The effects of infiltration on protein release from multi-phase microspheres fabricated via solvent removal

Multi-phase polymer microspheres for drug encapsulation have been fabricated via solvent removal using poly(L-lactic) acid (PLLA) and poly(fumaric-co-sebacic) anhydride (P(FA:SA)20:80). A process of protein infiltration by the polymer solution was studied to determine the effect on protein release. Additionally, multiple variations of the infiltration process were investigated. The mechanisms involved in the different infiltration methods were looked at to determine if polymer degradation was occurring or if the protein was aggregating as a result of the infiltration process. Multiple drugs were used in these studies: FITC-labelled bovine serum albumin (BSA), a model drug and antide (a GnRH antagonist), which is a therapeutic agent. Characterization and comparison of the various microsphere batches was performed via scanning-electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), gel-permeation chromatography (GPC) and differential-scanning calorimetry (DSC). Protein infiltration by the polymer solution was successful in decreasing the initial burst of drug with insignificant differences between the various methods of infiltration. Furthermore, there were minimal differences in polymer degradation due to the different methods of infiltration and there were no significant differences in the degree of crystallinity of the polymers in the various batches fabricated with and without infiltration.     

Preparation and in vitro release behaviour of 5-fluorouracil-loaded microspheres based on poly (L-lactide) and its carbonate copolymers

A modified oil-in-oil (o/o) emulsion solvent evaporation technique was adopted to prepare 5-fluorouracil (5-Fu)-loaded poly (L-lactide) (PLLA) or its carbonate copolymer microspheres. The disperse phase was a drug:polymer solution using a solvent mixture of N,N-dimethylformamide (DMF) and acetonitrile and the continuous phase was liquid paraffin containing 1-10% (w/v) Span 80(R). The effects of preparative parameters, such as the composition of the inner oil phase, drug:polymer ratio, polymer concentration and agitation rate, on 5-Fu entrapment efficiency and microsphere characteristics were investigated. By introducing 25% (v/v) DMF into the inner oil phase, microspheres with high drug entrapment efficiency and an ameliorated burst effect were achieved. Using this modified method, microspheres with various particle sizes could be produced with a high 5-Fu entrapment efficiency (about 80%). In vitro drug release tests showed a burst release of 5-Fu from PLLA microspheres, followed by a sustained release over 50 days. In the case of poly (L-lactide-co-1,3-trimethylene carbonate) (PLTMC) and poly (L-lactide-co-2,2-dimethyl-1,3-trimethylene carbonate) (PLDTMC), the drug release could be continued for over 60 days.     

Enhancing the oral bioavailability of the poorly soluble drug dicumarol with a bioadhesive polymer

This article investigates the effect of particle size and the incorporation of a bioadhesive polymer, poly(fumaric-co-sebacic) anhydride p(FA:SA), on the relative bioavailability of dicumarol. A novel method was used to reduce particle size of the drug, and encapsulated formulations were fabricated using a phase inversion technique to produce nanospheres and microspheres with varying size. Groups of Yorkshire swine were catheterized and gavaged after fasting for 12 h with each formulation in a 50 mg/mL suspension. Blood was collected at different time points, from 0 to 96 h, and pharmacokinetic analysis revealed that formulations incorporating the smaller drug particles showed the highest bioavailability: micronized drug with 7% p(FA:SA) 17:83 polymer had 190% relative bioavailability, and phase inverted p(FA:SA) 17:83 microspheres with 31% (w/w) loading had 198% relative bioavailability to spray dried formulation. Formulations with larger drug particles achieved 71% relative bioavailability. A nonadhesive formulation, fabricated with poly(lactic acid) (PLA), showed 91% relative bioavailability. Both particle size and polymer composition play a role in oral absorption of dicumarol.     

Effect of manufacturing conditions on the formation of double-walled polymer microspheres

