Relationship between internal phase volume and emulsion stability: the cetyl alcohol/stearyl alcohol system

The main objective of this study was to optimize the stability of cetyl alcohol/stearyl alcohol emulsions in terms of percentage of internal phase volume, emulsifier type and concentration, and amount of external phase (water). Creams (o/w emulsions) were prepared by phase inversion and physical properties as particle size of the internal phase, apparent viscosity, and sedimentation volume evaluated. Stability was performed at room temperature, 40 degrees C, 50 degrees C, and under stress conditions. High hydrophilic lipophilic balance (HLB) nonionic surfactants as tween 80, tween 20, Myrj 52, Brij 35, and low HLB span 60 were used as emulsifying agents. The percentage of internal phase components (cetyl alcohol and stearyl alcohol), percentage of emulsifying agents, and percentage of aqueous external phase were varied, and stability was investigated. As the level of emulsifier agent (tween 80 and span 60) increased from 3% to 15%, and the percent of the internal phase remained constant at 30%, the particle size of the internal phase decreased and the cream became more stable. Formulations of the same composition, but prepared using Myrj 53 and tween 20 as emulsifiers, showed a larger particle size than formulations prepared using tween 80 and Brij 35. As the level of the internal phase volume increased and consequently the amount of water decreased, emulsion viscosity increased. The best formulation containing 30% internal phase (50% cetyl alcohol, 35% stearyl alcohol), 15% emulsifying agents (tween 80/span 60 ratio of 3:1), and 70% water was selected, and effects of process temperature and cooling rate on emulsion stability investigated. This formulation was further investigated in terms of stability of a 1% hydrocortisone addition by varying the percentage (30%, 35%, 40%, and 45%) of internal phase and percentage of water (70%, 65%, 60%, and 55%). The best formulation contained 45% internal phase (22.5 g cetyl alcohol, 15.75 g stearyl alcohol, 15% emulsifying agent, which is equivalent to 5 g tween 80 and 1.7 g span 60), and 55% w/w water, was manufactured under different manufacturing processes. Emulsions prepared by homogenization at the beginning of the process of emulsification were stable with small internal phase particle diameter. This study demonstrates that at every cetyl alcohol/stearyl alcohol ratio there is a phase volume/emulsifier HLB ratio, which results in optimum stability.     

Process and formulation variables in the preparation of wax microparticles by a melt dispersion technique. II. W/O/W multiple emulsion technique for water-soluble drugs.

Pseudoephedrine HCl-carnauba wax microparticles were prepared by a multiple emulsion-melt dispersion technique. A heated aqueous drug solution was emulsified into the wax melt (W/O emulsion), followed by emulsification of this primary emulsion into a heated external aqueous phase (W/O/W emulsion). The drug-containing microparticles were formed after cooling and congealing of the wax phase. The encapsulation efficiencies were above 80 per cent and actual drug loadings close to 50 per cent were achieved. The surface of the microparticles had submicron pores and drug crystals were visible on cross-sections. The drug loading depended on the rate of cooling and the volume of the internal aqueous phase but was insensitive to the volume of the continuous phase. The drug release was much faster when compared to the release from polymeric microspheres.     

Preparation and characterization of poly(methyl methacrylate) - iron (III) oxide microparticles using a modified solvent evaporation method

At present, there is widespread interest in developing new, biocompatible microparticles made from polymers such as poly(methyl methacrylate) (PMMA) that could have applications ranging from diagnostic imaging to drug delivery. In these experiments, there were two primary objectives: (1) to stabilize a suspension of iron (III) oxide (alpha-Fe(2)O(3); mean diameter = 100 nm) nanoparticles in a solution of PMMA by using an emulsifier and different mixtures of two miscible solvents; and (2) to fabricate PMMA-alpha-Fe(2)O(3) microparticles by using an oil-in-water (o/w) solvent evaporation method. By accomplishing the first objective, it was hypothesized that the encapsulation efficiency of alpha-Fe(2)O(3) within PMMA microparticles would improve and induce the clustering of alpha-Fe(2)O(3) along the circumferential edges of the microparticles. Of the seven emulsifiers tested, Tween 80 was selected primarily for its hydrophilicity and its ability to produce a stable alpha-Fe(2)O(3) dispersion. As a result, 22 batches of microspheres (11 with Tween 80 and 11 without) were made and the solvent (dichloromethane) to co-solvent (ethyl acetate) ratios were varied. Particles made with solvent mixtures of >50% ethyl acetate (<50% dichloromethane) were more likely to be hollow and had larger mean volumetric particle diameters (>5 microns) than particles made with mixtures containing >50% dichloromethane. Particles made with Tween 80 were larger, more porous, and had alpha-Fe(2)O(3) aligned along the circumferential edges of the particles. The use of solvent mixtures did not improve the encapsulation efficiency of alpha-Fe(2)O(3) but the use of ethyl acetate helped to induce the clustering of alpha-Fe(2)O(3) along the peripheries of the microparticles.     

