PLGA microdevices for retinoids sustained release produced by supercritical emulsion extraction: Continuous versus batch operation layouts

Retinyl acetate (RA) was selected as a model compound to be entrapped in poly(lactic‐co‐glycolic)acid (PLGA) microspheres using supercritical emulsion extraction (SEE). Several oil‐in‐water emulsions prepared using acetone and aqueous glycerol (80% glycerol, 20% water) were processed using supercritical carbon dioxide (SC‐CO₂) to extract the oily phase and to induce microspheres formation. The characteristics of the microspheres obtained by conventional liquid emulsion extraction and SEE were also compared: SEE produced spherical and free flowing microspheres, whereas the conventional liquid–liquid extraction showed large intraparticles aggregation. Emulsion extraction by SC‐CO₂ technology was tested using two different operation layouts: batch (SEE‐B) and continuous (SEE‐C). SEE‐C was performed using a packed tower to produce emulsion/SC‐CO₂ contact in countercurrent mode, allowing higher microsphere recovery and process efficiencies. Operating at 80 bar and 36°C, SEE‐C produced PLGA/RA microspheres with mean sizes between 3.3 and 4.5 μm with an excellent encapsulation efficiency of 80%–90%. Almost all the drug was released in about 6 days when charged at 2.7% (w/w), whereas only 40% and 10% of RA were released in the same period of time when the charge was 5.2% and 8.8% (w/w), respectively. Release kinetics constants calculated from the experimental data, using a mathematical model, were also proposed and discussed. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4357–4367, 2011     

Alendronate PLGA microspheres with high loading efficiency for dental applications

Purpose: Alendronate sodium, used systemically as a bone protective agent, proved to also be effective locally in various dental bone applications. Development of alendronate-loaded microspheres with high loading efficiency for such applications would be greatly challenged by the hydrophilicity and low MW of the drug. The aim of this study was to incorporate alendronate sodium, into poly (lactide-co-glycolide) (PLGA) microspheres (MS) with high loading efficiency.

Methods: Three multiple emulsion methods: water-in-oil-in-water (W/O/W), water-in-oil-in-oil (W/O₁/O₂) and solid-in-oil-in-oil (S/O₁/O₂) were tested. In addition to entrapment efficiency, MS were characterized for surface morphology, particle size, in vitro drug release and in vitro degradation of the polymer matrix. Alendronate microspheres with maximum drug loading and good overall in vitro performance were obtained using the W/O₁/O₂ emulsion technique.

Results: Drug release from the microspheres exhibited a triphasic release pattern over a period of 13 days, the last fast release phase being associated with more rapid degradation of the PLGA matrix.

Conclusions: Biocompatible, biodegradable PLGA microspheres incorporating alendronate sodium with high loading efficiency obtained in this study may offer promise as a delivery system for bisphosphonates in dental and probably other clinical applications.     

Alendronate PLGA microspheres with high loading efficiency for dental applications

PURPOSE: Alendronate sodium, used systemically as a bone protective agent, proved to also be effective locally in various dental bone applications. Development of alendronate-loaded microspheres with high loading efficiency for such applications would be greatly challenged by the hydrophilicity and low MW of the drug. The aim of this study was to incorporate alendronate sodium, into poly (lactide-co-glycolide) (PLGA) microspheres (MS) with high loading efficiency. METHODS: Three multiple emulsion methods: water-in-oil-in-water (W/O/W), water-in-oil-in-oil (W/O(1)/O(2)) and solid-in-oil-in-oil (S/O(1)/O(2)) were tested. In addition to entrapment efficiency, MS were characterized for surface morphology, particle size, in vitro drug release and in vitro degradation of the polymer matrix. Alendronate microspheres with maximum drug loading and good overall in vitro performance were obtained using the W/O(1)/O(2) emulsion technique. RESULTS: Drug release from the microspheres exhibited a triphasic release pattern over a period of 13 days, the last fast release phase being associated with more rapid degradation of the PLGA matrix. CONCLUSIONS: Biocompatible, biodegradable PLGA microspheres incorporating alendronate sodium with high loading efficiency obtained in this study may offer promise as a delivery system for bisphosphonates in dental and probably other clinical applications.     

Protein loaded biodegradable microspheres based on PLGA-protein bioconjugates.

