RG 502H Research Articles

Long-Lasting In Situ Forming Implant Loaded with Bupivacaine: Investigation on Polymeric and Non-Polymeric Carrier and Solvent Effect.

Typically, in situ forming implants utilize Poly (lactide- co- glycolide) (PLGA) as carrier and N-methyl-2-pyrrolidone (NMP) as solvent. However, it is essential to develop different carriers to release various drugs in a controlled and sustained manner with economic and safety considerations. The present study aims to evaluate the in-vitro release of Bupivacaine HCl from in situ forming systems as post-operative local anesthesia. We used Sucrose acetate isobutyrate (SAIB), PLGA 50:50, and a mixture of them as carriers to compare the release behavior. Besides, the effect of PLGA molecular weight (RG 502H, RG 503H, and RG 504H), solvent type, and solvent concentration on the drug release profile has been evaluated. The formulations were characterized by investigating their in-vitro drug release, rheological properties, solubility, and DSC, in addition to their morphological properties. Furthermore, the Korsmeyer-Peppas and Weibull models were applied to the experimental data. Results revealed that using a mixture of SAIB and PLGA compared to using them solely can extend the Bupivacaine HCl release from 3 days to two weeks. The DSC results demonstrated the compatibility of the mixture by showing a single Tg. The formulation with NMP exhibited a higher burst release and final release in comparison with other solvents by 30% and 96%, respectively. Increasing the solvent concentration from 12% to 32% raised the drug release significantly, which confirmed the larger porosity in the morphology results. From the Korsmeyer-Peppas model, the mechanism of drug release has been predicted to be non-Fickian diffusion.

In-situ forming PLGA implants: How additives affect swelling and drug release

The aim of this study was to investigate the impact of the addition of very different types of additives on the key features of in-situ forming implants based on poly(D,L-lactic-co-glycolic acid) (PLGA, Resomer RG 502H) loaded with dexamethasone. All ingredients were dissolved in N-methyl-pyrrolidone (NMP), the implants formed upon solvent exchange. Crosslinked poly(acrylic acid) (Carbopol), poly(ethylene glycol) (PEG 400), hydroxypropyl methylcellulose (HPMC K100, HPMC E15), stearic acid and acetyltributyl citrate (ATBC) were studied as additives, in concentrations up to 5% (except for ATBC: up to 20%). Dynamic changes in the implants' wet mass, pH of the release medium, NMP leaching as well as dexamethasone release were monitored upon exposure to phosphate buffer pH 7.4. Also the implants’ inner and outer morphology was studied, using optical and scanning electron microscopy. Interestingly, the addition of the very different types of additives partially substantially altered the morphology and swelling kinetics of the investigated in-situ forming PLGA implants, whereas the impact on dexamethasone release was rather limited in all cases. Generally, the release rate slightly increased in the presence of the additives, only in the case of ATBC it slightly decreased. The overall limited effect on drug release might at least partially be attributed to the fact that: (i) water-soluble additives might rapidly leach out into the aqueous release medium during implant formation and/or promote implant swelling, and (ii) lipophilic additives might induce phase separation.

Often neglected: PLGA/PLA swelling orchestrates drug release: HME implants

Different types of poly(lactic-co-glycolic acid) (PLGA)- and poly(lactic acid) (PLA)-based implants for controlled dexamethasone release were prepared by hot melt extrusion (HME). The lactic acid:glycolic acid ratio was varied (50:50, 75:25, 100:0) as well as the drug loading (1–15%). Resomer RG 502H, RG 752H and R 202H (all with –COOH end groups) were studied. The implants were characterized before and after exposure to phosphate buffer pH 7.4 at 37 °C. Interestingly, in all cases polymer swelling seems to play an “orchestrating” role for drug release: At early time points, the amounts of water penetrating into the systems are limited (since the macromolecules are hydrophobic and highly entangled). Consequently, only small amounts of drug can dissolve and the dissolved drug molecules are not sufficiently mobile to diffuse out to a noteworthy extent (negligible dexamethasone release for up to 6 weeks). However, the water that is able to enter the implants at early time points cleaves the polyesters right from the beginning. Due to the newly generated –COOH end groups and decreased chain length, the macromolecules become more and more hydrophilic and less entangled. In addition, water-soluble polymer degradation products build up a steadily increasing osmotic pressure, attracting water into the system. Once a critical polymer molecular weight threshold range (around 8 kDa) is reached, substantial implant swelling starts: The systems' volume increases up to 600–1700% and the water contents exceeds 80–90% (partially approaching 100%). Under these fundamentally altered conditions, significant drug amounts can dissolve and the dissolved drug molecules are sufficiently mobile to diffuse out of the implants: Drug release sets on. In brief, polymer swelling “orchestrates” the involved mass transport phenomena: It enables drug release after a certain lag time by fundamentally changing the conditions for drug dissolution and diffusion. Note that in other types of implants, additional mass transport phenomena might be involved, e.g. no burst release was observed from the investigated, initially non-porous implants.

