Biodegradable Microparticulates of Beta-Estradiol: Preparation and In Vitro Characterization

ABSTRACT

Beta-estradiol has been recommended for the long-term therapy of osteoporosis and its oral formulations are subjected to intensive first pass metabolism. The present investigation was aimed at preparing and characterizing biodegradable microparticles of beta-estradiol with polymers such as PLA, PLGA 85/15, PLGA 75/25, and their mixtures. The microparticles were prepared by solvent evaporation method using methylene chloride as a solvent and polyvinyl alcohol as a surfactant. The drug-polymer ratios were 1:3, 1:5, and 1:7. The prepared microparticles (twelve formulations) were tested for encapsulation efficiency and in vitro drug release in 50% methyl alcohol/phosphate buffer pH 7.4. The results showed that the encapsulation efficiency varied from 81 to 100% and the formulation fabricated from PLGA 85/15 (1:3) showed less burst and consistent long time release. This formulation when further characterized displayed irregular spherical shape with an average particle size of 72 µm. The crystallinity of the drug was reduced when investigated using X-ray diffractometry. No chemical interaction between the drug and the polymer was observed as evidenced by FT-IR analysis. The results indicated that beta-estradiol biodegradable microparticles with PLGA 85/15 (1:3) could be a suitable approach for long term therapy of osteoporosis.     

Polymeric nanospheres fabricated with natural emulsifiers for clinical administration of an anticancer drug paclitaxel (Taxol®)

Paclitaxel (Taxol®) is one of the most effective anticancer drugs found from nature in recent decades, which can treat various cancers including ovarian, breast, brain, colon and lung cancer, and AIDS-related cancer. Due to its low aqueous solubility, adjuvants such as Cremophor EL, which causes serious side effects, have to be used in its administration. Our aim is to develop an alternative delivery system to achieve better therapeutic effects with minimum side effects. Paclitaxel-loaded nanospheres of biodegradable polymers were prepared by an improved solvent extraction/evaporation technique. Phospholipids, cholesterol and vitamins were used to replace traditional chemical emulsifiers to achieve high encapsulation efficiency (EE) and desired release rate of the drug. Nanospheres prepared under various conditions are characterized by the light scattering for size and size distribution, the scanning electron microscopy (SEM) and the atomic force microscopy (AFM) for surface morphology; differential scanning calorimetry (DSC) for the physical status of the drug within the polymeric matrix; the zeta-potential measurement for the surface charge properties; and X-ray photoelectron spectroscopy (XPS) for the surface chemistry. In-vitro release kinetics were measured by high-performance liquid chromatography (HPLC). Best design was pursued to develop a product for cancer chemotherapy.     

Preparation and characterization of novel sinomenine microcapsules for oral controlled drug delivery

Background: Developing a sustained release drug to cure arthritis is needed. Sinomenine (SIN) is abstracted from sinomenium acutum and widely used in the treatment of various rheumatism and arrhythmia with few side effects. The primary aim of this study is to develop SIN microcapsules with polyelectrolyte multilayers for controlled drug release. Method: SIN microcrystals were encapsulated with chitosan, gelatin, and alginate by layer-by-layer technique, such as (gelatin/alginate)₄ and (chitosan/alginate)₆. The size distribution, zeta-potential, stability, and morphology of the microcapsules were characterized by a particle size analyzer, zetasizer, ultraviolet spectroscopy, and transmission electron microscope, respectively. The in vitro controlled release pattern of SIN was studied using a diffusion cell assembly at physiological pH of 6.8 or 1.4. Results: Light stability of these microcapsules was improved after microencapsulation. Compared with release rate of the SIN microcapsules coated by the poly(dimethyldiallyl ammonium chloride)/alginate and gelatin/alginate multilayers, release rate of the SIN microcapsules coated with chitosan/alginate multilayers was fast. Release rate progressively decreased with the increase of chitosan/alginate bilayer number and the decrease of pH value of release medium. Conclusion: These novel SIN microcapsules may be developed into oral controlled drug delivery for rheumatism and arthritis.     

生物可降解聚乳酸骨科材料研究进展

在骨外科中，聚乳酸中已成为十分重要的生物可降解高分子材料，用作为固定器材，骨诱生支撑体和药物控制缓释材料，本文树其研究进展作了综合评述，对存在问题也进行了一些讨论。     

Sildenafil vaginal suppositories: preparation,characterization, in vitro and in vivo evaluation

Aim: The main objective was to investigate the in vitro release profile/kinetics, and in vivo plasma pharmacokinetics (PK) and organ biodistribution (BD) of the prepared sildenafil vaginal suppositories (SVS).

Methods: Suppositories containing 25?mg of sildenafil were prepared by the cream melting technique using Witepsol H-15 as a suppository base. The suppositories were characterized for weight variation, content uniformity, hardness, disintegration time and crystallinity change. The in vitro dissolution in pH 4.5, and in vivo plasma PK and organ BD of sildenafil from SVS in female Sprague Dawley rats, were also investigated.