Biodegradable poly(D,L-lactic-co-glycolic acid) (PLGA) was chemically conjugated to lysozyme, a model protein drug, by coupling a terminal carboxylic acid in PLGA with primary amine groups present in lysozyme. The conjugation was carried out in dimethylsulphoxide (DMSO) by using carbodiimide as a coupling agent. The PLGA-lysozyme conjugate, dissolved in a co-solvent system of DMSO and methylene chloride, was directly formulated into microspheres by an oil-in-water (O/W) single emulsion solvent evaporation technique. Morphological characteristics of the resultant microspheres, loading efficiencies, and protein release behaviours with protein instability problems were investigated in comparison with those of the microspheres prepared by water-in-oil-water (W/O/W) double emulsion and O/W single emulsion techniques which employed PLGA with unconjugated lysozyme for the formulation.     

Particle size and loading efficiency of poly(D,L-lactic-coglycolic acid) multiphase microspheres containing water soluble substances prepared by the hydrous and anhydrous solvent evaporation methods

PLGA multiphase microspheres were prepared by the multiple emulsion solvent evaporation method using acetonitrile as the polymer solvent and mineral oil as the evaporation medium. The preparation process was further developed in the present study to reduce the particle size and to increase the loading capacity of brilliant blue, bovine serum albumin (BSA) and tumour necrosis factor-alpha (TNF-alpha) which were used as water soluble model drug substances. Sorbitan sesqui-oleate (SO-15EX), present at the 1% w/w level in the evaporation medium, prevented agglomeration of the microspheres containing a solid-in-oil (S/O) suspension as the core phase. This S/O suspension core provided significantly higher loading efficiency of the proteins to the W/O emulsion core. The W/O emulsion system resulted in agglomeration of the protein-loaded microspheres and the loading efficiency decreased significantly. When brilliant blue was included as the model compound, the loading efficiencies were not influenced by the core type. Heavy mineral oil was employed to stabilize the dispersed unhardened microspheres rather than light mineral oil that was reported previously. This anhydrous emulsion system employing the S/O suspension core and containing a dispersion of TNF-alpha enabled the encapsulation of this protein without loss of activity. It was concluded that the anhydrous emulsion system is asuitable approach toprepare multiple microspheres as an alternative to the W/O emulsion system, especially when solvent sensitive proteins are incorporated into the microspheres.     

Sustained release of a water-soluble GP IIb/IIIa antagonist from copoly(dl-lactic/glycolic)acid microspheres

Sustained release of TAK-029 [4-(4-amidinobenzoylglycyl)-3-methoxycarbonyl-2-oxopiperazine-l-acetic acid], a glycoprotein (GP) IIb/IIIa antagonist, from injectable microspheres was achieved by a W/O/W emulsion solvent evaporation technique using copoly(d-lactic/glycolic)acid (PLGA). Entrapment of the drug into microspheres increased with addition of sodium chloride into an external aqueous polyvinyl alcohol solution. Addition of l-arginine to an internal water phase dose-dependently reduced initial burst of the drug from the microspheres in vitro and in vivo, probably by forming hydrophobic diffusion barriers with rigid inner structure and increased glass transition temperature (T_g). Microspheres obtained using sodium chloride and l-arginine demonstrated sustained plasma levels of TAK-029 for 3 weeks after subcutaneous injection in rats, while causing a slight increase of its plasma levels in 2–3 weeks.     

Selection of the solvent system for the preparation of poly(d,l-lactic-co-glycolic acid) microspheres containing tumor necrosis factor-alpha (TNF-α)

Dichloromethane (DCM) and acetonitrile (ACN) are the most commonly used solvents for polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA). In order to select a suitable solvent system for the preparation of PLGA microspheres containing tumor necrosis factor-alpha (TNF-α), the stability of TNF-α when mixed with DCM and ACN under various phase conditions was investigated. When the TNF-α solution was emulsified into DCM to form a W/O emulsion prior to solvent evaporation using the W/O/W technique, a significant loss in activity of TNF-α was found. When the TNF-α was dispersed as a dry powder in the DCM phase, the protein was inactivated due to immediate hydration under the conditions of the solid/O/W system. Since TNF-α also was inactivated in a buffered saline containing ACN, the stability of the protein in microspheres prepared from an anhydrous solvent system was studied using ACN as the polymer solvent. Multiphase microspheres prepared by an anhydrous multiple emulsion process had a significantly higher loading efficiency of intact TNF-α than conventional matrix-type microspheres prepared by an anhydrous method using TNF-α powder and ACN.     