Er:YAG fractional laser ablation for cutaneous co-delivery of pentoxifylline and d-α-tocopherol succinate: A new approach for topical treatment of radiation-induced skin fibrosis

Radiation induced fibrosis is a common side-effect after radiotherapy. Pentoxifylline is reported to reverse radiation injuries when used in conjunction with D-α-tocopherol. However, pentoxifylline has a short half-life, limited oral bioavailability, and induces several systemic adverse effects. The objective of this study was to investigate the feasibility of using Er:YAG fractional laser ablation to enable simultaneous cutaneous delivery of pentoxifylline and D- α -tocopherol succinate from poly(lactide-co-glycolide) microparticles prepared using the freeze-fracture technique. In vitro release experiments demonstrated the different release profiles of the two molecules, which were influenced by their very different lipophilicities and aqueous solubilities. Experiments were then performed to investigate the effect of laser fluence on pore depth and so determine the pore volume available to host the topically applied microparticles. Application of the pentoxifylline and D-α-tocopherol succinate containing microparticles, prepared with RESOMER® RG 502H, to laser porated skin for 48 h, resulted in simultaneous delivery of pentoxifylline (69.63 ± 6.41 μg/cm2; delivery efficiency 46.4%) and D-α-tocopherol succinate (33.25 ± 8.91 μg/cm2; delivery efficiency 22.2%). After deposition into the micropores, the poly(lactide-co-glycolide) microparticles containing pentoxifylline and D-α-tocopherol succinate could serve as an intraepidermal depot to enable sustained drug delivery after micropore closure and thereby reduce the need for repeated microporation.

Sustained-Release Delivery System of a Slow Hydrogen Sulfide Donor, GYY 4137, for Potential Application in Glaucoma.

Hydrogen sulfide (H2S) targets both underlying factors in glaucoma pathogenesis by reducing elevated intraocular pressure (IOP) and providing retinal neuroprotection, whereas the current clinical approaches targets only reducing IOP. Therefore, H2S could be a potential superior candidate for glaucoma pharmacotherapy. However, H2S could be toxic in a concentration greater than 200μM and its donors are unstable in water. Therefore, this study investigated the preparation and characterization of a non-aqueous in situ gelling sustained-release delivery system for H2S donors. The delivery system was prepared by dissolving GYY 4137, a H2S donor, in poly lactide-co-glycolide polymer (PLGA) (Resomer® RG 502H) solution prepared by dissolving polymer in a mixture of benzyl alcohol and benzyl benzoate in a ratio of 7:3, respectively. The GYY 4137 formulation was characterized for syringeability/injectability, change in pH and tonicity, moisture content, GYY 4137 degradation, and toxicity using rheometer, pH and osmometer, Karl Fisher titrimeter, NMR spectrometer, and Y79 retinoblastoma cells, respectively. The formulation was easily syringeable and injectable as evidenced by rheological data (plastic flow pattern with 43.89 ± 3.21cP viscosity and 1.12 ± 0.15Pa yield value). The pH, tonicity, and moisture content values were within acceptable range. NMR spectroscopy indicated presence of 4-methoxyphenylphosphonic acid (GYY 4137 degradation product). The GYY 4137 formulation did not show any significant (p < 0.05) toxicity except the solvent mixture. A sustained release of H2S was observed up to 72h. The in situ gel forming PLGA-based system can be manipulated to achieve sustained release of H2S from its donor GYY 4137.

