Formulation and Evaluation of PLA and PLGA In Situ Implants Containing Secnidazole and/or Doxycycline for Treatment of Periodontitis

The purpose of this study is to formulate in situ implants containing doxycycline hydrochloride and/or secnidazole that could be used in the treatment of periodontitis by direct periodontal intrapocket administration. Biodegradable polymers [poly (lactide) (PLA) and poly (lactide-co-glycolide) (PLGA)], each polymer in two concentrations 25%w/w, 35%w/w were used to formulate the in situ implants. The rheological behavior, in vitro drug release and the antimicrobial activity of the prepared implants were evaluated. Increasing the concentration of each polymer increases the viscosity and decreases the percent of the drugs released after 24 h. PLA implants showed a slower drugs release rate than PLGA implants in which the implants composed of 25% PLGA showed the fastest drugs release. The in vitro drug release and antimicrobial activity results were compared with results of Atridox. Results revealed that the pharmaceutical formulation based on 25% PLGA containing secnidazole and doxycycline hydrochloride has promising activity in treating periodontitis in comparison with Atridox.     

The Biodegradation of Zein <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> and its Application in Implants

A unique polymer-based sustained-release implant drug delivery system was prepared by using biocompatible and biodegradable Zein as the skeleton meterial. After preparing Zein colloids, the Zein-loaded implant rods were formulated by injection molding followed by evaporating the solvent, and being coated with poly(lactic-co-glycolic) acid (PLGA) solution. Drug release kinetics was examined by using Fluorouracil (5-FU) as model drug. Nearly zero-order release was achieved for the model drugs for a period of 0–25 days when the implants were incubated in distilled water at 37°C. And then the degradation kinetics of the rods in vivo and in vitro were evaluated, which indicated that Zein could be absorbed by body and has good degradation property. The effects of different ratios of Zein/5-FU and the rods’ diameter on drug release were studied, respectively. The plasma concentration of 5-FU in the implants were determined by HPLC after implanting a single dose of the implants in rats. All data were subsequently processed by using the computer program 3P97, and the values were showed as follows: the area under the plasma concentration–time curve (AUC) value was 321.88 (μg/ml) × day, and the mean residence time (MRT) value was 23.05 days. The sustained-release implants of Zein/5-FU were successfully formulated. The uniqueness of the article is that Zein has been used as a skeleton material in implant delivery system for the first time and zero-order release kinetics has been obtained successfully.     

Evaluation of a Prednisolone Acetate-Loaded Subconjunctival Implant for the Treatment of Recurrent Uveitis in a Rabbit Model

Aim

To assess the efficacy of a biodegradable, prednisolone acetate implant in a rabbit uveitis model.

Methods

Randomized, controlled study of biodegradable microfilms preloaded with prednisolone acetate (PA) in a rabbit uveitis model. Experimental uveitis was induced by unilateral intravitreal injection of Mycobacterium tuberculosis H37Ra antigen (50 ug; 1 ug/uL) in preimmunized rabbits. PA-loaded poly[d,l-lactide-co-ε-caprolactone] (PLC) microfilms (n = 10) and blank microfilms (n = 6) were implanted subconjunctivally. An estimate of PA release in vivo was calculated from measured residual PA amounts in microfilms after the rabbits were sacrificed. The eyes were clinically monitored for ocular inflammation for 28 days. Histopathological examination of the enucleated eyes was performed at the end of the study period.

Results

In vitro studies revealed that sandwich PA-loaded microfilm formulations exhibited higher release kinetic compared to homogenous PA-loaded microfilms. The 60–40–60% microfilm released an average of 0.034 mg/day of PA over the period of 60 days in vitro; and we found that approximately 0.12 mg/day PA was released in vivo. Animals implanted with the PA-loaded microfilms exhibited significantly lowered median inflammatory scores when compared against the control group in this model for recurrent uveitis (P<0.001). The implants were clinically well tolerated by all the animals. Histology results showed no significant scarring or inflammation around the PA-loaded microfilms.

