Release kinetics of fluphenazine from biodegradable microspheres.

Fluphenazine-loaded microspheres were prepared using biodegradable lactide and lactide-co-glycolide polymers. Sustained release of fluphenazine was achieved with fluphenazine loadings of up to 30 per cent in both the lactide and lactide-co-glycolide polymers. Fluphenazine release from microspheres was found to increase with increasing drug loading and was most rapid from the poly-L-lactide-co-glycolide microspheres. The release profiles showed a 'lag' period followed by an accelerating release phase and in some cases a decay period, i.e. the release profiles were sigmoidal and fitted the Prout-Tomkins equation (Prout and Tompkins 1944). Consequently it was considered that polymer degradation, the primary rate-determining step controlling drug release, occurred by a mechanism involving propagation of active sites, drug release reflecting the spread of this degradation throughout the polymer.     

Comparative assessment of in vitro release kinetics of calcitonin polypeptide from biodegradable microspheres

The objective of our study was to compare the in vitro release kinetics of a sustained-release injectable microsphere formulation of the polypeptide drug, calcitonin (CT), to optimize the characteristics of drug release from poly-(lactide-co-glycolide) (PLGA) copolymer biodegradable microspheres. A modified solvent evaporation and double emulsion technique was used to prepare the microspheres. Release kinetic studies were carried out in silanized tubes and dialysis bags, whereby microspheres were suspended and incubated in phosphate buffered saline, sampled at fixed intervals, and analyzed for drug content using a modified Lowry protein assay procedure. An initial burst was observed whereby about 50% of the total dose of the drug was released from the microspheres within 24 hr and 75% within 3 days. This was followed by a period of slow release over a period of 3 weeks in which another 10-15% of drug was released. Drug release from the dialysis bags was more gradual, and 50% CT was released only after 4 days and 75% after 12 days of release. Scanning electron micrographs revealed spherical particles with channel-like structures and a porous surface after being suspended in an aqueous solution for 5 days. Differential scanning calorimetric studies revealed that CT was present as a mix of amorphous and crystalline forms within the microspheres. Overall, these studies demonstrated that sustained release of CT from PLGA microspheres over a 3-week period is feasible and that release of drug from dialysis bags was more predictable than from tubes.     

Optimizing double emulsion process to decrease the burst release of protein from biodegradable polymer microspheres

The process parameters such as the compositions of inner and outer aqueous phase and emulsification technique of the primary emulsion were optimized to decrease the burst release of BSA from biodegradable polymer microspheres in double emulsion method. It was found that diminished burst release of -14% was achieved for the microspheres produced by formulations, where no phosphate was present in the inner water phase (non-buffered system). Primary emulsion made by probe sonication rather than homogenization or mechanical stirring led to microspheres with insignificant burst effect. Microspheres obtained using 0.1% aqueous Tween 80 solution as the outer aqueous phase, frequently exhibit reduced burst effect of 2.7%. Low microsphere yield (52.1%), however, was observed. Microsphere yield was, therefore, enhanced by addition of additive such as sodium chloride, glucose or mannitol into the outer aqueous phase. Decrease in BSA entrapment was observed in the presence of sodium chloride, but reduction in entrapment efficiency was observed in the case of glucose. Burst release increased from 2.7% to 9.5% or 3.4% as 2.5% sodium chloride or 7.5% glucose was added into the outer aqueous phase respectively. Marked burst release (>20%) was observed in the presence of additive of higher concentration independent of sodium chloride or glucose. As far as surfactant type was concerned, diminished burst was found when PVP or Tween 80 rather than PVA was utilized as the surfactant during microsphere preparation. In addition to PLGA, the copolymers of L-lactide (LLA) and dimethyl trimethylene carbonate (DTC) or trimethylene carbonate (TMC) were also evaluated. Insignificant burst effect was found for the microspheres composed of DTC or TMC copolymers.     

