载碘胺铂壳聚糖微球的制备及其抗人肝癌细胞活性研究

采用乳化交联法制备了载碘胺铂壳聚糖微球,用扫描电镜和红外光谱对其结构及形貌进行了表征。载碘胺铂壳聚糖微球的平均载药量为(46.48±4.42)%,平均包封率为(91.39±2.45)%,缓释测试符合一级释药方程。MTT实验证明载碘胺铂壳聚糖微球能抑制肝癌细胞生长,且比单纯使用碘胺铂高。     

光热敏感型羧甲基壳聚糖纳米微球的制备及光热性能

羧甲基壳聚糖因其具有良好的水溶性和生物相容性,被广泛应用于生物医学领域。以天然可降解高分子羧甲基壳聚糖为载体,在引发剂过硫酸钾的作用下,通过自由基组合法将N-异丙基丙烯酰胺接枝到羧甲基壳聚糖上,然后在香草醛的交联作用下,采用乳化交联法制备一种负载光敏剂吲哚菁绿(ICG)的新型光热敏感型羧甲基壳聚糖微球,通过傅里叶红外(FT-IR)、核磁(1H-NMR)及扫描电镜(SEM)对共聚物结构及微球形貌进行表征,考察了油水比、转速、香草醛、乳化时间对该纳米微球包载阿霉素载药量的影响,并研究了其光热性能。结果表明,FT-IR和1H-NMR分析证明,N-异丙基丙烯酰胺成功接枝到羧甲基壳聚糖上;SEM分析可知,纳米微球外观呈球状,分布均匀,平均粒径为143 nm。油水比为20∶1,转速为600 r/min,香草醛量为1 mL,乳化时间3 h的微球载药量最高为19.32%。同时,通过改变外界环境条件,纳米微球能缓慢靶向释放药物,具有良好的光热敏感性,该纳米微球在药物控释及药物载体等领域有广泛的应用前景。     

Characteristics and degradation of chitosan/cellulose acetate microspheres with different model drugs

In this study, chitosan/cellulose acetate microspheres (CCAM) were prepared by W/O/W emulsification and solvent evaporation as a drug delivery system. The microspheres were spherical, free-flowing and non-aggregated. The CCAM had good flow and suspension ability. The loading efficiency of different model drugs increased with the increasing hydrophobicity of the drug. The loading efficiency of 6-mercaptopurine (6-MP) was more than 30% whereas that of ranitidine hydrochloride (RT) or acetaminophen (ACP) was only 10%. The pH values of solution affected the swelling ability of CCAM and the relative humidity had little effect on the characteristics of CCAM when it was not more than 75%. The CCAM system had a good effect on the controlled release of different model drugs. However, the release rate became slower with the increase of the hydrophobicity of drugs. The release rate of CCAM loaded with hydrophilic RT was almost 60% during 48 h and the release rate of CCAM loaded with hydrophobic drug of 6-MP was not more than 30%. In the meantime, the CCAM system was degradable in vitro and the degradation rate was faster in lysozyme solution than that in the medium of PBS. So the CCAM system was a degradable promising drug delivery system especially for hydrophobic drugs.     

Characteristics and degradation of chitosan/cellulose acetate microspheres with different model drugs

In this study, chitosan/cellulose acetate microspheres (CCAM) were prepared by W/O/W emulsification and solvent evaporation as a drug delivery system. The microspheres were spherical, free-flowing and non-aggregated. The CCAM had good flow and suspension ability. The loading efficiency of different model drugs increased with the increasing hydrophobicity of the drug. The loading efficiency of 6-mercaptopurine (6-MP) was more than 30% whereas that of ranitidine hydrochloride (RT) or acetaminophen (ACP) was only 10%. The pH values of solution affected the swelling ability of CCAM and the relative humidity had little effect on the characteristics of CCAM when it was not more than 75%. The CCAM system had a good effect on the controlled release of different model drugs. However, the release rate became slower with the increase of the hydrophobicity of drugs. The release rate of CCAM loaded with hydrophilic RT was almost 60% during 48 h and the release rate of CCAM loaded with hydrophobic drug of 6-MP was not more than 30%. In the meantime, the CCAM system was degradable in vitro and the degradation rate was faster in lysozyme solution than that in the medium of PBS. So the CCAM system was a degradable promising drug delivery system especially for hydrophobic drugs.     