Conclusion

Our pilot study demonstrated that a subconjunctival PA-loaded implant is effective in suppressing inflammation in the rabbit model of uveitis, by providing therapeutic levels of PA that attenuated the inflammatory response even after a rechallenge. Longer term studies are now needed to establish the therapeutic potential of such a delivery system for treatment of ocular inflammation.     

PLGA microsphere construct coated with TGF-beta 3 loaded nanoparticles for neocartilage formation

Polymeric microsphere system has been widely used in tissue-regeneration matrix and drug delivery systems. To apply these biomaterials as novel cell supporting matrix for stem cell delivery, we have devised a novel method for the fabrication of nanostructured 3D scaffolds that growth factor loaded heparin/poly(L-lysine) nanoparticles were physically attached on the positively charged surface of PLGA microspheres precoated with low molecular weight of poly(ethyleneimmine) (PEI) via a layer-by-layer (LbL) system. Based on a previous study, we have prepared poly(lactide-co-glycolide) (PLGA) microspheres harboring heparin/poly(L-lysine) loaded with growth factors. Growth factor loaded heparin/poly(L-lysine) nanoparticles, which were simply produced as polyion complex micelles (PICM) with diameters of 50-150 nm, were fabricated in the first step. Microsphere matrix (size, 20 approximately 80 nm) containing TGF-beta 3 showed a significantly higher number of specific lacunae phenotypes at the end of the 4 week study in vitro culture of mesenchymal stem cells. Thus, growth factor delivery of PLGA microsphere can be used to engineer synthetic extracellular matrix. This PLGA microsphere matrix containing TGF-beta 3 showed promise as coatings for implantable biomedical devices to improve biocompatibility and ensure in vivo performance.     

Biodegradation and in vivo biocompatibility of rosin: a natural film-forming polymer

The specific aim of the present study was to investigate the biodegradation and biocompatibility characteristics of rosin, a natural film-forming polymer. Both in vitro as well as in vivo methods were used for assessment of the same. The in vitro degradation of rosin films was followed in pH 7.4 phosphate buffered saline at 37°C and in vivo by subdermal implantation in rats for up to 90 days. Initial biocompatibility was followed on postoperative days 7, 14, 21, and 28 by histological observations of the surrounding tissues around the implanted films. Poly (DL-lactic-co-glycolic acid) (PLGA) (50∶50) was used as reference material for biocompatibility. Rate and extent of degradation were followed in terms of dry film weight loss, molecular weight (MW) decline, and surface morphological changes. Although the rate of in vitro degradation was slow, rosin-free films showed complete degradation between 60 and 90 days following subdermal implantation in rats. The films degraded following different rates, in vitro and in vivo, but the mechanism followed was primarily bulk degradation. Rosin films demonstrated inflammatory reactions similar to PLGA, indicative of good biocompatibility. Good biocompatibility comparable to PLGA is demonstrated by the absence of necrosis or abscess formation in the surrounding tissues. The study provides valuable insight, which may lead to new applications of rosin in the field of drug delivery.     

On‐Resin Synthesis of an Acylated and Fluorescence‐Labeled Cyclic Integrin Ligand for Modification of Poly(lactic‐co‐glycolic acid)

Cyclic Arg‐Gly‐Asp (RGD) peptides show remarkable affinity and specificity to integrin receptors and mediate important physiological effects in tumor angiogenesis. Additionally, they are one of the keyplayers in improving the biocompatibility of biomaterials. The fully biodegradable polymer poly(lactic‐co‐glycolic acid) (PLGA) is frequently used for biomedical implants and can be applied as nanoparticles for drug delivery. The aim of this work was the generation of a lipidated c[RGDfK] peptide including a second functionality for coating of hydrophobic PLGA. Therefore, we established a general and straightforward strategy for the introduction of two different modifications into the same c[RGDfK] peptide. This allowed the generation of a palmitoylated integrin‐binding lipopeptide that shows high affinity to PLGA. Additionally, we coupled 5(6)‐carboxyfluorescein to the second site for modification to enable sensitive quantification of the immobilized lipopeptide on PLGA. In conclusion, we present a synthesis protocol that enables the preparation of c[RGDfK] lipopeptides with a strong affinity to PLGA and an additional site for modifications. This will provide the opportunity to introduce a variety of effector molecules site‐specifically to the c[RGDfK] lipopeptide, which will enable the introduction of multifunctionality into c[RGDfK]‐coated PLGA devices or nanoparticles.     