This paper discusses the optimization of the solvent evaporation process to produce double-walled (DW) microspheres in a single-step. Five process variables were studied: polymer solution concentration, polymer weight ratio, polymer solution volume ratios, encapsulation temperature, and air flow rate across the top of the encapsulation vessel. The effects of these variables on the process efficiency (defined here as the percentage of microspheres with a DW configuration compared to the total number of microspheres) were examined. Total polymer concentrations of less than 20% (w/v) produced microspheres with high efficiency, with phase separation consistent across all size fractions in each batch. Changing the volume ratio of the two polymer solutions had no significant effect on the process efficiency. The weight ratio of the polymers greatly influenced the process efficiency, resulting in a low 63% efficiency for the 1:3 Poly-L-lactide (PLLA): Poly(carboxyphenoxypropane-co-sebacic)anhydride 20:80 (P(CPP:SA 20:80)) weight ratio and 0% for the 3:1 weight ratio. The 1:3 weight ratio also caused the polymers to reverse their orientation, although the efficiency for this switch was still relatively low. The temperature of the non-solvent bath affected the efficiency of certain pairs of polymers, but not all. The PLLA/Poly(lactide-co-glycolide) 50:50 (PLGA) pair was most sensitive to temperature, due to the chemical similarity of the two polymers which narrowed the range of acceptable conditions for encapsulation. Pairs of polymers which phase separated readily (e.g. polystyrene and PLLA) were the least sensitive to temperature changes. Process yield and size distribution show no clear trends with respect to air flow rate across the top of the reaction vessel. The efficiency of the process to produce DW microspheres increased and the process time decreased with increasing air flow across the surface of the encapsulation vessel.     

Controlled delivery of a hydrophilic drug from a biodegradable microsphere system by supercritical anti-solvent precipitation technique

The purpose of this study was to prepare microspheres loaded with hydrophilic drug, bupivacaine HCl using poly(D,L-lactic-co-glycolic acid) (PLGA) and poly(L-lactic acid) (PLLA). Microspheres were prepared with varying the PLGA/PLLA ratio with two different levels of bupivacaine HCl (5 and 10%) using a supercritical anti-solvent (SAS) technique. Microspheres ranging from 4-10 microm in geometric mean diameter could be prepared, with high loading efficiency. Powder X-ray diffraction (PXRD) revealed that bupivacaine HCl retained its crystalline state within the polymer and was present as a dispersion within the polymer phase after SAS processing. The release of bupivacaine HCl from biodegradable polymer microspheres was rapid up to 4 h, thereafter bupivacaine HCl was continuously and slowly released for at least 7 days according to the PLGA/PLLA ratio and the molecular weight of PLLA.     

The role of microsphere fabrication methods on the stability and release kinetics of ovalbumin encapsulated in polyanhydride microspheres

The effect of microsphere fabrication methods on the stability and release kinetics of ovalbumin encapsulated in polyanhydride microspheres was investigated. The polyanhydrides used were poly(sebacic anhydride) (poly(SA)) and a 20:80 random copolymer of poly[1,6-bis(p-carboxyphenoxy)hexane] (poly(CPH)) and poly(SA). Microspheres were fabricated using three double emulsion methods (water/oil/water, water/oil/oil and solid/oil/oil) and cryogenic atomization. The encapsulation efficiency was highest for cryogenic atomization and lowest when the w/o/w technique was used. Microspheres fabricated by the s/o/o method had the largest initial burst of released protein. All the methods resulted in zero-order release of the protein after the burst. The release of ovalbumin from poly(SA) and 20:80 (CPH:SA) microspheres lasted approximately 3 and approximately 6 weeks, respectively. For all fabrication methods the primary structure of released ovalbumin was conserved as determined by gel electrophoresis. The secondary structure of ovalbumin encapsulated in 20:80 (CPH:SA) w/o/w microspheres was not conserved.     

Paclitaxel-loaded poly(L-lactic acid) microspheres 3: blending low and high molecular weight polymers to control morphology and drug release

Microspheres were prepared from paclitaxel and binary polymer blends incorporating 1, 3, 40k and 100k g/mol PLLA. Thermal analysis was performed by DSC and in vitro paclitaxel release profiles were determined at 37 degrees C in phosphate buffer using an HPLC assay. In microspheres made with 3k/40k PLLA blends, the glass transition (Tg), crystallinity and melting temperature (Tm) all decreased with an increasing proportion of low molecular weight polymer in the blend. Similar trends were observed for 1k/100k blends. Tm values ranged from 175 to 110 degrees C and Tg values between 66 and 37 degrees C. However, for 1k/100k blends, melting point depression was linearly dependent on blend composition when plotted as 1/Tm = 0.000109 x (%1k in blend) + 0.0223, R2 = 0.97. A similar plot with data from the 3k/40k system yielded a non-linear relationship. Furthermore, the decrease in Tg for both 1k/100k and 3k/40k blends followed the Fox equation, although experimental values were consistently 1-2 degrees C above predicted values. Paclitaxel release from microspheres made with a 1k/100k blend occurred in four distinct phases: a burst phase (day 0), a slower phase, a second burst (day 35) and a second slower phase (until day 70). The second burst coincided with visible degradation of the microspheres. Blends of low and high molecular weight PLLA display thermal properties indicating that 1k g/mol PLLA behaves as a diluent when blended with 100k g/mol PLLA, being excluded from the crystalline domains in the polymer matrix. In contrast, 3k g/mol PLLA is incorporated in both amorphous and crystalline regions of the polymer blend. Paclitaxel release profiles from 1k/100k PLLA microspheres demonstrate a multiphase profile due to the effects of both diffusion and degradation controlled release mechanisms.     