Sustained release optimized formulation of anastrozole-loaded chitosan microspheres: in vitro and in vivo evaluation

The purpose of this study was to develop sustained release formulation of anastrozole-loaded chitosan microspheres for treatment of breast cancer. Chitosan microspheres cross-linked with two different cross-linking agents viz, tripolyphosphate (TPP) and glutaraldehyde (GA) were prepared using single emulsion (w/o) method. A reverse phase HPLC method was developed and used for quantification of drug in microspheres and rat plasma. Influence of cross-linking agents on the properties of chitosan microspheres was extensively investigated. Formulations were characterized for encapsulation efficiency (EE), compatibility of drug with excipients, particle size, surface morphology, swelling capacity, erosion and drug release profile in phosphate buffer pH 7.4. EE varied from 30.4 ± 1.2 to 69.2 ± 3.2% and mean particle size distribution ranged from 72.5 ± 0.5 to 157.9 ± 1.5 μm. SEM analysis revealed smooth and spherical nature of microspheres. TPP microspheres exhibited higher swelling capacity, percentage erosion and drug release compared to GA microspheres. Release of anastrozole (ANS) was rapid up to 4 h followed by slow release status. FTIR analysis revealed no chemical interaction between drug and polymer. DSC analysis indicated ANS trapped in the microspheres existed in amorphous form in polymer matrix. The highest correlation coefficients (R ²) were obtained for Higuchi model, suggesting a diffusion controlled mechanism. There was significant difference in the pharmacokinetic parameters (AUC_0−∞, Kel and t_1/2) when ANS was formulated in the form of microspheres compared to pure drug. This may be attributed to slow release rate of ANS from chitosan microspheres and was detectable in rat plasma up to 48 h which correlates well with the in vitro release data.     

Preparation and characterization of novel multi-core chitosan microspheres for stomach-specific delivery of hydrophilic antibiotics

Insufficient gastric mucosa drug concentration and short contact time were the main reason for the lack of eradication efficacy of Helicobacter pylori for peptic ulcer patients. Novel multi-core chitosan microspheres were prepared for stomach-specific delivery of hydrophilic antibiotics for the treatment of peptic ulcer. Chitosan microspheres with multiple Eudragit L100 cores were easily prepared by a new emulsification/coagulation encapsulating method. Swelling behaviors, surface amino groups and mucin absorption ability were investigated and the formulation that showed best mucoadhesive potential was adopted. The multi-core chitosan microspheres exhibited good mucoadhesiveness as well as controlled release manner for incorporated antibiotics in acidic environment. The release rate could be easily modulated with accumulative release ranging from 47.3 to 79.3% in 6 h. Accordingly, the multi-core chitosan microspheres could serve as a satisfactory vehicle for stomach-specific delivery of hydrophilic antibiotics.     

Ondansetron-loaded chitosan microspheres for nasal antiemetic drug delivery: an alternative approach to oral and parenteral routes

Background: The aim of this study was to develop chitosan microspheres for nasal delivery of ondansetron hydrochloride (OND). Method: Microspheres were prepared with spray-drying method using glutaraldehyde as the crosslinking agent. Microspheres were characterized in terms of morphology, particle size, zeta potential, production yield, drug content, encapsulation efficiency, and in vitro drug release. Results: All microspheres were spherical in shape with smooth surface and positively charged. Microspheres had also high encapsulation efficiency and the suitable particle size for nasal administration. In vitro studies indicated that all crosslinked microspheres had a significant burst effect, and sustained drug release pattern was observed until 24 hours following burst drug release. Nasal absorption of OND from crosslinked chitosan microspheres was evaluated in rats, and pharmacokinetic parameters of OND calculated from nasal microsphere administration were compared with those of both nasal and parenteral administration of aqueous solutions of OND. In vivo data also supported that OND-loaded microspheres were also able to attain a sustained plasma profile and significantly larger area under the curve values with respect to nasal aqueous solution of OND. Conclusion: Based on in vitro and in vivo data, it could be concluded that crosslinked chitosan microspheres are considered as a nasal delivery system of OND.     