Miscibility of bioerodible polyphosphazene/poly(lactide-co-glycolide) blends

We have previously demonstrated the feasibility of blending bioerodible polyphosphazenes with poly(lactide-co-glycolide) (PLGA) to form versatile polymeric materials with altered bioerosion properties. These studies demonstrated the effective neutralization of the acidic degradation products of PLGA by the polyphosphazene hydrolysis products. In the present study, five new polymers of dipeptide polyphosphazenes poly[(ethyl glycinato)x(glycyl-ethyl glycinato)yphosphazene] and novel blends of these polyphosphazenes with poly(lactide-co-glycolide) (PLGA) were synthesized and fabricated. The miscibility was analyzed using differential scanning calorimetry and scanning electron microscopy. Hydrogen bonding within the blends was assessed by attenuated total reflectance infrared spectroscopy. The phosphazene component of the blend contained varying ratios of the glycyl-glycine ethyl ester to the glycine ethyl ester. Poly[(ethyl glycinato)0.5(glycine ethyl glycinato)1.5phosphazene formed completely miscible blends with PLGA (50:50) and PLGA (85:15). This is ascribed to the multiple hydrogen-bonding sites within the side groups of the polyphosphazene. The components of the blend act as plasticizers for each other because a glass transition temperature for each blend was detected at a lower temperature than for each individual polymer. A hydrolysis study showed that unblended solid poly[(ethyl glycinato)0.5(glycyl ethyl glycinato)1.5phosphazene] hydrolyzed in less than 1 week. However, the blends degraded at a slower rate than both parent polymers. This is attributed to the buffering capacity of the polyphosphazene hydrolysis products, which increases the pH of the degradation media from 2.5 to 4, thereby slowing the degradation rate of PLGA.     

Targeted novel surface-modified nanoparticles for interferon delivery for the treatment of hepatitis B

The purpose of the present work was to develop hepatitis B surface antigen (HBsAg) surface-adsorbed cationic poly (d,l-lactic-co-glycolic acid) PLGA nanoparticles for interferon alpha (IFNα) delivery targeted to hepatocytes. Cationic PLGA nanoparticles loaded with IFNα were prepared using the double emulsification technique. Delipidated HBsAg was passively adsorbed on the surface of nanoparticles by using the simple dipping and drying method. Surface morphology and size distribution of nanoparticles were analyzed by scanning electron microscopy and dynamic light-scattering method, respectively. The biodistribution behavior of plain and HBsAg-coated (99m)Tc-tagged PLGA nanoparticles was also examined followed by intravenous injection. The results revealed that ～75% of the radioactivity was recovered in the liver after 4 h of injection that was nearly 3-fold greater in magnitude than the plain PLGA nanoparticles. These data demonstrated that the novel formulation of nanoparticles has potential application in hepatic-targeted drug delivery.     

Preparation,in vitro release,in vivo absorption and biocompatibility studies of insulin-loaded microspheres in rabbits

The purpose of this study was to develop a single-dose insulin delivery system based on poly (lactide-co-glycolide) (PLGA) microspheres to provide basal insulin level for a prolonged period. Insulin-loaded PLGA microspheres were prepared by water-in-oil-in-water double emulsion (batch A) and solid-in-oil-in-water emulsion (batch B) methods. Microspheres were characterized for physical characteristics and in vitro release. In vivo absorption of insulin and biocompatibility of insulin-loaded PLGA microspheres were performed in diabetic New Zealand white rabbits. Light and transmission electron microscopy were performed on the skin tissues excised from microspheres injected sites in order to study the biocompatibility. The burst release of insulin was high (47%) from batch B and low (5%) from batch A. Therefore, we mixed microspheres of batch A and B in ratio of 3:1 w/w, which produced desirable in vitro release profile. In vivo absorption study showed that insulin-loaded microspheres provided a serum insulin level of 20-40 microU/ml up to 40 days. Biocompatibility study provided evidence of normal inflammatory and foreign body reactions, which were characterized by the presence of macrophages, fibroblasts and foreign body giant cells. Neither necrosis nor tissue damage was identified. At the end of 12 weeks, no distinct histological differences were observed in comparison to the control tissue samples. In conclusion, insulin-loaded PLGA microspheres controlled the in vivo absorption of insulin to maintain the basal insulin level for longer period and the delivery system was biocompatible.     