Sterilized ibuprofen-loaded poly(D,L-lactide-co-glycolide) microspheres for intra-articular administration: effect of γ-irradiation and storage

The aim of this study was to prepare and characterize a controlled-release system (microspheres) loaded with ibuprofen, for intra-articular administration, to extend its anti-inflammatory effect in the knee joint cavity. Among the bioresorbable polymers employed, poly(D,L-lactic-co-glycolic) acid (PLGA) (13?137?Da) was chosen because of its high biocompatiblity. Microspheres were produced by the solvent evaporation process from an O/W emulsion. Labrafil M 1944 CS was included in the formulation as an additive in order to modulate the release rate of the non-steroidal anti-inflammatory drug (NSAID). Once prepared, the microspheres were sobre-sterilized by γ-irradiation. The effect of the irradiation dose (25?kGy) exposure, at low temperature, on the formulation was evaluated. The sterilization procedure employed did not alter the physico-chemical characteristics of the formulation. Dissolution profiles of formulations behaved similarly and overlapped (f₂?=?87.23, f₁?=?4.2) before and after sterilization. Size Exclusion Chromatography (SEC) revealed no significant changes in the polymer molecular weight. Additionally, a stability study of the sterilized formulation was carried out using microsphere storage conditions of 4°C in a vacuum desiccator for 1 year. The results obtained after storing the sterilized microspheres show no significant alterations in the ibuprofen release rate (f₂?=?85.06, f₁?=?4.32) or in the molecular weight of the PLGA (12?957?Da). The employment of low molecular weight PLGA polymers resulted as advantageous, due to the practical absence of degradation after gamma irradiation (25?kGy) exposure at low temperature.     

Microencapsulation of PEGylated Adenovirus within PLGA Microspheres for Enhanced Stability and Gene Transfection Efficiency

Purpose Green fluorescent protein (GFP) encoding adenovirus (ADV) was surface modified with polyethylene glycol (PEG) for microencapsulation within poly(lactic-co-glycolic acid) (PLGA) microspheres with the aim of improving stability and gene transfection activity. Methods A series of PEGylated ADV (PEG-ADV) with different PEG seeding densities on the viral surface was prepared and the GFP expression efficiency of each PEG-ADV in the series determined. The physical stabilities of naked ADV and PEG-ADV were comparatively evaluated by exerting a high shear homogenization process or by exposure to low pH. Naked ADV or PEG-ADV was microencapsulated within PLGA microspheres using a water-in-oil-in-water (W/O/W) double emulsion and solvent evaporation method. In vitro cumulative ADV and PEG-ADV release profiles from PLGA microspheres were determined over a 10-day period. GFP transfection efficiencies into HeLa cells were quantified, and the relative extent of the immune response for ADV and PEG-ADV encapsulated within PLGA microspheres was analyzed using macrophage cells. Results The physical stability of PEGylated ADV was greatly enhanced relative to that of naked ADV under the simulated W/O/W formulation conditions, such as exposure to an aqueous/organic interface during high shear-stressed homogenization. PEG-ADV was also more stable than ADV at low pH. ADV and PEG-AD were both released from PLGA microspheres similarly in a sustained fashion. However, when the ADV and PEG-ADV encapsulated microspheres transfected into HeLa cells, PEG-ADV microspheres demonstrated a higher GFP gene transfection efficiency than ADV microspheres. The PEG-ADV microspheres also exhibited a reduced extent of innate immune response for macrophage cells. Conclusions PEGylated ADV could be more safely microencapsulated within PLGA microspheres than naked ADV due to their enhanced physical stability under the harsh formulation conditions and acidic microenvironmental conditions of the microsphere, thereby increasing gene transfection efficiency.     

Influence of the primary emulsification procedure on the characteristics of small protein-loaded PLGA microparticles for antigen delivery

Microparticles prepared from poly(lactic-co-glycolic acid) (PLGA) using a W₁/O/W₂ double emulsion solvent evaporation method are suitable vehicles for the delivery of proteins to antigen presenting cells, e.g. dendritic cells. In this study, the influence of different techniques for the preparation of the primary W₁/O emulsion was investigated with respect to the protein localization within the microparticles, morphological characteristics of these particles, protein burst release and the native state of the released protein. Bovine serum albumin bearing fluorescein isothiocyanate (FITC-BSA) was used as model protein. A static micromixer was applied for the preparation of the W₁/O/W₂ double emulsion. Employing a rotor-stator homogenizer (Ultra-Turrax®) for primary emulsification, microcapsules with a high burst release were produced, because nearly all FITC-BSA was attached to the outside of the particle wall. Using a high pressure homogenizer or an ultrasonic procedure resulted in the formation of microspheres with homogeneous protein distribution and a reduced burst release.     