Aqueous Preparation and Evaluation of Albumin‐Chitosan Microspheres Containing Indomethacin

Controlled‐release egg albumin‐chitosan microspheres containing indomethacin as a model drug were successfully prepared by coacervation method. The proposed method can offer a simple method for microsphere preparation in an aqueous system with the elimination of the use of organic solvents that are usually needed in conventional techniques of microencapsulation. The interaction between negatively charged egg albumin molecules in phosphate buffer, pH 7.2, or sodium hydroxide solution and positively charged chitosan molecules dissolved in diluted acetic acid to form an insoluble precipitate was the principle for the formation of the microspheres. The effects of many process variables, such as amount of formaldehyde as a cross‐linking agent, stirring time, final pH of encapsulation medium, initial drug loading, and albumin concentration or albumin‐to‐chitosan weight ratio, on the properties of the prepared microspheres were investigated. Incorporation efficiencies of the microspheres to the drug were high in most cases and ranged between 63.3 ± 3.6% and 92.39 ± 3.2%, while particle sizes were 435.2 ± 12.6 up to 693.9 ± 34.6 µm for the different tested batches. On the other hand, the values of angles of repose and compressibility indices were in the range of 23.5 ± 0.4 to 32.0 ± 0.7 degrees and 11.1 ± 0.7% to 23.6 ± 0.7% respectively, which indicate overall good free flowing nature of the microspheres of all batches. The maximum required amount of the cross‐linking agent was determined to avoid excessive unnecessary chemicals. It was also noticed that excessive time of stirring and excessive initial drug loading are not recommended as it may lead to microspheres of low properties. The pH of the encapsulation media (pH 3.77 up to pH 4.91) significantly affected the properties of the microspheres. As the pH of the encapsulation media was increased, the incorporation efficiency, particle size, and flowability decreased, along with increase of drug release rate, which could be related to incomplete cross linking of the microspheres matrix. It was also observed that high concentration of albumin solution and accordingly the increase of albumin‐to‐chitosan weight ratio were accompanied with increases in incorporation efficiency and particle size with improved microsphere flowability and slow indomethacin release. Thus, the proposed microspheres showed the ability to control the release of indomethacin, and their properties were highly affected by many process variables that could be controlled to obtain an optimized system.     

Release behavior and kinetic evaluation of berberine hydrochloride from ethyl cellulose/chitosan microspheres

Novel ethyl cellulose/chitosan microspheres （ECCMs） were prepared by the method of w/o/w emulsion and solvent evaporation. The microspheres were spherical, adhesive, and aggregated loosely with a size not bigger than 5 pm. The drug loading efficiency of berberine hydrochloride （BH） loaded in microspheres were affected by chitosan （CS） concentration, EC concentration and the volume ratio of V（CS）/V（EC）. ECCMs prepared had sustained release efficiency on BH which was changed with different preparation parameters. In addition, the pH value of release media had obvious effect on the release character of ECCMs. The release rate of BH from sample B was only a little more than 30% in diluted hydrochloric acid （dHCl） and that was almost 90% in PBS during 24 h. Furthermore, the drug release data were fitted to different kinetic models to analyze the release kinetics and the mechanism from the microspheres. The released results of BH indicated that ECCMs exhibited non-Fickian diffusion mechanism in dHCI and diffusion-controlled drug release based on Fickian diffusion in PBS. So the ECCMs might be an ideal sustained release system especially in dHCl and the drug release was governed by both diffusion of the drug and dissolution of the polymeric network.     

Formulation and In Vitro Evaluation of Bisphosphonate Loaded Microspheres for Implantation in Osteolysis

ABSTRACT

Chitosan and poly(lactide-co-glycolide) acid (PLGA) microspheres loaded with alendronate sodium (AS) were prepared for orthopedic as well as dental applications. In orthopedics the aim was to make the total joint prostheses stay in the body for a long time without causing bone tissue loss, while in dentistry it was aimed to treat the alveolar bone resorption caused by periodontitis and also to make the dental treatment using implants easier by reducing the bone loss in patients with osteoporosis. Solvent evaporation method was used to prepare AS loaded PLGA microspheres and emulsion polimerization method was used to prepare AS loaded chitosan microspheres. Particle size, loading efficacy, surface characteristics, and in vitro release characteristics were examined on prepared formulations. After the examination of the scanning electron microscopy photographs of microspheres, chitosan microspheres were observed to have spherical structure and smooth surface characteristics while PLGA microspheres were observed to have spherical porous surface structure. Loading efficacy was found to be 3.30% for chitosan microspheres and 7.70% for PLGA microspheres. It was observed that 85% of AS had been released at the end of the third day from chitosan microspheres whereas 58% was released at the end of the fifth day from PLGA microspheres. It was found that chitosan microspheres gave first order release while PLGA microspheres gave zero order release.     