Formulation and in vitro transfection efficiency of poly (D, L-lactideco-glycolide) microspheres containing plasmid DNA for gene delivery

The stability, in vitro release, and in vitro cell transfection efficiency of plasmid DNA (pDNA) poly (D,L.-lactide-co-glycolide) (PLGA) microsphere formulations were investigated. PLGA microspheres containing free and polylysine (PLL)-complexed pDNA were prepared by a water-oil-water solvent extraction/evaporation technique. Encapsulation enhanced the retention of the supereoiled structure of pDNA as determined by gel electrophoresis. PLL complexation of pDNA prior to encapsulation increased both the stability of the supercoiled form and the encapsulation efficiency. Free pDNA was completely degraded after exposure to DNase while encapsulation protected the pDNA from enzymatic degradation. Rapid initial in vitro release of pDNA was obtained from microspheres containing free pDNA. while the release from microspheres containing PLL-complexed pDNA was sustained for more than 42 days. Bioactivity of encapsulated pDNA determined by in vitro cell transfection using Chinese hamster ovary cells (CHO) showed that the bioactivity of encapsulated pDNA was retained in both formulations but to a greater extent with PLL-complexed pDNA microspheres. These results demonstrated that PLGA microspheres could be used to formulate a controlledrelease delivery system for pDNA that can protect the pDNA from DNase degradation without loss of functional activity.     

Kinetically controlled cellular interactions of polymer-polymer and polymer-liposome nanohybrid systems

Although bioactive polymers such as cationic polymers have demonstrated potential as drug carriers and nonviral gene delivery vectors, high toxicity and uncontrolled, instantaneous cellular interactions of those vectors have hindered the successful implementation In Vivo. Fine control over the cellular interactions of a potential drug/gene delivery vector would be thus desirable. Herein, we have designed nanohybrid systems (100-150 nm in diameter) that combine the polycations with protective outer layers consisting of biodegradable polymeric nanoparticles (NPs) or liposomes. A commonly used polycation polyethylenimine (PEI) was employed after conjugation with rhodamine (RITC). The PEI-RITC conjugates were then encapsulated into (i) polymeric NPs made of either poly(lactide-co-glycolide) (PLGA) or poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PEG-PLGA); or (ii) PEGylated liposomes, resulting in three nanohybrid systems. Through the nanohybridization, both cellular uptake and cytotoxicity of the nanohybrids were kinetically controlled. The cytotoxicity assay using MCF-7 cells revealed that liposome-based nanohybrids exhibited the least toxicity, followed by PEG-PLGA- and PLGA-based NPs after 24 h incubation. The different kinetics of cellular uptake was also observed, the liposome-based systems being the fastest and PLGA-based systems being the slowest. The results present a potential delivery platform with enhanced control over its biological interaction kinetics and passive targeting capability through size control.     

Etoposide-Loaded Poly(Lactic-co-Glycolic Acid) Intravitreal Implants: <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Evaluation

Etoposide-loaded poly(lactic-co-glycolic acid) implants were developed for intravitreal application. Implants were prepared by a solvent-casting method and characterized in terms of content uniformity, morphology, drug-polymer interaction, stability, and sterility. In vitro drug release was investigated and the implant degradation was monitored by the percent of mass loss. Implants were inserted into the vitreous cavity of rabbits’ eye and the in vivo etoposide release profile was determined. Clinical examination and the Hen Egg Test-Chorioallantoic Membrane (HET-CAM) method were performed to evaluate the implant tolerance. The original chemical structure of the etoposide was preserved after incorporation in the polymeric matrix, which the drug was dispersed uniformly. In vitro, implants promoted sustained release of the drug and approximately 57% of the etoposide was released in 50 days. In vivo, devices released approximately 63% of the loaded drug in 42 days. Ophthalmic examination and HET-CAM assay revealed no evidence of toxic effects of implants. These results tend to show that etoposide-loaded implants could be potentially useful as an intraocular etoposide delivery system in the future.     

