Vancomycin release kinetics from Mg–Ca silicate porous microspheres developed for controlled drug delivery

In this work, sol-gel derived bredigite (MgCa₇Si₄O₁₆), akermanite (MgCa₂Si₂O₇), and diopside (MgCaSi₂O₆) porous microspheres were loaded with vancomycin, and the release kinetics of this drug from them was evaluated. In this regard, mathematical models of Higuchi, Peppas, Baker-Lonsdale, Hixson-Crowell, first order, and zero order were considered in terms of linear and nonlinear regression analyses. Using the goodness of fitting correlation coefficients, the number of release stages was determined, and then diffusion- and degradation-controlled mechanisms were assigned to each stage. It was found that the diopside microspheres presented a two-step diffusional drug delivery. For akermanite and bredigite, an initial burst diffusion-controlled release followed by a sustained mixed-mode release mechanism of diffusion and degradation was identified, with the domination of the latter especially for bredigite.     

Multiparticulation of ciprofloxacin HCl-encapsulated chitosan microspheres using poly(dl-lactide-co-glycolide)

In this study, we prepared poly(dl-lactide-co-glycolide) (PLGA)-coated chitosan oligosaccharide (COS) microspheres. Ciprofloxacin HCl (CIP)-encapsulated COS microspheres were prepared by the pressure homogenization and spray drying technique. The microspheres have spherical shapes and their particle size was in the range of 2–3 μm in diameter. When they were coated with PLGA, PLGA-coated COS microspheres showed rough spherical surfaces, indicating that COS microspheres might be existed on the surface of particles in addition to the inside of particles. The efficiency of loading and size of particle were increased with the increase of the amount of PLGA feeding amount. At the effect of PLGA series, the loading efficiency and particle size were in the order of RG504H > RG503H > RG502H. Drug release rate was decreased with the increase of the amount of PLGA feeding and initial burst was 3–10 days according to the PLGA feeding amount. At the effect of PLGA series, drug release rate was in the order of RG502H > RG503H > RG504H. When acetone was used, drug release rate was slightly increased. PLGA-coated COS microspheres were successfully prepared and characterized.     

Mechanical strength and biocompatibility of bredigite (Ca7MgSi4O16) tissue-engineering scaffolds modified by aliphatic polyester coatings

Bredigite (Ca₇MgSi₄O₁₆) is a bioceramic with excellent bioactivity and bioresorbability; nonetheless, its inadequate mechanical strength and biocompatibility limit its tissue-engineering application. In this research, interconnected porous bredigite scaffolds were fabricated by sol-gel, sacrificial sponge replica and sintering processes for bone tissue engineering. In order to improve their strength and cytocompatibility, the scaffolds were coated with poly(lactic-co-glycolic acid) (PLGA) via immersion in acetone-based solutions containing different concentrations (5, 10 and 15% w/v) of the polymer. Based on the results, the PLGA coatings to 10% do not suppress the porosity characteristics of the scaffolds appropriate for tissue engineering. It was also found that the polymeric coatings significantly enhance the compressive strength of the ceramic scaffolds, where this alteration is improved by increasing the PLGA concentration of the coating solution. In addition, the viability of stem cells on the bredigite scaffolds are improved by using the PLGA coatings, with the optimal concentration of 10% PLGA according to MTT and cell attachment studies.     

Effects of drug and polymer molecular weight on drug release from PLGA‐mPEG microspheres

This study investigated the effects of drug and polymer molecular weight on release kinetics from poly (g ‐co‐glycolic acid)‐methoxypoly(ethyleneglycol) (PLGA‐mPEG) microspheres. Bovine serum albumin (BSA, 66 kDa), lysozyme (LZ, 13.4 kDa), and vancomycin (VM, 1.45 kDa) were employed as the model drugs, and encapsulated in PLGA‐mPEG microspheres of different molecular weight. Release of macromolecular BSA was mainly dependent on diffusion of drug at/ near the surface of the matrix initially and dependent on degradation of matrix at later stages, while, the small drug of vancomycin seemed to depend totally on diffusion for the duration of the release study. The release behavior of lysozyme was similar to bovine serum albumin, except a shorter lag period. PLGA‐mPEG molecular weight also affected the release behavior of bovine serum albumin and lysozyme, but not obviously. PLGA‐mPEG microspheres in smaller molecular weight seemed to degrade more quickly to obtain a mass lose and matrix erosion, and thus, an accelerated release rate of bovine serum albumin and lysozyme. Vancomycin released much faster than bovine serum albumin and lysozyme, and exhibited no lag period, as it is thought to be diffusion‐controlled. Besides, vancomycin showed no difference in release behavior as PLGA‐mPEG molecular weight change. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41431.     