预交联法制备海藻酸钠复合微球及其缓释性能

采用预交联法制备海藻酸钠(SA)/凹土(ATP)复合微球(PCM)以克服常规制备方法导致微球交联不均匀的缺陷,从而改善微球的缓释性能。将ATP先与Ca~(2+)进行部分离子交换制备Ca~(2+)-ATP,然后在与SA复合过程中同时进行预交联形成交联密度有所提高的微球内核,再采用滴注法制备该复合微球。利用红外光谱、扫描电镜和电子照片对微球结构和形貌进行表征,考察了Ca~(2+)浓度对PCM力学强度、溶胀率、载药和缓释性能的影响。结果表明,PCM在1h的累计释放率由预交联前的68%降为50%,显著改善了微球的"突释"。释放动力学研究表明,微球的释药可用Ritger-Peppas方程很好地拟合,释药速率受骨架溶蚀和药物扩散双重控制。     

Improvement of dissolution behavior of poorly water soluble drugs by biodegradable polymeric submicron carriers containing sparingly methylated β-cyclodextrin

The objective of this study was to develop submicron carriers of two drugs that are practically insoluble in water, i.e. meloxicam and aceclofenac, to improve their dissolution behavior. The phase solubility of the drugs was studied using different concentrations of sparingly methylated β-cyclodextrin, Kleptose^® Crysmeβ (Crysmeb), in the presence and absence of 0.2 % w/v water-soluble chitosan. Drug-loaded submicron particles (SMPs) were prepared using chitosan chlorhydrate and Crysmeb by the ionotropic gelation method. The SMPs were characterized in terms of powder X-ray diffraction, Fourier transforms infrared spectroscopy, size determination, process yield, drug loading, encapsulation efficiency, surface morphology and in vitro release. The drug loading in the SMPs was enhanced in the presence of Crysmeb. The in vitro drug release was found to be enhanced with SMPs prepared using higher concentrations of Crysmeb. These results indicate that SMPs formed from chitosan chlorhydrate and Crysmeb are promising submicron carriers for enhancing the dissolution of meloxicam and aceclofenac.     

Formulation and in vitro evaluation of bisphosphonate loaded microspheres for implantation in osteolysis

Chitosan and poly(lactide-co-glycolide) acid (PLGA) microspheres loaded with alendronate sodium (AS) were prepared for orthopedic as well as dental applications. In orthopedics the aim was to make the total joint prostheses stay in the body for a long time without causing bone tissue loss, while in dentistry it was aimed to treat the alveolar bone resorption caused by periodontitis and also to make the dental treatment using implants easier by reducing the bone loss in patients with osteoporosis. Solvent evaporation method was used to prepare AS loaded PLGA microspheres and emulsion polimerization method was used to prepare AS loaded chitosan microspheres. Particle size, loading efficacy, surface characteristics, and in vitro release characteristics were examined on prepared formulations. After the examination of the scanning electron microscopy photographs of microspheres, chitosan microspheres were observed to have spherical structure and smooth surface characteristics while PLGA microspheres were observed to have spherical porous surface structure. Loading efficacy was found to be 3.30% for chitosan microspheres and 7.70% for PLGA microspheres. It was observed that 85% of AS had been released at the end of the third day from chitosan microspheres whereas 58% was released at the end of the fifth day from PLGA microspheres. It was found that chitosan microspheres gave first order release while PLGA microspheres gave zero order release.     