Comparative study of some biodegradable polymers on the entrapment efficiency and release behavior of etoposide from microspheres

Etoposide-loaded biodegradable microspheres of poly lactic-co-glycolide (PLGA) 50:50, PLGA 75:25, and polycaprolactone (PCL) were prepared by simple o/w emulsification solvent evaparation method and characterized by size analysis and microscopy. The influence of drug to polymer ratio on the entrapment of etoposide was studied. Of all the three types of microspheres, polycaprolactone microspheres (PCL MS) showed the highest entrapment efficiency (94.64%), followed by PLGA 75:25 microspheres (PLGA 75:25 MS) (88.64%) and PLGA 50:50 microspheres (PLGA 50:50 MS) (79.19%). The drug to polymer ratio of 1:20 gave the highest entrapment efficiency for all the three types of microspheres. The in vitro release of etoposide from the three microsphere formulations were studied in phosphate buffer pH 7.4 (pH 7.4 PB) containing 0.1% Tween 80. The microspheres showed an initial burst release, which was highest from the PLGA 50:50 MS and least from the PCL MS. PCL MS microspheres showed the lower and slow drug release than the remaining formulations. The release of etoposide from all the three microsphere formulations followed Higuchi's diffusion pattern. The microspheres in the dissolution medium for 28 days appeared irregular in shape and slightly fragmented.     

An analysis of first-order release kinetics from albumin microspheres.

Release rates from BSA microspheres prepared from various conditions are analysed using a previously reported equation expressing the first-order release rate constant. The permeability constants calculated applying the equation on experimental release rates are in good agreement with the constants measured from permeation studies using planar membrane, for various preparation conditions. It is shown that the equation expressing the first-order release rate constant is valid more extensively. The permeability constant varies depending on the preparation conditions, and the reason for variation is shown clearly to be the difference in degree of swelling of the polymer. It was found from regression analysis that there is relatively simple correlation between unknown parameters of the equation and the preparation conditions. Release rate constants can be calculated applying the equation on the known parameters and the estimated values of the unknown parameters from the correlation. Good agreement was found between the calculated values and experimental ones; therefore, at least as far as we examined here, the release rate constant of the microsphere can be estimated from the preparation conditions.     

Controlled release of drugs from injectable in situ formed biodegradable PLGA microspheres: effect of various formulation variables.

A novel in situ method for the preparation of injectable biodegradable poly(lactide-co-glycolide) (PLGA) microspheres for the controlled delivery of drugs is described here. A stable dispersion of PLGA microglobules ('premicrospheres' or 'embryonic microspheres') in a vehicle mixture on injection, comes in contact with water from aqueous buffer or physiological fluid, thereby hardening the microglobules into solid matrix type microparticles entrapping the drug (in situ formed microspheres). The drug is then released from these microspheres in a controlled fashion. The effect of the following formulation variables on the characteristics of the novel drug delivery system (NDDS) was investigated: (i) the concentrations of polyethylene glycol 400 (PEG 400), the encapsulated drug, and the hydrophilic excipient (mannitol); and (ii) the types of encapsulated drug (micromolecules and macromolecules such as protein) and vehicles (replacing triacetin and Miglyol 812 by triethyl citrate and soybean oil respectively). Also, the effect of formulation, process, and storage (15 days/4 degrees C) conditions on the physical stability of the encapsulated protein was evaluated. The in vitro drug release was enhanced with decrease in the PEG 400 concentration and increase in the drug and mannitol concentration. The drug release was retarded with increase in the molecular weight of the encapsulated drug. Substitution of triacetin by triethyl citrate and miglyol 812 by soybean oil resulted in variation in the release of the drug from the in situ formed microspheres. A preliminary investigation of the physical stability of the myoglobin revealed that the alpha-helical structure was unaffected by the formulation, process, and the storage conditions.     