Process and formulation variables in the preparation of wax microparticles by a melt dispersion technique. II. W/O/W multiple emulsion technique for water-soluble drugs

Abstract

Pseudoephedrine HCl-carnauba wax microparticles were prepared by a multiple emulsion-melt dispersion technique. A heated aqueous drug solution was emulsified into the wax melt (W/O emulsion), followed by emulsification of this primary emulsion into a heated external aqueous phase (W/O/W emulsion). The drug-containing microparticles were formed after cooling and congealing of the wax phase. The encapsulation efficiencies were above 80 per cent and actual drug loadings close to 50 per cent were achieved. The surface of the microparticles had submicron pores and drug crystals were visible on cross-sections. The drug loading depended on the rate of cooling and the volume of the internal aqueous phase but was insensitive to the volume of the continuous phase. The drug release was much faster when compared to the release from polymeric microspheres.     

Alginate microspheres prepared by internal gelation: development and effect on insulin stability

Recombinant human insulin was encapsulated within alginate microspheres by the emulsification/internal gelation technique with the objective of preserving protein stability during encapsulation procedure. The influence of process and formulation parameters was evaluated on the morphology and encapsulation efficiency of insulin. The in vitro release of insulin from microspheres was studied under simulated gastrointestinal conditions and the in vivo activity of protein after processing was assessed by subcutaneous administration of extracted insulin from microspheres to streptozotocin-induced diabetic rats. Microspheres mean diameter, ranging from 21 to 287 microm, decreased with the internal phase ratio, emulsifier concentration, mixer rotational speed and increased with alginate concentration. Insulin encapsulation efficiency, near 75%, was not affected by emulsifier concentration, mixer rotational speed and zinc/insulin hexamer molar ratio but decreased either by increasing internal phase ratio and calcium/alginate mass ratio or by decreasing acid/calcium molar ratio and alginate concentration. A high insulin release, above 75%, was obtained at pH 1.2 and under simulated intestinal pH a complete dissolution of microspheres occurred. Extracted insulin from microspheres decreased hyperglycemia of diabetic rats proving to be bioactive and showing that encapsulation in alginate microspheres using the emulsification/internal gelation is an appropriate method for protein encapsulation.     

Thymosin-loaded enteric microspheres for oral administration: preparation and in vitro release studies

Thymosin, a water-soluble polypeptide compound, was encapsulated within enteric microspheres of acrylic acid resin II by modified oil in oil (o/o) emulsion solvent evaporation method. The mixture emulsifier composed of lecithin and Span 80 was critical to the formation of sphere-shaped thymosin microparticles. Optimizing process parameters, such as the volume ratio of organic solvent to water, initial drug feed and polymer concentration, resulted in high drug encapsulation efficiency of 89.7% (6% polymer concentration and 0.5% initial drug feed). In vitro release studies suggested that thymosin release from microspheres exhibited pH dependent profiles. For formulation with 6% polymer concentration and 0.5% initial drug feed, 68.7% thymosin was released within 4h in pH 6.8 PBS buffer, while only 6.5% was observed in acid medium.     

