial sleeve (Smith and Nephew, Memphis, Tennessee) inhibits bacterial colonization on external fixation pins and wires by providing sustained local delivery of gentamicin to the pin or wire site. In order for local antibiotic delivery to be bactericidal, (1) the antibiotic must be effective against pathogens common to pin-track infections and (2) the sleeve must deliver an effective dose into the pin track in a sustained manner. The purpose of the present study was to evaluate the results of in vitro testing in order to establish the long-term bactericidal properties of the OrthoGuard AB antimicrobial sleeve. The OrthoGuard AB sleeve consists of polyurethane tubing that has a thin gentamicin-loaded coating on its inner and outer surfaces. After insertion of the fixation pin or wire, the sleeve is placed over the pin or wire and is manually pushed through the subcutaneous tissue up to the point of contact with the bone (Fig. 1). The sleeve is measured and cut before placement so that at least 1 cm of the sleeve is protruding from the skin surface in order to allow for …

Release mechanisms from gentamicin loaded poly(lactic-co-glycolic acid) (PLGA) microparticles

To provide local gentamicin delivery for 1 week based on a biodegradable system, poly(lactic-co-glycolic acid) (PLGA) microparticles were developed utilizing a 50/50 blend of Resomer® RG 502H, an uncapped variety of 13.5 kD, and Resomer® RG 503, an endcapped polymer of 36.2 kD. The liberation mechanism was investigated by analysis of morphological changes and thermal analysis focusing on the polymer glass transition temperature (Tg) and the mechanical properties. The release of gentamicin was related to a structural breakdown of the particles reaching a critical molecular weight. A Tg of < 37°C in the hydrated state was not indicative of collapse and agglomeration of the particles because the mechanical strength of the polymer structures in the rubbery state may still render sufficient support. As the gap between incubation temperature and Tg widened, the mechanical stability of the PLGA microparticles decreased and became decisive. Particles prepared with RG 502H show a lower ability to bear mechanical stress than RG 503 and 50/50 RG 502H/RG 503 microparticles. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91: 845–855, 2002