Preparation and characterization of theophylline loaded chitosan/β-cyclodextrin microspheres

The purpose of this project was to develop sustained release chitosan/β-cyclodextrin microspheres of theophylline (TH) prepared by spray drying method. The effect of several formulation variables on the characteristics of microspheres was studied. The B microspheres had a narrower particle size distribution with the diameter between l and 10 μm. SEM showed spherical microspheres with smooth or slightly wrinkled surfaces. FT-IR spectroscopy revealed that hydrogen bonds were formed between TH and chitosan or β-cyclodextrin. The drug entrapments significantly increased from 13.33 to 35.70% with an increase of the ratio of drug/polymer. The encapsulation efficiencies were from 85.16 to 91.40%. The in vitro release of TH from microspheres was related to the pH of the medium, swelling ability, especially in the ratio of drug/polymer. The B microspheres had a prolonged release pattern with the release rate of 60.20% (pH 6.8) within 8 h.     

Controlled dual release of hydrophobic and hydrophilic drugs from electrospun poly(l-lactic acid) fiber mats loaded with chitosan microspheres

This work is to develop novel electrospun poly(l-lactic acid) (PLLA) fiber mats for controllable delivery of hydrophobic and hydrophilic drugs. For this aim, bovine serum albumin (BSA, used as a hydrophilic model drug) was firstly enveloped into chitosan microspheres by spray drying. Benzoin (used as a hydrophobic model drug) was directly dissolved in PLLA solution and then the chitosan microspheres were suspended into the PLLA solution, which was used to prepare PLLA fiber mats by electrospinning. Polyvinylpyrrolidone (PVP) was added into the PLLA solution to tune the drug release behaviors. The results showed that the chitosan microspheres were uniformly distributed in the fibers. BSA had a short-term release while benzoin had a long-term and sustained release in all the dual drug delivery systems, and the release of both hydrophobic and hydrophilic drugs could be adjusted by changing the ratio of PVP/PLLA.     

Control of drug loading efficiency and drug release behavior in preparation of hydrophilic-drug-containing monodisperse PLGA microspheres

We prepared monodisperse poly(lactide-co-glycolide) (PLGA) microspheres containing blue dextran (BLD)—a hydrophilic drug—by membrane emulsification technique. The effects of electrolyte addition to the w₂ phase and significance of the droplet size ratio between primary (w₁/o) and secondary (w₁/o/w₂) emulsions during the preparation of these microspheres was examined. The droplet size ratio was evaluated from the effect of stirring rate of the homogenizer when preparing the primary emulsion. The drug loading efficiency of BLD in these microspheres increased with stirring rate. It increased to approximately 90% when 2.0% NaCl was added to the w₂ phase. Drug release from these microspheres was slower than that when they were prepared without electrolyte addition. Despite the very high efficiency drug release was gradual because BLD was distributed at the microspheres core. Relatively monodisperse hydrophilic-drug-containing PLGA microspheres with controlled drug loading efficiency and drug release behavior were prepared.     

The Effect of Chitosan Molecular Weight on the Characteristics of Spray-Dried Methotrexate-Loaded Chitosan Microspheres for Nasal Administration

In this article, the effect of the chitosan molecular weight (MW) on the characteristics of methotrexate (MTX)-encapsulated non-cross-linked chitosan microspheres was studied. Microspheres composed of low-molecular-weight (LMW, 40,000 Da), medium-molecular-weight (MMW, 480,000 Da) and high-molecular-weight (HMW, 850,000 Da) chitosan with the same degree of deacetylation (96%) were obtained by a simple spray-drying method. The MW of chitosan had a noticeable influence on the size distribution, encapsulation efficiency, micromeritic properties (angle of repose and bulk density), controlled release behavior, and mucoadhesive properties. The entrapment efficiencies were in the range of 90–99%. Spray-dried microspheres had a D₅₀ value of 3.3–4.9 μm, which was suitable for nasal insufflations. The microspheres with LMW chitosan have the best flowability and highest bulk density but were found to be poor in terms of adhesion and in controlling the release behavior of MTX. The MMW chitosan microspheres exhibited the strongest adhesion to the mucosal surface, and the angle of repose values were between 34 and 47 degrees. They could control the release rate by modifying the drug/polymer ratios. Microspheres with HMW chitosan exhibited a lower adhesion than MMW chitosan and a lower release rate of MTX. The physical state of MTX in the chitosan matrix was studied by differential scanning calorimetry, which indicated the presence of a solid dispersion of the amorphous drug in the chitosan matrix. Nasal ciliotoxity showed only minor cilia irritation due to the microspheres, and consequently, they are suitable for nasal drug delivery.     