In vivo evaluation of 3-dimensional PLGA/Atelocollagen/Fibrin scaffolds for intervertebral disc (IVD) regeneration

Poly (lactic-co-glycolic acid) (PLGA) is a widely used synthetic biomaterial in tissue engineering. Incorporation of natural atelocollagen and fibrin may provide PLGA a better surface property for cellular adhesion and proliferation. This paper aims to evaluate PLGA/Atelocollagen/Fibrin hybrid scaffolds seeded with IVD’s annulus fibrosus (AF) cells after in vivo implantation. Porous 3D PLGA were fabricated via solvent-casting and salt-leaching technique. PLGA was crosslinked with atelocollagen (PA). Fibrin was pipetted onto PLGA (PF) and PA (PAF) scaffolds. Rabbits’ AF cells were seeded onto each scaffold groups i.e. PLGA only, PA, PF and PAF. The “cells-scaffolds” constructs were cultured for three-weeks and implanted subcutaneously in athymic nude mice for four-week. All constructs were evaluated for gross morphology, histology, immunohistochemistry (IHC) against collagen I and II with PLGA construct as control group. Sulphated glycosaminoglycan (sGAG) and DNA contents were compared to that of monolayer AF culture. All groups exhibited significant reduction in size but showed increment in weight. Histology analysis indicated high cellular density, supported by high DNA content in all groups. The IHC showed presence of collagen I and II. The PAF showed a significantly higher sGAG content than the other groups. Degradation of PLGA did not hinder tissue formation. Atelocollagen and fibrin may contribute to a higher cellular proliferation and extracellular matrix production in PLGA. Further evaluation using gene expression shall be performed to study the intrinsic properties and possible mechanisms involved. PLGA/Atelocollagen/Fibrin hybrid scaffolds may become potential candidate for tissue engineering application.

Sustained release of bioactive glycosylated glial cell-line derived neurotrophic factor from biodegradable polymeric microspheres

Glial cell-line derived neurotrophic factor (GDNF), a potent neurotrophic factor for dopaminergic neurons, appeared as a promising candidate for treating Parkinson’s disease. GDNF microencapsulation could ensure protection against degradation due to the fragile nature of the protein. Poly(lactide-co-glycolide) (PLGA) microparticles loaded with recombinant glycosylated GDNF obtained in a mammalian cell line were prepared by TROMS, a semi-industrial technique capable of encapsulating fragile molecules maintaining their native properties. The effects of several parameters as PLGA copolymer type, PEG 400 quantity co-encapsulated with GDNF or drug loading, on the properties of the particles were investigated. Microparticles showed a mean diameter between 8 and 30 μm, compatible with their stereotaxic implantation. The drug entrapment efficiency ranged from 50.6% to 100% depending on the microsphere composition. GDNF was better encapsulated using hydrophilic polymers with high molecular weight such as RG 503H. In vitro drug release was influenced by the polymer type as well as by the amount of PEG 400 co-encapsulated with GDNF. Microparticles prepared using PLGA RG 503H released 67% of the total protein content within 40 days. Moreover, very low concentrations of poly(vinyl alcohol) were detected after microparticles washing and freeze-drying. Finally, a PC-12 bioassay demonstrated that the in vitro GDNF released was bioactive.

Controlled Delivery of Ganciclovir to the Retina with Drug-Loaded Poly(D,L-lactide-co-glycolide) (PLGA) Microspheres Dispersed in PLGA-PEG-PLGA Gel: A Novel Intravitreal Delivery System for the Treatment of Cytomegalovirus Retinitis

The aim of this study was to develop a formulation for intravitreal delivery by dispersing ganciclovir (GCV)-loaded Poly(d,L-lactide-co-glycolide (PLGA) microspheres in thermogelling PLGA-PEG-PLGA gel and to study the mechanism of drug-release characteristics both in vitro and in vivo. PLGA microspheres of GCV were prepared by the solvent evaporation method from Resomer RG 502H (D,L-lactide:glycolide::50:50; Mw, 8000 Da) and a 1:3 polymer blend of Resomer RG 502H and PLGA 6535 (D,L-lactide:glycolide::65:35; Mw, 45,000-75,000 Da). The prepared microspheres were dispersed uniformly and as a mixture (1:1) in 23% w/w of PLGA-PEG-PLGA aqueous gel solutions. GCV release in the aqueous medium was studied in vitro. A conscious rabbit microdialysis model with permanently implanted probes was selected as the method for investigating the vitreous GCV levels following an intravitreal administration of the formulation. The formulation prepared, by a physical mixture of microspheres, was prepared from Resomer RG 502H, and the polymer blend exhibited fairly constant in vitro GCV release profiles. The amounts of GCV entrapped in the microspheres were sufficient to administer therapeutically relevant doses in 60 microL of the formulation. The vitreal elimination half-life of GCV in the conscious rabbit microdialysis model was 6.45 +/- 0.83 h, with an apparent volume of distribution (V(z)) of 1.18 +/- 0.61 mL. A direct vitreous injection of GCV resulted in the maintenance of concentrations in the vitreous for only 54 h, whereas the gel formulation produced steady-state GCV levels in the vitreous for at least 14 days. PLGA microspheres containing GCV were prepared by two kinds of PLGA polymers and their blend (1:3). A formulation suitable for in vivo administration was prepared by dispersing GCV-loaded microspheres in a thermogelling PLGA-PEG-PLGA solution. An ideal in vitro release of encapsulated GCV was obtained by physically mixing microspheres prepared from different polymer blends prior to its dispersion in the thermogelling polymer. The formulation maintained mean vitreal concentrations of GCV at approximately 0.8 microg/mL for 14 days, whereas direct injections could maintain drug levels above 0.8 microg/mL for 54 h only.