Controlled release of anti-cocaine catalytic antibody from biodegradable polymer microspheres

Recent reports have shown that anti-cocaine catalytic monoclonal antibody 15A10 reduces the toxic effect of cocaine by increasing its breakdown to systemically inert products ecgonine methylester and benzoic acid. This study reports the microencapsulation of antibody 15A10 using biodegradable poly (lactic-glycolic) acid (PLGA) by double emulsion technique. Formulation parameters such as protein loading, polymer molecular weight and the presence of zinc carbonate were studied for their effects on in-vitro release of antibody from microspheres. The initial burst release was decreased by the reduction of the protein (as % of total ingredients) in the formulation. Although changing the polymer molecular weight did not cause a reduction in initial burst release, it was effective in improving the release rate. The inclusion of zinc carbonate in microsphere preparation resulted in increase in initial burst release. An in-vivo study in mice revealed the presence of antibody in blood up to ten days following subcutaneous injections. These data demonstrate a potential for a sustained-release formulation of monoclonal antibody 15A10 for treatment of cocaine addiction.     

Sustained release of protein from poly(ethylene glycol) incorporated amphiphilic comb like polymers

Amphiphilic comb like macromonomer containing hydrophilic poly(ethylene glycol) groups covalently linked to poly(hydromethyl siloxane) (PHMS) were prepared by hydrosilylation reaction. The epoxy reacting sites were introduced to this amphiphilic system by the reaction with allyl epoxy propyl ether (AEPE). Bovine serum albumin (BSA), a model protein drug was loaded to the PEG-PDMS system and very thin membranes were made from this macromonomer adopting solution casting technique. The in vitro protein release studies at various pH conditions showed a controlled release profile without exhibiting any initial burst. The control of the initial burst might be due to the strong linkages of the protein with the membrane and the aggregation of the protein at the surface. The morphology of the membrane before and after the protein release, and the mechanical strength were evaluated. The surface properties of the membrane were studied using the contact angle measurements.     

Effect of morphological properties on drug release from biodegradable microspheres]

The morphological properties of poly(beta-hydroxybutyric acid) (PHB) or poly(L-lactic acid) microspheres loading flomoxef sodium (FMOX) were investigated with regard to FMOX release. The release profiles of FMOX from the microspheres could be divided into two types, a sustained release type and a burst one. Two representative PHB microspheres, the release profiles of which were quite different from those of FMOX, were compared in detail from a morphological point of view. The shapes of their surfaces and sections were observed by using scanning electron microscopy (SEM), and FMOX distribution was analyzed by using electron probe microanalysis. The crystallinity of polymers was further measured by powder X-ray diffratometry. There was little difference in the FMOX distribution and their microscopic properties such as sphere size, specific surface area, shape of surface and section. In contrast, water penetration into the inside of the microspheres was found to be clearly different by use of cryogenic SEM. A significant difference was also observed in the crystallinity of polymers forming the microspheres. The release of FMOX from the microspheres was affected by the crystallinity of polymers forming the microspheres, and burst phenomena occurred in case the polymer was highly crystallized. It was speculated that the crystallization of polymer induced micro voids in the microspheres which functioned as channels for water penetration.     

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 30mum, 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 release of liposomes from biodegradable dextran microspheres: a novel delivery concept

PURPOSE: To design liposome-loaded microspheres, which release the liposomes in a time-controlled manner and in intact form. METHODS: Liposomes were encapsulated in biodegradable dextran-based microspheres, which were prepared using an aqueous two phase system consisting of poly(ethylene glycol) and methacrylated dextran. The effects of liposome size and membrane fluidity, microsphere water content, degree of methacrylate substitution, and type of dextran derivative used, on encapsulation efficiency, release, and integrity of the liposomes were investigated. RESULTS: Liposomes were entrapped in dextran-based microspheres quantitatively and with full preservation of their integrity. Liposomes with a low, as well as with a high membrane fluidity, were released from the microspheres in their intact form and with preservation of their size. Release kinetics depended only on the degradation rate of the microspheres. For rapidly degrading systems, pulsed release was observed and the time after which the pulse occurred (from 5 until 25 days) could be tailored by the gel characteristics such as initial water content, degree of methacrylate substitution, and type of hydrolytically sensitive spacer present in the cross-links. This delay time was not dependent on the size of the liposomes in the range studied (0.1-0.2 microm). Microspheres which degraded more slowly showed, after a certain delay time, sustained release of the liposomes extended up to 100 days. CONCLUSIONS: A novel drug delivery concept based on the encapsulation of liposomes in biodegradable dextran-based microspheres was designed. The system released the liposomes in intact form in a controlled way after a prolonged period of time.     