Dissolution behavior of CaO-MgO-SiO2-based bioceramic powders in simulated physiological environments

In this study, the dissolution behavior of CaO-MgO-SiO₂-based bioceramics was investigated in vitro by using a stage-by-stage simulating physiological environment method. Preliminary dissolution rules of CaO-MgO-SiO₂-based bioceramics are presented by soaking akermanite, bredigite, and diopside powders in saline solution. Dissolved Ca and Mg ion concentrations were proportional to the chemical composition of the bioceramics, while the dissolution of Si ion was more affected by their crystal structure. The analysis of zeta potential indicated that ions (possibly including both the dissolved and intrinsic ions) would be adsorbed on the surface of bioceramic powders during soaking in saline solution. Further studies of the dissolution of akermanite powder was performed using different solid-liquid ratios in simulated body fluid (SBF) and α-MEM culture medium. It was found that hydroxyapatite was formed on the surface of akermanite in SBF and amino-containing compounds attracted to the surface of the powders in α-MEM culture medium would impede the diffusion of ions to delay ions release and weaken hydroxyapatite formation. When akermanite powders were co-cultured with BMSCs, HUVECs, or L929 cells, the concentrations of Ca, Mg and Si ions in the solution were lower than that in cell-free medium. Additionally, the pH value gradually decreased with soaking time, unlike what occurs when the materials are soaked in cell-free media, suggesting effects due to the cellular intake of related ions and the release of acidic cellular metabolites. The akermanite extracts in a certain concentration range could promote cell proliferation via cellular intake of related ions. In turn, this ion consumption would affect the dissolution behavior of bioceramics in simulated physiological environments.     

Review on calcium silicate-based bioceramics in bone tissue engineering

Calcium (Ca) and silica (Si) ions have attracted intense interest in biomedical applications. The two ions are directly involved in many biological processes; for instance, Ca plays a key role in regulating cellular responses to bioceramics, promoting cell growth, and differentiation into osteoblasts. Si plays a significant role in bone calcification and is helpful for bone density improvement and inhibiting osteoporosis. Calcium silicate ceramics including a large group of trace metal containing calcium silicate-based compounds are involved in biomedical applications such as repairing hard tissue texture, bone scaffolds, bone cements, or implant coatings. The aim of the study is to provide a comprehensive overview of developments in research on calcium silicate-based ceramics, such as wollastonite (CaSiO₃), diopside (CaMgSi₂O₆), akermanite (Ca₂MgSi₂O₇), bredigite (Ca₇Mg(SiO₄)₄), merwinite (Ca₃MgSi₂O₈), monticellite (CaMgSiO₄), hardystonite (Ca₂Zn(Si₂O₇), and baghdadite (Ca₃ZrSi₂O₉), including degradation, apatite mineralization, and mechanical properties. Finally, the biological in vitro and in vivo presentation for bone tissue repair are summarized, which show promise with regard to application of calcium silicate-based ceramics as bone repair and replacement materials.     

Biomineralization,strength and cytocompatibility improvement of bredigite scaffolds through doping/coating

Coprecipitation-derived, sacrificial polymeric (urethane) foam-fabricated bredigite (Ca₇MgSi₄O₁₆) scaffolds were processed by individual and combined treatments of fluoride doping and poly (lactic-co-glycolic acid) (PLGA) coating and then studied in terms of structure, mechanical strength, bioactivity and cell biocompatibility in vitro. According to scanning electron microscopy and Archimedes porosimetry, the geometrical characteristics of pores for all the scaffolds are in the appropriate range for hard tissue regeneration applications. The apatite-formation ability of the samples immersed in a simulated body fluid is improved by doping for both the bare and coated conditions, based on microscopic and energy-dispersive X-ray spectroscopic analyses. Both the treatments advantageously buffer physiological pH changes imposed due to the fast bioresorption of the ceramic. Also, the biodegradable PLGA coating typically enhances the compressive strength of the scaffolds, which is critical for bone tissue engineering. In accordance with the MTT assay on osteoblast-like cells (MG-63) cultures, both the processes individually enhance the cell viability, while the highest improvement is obtained for the combined application of them. It is finally concluded that fluoride doping and PLGA coating are impressive approaches to improve the bioperformance of bredigite-based scaffolds.     