Preparation of Cyclosporin A-loaded Nanoparticles Containing Ethyl Myristate or Chitosan and Pharmacokinetics in Rats

An oil-in-water solvent evaporation method was used to prepare the cyclosporin A (CyA)-loaded nanoparticles varying in poly (D,L-lactide-co-glycolide) (PLGA) polymer (RG 502H, RG 503H) and the amount of additive ethyl myristate (EM) or chitosan (CS). The particles were characterized for drug loading and entrapment efficiency by HPLC, surface morphology by scanning electron microscopy, particle size by dynamic light scattering and surface charge by Zetapotential. The results showed drug loadings ranging from 10.9% to 15.8% with high encapsulation efficiency (82.0-97.8%). SEM and DLS studies showed discrete and spherical particles with smooth surfaces and mean size ranging 257.6-721.7 nm. The additive EM or CS did not change the mean sizes of the nanoparticles, whereas by the coating effect of CS, the Zetapotential values of the CS-added nanoparticles were moved to the more positive direction as the amount of CS was increased. From the pharmacokinetic analysis, the nanoparticles formulations showed the higher bioavailability and MRT than While little adding effect of EM or CS was detected in pharmacokinetic profile when RG 503H was used as polymer carrier, more noticeable different pharmacokinetic behaviors could be observed in case of RC 502H. EM incorporation was found to elevate the , whereas CS coating resulted in the decrease of F and , which seems to be due to the function of CS as a barrier and a mucoadhesive coating.

Effect of poly(lactide-co-glycolide) molecular weight on the release of dexamethasone sodium phosphate from microparticles

The objective of this study was to investigate the effect of poly(lactide-co-glycolide) (PLGA) molecular weight (Resomer® RG 502H, RG 503H, and RG 504H) on the release behavior of dexamethasone sodium phosphate-loaded microparticles. The microparticles were prepared by three modifications of the solvent evaporation method (O/W-cosolvent, O/W-dispersion, and W/O/W-methods). The encapsulation efficiency of microparticles prepared by the cosolvent- and W/O/W-methods increased from ∼50% to >90% upon addition of NaCl to the external aqueous phase, while the dispersion method resulted in lower encapsulation efficiencies. The release of dexamethasone sodium phosphate from PLGA microparticles (>50 µm) was biphasic. The initial burst release correlated well with the porosity of the microparticles, both of which increased with increasing polymer molecular weight (RG 504H > 503H > 502H). The burst was also dependent on the method of preparation and was in the order of dispersion method > WOW method > consolvent method. In contrast to the higher molecular weight PLGA microparticles, the release from RG 502H microparticles prepared by cosolvent method was not affected by volume of organic solvent (1.5–3.0 ml) and drug loading (4–13%). An initial burst of ∼10% followed by a 5-week sustained release phase was obtained. Microparticles with a size <50 µm released in a triphasic manner; an initial burst was followed by a slow release phase and then by a second burst.