Simulation of drug release from biodegradable polymeric microspheres with bulk and surface erosions

New models are developed to account for the kinetics of drug release from porous, biodegradable polymeric microspheres under the schemes of bulk erosion and surface erosion of the polymer matrix, respectively. Three mechanisms of drug release, namely, drug diffusion, drug dissolution, and polymer erosion jointly govern the overall release process. For bulk erosion, the model incorporates an erosion term into the dissolution and diffusion equation and is solved numerically for various boundary conditions. Dissolution and erosion are defined in the model by introducing three equations which take into account the drug concentration in the liquid phase, virtual solid phase, and effective solid phase. For surface erosion, drug concentrations in liquid and solid phases are defined and a substitution is introduced to convert the moving-boundary problem to a fixed-boundary problem. The resulting differential equations are solved simultaneously to obtain the concentration profile in the liquid and solid phases, respectively. Numerical solutions are provided to illustrate the effects of drug dissolution constant, drug diffusion coefficient, and erosion rate constant. In general, increasing erosion rate, diffusivity, dissolution, and decreasing particle radius enhance the drug release rate. Predictions from the models are also compared with experimental data to verify their validity and possible improvements are proposed.     

Characterization of biodegradable poly(d,l-lactide-co-glycolide) polymers and microspheres

Characterization of biodegradable polymers used for controlled drug delivery is essential to ensure reproducibility of in vitro and in vivo performance. Selected characterization techniques established for poly(d,l-lactide-co-glycolide) (PLGA) copolymers included DSC to analyse thermal behavior, ¹³C-NMR to determine exact comonomer ratios and comonomer sequencing, cloud point titration to establish solubility, SEC to monitor molecular weight averages and polydispersity, SEM to observe surface morphology, BET gas adsorption to analyse surface area, tapped bulk density measurements to suggest internal pore structure and porosity and finally in vitro degradation to analyse degradation times and profiles. Comonomer ratios of 50:50 PLGAs were found to be closer to stated values for Boehringer Ingelheim polymers than for polymers from two other suppliers. Implementing such a characterization program for biodegradable polymers ensures the production of reproducible and reliable controlled drug delivery systems.     

局部麻醉药生物可降解缓释微球的研究进展

综述了局部麻醉药生物可降解缓释聚乳酸（PLA）微球的制备、工艺、体外释放、体内评价及相关影响因素;探讨微球制剂的载药、释药机制,为处方设计和水溶性水分子药物微球制剂的开发提供指导。     

Controlled release of huperzine A from biodegradable microspheres: In vitro and in vivo studies

This paper describes the effect on Sun Protection Factor (SPF) of the combination of inorganic and organic filters in sunscreen products as determined by an in vitro method. O/W emulsions containing inorganic filters, such as titanium dioxide and zinc oxide, combined with 18 EU-authorized UV-B organic filters were tested. SPF measurements were carried out using a spectrophotometer equipped with an integrating sphere.

This study observed a synergic effect when titanium dioxide was combined with either anisotriazine or octyldimethylPABA. The combination of zinc oxide with 11 UV-B organic filters also exhibited a similar synergy; however, the measured SPF was systematically lower than the protection factor achieved with titanium dioxide.     

Compressed biodegradable matrices of spray-dried PLGA microspheres for the modified release of ketoprofen

A spray-drying technique was used to prepare poly(lactide-co-glycolide) (PLGA) drug loaded microspheres. Ketoprofen was chosen as a model NSAID drug. The microspheres were characterized in terms of morphology, drug content and release behaviour. The spray-dried particles were subject to a direct compression process for the preparation of biodegradable matrix tablets. The spray-dried powders were found to have good compaction properties. Tablets were also prepared from a mixture of microspheres and microcrystalline cellulose, mannitol and hydroxypropylmethylcellulose or sodium alginate. The release of ketoprofen in phosphate buffer (pH 7.4) was significantly sustained, indicating the suitability of using tabletted spray-dried PLGA microspheres for controlled drug delivery. The results show that spray-dried PLGA particles have promising properties as direct compression and release controlling excipients in matrix tablets for oral administration.     