Impact of PLGA molecular behavior in the feed solution on the drug release kinetics of spray dried microparticles

The purpose of this study was to understand the impact of the poly (lactic-co-glycolic acid) (PLGA) molecular behavior in the feed solution on the drug release kinetics of PLGA microparticles prepared via spray drying. The PLGA molecular behavior in the feed solutions were characterized by using tube viscometry, which provides information about the polymer coil radius (R_coil), the Martin constant (K_m), and the overlap concentration (c*). The particle size and the drug surface enrichment were investigated by using scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS), respectively. The drug release profiles were characterized by using the USP paddle method and analyzed by using the Crank's diffusion model to calculate the kinetic parameters. Multivariate data analysis using principal component analysis (PCA) was employed to display the relationship between the PLGA molecular behavior, particle properties and the drug release kinetics from the spray dried PLGA microparticles. Rheological studies suggested that an increased molar ratio of a poor solvent (methanol) in the solvent system resulted in a decreased R_coil, the increase in K_m and c*. The higher effective diffusion coefficient of drug calculated by using the Crank's diffusion model was observed in the polymer matrix prepared at an acetone-to-methanol molar ratio of 69:31. The PCA models indicated that the drug surface enrichment and the K_m were directly proportional to the drug burst release, while the entanglement index was inversely correlated. Further, the particle size had a less significant impact on the drug burst release. This study implies that the polymer molecular behavior would influence the microscopic connectivity and diffusivity of polymer matrix, which eventually affects the drug release kinetics.     

Rapid microwave synthesis of hydroxyapatite phosphate microspheres with hierarchical porous structure

Hierarchical Hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂, HA) microspheres can be applied as microcarriers in cell carriers and drug delivery. However, it is difficult to prepare monodispersed and hierarchical microspheres in short time with conventional method. Here, we report the preparation of hierarchical HA microspheres through a novel microwave-assisted method in several minutes, where similar structured calcium carbonate (CaCO₃) microspheres acts as sacrificial hard-templates. The SEM images indicated that surface microstructure and microspheres size were effectively controlled by changing starting parameters such as microwave react time and stirring speed. XRD patterns and BET results further proved that the pure HA microspheres with great specific surface area can be prepared in a short time. The Ca ions release of samples showed that the degradation of HA microspheres decreased with microwave processing time of samples. Drug release of samples showed that on one hand vancomycin release concentration decreased with microwave processing time of samples, on the other hand increased obviously with the lower pH value of buffer solution. Human osteoblasts-like cells were cultured with different concentration of microspheres extracts to investigate in vitro biocompatibility. The results of the CCK-8 assay and Live/Dead staining proved that the cells grew well in all sample extracts, suggesting that cells responded well to the microspheres. Our work provides a novel and rapid way to produce hierarchical HA microspheres for bone repair or drug delivery.     

Enhancement in the osteogenesis and angiogenesis of calcium phosphate cement by incorporating magnesium-containing silicates