In vitro study of lysozyme in poly(lactide- co-glycolide) microspheres with sucrose acetate isobutyrate

This study investigated the suitability of microsphere formulations for extended protein delivery and complete protein release. These microspheres were prepared by a multi-emulsion method and prepared using a mixture of poly(lactide- co-glycolide) (PLGA), RG 502H (lactide:glycolide = 50:50, M W 9300) and sucrose acetate isobutyrate (SAIB). SAIB embedded into the microspheres and mixed with PLGA, improved the efficiency of enzyme encapsulation. The in vitro release rate of lysozyme (Lys) from the microspheres was reduced due to the high viscosity of the added SAIB and less degradation of PLGA by SAIB. These properties enabled prolonged release of Lys for up to 2 months, characterized by a minimal initial burst of Lys and nearly zero-order protein release kinetics result from co-administration of sorbitan monooleate 80. When it is considered that degradation products of SAIB are inactive for labile proteins, SAIB may be regarded as a promising candidate for long-acting protein delivery.

Sterilization of gentamicin containing collagen/PLGA microparticle composites

In order to achieve implants which provide sustained release of gentamicin, microparticles based on a 50/50 Resomer ® 503/Resomer ® 502H blend were combined with collagen in order to achieve their fixation and to utilize the favorable effect of collagen on wound healing. Ethylene oxide treatment as well as β- and γ-irradiation were tested for sterilization of the collagen/PLGA-microparticle composite. All methods resulted in a decrease of molecular weight and glass transition temperature of polymer raw material and microparticles. In addition, ethylene oxide treatment yielded aggregation of microparticles leading to a substantial increase in the initially liberated gentamicin dose. Furthermore, chemical changes of gentamicin after ethylene oxide sterilization could be identified using NMR spectroscopy. Despite a decrease in the molecular weight and glass transition temperature after irradiation, neither morphological changes of the composites nor changes regarding the gentamicin release profile from β- and γ-sterilized material were observed. Free radicals, which could only be detected in gentamicin drug substance and at marginal level in gentamicin-loaded MPs, disappeared within 4 weeks. Additional microbiological testing verified the microbiological activity of gentamicin liberated from β-sterilized composites. Storage of β-sterilized composite at 4 °C/35% r.h. for 3 months did not influence morphology, molecular weight, glass transition temperature, and release profiles of microparticles and composites. However, at 25 °C/60% r.h. and 40 °C/75% r.h. a marked decrease in molecular weight and glass transition temperature resulted. This effect was due to a higher humidity, water uptake into polymers, and subsequent hydrolysis of polymers and microparticles, which was more pronounced for RG 502H because of its hydrophilicity. Upon storage at 25 °C/60% r.h. and 40 °C/75% r.h. particles collapsed resulting in an increased gentamicin liberation. Thus, all sterilization techniques have their pros and cons, but based on drug release profile and chemical changes of gentamicin irradiation treatment appears to be more suitable for collagen/gentamicin-loaded PLGA microparticle composites.

Effect of Polymer Blending on the Release of Ganciclovir from PLGA Microspheres

The aim of the study is to investigate the effect of polymer blending on entrapment and release of ganciclovir (GCV) from poly(D,L-lactide-co-glycolide) (PLGA) microspheres using a set of empirical equations. Two grades of PLGA, PLGA 7525 [D,L-lactide:glycolide(75:25), MW 90,000-126,000 Da] and Resomer RG 502H [D,L-lactide:glycolide(50:50), MW 8000 Da], were employed in the preparation of PLGA microspheres. Five sets of microsphere batches were prepared with two pure polymers and their 1:3, 1:1, and 3:1 blends. Drug entrapment, surface morphology, particle size analysis, drug release, and differential scanning calorimetric studies were performed. In vitro drug-release data were fitted to a set of empirical sigmoidal equations by nonlinear regression analysis that could effectively predict various parameters that characterize both diffusion and degradation cum diffusion-controlled release phases of GCV. Entrapment efficiencies of GCV ranged from 47 to 73%. Higher amounts of GCV were entrapped in polymer blend microspheres relative to individual polymers. Triphasic GCV release profiles were observed, which consisted of both diffusion and degradation cum diffusion-controlled phases. In vitro GCV release was shortest for Resomer RG 502H microsphere (10 days) and longest for PLGA 7525 microspheres (90 days). Upon blending, the duration of release gradually decreased as the content of Resomer RG 502H in the matrix was raised. Equations effectively estimated the drug-release rate constants during both the phases with high R2 values (>0.990). GCV release was slower from the blend microsphere during the initial diffusion phase. Majority of entrapped drug (70-95%) was released during the matrix degradation cum diffusion phase. Drug entrapment and release parameters estimated by the equations indicate more efficient matrix packing between PLGA 7525 and Resomer RG 502H in polymer-blended microspheres. The overall duration of drug release diminishes with rising content of Resomer RG 502H in the matrix. Differential scanning calorimetry studies indicate stronger binding between the polymers in the PLGA 7525/Resomer RG 502HColon, two colons 3:1 blend. Polymer blending can effectively alter drug-release rates of controlled delivery systems in the absence of any additives.