The role of microsphere fabrication methods on the stability and release kinetics of ovalbumin encapsulated in polyanhydride microspheres

The effect of microsphere fabrication methods on the stability and release kinetics of ovalbumin encapsulated in polyanhydride microspheres was investigated. The polyanhydrides used were poly(sebacic anhydride) (poly(SA)) and a 20:80 random copolymer of poly[1,6-bis(p-carboxyphenoxy)hexane] (poly(CPH)) and poly(SA). Microspheres were fabricated using three double emulsion methods (water/oil/water, water/oil/oil and solid/oil/oil) and cryogenic atomization. The encapsulation efficiency was highest for cryogenic atomization and lowest when the w/o/w technique was used. Microspheres fabricated by the s/o/o method had the largest initial burst of released protein. All the methods resulted in zero-order release of the protein after the burst. The release of ovalbumin from poly(SA) and 20:80 (CPH:SA) microspheres lasted ～3 and ～6 weeks, respectively. For all fabrication methods the primary structure of released ovalbumin was conserved as determined by gel electrophoresis. The secondary structure of ovalbumin encapsulated in 20:80 (CPH:SA) w/o/w microspheres was not conserved.     

Degradation behaviour of microspheres prepared by spray-drying poly(D,L-lactide) and poly(D,L-lactide-co-glycolide) polymers

Polymeric microsphere degradation must be taken into account in the design of drug delivery systems to be injected in in vivo systems, thus a prior analysis of in vitro degradation behaviour of microspheres appears to be necessary. In this study degradation characteristics of poly(lactide-co-glycolide) (PLGA) and poly(D,L-lactide) (PLA) microspheres prepared by the spray-drying technique have been examined. It was found that a slow decrease in molecular weight took place during the first stage of degradation, and the value of the rate constant decreased with the increase of the percentage of lactic acid of the polymer in a linear way. Thus, the period of time of this first stage decreased with the increase of content of glycolidyl units of the polymer, and it was the unique stage observed in PLA microspheres after 5 months of study. During this period of time, significant mass loss was not observed in the microspheres. The second stage of degradation of PLGA microspheres showed a larger rate constant, whose value increased with the content of glycolidyl units of the polymer. Mass loss was observed from number-average molecular weight about 6000. A sharp decrease of glass transition temperature (T(g)) was observed coinciding with the start of mass loss. This fact was accompanied by a physical change of the samples, fusion of microspheres to form large particles, which also fusion to form a unique mass of polymer; moment from that the degradation process was quicker.     

Controlled delivery of a hydrophilic drug from a biodegradable microsphere system by supercritical anti-solvent precipitation technique

The purpose of this study was to prepare microspheres loaded with hydrophilic drug, bupivacaine HCl using poly(D,L-lactic-co-glycolic acid) (PLGA) and poly(L-lactic acid) (PLLA). Microspheres were prepared with varying the PLGA/PLLA ratio with two different levels of bupivacaine HCl (5 and 10%) using a supercritical anti-solvent (SAS) technique. Microspheres ranging from 4–10?µm in geometric mean diameter could be prepared, with high loading efficiency. Powder X-ray diffraction (PXRD) revealed that bupivacaine HCl retained its crystalline state within the polymer and was present as a dispersion within the polymer phase after SAS processing. The release of bupivacaine HCl from biodegradable polymer microspheres was rapid up to 4?h, thereafter bupivacaine HCl was continuously and slowly released for at least 7 days according to the PLGA/PLLA ratio and the molecular weight of PLLA.     