Based on the good osteogenic and angiogenic effects of silicon and magnesium elements, three types of micro-nano magnesium-containing silicates (MS), including akermanite (Ake, Ca₂MgSi₂O₇), diopside (Dio, CaMgSi₂O₆) and forsterite (For, Mg₂SiO₄), were incorporated into calcium phosphate cement (CPC) to improve its osteogenic and angiogenic performances for clinical application. In this present work, the physicochemical properties, osteogenesis and angiogenesis of MS/CPCs (Ake/CPCs, Dio/CPCs and For/CPCs) were investigated systematically and comparatively. The results showed that all MS/CPCs had good biomineralization and significantly stimulated the osteogenic differentiation of mBMSCs and angiogenic differentiation of HUVECs, respectively. Besides, the stimulating effects were related to not only the category of MS, but also the content of MS. The For/CPCs had a good angiogenic property but their initial setting times were beyond 60 min. The Dio/CPCs showed the lowest biological performance among the three groups of MS/CPCs due to the lower ion release (Si and Mg). The Ake was the ideal modifier that could provide CPC with appropriate physicochemical properties, better osteogenesis and angiogenesis. Simultaneously, a higher addition (10 wt%) of akermanite resulted in the best potential to bone regeneration. Taken together, this research provides an effective approach to improve the overall performance of CPC, and 10Ake/CPC is of great promising prospect in bone repair.     

含紫杉醇PLGA缓释微球的研制及理化性质

目的研制含紫杉醇的聚乳酸和乙醇酸的共聚物[Poly(lactic-co-glycolic acid),PLGA]生物可降解高分子微球,并对其药物释放动力学进行分析。方法使用相对分子质量为20000的PLGA作为造粒对象,对不同溶剂的PLGA溶液进行喷雾化造粒,以优化出最佳造粒参数。在此条件下对含紫杉醇的PLGA溶液进行喷雾化造粒,制备紫杉醇/PLGA微球。结果形成单分散粒子的条件是较高的应用电压和较低的溶液流率,5%(wt)的PLGA溶液浓度溶于5∶1的氯仿和DMF的混合溶剂(v/v)中。在优化的喷雾参数下,得到了粒径均一、直径为300nm的单分散载紫杉醇的PLGA微粒。当紫杉醇在微球中含量较低时(2%),药物释放呈零级释放模式。较高的载药浓度(>5%)会在初期有轻微药物突释,然后呈零级释放模式。结论电喷雾化技术制备载药微粒是简单可行的新制药技术。含紫杉醇的PLGA微粒有望成为新一代抗癌药物剂型。     

Comparison of the degradation and release behaviors of poly(lactide‐co‐glycolide)–methoxypoly(ethylene glycol) microspheres prepared with single‐ and double‐emulsion evaporation methods

The purpose of this study was to compare the degradation and release behaviors of poly(lactide‐co‐glycolide) (PLGA)–methoxypoly(ethylene glycol) microspheres fabricated by the single‐emulsion evaporation method (DEEM) and double‐emulsion evaporation methods (DEEM). Vancomycin and mizolastine were used as the hydrophilic and hydrophobic model drugs, and they were encapsulated into microspheres through DEEM and SEEM, respectively. The two types of microspheres were similar in size distribution, but the mizolastine‐loaded microspheres showed a much higher encapsulation efficiency than those loaded with vancomycin. Scanning electron microscopy, size, and molecular weight (Mw) analyses during the degradation revealed that the microspheres fabricated by DEEM underwent a bulk degradation process and showed a faster MW reduction rate during the early degradation period than the microspheres fabricated by SEEM, which exhibited a surface‐to‐bulk degradation process according to the Mw and morphological changes. The mass loss rates of the two types of microspheres were similar, but the mean size decrease rates showed a little difference. The mizolastine‐loaded microspheres exhibited an approximately linear release profile after the initial burst release, whereas the vancomycin‐loaded microspheres showed a more severe burst release, a faster release rate, and thus, a shorter time to full release. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41943.     

Preparation of magnetic poly(lactic‐co‐glycolic acid) microspheres with a controllable particle size based on a composite emulsion and their release properties for curcumin loading