The surface roughness of lactose particles can be modulated by wet-smoothing using a high-shear mixer

The purpose of this research was to encapsulate superoxide dismutase (SOD) and catalase (CAT) in biodegradable microspheres (MS) to obtain suitable sustained protein delivery. A modified water/oil/water double emulsion method was used for poly(D,L-lactide-co-glycolide) (PLGA) and poly(D,L-lactide) PLA MS preparation co-encapsulating mannitol, trehalose, and PEG400 for protein stabilization. Size, morphology, porosity, mass loss, mass balance, in vitro release and in vitro activity were assessed by using BCA protein assay, scanning electron microscopy, BET surface area, and particle-sizing techniques. In vitro activity retention within MS was evaluated by nicotinammide adenine dinucleotide oxidation and H₂O₂ consumption assays. SOD encapsulation efficiency resulted in 30% to 34% for PLAMS and up to 51% for PLGA MS, whereas CAT encapsulation was 34% and 45% for PLGA and PLAMS, respectively. All MS were spherical with a smooth surface and low porosity. Particle mean diameters ranged from 10 to 17 μm. CAT release was prolonged, but the results were incomplete for both PLA and PLGA MS, whereas SOD was completely released from PLGA MS in a sustained manner after 2 months. CAT results were less stable and showed a stronger interaction than SOD with the polymers. Mass loss and mass balance correlated well with the release profiles. SOD and CAT in vitro activity was preserved in all the preparations, and SOD was better stabilized in PLGA MS. PLGA MS can be useful for SOD delivery in its native form and is promising as a new depot system.     

Accelerated Polymer Biodegradation of Risperidone Poly(d, l-Lactide-Co-Glycolide) Microspheres

The influence of a tertiary amine, namely risperidone (pKa = 7.9) on the degradation of poly(d, l lactide-co-glycolide) (PLGA) microspheres was elucidated. Risperidone and blank microspheres were fabricated at two lactide/glycolide ratios, 65:35 and 85:15. The microspheres were characterized for drug loading by high-performance liquid chromatography, particle size by laser diffractometry, and surface morphology by scanning electron microscopy. Polymer degradation studies were carried out with drug-loaded microspheres and blank microspheres in presence of free risperidone in 0.02 M PBS containing 0.02% Tween®80 at 37°C. Molecular weight was monitored by gel permeation chromatography. Risperidone and blank microspheres had similar size distribution and were spherical with a relatively nonporous smooth surface. The presence of risperidone within the microspheres enhanced the hydrolytic degradation in both polymeric matrices with faster degradation occurring in 65:35 PLGA. The molecular weight decreased according to pseudo-first-order kinetics for all the formulations. During the degradation study, the surface morphology of drug-loaded microspheres was affected by the presence of risperidone and resulted in shriveled microspheres in which there appeared to be an intrabatch variation with the larger microspheres being less shriveled than the smaller ones. When blank microspheres were incubated in free risperidone solutions, a concentration-dependent effect on the development of surface porosity could be observed. Risperidone accelerates the hydrolytic degradation of PLGA, presumably within the microenvironment of the drug-loaded particles, and this phenomenon must be taken into consideration in designing PLGA dosage forms of tertiary amine drugs.Key words: mass loss, microencapsulation, PLGA microspheres, polymer degradation, risperidone, tertiary amine drug     