Phase separation behavior of fusidic acid and rifampicin in PLGA microspheres

The purpose of this study was to characterize the phase separation behavior of fusidic acid (FA) and rifampicin (RIF) in poly(d,l-lactic acid-co-glycolic acid) (PLGA) using a model microsphere formulation. To accomplish this, microspheres containing 20% FA with 0%, 5%, 10%, 20%, and 30% RIF and 20% RIF with 30%, 20% 10%, 5%, and 0% FA were prepared by solvent evaporation. Drug-polymer and drug-drug compatibility and miscibility were characterized using laser confocal microscopy, Raman spectroscopy, XRPD, DSC, and real-time video recordings of single-microsphere formation. The encapsulation of FA and RIF alone, or in combination, results in a liquid-liquid phase separation of solvent-and-drug-rich microdomains that are excluded from the polymer bulk during microsphere hardening, resulting in amorphous spherical drug-rich domains within the polymer bulk and on the microsphere surface. FA and RIF phase separate from PLGA at relative droplet volumes of 0.311 ± 0.014 and 0.194 ± 0.000, respectively, predictive of the incompatibility of each drug and PLGA. When coloaded, FA and RIF phase separate in a single event at the relative droplet volume 0.251 ± 0.002, intermediate between each of the monoloaded formulations and dependent on the relative contribution of FA or RIF. The release of FA and RIF from phase-separated microspheres was characterized exclusively by a burst release and was dependent on the phase exclusion of surface drug-rich domains. Phase separation results in coalescence of drug-rich microdroplets and polymer phase exclusion, and it is dependent on the compatibility between FA and RIF and PLGA. FA and RIF are mutually miscible in all proportions as an amorphous glass, and they phase separate from the polymer as such. These drug-rich domains were excluded to the surface of the microspheres, and subsequent release of both drugs from the microspheres was rapid and reflected this surface location.     

Degradation kinetics of high molecular weight poly(L-lactide) microspheres and release mechanism of lipid:DNA complexes

Plasmid DNA encoding the green lantern protein was ion-paired with 1,2-dioleoyl, 3-trimethylammonium propane (DOTAP) at a (+/-) charge ratio of (1:1) to form a hydrophobic ion-pair (HIP) complex using the Bligh and Dyer method, and transferred into methylene chloride. Precipitation with a compressed antisolvent (PCA) was then employed to encapsulate plasmid DNA into poly(L-lactide) (PLLA) microspheres. The hydrophobicity of DOTAP:DNA complexes allowed consistently high encapsulation efficiencies (>70%) to be achieved. Release of the DOTAP:DNA complex from PLLA microspheres exhibited minimal burst and a short (ca. 1 week) lag phase, followed by sustained release over a 20 week period. Release kinetics were consistent with a simple Fickian diffusion model. No correlation was identified between release rate of soluble poly(L-lactide) species (< or =10 lactate units) from PLLA and the DNA release kinetics. Only approximately 12% of the polymer was degraded into soluble poly(L-lactide) over the time frame where approximately 90% of the plasmid load had been released.     

Methotrexate loaded poly(L-lactic acid) microspheres for intra-articular delivery of methotrexate to the joint

A controlled release delivery system that localizes methotrexate (MTX) in the synovial joint is needed to treat inflammation in rheumatoid arthritis (RA). The purpose of this work was to develop and characterize MTX loaded poly(l-lactic acid) (PLLA) microspheres and evaluate in vivo tolerability and MTX plasma concentrations following intra-articular injection into healthy rabbits. MTX loaded PLLA (2 kg/mole) microspheres were prepared using the solvent evaporation method and characterized in terms of size, molecular weight, thermal properties, and release rates into phosphate buffered saline (PBS) (pH 7.4) at 37 degrees C. Biocompatibility was evaluated by observing the swelling of the joints of the rabbits and histological analysis following the injection of the microspheres. MTX concentrations in the plasma and urine samples of rabbits were evaluated by high-performance liquid chromatography (HPLC). MTX loaded microspheres showed a rapid burst phase followed by a slow release phase. MTX loaded and control microspheres were biocompatible and plasma concentrations of MTX were tenfold higher in rabbits injected intra-articularly with free MTX than MTX microspheres. MTX microspheres may retain the drug in the joint by reducing clearance from the joint into the blood.     

Preparation and characterization of injectable microspheres of contraceptive hormones

Present study describes the development of a new formulation of levonorgestrel and ethinylestradiol based on double emulsion-solvent evaporation technique using poly(epsilon-caprolactone) (PCL) as biodegradable polymer. The effect of polymer concentration on microspheres and entrapment of drug into microspheres were studied. PCL was selected because of its hydrophobicity and advantages over other biodegradable polymers. Characterization of biodegradable polymer used for controlled drug delivery is essential to ensure reproducibility of in vitro and in vivo performances. The selected characterisation techniques established for PCL microspheres include its loading and entrapment efficiencies, DSC to analyse thermal behaviour, SEM to observe surface morphology, drug content of microspheres and in vitro release of drugs from microspheres. The SEM reports showed that microspheres were with smooth surface and DSC thermograms revealed no interaction between drug and polymer. The entrapment was found to be 58 and 47% for 1:10 and 1:5 batches and in vitro release studies showed that about 69.7% of LNG and 66.7% of EE from 1:10 batch and about 80% of LNG and 75.5% of EE from 1:5 batch for 150 days.     