Formulation,development, and performance evaluation of metoclopramide HCl oro-dispersible sustained release tablet

The present study was undertaken to develop and evaluate an oro-dispersible, sustained release tablet of metoclopramide HCl. The technology was comprised of developing sustained release microparticles, and compression of resultant microspheres into a fast dispersible tablet by direct compression. The microspheres of metoclopramide HCl were prepared by an emulsification-solvent evaporation method using ethylcellulose as the matrix polymer. The prepared microspheres were evaluated for morphology, particle size, entrapment efficiency, and in vitro drug release characteristics. Scanning electron microscopy demonstrated spherical particles with a mean diameter of 81.27 ± 5.87 μm and the drug encapsulation efficiency was found to be 70.15 ± 3.06%. The process and formulation variables such as rotation speed, polymer concentration, and drug concentration influenced the drug encapsulation efficiency and in vitro drug release. Optimized microspheres were compressed into tablets which were comprised of metoclopramide HCl microspheres, 53% (w/v) of D-mannitol granules, 7% (w/w) of Polyplasdone XL 10, and 0.5% (w/w) of calcium stearate. The tablets demonstrated a hardness of 59 ± 3 N, friability of 0.21% and disintegration time of 27 ± 3 sec. The formulations were subjected to stability studies as per ICH guidelines and were found to be stable after a 6 month study. In vivo experiments conducted in rats demonstrated that a constant level of metoclopramide HCl in plasma could be maintained for up to 20 h at a suitable concentration for antiemetic activity. An appropriate combination of excipients made it possible to obtain orally disintegrating sustained release tablets of metoclopramide HCl using simple and conventional techniques.     

正交试验优选α-细辛脑明胶微球制备工艺

目的:优选α-细辛脑明胶微球的制备工艺。方法:采用乳化缩聚法制备α-细辛脑明胶微球,以明胶浓度、乳化剂用量、搅拌速度、投料比为考察因素,以载药量和包封率的综合评分为评价指标,采用正交试验优化工艺,并观察微球形态、粒径分布。结果:最优工艺为明胶浓度20%、乳化剂用量3.0mL、搅拌速度800r·min-1、投料比1∶2;所制得的微球球形圆整,平均载药量为3.98%,平均包封率为24.25%。结论:所选工艺稳定,各项质量指标良好。     

Reverse micelle-based microencapsulation of oxytetracycline hydrochloride into poly-d,l-lactide-co-glycolide microspheres

The objectives of this study were to solubilize oxytetracycline hydrochloride (HCl) in reverse micelles to prepare poly-d,l-lactide-co-glycolide (PLGA) microspheres and to explore parameters affecting its encapsulation efficiency. Oxytetracycline HCl was dissolved in the reverse micelles consisting of cetyltrimethylammonium bromide, water, and ethyl formate. A PLGA polymer was then dissolved in the reverse micellar solution, and a modified solvent quenching procedure was carried out to prepare PLGA microspheres. Encapsulation efficiencies of oxytetracycline HCl ranged from 2.3 ± 0.2 to 24.9 ± 4.6%, depending on experimental conditions. Important parameters affecting its encapsulation efficiency included the amounts of water used to prepare the reverse micelles and PLGA polymer. With regard to microsphere morphology, the reverse micellar process produced the microspheres with smooth and pore-free surfaces. In particular, their internal matrices did not possess hollow cavities that were frequently observed when a typical double emulsion technique was used to make microspheres. In summary, it was possible to encapsulate oxytetracycline HCl into PLGA microspheres via the ethyl formate-based reverse micellar technique. We also anticipate that the use of ethyl formate could avoid environmental and human toxicity issues associated with methylene chloride.     

Investigation on process parameters involved in preparation of poly-DL-lactide-poly(ethylene glycol) microspheres containing Leptospira Interrogans antigens

Block copolymer, poly-DL-lactide-poly(ethylene glycol) (PELA) with 11.5% of poly(ethylene glycol) (PEG) content was prepared by bulk ring-opening polymerization using stannous chloride as initiator. PELA microspheres with entrapped Leptospira Interrogans antigens, outer membrane protein (OMP) were elaborated by solvent extraction method based on the formation of multiple w/o/w emulsion, and the resulting microspheres were characterized with respect to particle size, OMP entrapment and morphology characteristics. The purpose of the present study is to perform the optimization of preparative parameters for OMP-loaded PELA micropsheres to control particle size and improve the OMP encapsulation efficiency. Of all the parameters investigated, the polymer concentration of organic phase and the external aqueous phase volume play major roles on particle size, while the organic phase volume, internal aqueous phase volume and the addition of surfactant into the internal aqueous phase display considerable effects on OMP loading efficiency. A small volume of internal aqueous phase and intermediate volumes of organic phase and external aqueous phase were favorable to achieve micropsheres with a size of 1-2 microns and high antigen encapsulation efficiency (70-80%). In vitro OMP release profiles from PELA microspheres consist of a small burst release followed by a gradual release phase. The OMP release rate shows some relations with the porous and water-swollen inner structure of the microspheres matrix. The presence of surfactant in microspheres accelerates OMP release, but the OMP entrapment within microspheres shows limited effects on the release profile.     