Effects of solvent selection and fabrication method on the characteristics of biodegradable poly(lactide-co-glycolide) microspheres containing ovalbumin

To demonstrate the effect of formulation conditions on the controlled release of protein from poly(lactide-co-glycolide) (PLGA) microspheres for use as a parenteral drug carrier, ovalbumin (OVA) microspheres were prepared using the W/O/W multiple emulsion solvent evaporation and extraction method. Methylene chloride or ethyl acetate was applied as an organic phase and poly(vinyl alcohol) as a secondary emulsion stabilizer. Low loading efficiencies of less than 20% were observed and the in vitro release of OVA showed a burst effect in all batches of different microspheres, followed by a gradual release over the next 6 weeks. Formulation processes affected the size and morphology, drug content, and the controlled release of OVA from PLGA microspheres.     

Heparin Immobilized Porous PLGA Microspheres for Angiogenic Growth Factor Delivery

Purpose Heparin immobilized porous poly(d,l-lactic-co-glycolic acid) (PLGA) microspheres were prepared for sustained release of basic fibroblast growth factor (bFGF) to induce angiogenesis.Materials and Methods Porous PLGA microspheres having primary amine groups on the surface were prepared using an oil-in-water (O/W) single emulsion method using Pluronic F-127 as an extractable porogen. Heparin was surface immobilized via covalent conjugation. bFGF was loaded into the heparin functionalized (PLGA-heparin) microspheres by a simple dipping method. The bFGF loaded PLGA-heparin microspheres were tested for in vitro release and in vivo angiogenic activity.Results PLGA microspheres with an open-porous structure were formed. The amount of conjugated amine group onto the microspheres was 1.93 ± 0.01 nmol/mg-microspheres, while the amount of heparin was 95.8 pmol/mg-microspheres. PLGA-heparin microspheres released out bFGF in a more sustained manner with a smaller extent of initial burst than PLGA microspheres, indicating that surface immobilized heparin controlled the release rate of bFGF. Subcutaneous implantation of bFGF loaded PLGA-heparin microspheres in mice significantly induced the formation of new vascular microvessels.Conclusions PLGA microspheres with an open porous structure allowed significant amount of heparin immobilization and bFGF loading. bFGF loaded PLGA-HP microspheres showed sustained release profiles of bFGF in vitro, demonstrating reversible and specific binding of bFGF to immobilized heparin. They also induced local angiogenesis in vivo in an animal model.     

Utilization of an Amorphous Form of a Water-Soluble GPIIb/IIIa Antagonist for Controlled Release from Biodegradable Microspheres

Purpose. We prepared injectable microspheres for controlled release of TAK-029, a water-soluble GPIIb/IIIa antagonist and discussed the characteristics of controlled release from microspheres. Methods. Copoly(dl-lactic/glycolic)acid (PLGA) microspheres were used for controlled release of TAK-029 [4-(4-amidinobenzoylglycyl)-3-methoxycarbonyl-2-oxopiperazine-l-acetic acid]. They were prepared with a solid-in-oil-in-water (S/O/W) emulsion solvent evaporation technique using either a crystalline form or an amorphous form of the drug. Results. An amorphous form of TAK-029 gave more homogeneous S/O dispersion and higher viscosity than its crystalline form when added to dichloromethane solution of PLGA, resulting in a high drug entrapment into microspheres and a well-controlled release of the drug. Additions of sodium chloride into an external aqueous phase and L-arginine into an oil phase also increased entrapment of the drug, and reduced initial burst of the drug from the microspheres. The micro-spheres demonstrated a desirable plasma level profile in therapeutic range (20–100 ng/ml) for 3 weeks in rats after single subcutaneous injection. Conclusions. A well-controlled release of TAK-029, a water-soluble neutral drug, with small initial burst was achieved by utilizing its amorphous form as a result of possible interaction with PLGA and L-arginine.     