Influence of physico-chemical parameters on the release kinetics of ketoprofen from Poly(HEMA) crosslinked microspheres.

This report analyses the release of Ketoprofen from Poly(HEMA) microspheres crosslinked with EGDMA at different crosslinking ratios and loaded by soaking in saturated solutions of the drug. Release appears to be influenced by the dissolution of Ketoprofen in the hydrogel and it is strictly correlated with the diffusibility of the drug in the gelled matrix. The release rate of the drug in the hydrogel rises with the increase in the diffusional conductance and the release kinetics approaches zero order particularly at the higher values of the diffusional conductance.     

Streptomycin sulphate microspheres: dissolution rate studies and release kinetics. I

Targeting of drugs by microspheres, nanoparticles and liposomes is intended to increase the selective targeting to specific organs and to reduce their side effects. Streptomycin sulphate, a tuberculostatic antibiotic, is used as the active principle in this study. The aim is to accumulate the loaded microspheres in the lungs. The release of drugs associated with microsphere carriers has been found to be dependent on a number of factors. The aim of the investigation was to study the influence of the extent and nature of cross-linking, the type and the amount of the matrix material on the release characteristics of streptomycin sulphate microspheres. Human serum albumin and gelatin (Type B) were used as two different matrix materials. The crosslinking agents used were 2,3-butanedione and formaldehyde at different concentrations, and variable duration times. The in vitro release of streptomycin sulphate from microspheres is characteristically biphasic, with an initial fast release (the 'burst effect'), followed by a much slower release. Alteration in the characteristics of drug-loaded microspheres result in significant changes in the second (slow) phase of release. The release profiles of the different formulations has been studied and evaluated kinetically.     

Enzymatic synthesis and evaluation of new novel omega-pentadecalactone polymers for the production of biodegradable microspheres

Two novel co-polymers based on omega-pentadecalactone were enzymatically synthesized by a combination of ring-opening polymerization and polycondensation. Modified literature procedures enabled the production of the semi-crystalline materials with suitable molecular weights and melting characteristics. Microspheres were produced using an emulsion solvent evaporation method over a range of variables including manufacturing temperature, stirring speed and duration, surfactant concentration, continuous and disperse phase volume and polymer amount to establish how each variable affected the morphological characteristics of the microspheres. Results demonstrated that changes in emulsion viscosity influenced microsphere size. For polymer SH-L333, the microsphere surface was either smooth or porous depending on the manufacturing temperature used. For polymer SH-L334 the microsphere surface was rough or porous regardless of manufacturing temperature. This was possibly due to several combined factors including molecular weight and the greater hydrophilic nature of SH-L334. These new polymers have the potential for the manufacture of drug-loaded biodegradable microspheres for modified release drug delivery.     

Relationship between encapsulated drug particle size and initial release of recombinant human growth hormone from biodegradable microspheres

Protein microencapsulation in biodegradable polymers is a promising route to provide for sustained release. One important characteristic in this regard is the size of the particles encapsulated within the microspheres. In this investigation, we have employed spray-freeze drying to generate particles for encapsulation, and examined the effect of various atomization conditions. Conditions were identified resulting in minimization of the particle size for the therapeutic protein recombinant human growth hormone (rhGH). The polymer employed was poly(lactide-co-glycolide) (PLG). The greatest friability for the powder, and hence smallest particle size (e.g., sub-micron), was achieved as the mass flow ratio of atomization (air to liquid) was increased. Protein powders over a range of particle sizes were encapsulated in biodegradable microspheres using a cryogenic, non-aqueous process. The initial release (both in vitro and in vivo) from these batches was found to decrease with decreasing encapsulated protein particle size; these findings are consistent with the percolation theory. Hence, judicious selection of process variables to reduce the particle size of rhGH is one strategy that can be used to minimize initial release of the microencapsulated protein.