紫杉醇微球的处方工艺优化及其体外释放性研究

目的:优化紫杉醇聚[1,3-双(对羧基苯氧基)丙烷-癸二酸](P(CPP∶SA))微球处方工艺并评价其体外释放行为。方法:采用单乳化法制备药物缓释微球,以正交试验研究制备时搅拌速度(A)、处方中P(CPP∶SA)浓度(B)和乳化剂聚乙烯醇(PVA)的浓度(C)对微球包封率的影响;观察优化条件后制备的微球的外观形态,评价其体外释放行为。结果:当A为4000r.min-1、B为80mg.mL-1、C为1%时,所得微球形态完整,紫杉醇的包封率达到90%以上,体外持续释放30d,累积释药率达80%以上。结论:用优化条件制备的微球中紫杉醇的包封率高,并具有良好的体外缓释性。     

In vitro evaluation of gentamicin released from microparticles

In this study, the preparation, characterization and drug release behaviour of gentamicin (GM)-loaded poly(D,L-lactide-co-glycolide) microspheres are described. The microspheres were produced using a double emulsion solvent evaporation technique. All the microspheres preparation resulted in spherical shape and the mean diameter was 3 microm (for empty microspheres) and between 5 and 9 microm for microparticles loaded with GM. The encapsulation efficiency (EE) ranged from 3.4 to 90% depending on the formulation. Increasing the volume of the external aqueous phase, increased the EE. Encapsulation also depended on the pH value of the internal aqueous phase, the highest value was achieved when maintained the internal aqueous phase at pH 6, where GM was more soluble. Moreover, increasing nominal GM loading yielded lower encapsulation efficiencies. The release profiles of GM from microparticles resulted in biphasic patterns. After an initial burst, a continuous drug release was observed for up to 4 weeks. Finally, the formulations with higher loading released the drug faster.     

Effects of salt addition on the microencapsulation of proteins using W/O/W double emulsion technique

The influence of co-encapsulation of stabilizing additives together with BSA on microsphere characteristics using the modified water-in-oil-in-water emulsion solvent evaporation (W/O/W) method was investigated. For this purpose, poly(L-lactide) microspheres containing bovine serum albumin (BSA) were prepared. The morphology, porosity, specific surface area, particle size, encapsulation efficiency and kinetics of drug release of protein loaded microspheres were analysed in relation to the influence of co-encapsulated stabilizing additives such as electrolytes. High salt concentrations in the internal (W1) aqueous phase, often necessary to stabilize protein or antigen solutions, led to an increase in particle size, particle size distribution, porosity and specific surface area. Bulk density and encapsulation efficiency decreased. The release profile was characterized by a high initial burst due to the highly porous structure. Addition of salt to the external or continuous water phase (W2), however, stabilized the encapsulation process and, therefore, resulted in improved microsphere characteristics as a dense morphology, a reduced initial burst release, a drastically increased bulk density and encapsulation efficiency. Analysis of the specific surface area (BET) showed that the addition of salt to W2, regardless of the salt concentration in the W1 phase, decreased the surface area of the microspheres approximately 23-fold. Microsphere properties were influenced by salts additions through the osmotic pressure gradients between the two aqueous phases and the water flux during microsphere formation. Release profiles and encapsulation efficiencies correlated well with the porosity and the surface area of microspheres. Furthermore, the influence of a low molecular weight drug and different time-points of salt addition to W2 on microsphere characteristics were studied by encapsulation of acid orange 63 (AO63), confirming the results obtained with BSA. This study suggests that modification of the external water phase by adding salts is a simple and efficient method to encapsulate stabilized protein solution, with high encapsulation efficiency and good microsphere characteristics.     