Preparation of ONO-1301-loaded poly(lactide-co-glycolide) microspheres and their effect on nerve conduction velocity

Objectives The aim of this study was to prepare poly(lactide‐co‐glycolide) (PLGA) microspheres containing ONO‐1301, a novel long‐acting prostacyclin agonist with thromboxane synthase inhibitory activity, with 10% of drug released in the initial burst and a sustained‐release period of about 3 weeks after administration. The effect of PLGA type (molecular weight and the lactide/glycolide (L/G) ratio in PLGA), the preparative conditions and the particle size on the in‐vitro release profile were examined. The effect of optimized ONO‐1301‐loaded PLGA microspheres on delayed nerve condition velocity (NCV) was investigated in streptozotocin (STZ) induced diabetic rats. Methods ONO‐1301 PLGA microspheres were produced by the oil‐in‐water emulsion/solvent evaporation method. Drug release from the prepared microspheres was monitored in phosphate buffer solution at 37°C for 4 weeks by high‐performance liquid chromatography. The in‐vivo study was performed in STZ‐induced diabetic rats treated with optimized ONO‐1301 PLGA microspheres (10 mg/kg by intramuscular or subcutaneous injection every 3 weeks). NCV was measured in the thigh 4, 8 and 12 weeks after induction. Key findings The molecular weights of PLGA, the L/G ratio in PLGA and the particle diameter all affected the length of the sustained release period. Drug release from microspheres containing PLGA 5050 (MW 50 000, L/G 50/50), with an average diameter of about 30 µm, could be sustained for 3 weeks in vitro. In the in‐vivo study, delayed NCV was significantly increased by treatment with these ONO‐1301 PLGA microspheres once every 3 weeks, in comparison with vehicle only. Conclusion Local intramuscular injection of sustained‐release ONO‐1301 PLGA microspheres improved delayed NCV in STZ‐induced diabetic rats.     

Sustained release of low molecular weight heparin from PLGA microspheres prepared by a solid-in-oil-in-water emulsion method

Biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres for the sustained release of low molecular weight heparin (LMWH) were prepared by a soild-in-oil-in-water (s/o/w) emulsion method. Prior to encapsulation, the LMWH micro-particles were fabricated by a modified freezing-induced phase separation method. The micro-particles were subsequently encapsulated into PLGA microspheres. Process optimization revealed that the NaCl concentration in the outer phase of s/o/w emulsion played a critical role in determining the properties of the microspheres. When the NaCl concentration increased from 0% to 5%, the encapsulation efficiency significantly increased from 51.5% to 76.8%. The initial burst release also decreased from 37.3% to 12.4%. In vitro release tests showed that LMWH released from PLGA microspheres in a sustained manner for about 14 days. Single injection of LMWH-loaded PLGA microspheres into rabbits resulted in an elevation of an anti-factor Xa activity for about 6 days. Furthermore, the integrity of the encapsulated LMWH was preserved during encapsulation process.     

Preparation of multi-phase microspheres of poly(D,L-lactic acid) and poly(D,L-lactic-co-glycolic acid) containing a W/O emulsion by a multiple emulsion solvent evaporation technique.

Multi-phase microspheres of poly(D,L-lactic acid) (PLA) or poly(D,L-lactic-co-glycolic acid) (PLGA) containing a water-in-oil (W/O) emulsion were prepared by a multiple emulsion solvent evaporation technique. Acetonitrile was used as the solvent for the polymers and light mineral oil as the dispersion medium for the encapsulation procedure. Process and formulation parameters to optimize the microencapsulation of a W/O emulsion containing water-soluble drugs were investigated. Drug loading efficiencies of 80-100 per cent were obtained under specific preparative conditions. The drug loading efficiency in the microspheres was dependent upon the ratio of the W/O emulsion to polymer and the concentration of surfactant in the mineral oil. Compared to conventional microspheres, in which fine drug particles are homogeneously dispersed in the polymer beads, the multi-phase microspheres permit the higher encapsulation efficiency of water-soluble drugs and eliminate partitioning into the polymer-acetonitrile phase which results in low encapsulation efficiency with conventional solvent evaporation techniques.     