Because of their unique magnetic features and good biocompatibility, magnetic poly(lactic‐co‐glycolic) acid (PLGA) microspheres have great application potential in magnetic targeted drug‐delivery systems. In this research, magnetic PLGA microspheres with controllable particle sizes were successfully prepared from a composite emulsion with a T‐shaped microchannel reactor. A water‐in‐oil‐in‐water composite emulsion was generated by the injection of a dichloromethane/gelatin water‐in‐oil initial emulsion into the microchannel together with a coating aqueous phase, that is, the aqueous solution of glucose and poly(vinyl alcohol). The mean particle size of the microspheres could be controlled by the manipulation of the osmotic pressure difference between the internal and external aqueous phases via changes in the glucose concentration. Curcumin, a drug with an inhibitory effect on tumor cells, was used to exemplify the release properties of the magnetic PLGA microspheres. We found that the mean particle size of the microspheres ranged from 16 to 207 μm with glucose concentrations from 0 to 20 wt %. The resulting microspheres showed a rapid magnetic response, good superparamagnetism, and a considerable magnetocaloric effect, with a maximum magnetic entropy of 0.061 J·kg^?1·K^?1 at 325 K. An encapsulation efficiency of up to 77.9% was achieved at a loading ratio of 3.2% curcumin. A release ratio of 72.4% curcumin from the magnetic PLGA microspheres was achieved within 120 h in a phosphate‐buffered solution. The magnetic PLGA microspheres showed potential to be used as drug carriers for magnetic targeted tumor therapy. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43317.     

A Dissolution‐Diffusion Model and Quantitative Analysis of Drug Controlled Release from Biodegradable Polymer Microspheres

Controlled release behaviours of nifedipine loaded poly (D,L‐lactide) (PLA) and poly(D,L‐lactide‐co‐glycolide) (PLGA) microspheres are investigated and modelled in this paper. Based on the integrated consideration of diffusion, finite dissolution rate, moving front of dissolution and size distribution of microspheres, a mathematic model is presented to quantitatively describe the drug release kinetics. The coupled partial differential equations are numerically solved. Dynamic concentration profiles of both dissolved and undissolved drug in the microspheres are analyzed. In comparison with the diffusion model and Higuchi model, the proposed dissolution‐diffusion model is characteristic of describing the whole release process without limitation of different dissolution rate or dissolubility. The diffusion coefficient and the dissolution rate constants are evaluated from measured release profiles. The effects of microstructures of polymer microspheres on release behaviours are related to parameters of the model. Based on the mathematical model and in vitro release data, intrinsic mass transfer mechanism is further investigated.     

快速膜乳化法制备胸腺法新长效缓释微球

采用快速膜乳化技术结合溶剂蒸发法制备以生物可降解聚乳酸-羟基乙酸(PLGA)为载体的胸腺法新载药微球,考察了PLGA分子量、油相中PLGA和乳化剂浓度、外水相pH值和内水相体积等对微球包埋率和粒径的影响. 结果表明,制备粒径均一的PLGA载药微球的优化条件为：PLGA分子量51 kDa,油相中PLGA和乳化剂浓度为100和10 g/L,内水相体积0.5 mL,外水相pH值为3.5. 该条件下所制载药微球粒径均一性好(Span<0.7),药物包埋率高达80%以上,突释率24 h内低于20%,线性持续稳定释药时间长达30 d.     

In vitro release of complexed pDNA from biodegradable polymer films

The controlled delivery of low‐molecular weight drugs and proteins from biodegradable polymers has received considerable attention. However, controlled release studies of pDNA from such polymers have not been reported to date. In this study, a plasmid DNA was complexed with the cationic polymer called polyethylenimine (PEI). This gene vector has been shown to be very effective in transfecting cells. The complexed DNA were then incorporated into different types of poly‐lactic‐co‐glycolic acid (PLGA) film; PLGA 53/47 (M_w 90 kDa), 50/50 (M_w 11 kDa, end group is lauryl ester) and 75/25 (M_w 120 kDa). Their release profiles from a buffer solution were studied. An initial (small) burst release of PEI‐DNA from film was observed in PLGA 53/47 and 50/50, followed by a plateau phase and finally a rapid erosion‐controlled release. For PLGA 50/50, the rapid release started after 14 days; erosion‐controlled release for PLGA 53/47 started after 9 days; for PLGA 75/25, the release rate was governed by an initial burst release (10%) followed by a slow release controlled by diffusion. No obvious erosion‐controlled release rate was observed for this polymer up to 27 days. Thus, the controlled release of complexed DNA follows the general features exhibited by lower‐ M_w drugs. This is of significance in designing gene vector matrices that offer the promise of more lasting gene therapy compared with particulate formulations. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

In situ forming poly(lactic acid-co-glycolic acid) implants containing leuprolide acetate/β-cyclodextrin complexes: preparation,characterization, and in vitro drug release