pH-sensitive polymer nanospheres for use as a potential drug delivery vehicle

We report the development and characterization of pH-sensitive poly(2-tetrahydropyranyl methacrylate) [poly(THPMA)] nanospheres and demonstrate their feasibility as an effective drug delivery vehicle. Poly(THPMA) nanospheres were prepared using either the double emulsion or single emulsion method for the encapsulation of, respectively, water soluble (rhodamine B) or organic soluble (paclitaxel) payloads. The resulting nanospheres showed pH-dependent dissolution behavior, resulting in significant morphologic changes and loss of nanoparticle mass under mild acidic conditions (pH 5.1) with a half-life of 3.3 days, as compared to physiologic condition (pH 7.4) with a half-life of 6.2 days. The in vitro drug release profile of the paclitaxel-loaded poly(THPMA) nanospheres revealed that the rate of drug release in pH 5.1 acetate buffer was relatively faster than that in pH 7.4 HEPES buffer. Furthermore, poly(THPMA) nanospheres showed lower cytotoxicity and higher cellular uptake as compared to the FDA-approved PLGA-based nanospheres currently in clinical practice.     

In vitro investigation on poly(lactide)-Tween 80 copolymer nanoparticles fabricated by dialysis method for chemotherapy

Polysorbate 80 (Tween 80) has been widely used as an emulsifier with excellent effects in nanoparticles technology for biomedical applications. This work was thus triggered to synthesize poly(lactide)/Tween 80 copolymers with various copolymer blend ratio, which were synthesized by ring-opening polymerization and characterized by 1H NMR and TGA. Nanoparticles of poly(lactide)/Tween 80 copolymers were prepared by the dialysis method without surfactants/emulsifiers involved. Paclitaxel was chosen as a prototype anticancer drug due to its excellent therapeutic effects against a wide spectrum of cancers. The drug-loaded nanoparticles of poly(lactide)/Tween 80 copolymers were then characterized by various state-of-the-art techniques, including laser light scattering for particles size and size distribution, field emission scanning electron microscopy (FESEM) and atomic force microscopy (AFM) for surface morphology; laser Doppler anemometry for zeta potential; differential scanning calorimetry (DSC) for the physical status of the drug encapsulated in the polymeric matrix; X-ray photoelectron spectrometer (XPS) for surface chemistry; high performance liquid chromatography (HPLC) for drug encapsulation efficiency; and in vitro drug release kinetics. HT-29 cells and Glioma C6 cells were used as an in vitro model of the GI barrier for oral chemotherapy and a brain cancer model to evaluate in vitro cytotoxicity of the paclitaxel-loaded nanoparticles. The viability of C6 cells was decreased from 37.4 +/- 4.0% for poly(D,L-lactide-co-glycolic acid) (PLGA) nanoparticles to 17.8 +/- 4.2% for PLA-Tween 80-10 and 12.0 +/- 5.4% for PLA-Tween 80-20 copolymer nanoparticles, which was comparable with that for Taxol at the same 50 microg/mL drug concentration.     

Synthesis of poly(lactide-co-glycolide-co-ε-caprolactone)-graft-mannosylated poly(ethylene oxide) copolymers by combination of "clip" and "click" chemistries

Poly(lactide-co-glycolide) (PLGA) is extensively used in pharmaceutical applications, for example, in targeted drug delivery, because of biocompatibility and degradation rate, which is easily tuned by the copolymer composition. Nevertheless, synthesis of sugar-labeled amphiphilic copolymers with a PLGA backbone is quite a challenge because of high sensitivity to hydrolytic degradation. This Article reports on the synthesis of a new amphiphilic copolymer of PLGA grafted by mannosylated poly(ethylene oxide) (PEO). A novel building block, that is, α-methoxy-ω-alkyne PEO-clip-N-hydroxysuccinimide (NHS) ester, was prepared on purpose by photoreaction of a diazirine containing molecular clip. This PEO block was mannosylated by reaction of the NHS ester groups with an aminated sugar, that is, 2-aminoethyl-α-d-mannopyroside. Then, the alkyne ω-end-group of PEO was involved in a copper alkyne- azide coupling (CuAAC) with the pendent azides of the aliphatic copolyester. The targeted mannose-labeled poly(lactide-co-glycolide-co-ε-caprolactone)-graft-poly(ethylene oxide) copolymer was accordingly formed. Copolymerization of d,l-lactide and glycolide with α-chloro-ε-caprolactone, followed by substitution of chlorides by azides provided the azido-functional PLGA backbone. Finally, micelles of the amphiphilic mannosylated graft copolymer were prepared in water, and their interaction with Concanavalin A (ConA), a glyco-receptor protein, was studied by quartz crystal microbalance. This study concluded to the prospect of using this novel bioconjugate in targeted drug delivery.     