Niridazole Biodegradable Inserts for Local Long-Term Treatment of Periodontitis: Possible New Life for an Orphan Drug

Periodontal pocket inserts of niridazole (NZ) made with Resomer® (grades RG 503H and RG858, designated as RH and RG, respectively) were studied. Various formulation variables were evaluated to obtain a biodegradable delivery systems showing device degradation and drug depletion parallel to each other in vitro. Drug release from the prepared inserts was evaluated using a static dissolution setup (for 1 month). Incorporation of 3 parts of RG in 1 part of RH inserts caused a 50% decrease in the initial release rate. The RH-NZ inserts showed a spurt in release around the 10th day of the study, which coincided with the decrease in device weight, suggesting onset of device degradation. Pilot-scale clinical trials in 12 patients indicated improvements in clinical indices from the baseline values. The average pocket depth was reduced significantly (α = 0.05) from 6.34 ± 1.86 mm at baseline to 5.94 ± 0.28 mm after 28 days of treatment.

In situ forming microparticle system for controlled delivery of leuprolide acetate: Influence of the formulation and processing parameters

The objective of present study was to control the delivery of leuprolide acetate using in situ forming microparticle (ISM) systems. A solution of leuprolide acetate and poly(lactide-co-glycolide) (PLGA RG 503H) or poly(lactide) (PLA R 202H) in N-methyl-2-pyrrolideone (NMP) was emulsified into an external oil phase using a two-syringe/connector system. After injection into an aqueous environment, NMP diffusion led to polymer precipitation and microparticle formation in situ. ISM-systems were characterized with respect to particle morphology and the influence of formulation and processing parameters on the in vitro release. ISM from RG 503H showed a high initial release (approximately 40%), which could be attributed to the high porosity of microparticles. The initial release could be reduced by increasing the polymer concentration, increasing the amount and viscosity of the oil phase, and decreasing the drug loading. ISM-systems from R 202H had a much lower initial release (approximately 9%) compared to that from RG 503H, which was followed by a slow and continuous drug release. In comparison to conventional microparticles prepared by a solvent evaporation method, ISM from R 202H showed a lower initial release and a more linear continuous release.

Development of a novel formulation containing poly(d,l-lactide-co-glycolide) microspheres dispersed in PLGA–PEG–PLGA gel for sustained delivery of ganciclovir

The purpose of this work is to develop empirical equations for describing the in vitro ganciclovir (GCV) release from PLGA microspheres and also to develop and characterize a formulation containing GCV loaded PLGA microspheres dispersed in thermogelling PLGA–PEG–PLGA polymer gel. Effect of polymer chain length and polymer blending on GCV entrapment and release from PLGA microspheres is also examined. PLGA microspheres of GCV were prepared from two polymers PLGA 6535 (d,l-lactide:glycolide∷65:35, Mw=45,000–75,000 Da) and Resomer RG 502H (d,l-lactide:glycolide∷50:50, Mw=8000 Da) and a 3:1 mixture. PLGA–PEG–PLGA polymer was synthesized and characterized. In vitro GCV release studies were conducted with microspheres and microspheres dispersed in 23% w/v PLGA–PEG–PLGA solution. Polymer blended microspheres entrap more GCV (72.67±2.49%) than both PLGA 6535 (51.37±2.7%) and Resomer RG 502H (47.13±1.13%) microspheres. In vitro drug release data was fit to sigmoid equations and release parameters were estimated by nonlinear regression analysis. These equations effectively describe three different phases in GCV release from PLGA microspheres, initial diffusion, matrix hydration and degradation. The amount of drug release during the initial phase decreased for the blend microspheres indicating efficient packing between the PLGA 6535 and Resomer RG 502H in the microsphere matrix. Moreover, upon dispersion into the polymer gel, the rate of drug release during initial diffusion phases slowed relative to microspheres alone. In conclusion, this study reports the development of PLGA microspheres with high payloads and their PLGA–PEG–PLGA gel based formulations. Drug release equations have been developed that effectively describe the triphasic GCV release.