Preparation and in vivo evaluation of parenteral metoclopramide-loaded poly(alkylcyanoacrylate) nanospheres in rats

The influence of co-encapsulation of stabilizing additives together with BSA on microsphere characteristics using the modified water-in-oil-in-water emulsion solvent evaporation (W/O/W) method was investigated. For this purpose, poly(L-lactide) microspheres containing bovine serun albumin (BSA) were prepared. The morphology, porosity, specific surface area, particle size, encapsulation efficiency and kinetics of drug release of protein loaded microspheres were analysed in relation to the influence of co-encapsulated stabilizing additives such as electrolytes. High salt concentrations in the internal (W1) aqueous phase, often necessary to stabilize protein or antigen solutions, led to an increase in particle size, particle size distribution, porosity and specific surface area. Bulk density and encapsulation efficiency decreased. The release profile was characterized by a high initial burst due to the highly porous structure. Addition of salt to the external or continuous water phase (W2), however, stabilized the encapsulation process and, therefore, resulted in improved microsphere characteristics as a dense morphology, a reduced initial burst release, a drastically increased bulk density and encapsulation efficiency. Analysis of the specific surface area (BET) showed that the addition of salt to W2, regardless of the salt concentration in the W1 phase, decreased the surface area of the microspheres approximately 23-fold. Microsphere properties were influenced by salts additions through the osmotic pressure gradients between the two aqueous phases and the water flux during microsphere formation. Release profiles and encapsulation efficiencies correlated well with the porosity and the surface area of microspheres. Furthermore, the influence of a low molecular weight drug and different time-points of salt addition to W2 on microsphere characteristics were studied by encapsulation of acid orange 63 (AO63), confirming the results obtained with BSA. This study suggests that modification of the external water phase by adding salts is a simple and efficient method to encapsulate stabilized protein solution, with high encapsulation efficiency and good microsphere characteristics.     

利福平丝素蛋白载药微球的制备及性能研究

目的通过测定利福平丝素蛋白微球的载药量、包封率及释放度,考察乳化转速、有机溶剂与丝素蛋白溶液比例,对微球的制备方法进行优化,筛选微球的最佳制备方法。方法采用乳化法制备利福平丝素蛋白微球,以不同转速、有机溶剂与丝素蛋白溶液不同比例分别制备利福平丝素蛋白微球,采用扫描电镜观察微球的形态,用紫外分光光度法测定微球的载药量、包封率及释放度,以形态、载药量、包封率及释放度为指标,筛选微球的最佳制备方法。在此基础上,采用最佳处方制备3批利福平丝素蛋白微球,对微球的形态、粒径、包封率、载药量和释放度进行考察。结果有机溶剂与丝素蛋白溶液体积比为4∶1、转速为200 r·min^-1时所得利福平丝素微球形态均匀,近似球形,载药量和包封率较高,所得载药微球有较好的缓释作用。以最佳处方制得微球载药量为66.1%±0.87%,包封率为87.80%±2.23%。结论有机溶剂与丝素蛋白溶液体积比为4∶1、转速为200 r·min^-1时载药量、包封率和释放度较好,故选择此处方为利福平丝素蛋白微球的最佳制备处方。     

Preparation and characterization of poly(methyl methacrylate)—iron (III) oxide microparticles using a modified solvent evaporation method

At present, there is widespread interest in developing new, biocompatible microparticles made from polymers such as poly(methyl methacrylate) (PMMA) that could have applications ranging from diagnostic imaging to drug delivery. In these experiments, there were two primary objectives: (1) to stabilize a suspension of iron (III) oxide (α-Fe₂O₃; mean diameter?=?100?nm) nanoparticles in a solution of PMMA by using an emulsifier and different mixtures of two miscible solvents; and (2) to fabricate PMMA-α-Fe₂O₃ microparticles by using an oil-in-water (o/w) solvent evaporation method. By accomplishing the first objective, it was hypothesized that the encapsulation efficiency of α-Fe₂O₃ within PMMA microparticles would improve and induce the clustering of α-Fe₂O₃ along the circumferential edges of the microparticles. Of the seven emulsifiers tested, Tween 80 was selected primarily for its hydrophilicity and its ability to produce a stable α-Fe₂O₃ dispersion. As a result, 22 batches of microspheres (11 with Tween 80 and 11 without) were made and the solvent (dichloromethane) to co-solvent (ethyl acetate) ratios were varied. Particles made with solvent mixtures of >50% ethyl acetate (<50% dichloromethane) were more likely to be hollow and had larger mean volumetric particle diameters (>5 microns) than particles made with mixtures containing >50% dichloromethane. Particles made with Tween 80 were larger, more porous, and had α-Fe₂O₃ aligned along the circumferential edges of the particles. The use of solvent mixtures did not improve the encapsulation efficiency of α-Fe₂O₃ but the use of ethyl acetate helped to induce the clustering of α-Fe₂O₃ along the peripheries of the microparticles.     