Self-assembled micelles of biodegradable triblock copolymers based on poly(ethyl ethylene phosphate) and poly(-caprolactone) as drug carriers

A series of novel amphiphilic triblock copolymers of poly(ethyl ethylene phosphate) and poly(-caprolactone) (PEEP-PCL-PEEP) with various PEEP and PCL block lengths were synthesized and characterized. These triblock copolymers formed micelles composed of a hydrophobic core of poly(-caprolactone) (PCL) and a hydrophilic shell of poly(ethyl ethylene phosphate) (PEEP) in aqueous solution. The micelle morphology was spherical, determined by transmission electron microscopy. It was found that the size and critical micelle concentration values of the micelles depended on both hydrophobic PCL block length and PEEP hydrophilic block length. The in vitro degradation characteristics of the triblock copolymers were investigated in micellar form, showing that these copolymers were completely biodegradable under enzymatic catalysis of Pseudomonas lipase and phosphodiesterase I. These triblock copolymers were used for paclitaxel (PTX) encapsulation to demonstrate the potential in drug delivery. PTX was successfully loaded into the micelles, and the in vitro release profile was found to be correlative to the polymer composition. These biodegradable triblock copolymer micelles are potential as novel carriers for hydrophobic drug delivery.     

Formulation of anastrozole microparticles as biodegradable anticancer drug carriers

The purpose of this study was to develop poly(d,1-lactic-coglycolic acid) (PLGA)-based anastrozole microparticles for treatment of breast cancer. An emulsion/extraction method was used to prepare anastrozole sustained-release PLGA-based biodegradable microspheres. Gas chromatography with mass spectroscopy detection was used for the quantitation of the drug throughout the studies. Microparticles were formulated and characterized in terms of encapsulation efficiency, particle size distribution, surface morphology, and drug release profile. Preparative variables such as concentrations of stabilizer, drug-polymer ratio polymer viscosity, stirring rate, and ratio of internal to external phases were found to be important factors for the preparation of anastrozole-loaded PLGA microparticles. Fourier transform infrared with attenuated total reflectance (FTIR-ATR) analysis and differential scanning calorimetry (DSC) were employed to determine any interactions between drug and polymer. An attempt was made to fit the data to various dissolution kinetics models for multiparticulate systems, including the zero order, first order, square root of time kinetics, and biphasic models. The FTIR-ATR studies revealed no chemical interaction between the drug and the polymer. DSC results indicated that the anastrozole trapped in the microspheres existed in an amorphous or disordered-crystalline status in the polymer matrix. The highest correlation coefficients were obtained for the Higuchi model, suggesting a diffusion mechanism for the drug release. The results demonstrated that anastrozole microparticles with PLGA could be an alternative delivery method for the long-term treatment of breast cancer. Published: July 21, 2006     

How autocatalysis accelerates drug release from PLGA-based microparticles: a quantitative treatment

The major aim of this study was to better understand the importance of autocatalysis in poly(lactic-co-glycolic acid) (PLGA)-based microparticles used as controlled drug delivery systems. Upon contact with biological fluids, PLGA is degraded into shorter chain alcohols and acids. An accumulation of the latter can lead to significant drops in micro-pH and subsequent accelerated polymer degradation. The system size, determining the diffusion path lengths, plays a crucial role for the occurrence/absence of autocatalytic effects. Using an oil-in-water solvent-extraction/evaporation process, different-sized drug-free and drug-loaded, PLGA-based microparticles were prepared and physicochemically characterized (SEM, DSC, SEC, optical microscopy, and UV-spectrophotometry) before and upon exposure to simulated biological fluids. Based on these experimental results, an adequate mathematical theory was developed describing the dominating mass transfer processes and chemical reactions. Importantly, a quantitative relationship could be established between the dimension of the device and the resulting drug release patterns, taking the effects of autocatalysis into account.