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

Modifying the Release of Gentamicin from Microparticles Using a PLGA Blend

Carrier systems for local gentamicin (GS) treatment based on collagen sponges and polymethylmethacrylate beads show pharmacokinetic disadvantages in their GS-release profiles. Therefore, poly(lactic-co-glycolic acid) (PLGA) microparticles were devised. None of the five poly(α-hydroxy acid)s tested resulted in the desired antibiotic release over approximately one week. However, preparing microparticles from a 50/50 blend of Resomer® RG 502H, an uncapped variety, and Resomer RG 503, an endcapped polymer, yielded the targeted liberation profile. The mechanism of GS release was investigated by analyzing water uptake and polymer molecular weight. Release of GS from RG 502H particles occurred instantaneously and coincided with substantial water penetration. Particles prepared from RG 503 started out at a higher molecular weight and since the endcapped polymer takes up less water, the decrease in molecular weight was delayed. The threshold of collapse was reached after two weeks, which coincided with water penetration and GS release. For the 50/50 RG 502H/RG 503 blend, this process was delayed for two to three days. Hydrolysis occurred at the same rate as for RG 502H due to the high water content as a consequence of the uncapped polymer fraction and renders GS release over one week with release limited to 30% in the first two days due to the endcapped polymer fraction of higher molecular weight. Thus, the mixture of endcapped and uncapped Resomer exhibits a new quality for adjusting drug release from poly(α-hydroxy acid)s.

Gamma irradiation effects on poly( dl-lactictide-co-glycolide) microspheres

Gamma radiation treatment plays an increasingly important role in the sterilization/sanitization of pharmaceutical products. However, irradiation may affect the stability of the product and thus its safety of use. We investigated the influence of ionizing radiation on modified release microparticulate drug delivery systems made of two types of polylactide-co-glycolide copolymers (PLG): RG 503 and RG 503H; these polymers have identical molecular weights but different chemical structures. The effect of γ radiation on polymer stability of the raw polymers (P) and related microspheres (Ms) was evaluated. Samples were irradiated at different irradiation doses (5, 15 and 25 kGy) using 60Co as radiation source. The microspheres were prepared using the spray drying technique. Degradation of PLG and related microspheres was evaluated during six months in terms of average molecular weight ( M w) loss by gel permeation chromatography (GPC) and variation in glass transition temperature ( T g) using differential calorimetry (DSC). The presence of free radicals in the product was tested by electron paramagnetic resonance (EPR). Both P and Ms showed a trend in decreasing their M w at time 0 as a function of irradiation dose. For RG503 the decay in M w is always negligible for doses below 15 kGy while it is about 10% for 25 kGy. After 150 days M w decay was 25% in the microspheres and 20% in the raw polymer. It was not possible to evaluate the radiation effect, at different storage times, for RG503H because this polymer resulted to be unstable even in the regular storage conditions without being irradiated. The concentration of radiation-induced free radicals was higher in RG 503H (both P and Ms) and they were more stable than the free radicals species observed in the case of polymer RG 503. Alterations and/or production of new radicals were observed on exposure of RG 503H microspheres to the light. Radiolytic degradation of RG 503 under vacuum is characterized by a prevalence of the chain scission events leading to a decrease of M w. Some crosslinking can occur mainly in the post irradiation stage through the decay and coupling of the hydrogen abstraction radicals. A hydroperoxydative cycle, whose mechanism is suggested, is generated in the presence of oxygen.

Clonazepam microencapsulation in poly-D,L-lactide-coglycolide microspheres

The work is aimed at the preparation and characterization of biodegradable microspheres of poly-D,L-lactide-co-glycolide (PLGA), for the controlled release of clonazepam. The solubility characteristics of this drug make it an interesting example to evaluate the performances of the two most widely used microencapsulation techniques, emulsification solvent evaporation and spray-drying. Several biodegradable PLGA copolymers have been evaluated (RG 502H, RG 503H, RG 503, Boerhinger Ingelheim). They differ in terms of molecular weight and physico-chemical characteristics. The microspheres obtained have been characterized for their morphology, physico-chemical properties (DSC) and in vitro dissolution behaviour. Between the two preparation methods, only spray-drying was suitable for the microencapsulation of clonazepam in PLGA microspheres. In vitro dissolution tests highlight that more sustained release of drug is achieved with the higher (molecular weight) polymer.