PLGA microcapsules with novel dimpled surfaces for pulmonary delivery of DNA

We describe the fabrication of DNA-loaded poly(lactic-co-glycolic acid) (PLGA) microcapsules with novel surface morphologies that will be of use in pulmonary delivery. Our approach was to examine surface morphology and DNA encapsulation efficiency as a function of primary emulsion stability; using two surfactant series based on hydrophile-lipophile balance and hydrophobe molecular weight. Hydrophilic non-ionic surfactants yielded the most stable water-in-dichloromethane emulsions (HLB values >8). These surfactants normally favor convex (o/w) interfacial curvatures and therefore this atypical behavior suggested a relatively high surfactant solvation in the dichloromethane 'oil' phase. This was consistent with the large fall in the glass transition temperature for microspheres prepared with Tween 20, which therefore efficiently penetrated the PLGA matrix and acted as a plasiticizer. Blends of Pluronic triblock copolymers performed poorly as water-in-dichloromethane emulsifiers, and were therefore used to generate hollow microspheres ('microcapsules') with low densities (0.24 g/cm(3)). Although the Pluronic-stabilized emulsions resulted in lower DNA loading (15-28%), microspheres (approximately 8 microm) with novel dimpled surfaces were fabricated. The depth and definition of the dimples was greatest for triblock copolymers with high MW hydrophobe blocks. By cascade impaction, the geometric mean weight diameter of the microcapsules was 3.43 microm, suggesting that they will be of interest as biodegradable pulmonary delivery vehicles.     

Evaluation of ibuprofen-loaded microspheres prepared from novel copolyesters

The utility of two novel linear random copolyesters to encapsulate and control the release of ibuprofen, via microspheres, was investigated. Various manufacturing parameters, including temperature, disperse phase volume and polymer:ibuprofen ratios were altered during the microsphere production. The effects of these changes on the morphological characteristics of the microspheres, yield, drug loading, encapsulation efficiency and drug release rates were examined. The diameter of the microspheres ranged from 36 to 89 microm and showed both smooth and ridged surfaces. Microsphere diameter was probably determined by the internal phase volume, while surface morphology was controlled by manufacturing temperature. Greater encapsulation efficiency was obtained by increasing the polymer:ibuprofen ratio and by reducing the internal phase volume. For all batches there was an initial burst drug release into phosphate buffer (pH 7.4) over the first 2-4h, which was followed by a much slower release rate over the remaining time period. Drug release rates during both these phases were dependent upon the amount and nature of the polymer in the microspheres, noting that the more hydrophilic polymer provided faster release rates. Ibuprofen solubility appeared to play a dominant role in controlling release, although both encapsulation efficiency and microsphere morphology were also contributing factors.     

Influence of an optimized non-ionic emulsifier blend on properties of oil-in-water emulsions.

Properties of oil-in-water emulsions containing non-ionic emulsifiers were evaluated in relation to nature of the dispersed phase, emulsifier composition and processing parameters. Particle size of mineral oil (hydrocarbons)-in-water emulsions was independent of the HLB of an optimized emulsifier blend, whereas, the particle size of olive oil (triglycerides)-in-water emulsions was the smallest at the optimum HLB of the emulsifier blend. The non-ionic emulsifiers reduced the particle size of mineral oil emulsions more efficiently than that of olive oil emulsions. Contrary to previously published reports, the nature of the dispersed phase, HLB of the emulsifier blend or the initial particle size of emulsions showed no influence on the final particle stability of the emulsions. This difference was attributed to the optimization of the emulsifier blend and processing parameters in the preparation of emulsions.     

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。