Dissolution,Stability, and Morphological Properties of Conventional and Multiphase Poly(DL-Lactic-Co-Glycolic Acid) Microspheres Containing Water-Soluble Compounds

Multiphase microspheres of poly(DL-lactic-co-glycolic acid) (PLGA) containing water-soluble compounds were prepared by a multiple-emulsion solvent evaporation technique. These compounds were dissolved in the aqueous phase of a W/O emulsion with soybean oil as the oil phase. This emulsion was dispersed throughout the matrix of the microsphere. The morphological properties of the multiphase microspheres during in vitro dissolution studies were compared to those of conventional microspheres prepared from the same polymer. Drug release from the multiphase microspheres was characterized by an initial uniform release for the first 20 days followed by a more rapid phase of drug release. Chlorpheniramine maleate (CPM) and brilliant blue (BB) were the soluble model compounds investigated. The release rates of these agents from the multiphase microspheres were independent of the drug content in the microspheres. The release profiles from the conventional microspheres showed a lag time of 10 and 16 days for the CPM and BB, respectively. The dissolution rate of the model soluble compounds from the conventional microspheres increased as the loading in the microspheres increased. No differences in the degradation rate of the PLGA from the multiphase and the conventional microspheres were seen during the dissolution studies.     

Literature Alerts

Abstract

The aim of this work was to develop sustained local release systems for radioiodinated iodo-2′-deoxyuridine (¹²⁵IUdR) from biodegradable polymeric microspheres to facilitate the controlled delivery of ¹²⁵IUdR to brain tumours. The selective uptake of IUdR into the cell nucleus results in cell disruption over the short range of the low energy Auger electrons. The biodegradable micro-spheres can be precisely implanted in the brain by stereotactic techniques and the IUdR within the microspheres is protected from degradation and thus a sustained source of radiolabelled IUdR is available in the vicinity of the residual tumour cells. Poly(lactic-co-glycolic acid), PLGA (85:15), microspheres containing cold IUdR and the Auger-electron emitter ¹²⁵I, as ¹²⁵IUdR were prepared using the O/W, O/O and W/O/W emulsion-solvent evaporation methods. The W/O/W emulsion method was most effective in achieving good drug loading with the use of bovine plasma in the internal water phase. Also effective in improving the drug loading was the use of 20% acetone in the dichloromethane and the presence of Span 40 in the organic phase. Electrolytes (NaCl and IUdR) in the external acqueous phase also improved drug loading. After an initial rapid release from the microspheres, a sustained release was observed over 15 days for the 'cold' IUdR. The sustained release portions of the release curves showed Higuchi (t^1/2), diffusion controlled release kinetics. The radiolabelled IUdR microspheres showed a burst release effect of 30–40% followed by a sustained release over 35 days.     

Influence of drying processes on the structures,morphology and in vitro release profiles of risperidone-loaded PLGA microspheres

The purpose of this study was to investigate the influences of drying methods on the risperidone (RIS) release profiles of RIS-loaded PLGA microspheres. These microspheres were fabricated with an O/W emulsion solvent evaporation method. The wet microspheres were dried with freeze drying and vacuum drying methods. The microspheres were mono-dispersed spheres with an average diameter of 100?μm. Studies found that drying methods had great influence on the porosity, morphology, and release profiles of RIS-loaded PLGA microspheres. Specifically, the freeze-dried microspheres had higher porosity (78.46?±?1.64%) than those vacuum-dried ones (52.45?±?2.68%), and they showed higher RIS release rates (p?<?0.05). In the accelerated release tests (45?°C), these microspheres dried under the pressures of 700?mmHg and 200?mmHg gave faster release rates than those ones dried under the pressure of 450?mmHg. Importantly, the accelerated release test (45?°C) had a high correlation with the real-time test (37?°C) (R²?>?0.99). These studies exhibited a significance in the precise preparation of RIS-loaded PLGA microspheres.     

蛋白质/多肽药物聚乳酸/乳酸-羟基乙酸共聚物微球研究进展

缓释微粒给药系统是蛋白质/多肽药物传输系统的一个重要研究方向，聚乳酸和乳酸-羟基乙酸共聚物是制备缓释微球最常用的载体材料。蛋白质/多肽药物聚乳酸/乳酸-羟基乙酸共聚物微球常用的制备方法包括溶剂萃取/挥发法(复乳法)、相分离法和喷雾干燥法。本文总结了微球制备中面临的难点如蛋白质/多肽药物稳定性、包封率、药物突释和药物吸附等问题，并综述了保持药物结构稳定性和生物活性、提高包封率、改善药物释放曲线等微球制备方法和进展。