In situ forming implants (ISIs) based on poly(lactic acid-co-glycolic acid) (PLGA) containing leuprolide acetate/β-cyclodextrin (LA/β-CD) complexes were prepared. Incorporation of LA or complexes did not change T_g values of ISIs (48.4–49.6°C). ISIs containing complexes with more β-CD content showed higher surface and bulk porosity. Higher β-CD portion in complexes improved solvent release, decreased initial burst release and facilitated diffusion out of drug for corresponding ISIs. Complexation of LA with β-CD (1/10, w/w) significantly improved its stability within PLGA matrix before release (total LA release of 91.3%). ISIs did not show any cellular cytotoxic effects against L929 fibroblast cells.     

Novel method to synthesis of single phase zirconolite ceramic

Single phase zirconolite (CaZrTi₂O₇) was synthesised by a novel method using acid corrosion to treat zirconolite–diopside mixture powders (2CaZrTi₂O₇–Mg2Si₂O₆). The mixture powders were prepared by solid state reaction method at 1200°C for 2 h. Single phase zirconolite powders were obtained by acid corrosion method with 5% hydrofluoric acid on the zirconolite–diopside Synroc mixture powders and washed with 10% acetic acid.     

Intrinsic factor and vitamin B12 complex‐loaded poly[lactic‐co‐(glycolic acid)] microspheres: preparation,characterization and drug release

BACKGROUND: Vitamin B12 is an essential vitamin required by all mammals. Absorption of vitamin B12 is facilitated by binding of intrinsic factor–vitamin B₁₂ complex to specific receptors in the ileum. In humans a deficiency of this vitamin or a lack of intrinsic factor leads to pernicious anaemia. The major objective of the present study was to prepare intrinsic factor–vitamin B12 complex‐loaded poly[lactic‐co‐(glycolic acid)] (PLGA)‐based microparticles and to investigate their release kinetics. RESULTS: PLGA copolymer was synthesized by the ring‐opening polymerization method and characterized using gel permeation chromatography, Fourier transform infrared spectroscopy and ¹H NMR. The glass transition temperature measurement showed a single T_g at 40 °C. The intrinsic factor–vitamin B12 complex‐loaded PLGA microspheres were prepared by a water‐in‐oil‐in‐water double emulsion solvent extraction/evaporation technique. An environmental scanning electron microscopy investigation demonstrated that the PLGA particles had a mean particle diameter of 38 µm. Interestingly, different drug release patterns (bi‐ and triphasic ones) were observed for vitamin B12‐loaded and intrinsic factor–vitamin B12 complex‐loaded microspheres. In contrast to the rapid release of vitamin B12 by itself, in vitro release tests showed that intrinsic factor and vitamin B12 in the complex were released from PLGA microspheres in a sustained manner over 15 days. CONCLUSION: PLGA microspheres can be an effective carrier for the intrinsic factor–vitamin B12 complex. Copyright © 2007 Society of Chemical Industry     

Synthesis and characterization of star-shaped poly (lactide-co-glycolide) and its drug-loaded microspheres

The star-shaped poly (lactide-co-glycolide) (PLGA) was synthesized via the ring-opening polymerization of d,l-lactide and glycolide, with pentaerythritol as a multifunctional initiator and stannous 2-ethyl hexanoate as a catalyst. The structures of these polymers were characterized by ¹³C-NMR spectroscopy, while the molecular weight and polydispersity index (PDI) were determined by gel permeation chromatography (GPC). The glass transition temperature (T _g) of copolymer was determined by differential scanning calorimetry (DSC). Bovine serum albumin (BSA) loaded microspheres were fabricated using star-shaped PLGA by a W/O/W double emulsion solvent evaporation method. The results of characterization demonstrated that the particle size of the PLGA microspheres were about 80–150 μm, the maximum loading capacity and encapsulation efficiency of BSA-loaded microspheres were 67.51 μg/(mg microspheres) and 78.39%, respectively, which were better than linear PLGA. The in vitro release profiles of BSA in phosphate buffer saline (PBS) lasted for 37 h. Drug release profiles can be affected by polymer molecular weight and the ratio of polymer to drug. The maximum release percentage was 80%.