Multiparticulate Drug Delivery System for the Treatment of Diabetes Mellitus: In Vitro and In Vivo Evaluation

Biodegradable microspheres of poly(?)caprolactone were prepared by solvent evaporation method for controlled release of repaglinide. The prepared microspheres were spherical in shape having smooth surface. The average diameter was in the range of 24 to 31.04 µm. Drug entrapment efficiency of the prepared microspheres was in the range of 68.81% to 79.30%. Differential scanning calorimetry and x-ray diffraction analyses indicated the amorphous dispersion of drug in the microspheres. The drug release was continued up to 24 h depending upon the formulation variables; drug release was slow from the microspheres which were prepared with higher concentration of polymer and as the initial drug loading was increased, the drug release was also increased. A non-Fickian transport was the mechanism of drug release for all the microspheres. The in vivo anti-diabetic activity performed on steptozotocin induced rats indicated that the plain repaglinide has shown maximum percentage of reduction in blood glucose at the end of 3 h and then the percentage of reduction in blood glucose was decreased. While in case of rats treated with PCL5 microspheres, the percentage of reduction in glucose level was slow as compared to plain repaglinide within 3 h, but it was gradually increased to 74.86% at the end of 24 h.     

Controlled drug delivery systems based on thiolated chitosan microspheres

The aim of the present study was to verify the potential of chitosan-thio-butyl-amidine (TBA) microspheres as carrier systems for controlled drug delivery. In this study microspheres were prepared utilizing water in oil (w/o) emulsification solvent evaporation technique. A concentration of 0.5% of chitosan-TBA conjugate displaying 100 µM thiol groups per gram polymer was used in the aqueous phase of the emulsion in order to prepare microspheres. The obtained non-aggregated free-flowing microspheres were examined with conventional light microscope as well as scanning electron microscopy (SEM). The microscopic images indicated that the prepared chitosan-TBA microspheres were of spherical shape and smooth surface while microparticles obtained from the unmodified chitosan were of porous structure and non-spherical shape. Particle size distribution was determined to be in the range from 1 to 59 µm. The free thiol group content of chitosan-TBA microspheres prepared with an aqueous phase of pH 2, 5, and 6.5 were determined to be 71.4, 49.4, and 8.2 µM/g polymer, respectively. Furthermore, results attained from in vitro release studies with fluorescein isothiocyanate labelled dextran (FITC-dextran) loaded chitosan-TBA microspheres showed a controlled release rate for more than three hours while the control reached the maximum peak level of release already within an hour. According to these results, chitosan-TBA microspheres seem to be a promising tool in transmucosal drug delivery for poorly absorbed therapeutic agents.     

Controlled Drug Delivery Systems Based on Thiolated Chitosan Microspheres

The aim of the present study was to verify the potential of chitosan-thio-butyl-amidine (TBA) microspheres as carrier systems for controlled drug delivery. In this study microspheres were prepared utilizing water in oil (w/o) emulsification solvent evaporation technique. A concentration of 0.5% of chitosan-TBA conjugate displaying 100 µM thiol groups per gram polymer was used in the aqueous phase of the emulsion in order to prepare microspheres. The obtained non-aggregated free-flowing microspheres were examined with conventional light microscope as well as scanning electron microscopy (SEM). The microscopic images indicated that the prepared chitosan-TBA microspheres were of spherical shape and smooth surface while microparticles obtained from the unmodified chitosan were of porous structure and non-spherical shape. Particle size distribution was determined to be in the range from 1 to 59 µm. The free thiol group content of chitosan-TBA microspheres prepared with an aqueous phase of pH 2, 5, and 6.5 were determined to be 71.4, 49.4, and 8.2 µM/g polymer, respectively. Furthermore, results attained from in vitro release studies with fluorescein isothiocyanate labelled dextran (FITC-dextran) loaded chitosan-TBA microspheres showed a controlled release rate for more than three hours while the control reached the maximum peak level of release already within an hour. According to these results, chitosan-TBA microspheres seem to be a promising tool in transmucosal drug delivery for poorly absorbed therapeutic agents.