聚（L-乳酸）体内外降解相关性研究

目的考察聚（L-乳酸）（PLLA）植入剂体内外降解特性黏数和失重变化的相关性。方法以辛酸亚锡为催化剂,通过直接缩聚法制备聚（L-乳酸）（PLLA）树脂,经精制得药用辅料;将药用辅料通过特定设备压制成空白植入剂,考察其在大白兔体内的降解情况,并与其在pH7.4的磷酸盐缓冲液的体外降解相比较。结果聚（L-乳酸）植入剂样品降解后的特性黏数与降解时间（wk）呈指数关系,失重百分率与降解时间（wk）呈线性关系。结论体内的特性黏数与体外的特性黏数数值相近,体外失重比体内快。     

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.     

超微粒制备系统制备利培酮长效注射微球

目的:制备利培酮长效注射微球并进行体外释药动力学考察。方法:选用聚乳酸-羟基乙酸共聚物[poly(D,L-lactic-co-glycolic acid),PLGA]为载体,采用新型超微粒制备系统制备利培酮PLGA微球。以转碟上聚合物析出量、丝状物的形成和微粒表面形态为考察指标单因素实验优化制备工艺参数及处方;观察微球表面形态,测定其粒径、包封率、考察其体外释药动力学。结果:20%和30%载药量的微球表面均光滑圆整,分散性好;其包封率分别为94.7%和93.94%,中值粒径分别为31.65和28.13μm;持续释药时间均可达16 d,释放数据用释放动力学方程拟合符合一级和Higuchi方程。20%载药量微球1 h释药率仅为4.2%,突释率低,且其释放速率和释放时间与市售利醅酮微球(恒德)快速释放期基本一致而无延滞期。结论:超微粒制备系统(UPPS)可单步骤制备长效微球,工艺稳定,简单可行,有望成为一种适合工业微球制备技术。UPPS制备的20%载药量微球可开发为释放2周的制剂,由于无释放延滞期,将比市售品更具临床优势。     

PLGA-PEG microspheres of teverelix: influence of polymer type on microsphere characteristics and on teverelix in vitro release

Teverelix microspheres were produced by coacervation using a new type of poly(ester-carbonates) made of block copolymers of poly(lactic-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG). Five different PLGA-PEG copolymers and one PLGA were used. The 'stability window' has been determined for all polymers. It varied depending on the molecular weight and the weight percentage of PEG. With increasing core loading (from 9.4 to 34.2%), the microparticle size increased from 10-50 to 5-1000 micrometer. The core loading did not have any influence on encapsulation yield, which remained above 80%. The influence of polymer type on microsphere characteristics was studied at two different core loadings: 9.4 and 28%. At a low core loading, the nature of the polymer had no influence on microsphere characteristics whereas at 28%, only PLGA-PEG copolymers gave acceptable microparticles in term of particle size. At 28%, the glass transition temperature (T(g)) of loaded particles was 1-8 degrees C higher than the T(g) of the corresponding polymer. Increasing the core loading increased teverelix release whereas polymer degradation was decreased. All microparticles made of PLGA-PEG copolymers showed a faster release of teverelix than PLGA-based microspheres, whatever the core loading. One PLGA-PEG was selected on the basis of in vitro release rate for further in vivo investigations.     

PLGA and PHBV Microsphere Formulations and Solid-State Characterization: Possible Implications for Local Delivery of Fusidic Acid for the Treatment and Prevention of Orthopaedic Infections

Purpose  To develop and characterize the solid-state properties of poly(DL-lactic-co-glycolic acid) (PLGA) and poly(3-hydroxybutyric acid-co-3-hydroxyvaleric acid) (PHBV) microspheres for the localized and controlled release of fusidic acid (FA). Methods  The effects of FA loading and polymer composition on the mean diameter, encapsulation efficiency and FA released from the microspheres were determined. The solid-state and phase separation properties of the microspheres were characterized using DSC, XRPD, Raman spectroscopy, SEM, laser confocal and real time recording of single microspheres formation. Results  Above a loading of 1% (w/w) FA phase separated from PLGA polymer and formed distinct spherical FA-rich amorphous microdomains throughout the PLGA microsphere. For FA-loaded PLGA microspheres, encapsulation efficiency and cumulative release increased with initial drug loading. Similarly, cumulative release from FA-loaded PHBV microspheres was increased by FA loading. After the initial burst release, FA was released from PLGA microspheres much slower compared to PHBV microspheres. Conclusions  A unique phase separation phenomenon of FA in PLGA but not in PHBV polymers was observed, driven by coalescence of liquid microdroplets of a DCM-FA-rich phase in the forming microsphere. Electronic supplementary material   The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

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.