Results: The mean weight variation, content uniformity, hardness and disintegration time of the prepared SVS were 1.127?±?0.020?g, 98.25?±?2.50%, 2.5?±?0.08?kg and 9?±?1.0?min, respectively. The release of sildenafil from the SVS was more than 90% at 30?min, with a release kinetic of Hixson--Crowell model and non-Fickian diffusion (n?=?0.464). The plasma PK study demonstrated a significantly lower C_max (～10 times) and AUC_0–24?h (～13 times) of sildenafil in plasma following intravaginal (IVG) administration of suppositories compared to oral (PO) administration of sildenafil solution. Nevertheless, the organ BD study showed a phenomenally higher C_max (～40 times) and AUC_0–24?h (～20 times) of sildenafil in uterus following IVG administration of suppositories than PO administration of sildenafil solution.

Conclusion: This study demonstrated enhanced sildenafil exposure in the uterus following IVG administration of SVS, which could be used to target the uterus for therapeutic benefits.     

Development of ocular drug delivery systems using molecularly imprinted soft contact lenses

Recently, significant advances have been made in order to optimize drug delivery to ocular tissues. The main problems in ocular drug delivery are poor bioavailability and uncontrollable drug delivery of conventional ophthalmic preparations (e.g. eye drops). Hydrogels have been investigated since 1965 as new ocular drug delivery systems. Increase of hydrogel loading capacity, optimization of drug residence time on the ocular surface and biocompatibility with the eye tissue has been the main focus of previous studies. Molecular imprinting technology provided the opportunity to fulfill the above-mentioned objectives. Molecularly imprinted soft contact lenses (SCLs) have high potentials as novel drug delivery systems for the treatment of eye disorders. This technique is used for the preparation of polymers with specific binding sites for a template molecule. Previous studies indicated that molecular imprinting technology could be successfully applied for the preparation of SCLs as ocular drug delivery systems. Previous research, particularly in vivo studies, demonstrated that molecular imprinting is a versatile and effective method in optimizing the drug release behavior and enhancing the loading capacity of SCLs as new ocular drug delivery systems. This review highlights various potentials of molecularly imprinted contact lenses in enhancing the drug-loading capacity and controlling the drug release, compared to other ocular drug delivery systems. We have also studied the effects of contributing factors such as the type of comonomer, template/functional monomer molar ratio, crosslinker concentration in drug-loading capacity, and the release properties of molecularly imprinted hydrogels.     

温度敏感型可生物降解高分子凝胶的研究进展

温度敏感型高分子凝胶因能随环境温度的变化发生可逆的相变或体积变化而被作为药物控释体系的载体之一,成为近年来研究的热点.但目前许多温敏型凝胶的非生物降解性限制了其在生物医学领域中的实际应用.因此,在温敏聚合物中引入生物降解性物质,使凝胶同时具有温敏和生物降解功能,将其用于药物释放体系,具有广阔的应用前景.结合近年来的研究报道,阐述了几类重要的温敏可生物降解凝胶及其在药物控制释放中的应用.     

Cholesterol derivative-based liposomes for gemcitabine delivery: preparation,in vitro,and in vivo characterization

As an anti-tumor drug, gemcitabine (Gem) is commonly used for the treatment of non-small cell lung cancer and pancreatic cancer. However, there are several clinical drawbacks to using Gem, including its extremely short plasma half-life and side effects. To prolong its half-life and reduce its side effects, we synthesized a derivative of Gem using cholesterol (Chol). This derivative, called gemcitabine-cholesterol (Gem-Chol), was entrapped into liposomes by a thin-film dispersion method. The particle size of the Gem-Chol liposomes was 112.57?±?1.25?nm, the encapsulation efficiency was above 99%, and the drug loading efficiency was about 50%. In vitro studies revealed that the Gem-Chol liposomes showed delayed drug release and long-term stability at 4?°C for up to 2 months. In vivo studies also showed the superiority of the Gem-Chol liposomes, and compared with free Gem, the Gem-Chol liposomes had longer circulation time. Moreover, an anti-tumor study in H₂₂ and S180 tumor models showed that liposomal entrapment of Gem-Chol improved the anti-tumor effect of Gem. This study reports a potential formulation of Gem for clinical application.     

Hydrogel containing dexamethasone-loaded nanocapsules for cutaneous administration: preparation,characterization, and in vitro drug release study

Context: Our group previously reported the development of dexamethasone-loaded polymeric nanocapsules as an alternative for topical dermatological treatments. Objective: Our study aimed to prepare and characterize a hydrogel containing this system to improve the effectiveness of the glucocorticoid for cutaneous disorders. Methods: For the antiproliferative activity assay, a dexamethasone solution and D-NC were tested on Allium cepa root meristem model. D-NC were prepared by the interfacial deposition of preformed polymer. Hydrogels were prepared using Carbopol Ultrez® 10 NF, as polymer, and characterized according to the following characteristics: pH, drug content, spreadability, viscosity, and in vitro drug release. Results and Discussion: Nanocapsules showed mean particle size and zeta potential of 201 ± 6 and ?5.73 ± 0.42 nm, respectively. They demonstrated a lower mitotic index (4.62%) compared to free dexamethasone (8.60%). Semisolid formulations presented acidic pH values and adequate drug content (between 5.4% and 6.1% and 100% and 105%, respectively). The presence of nanocapsules in hydrogels led to a decrease in their spreadability factor. Intact nanoparticles were demonstrated by TEM as well as by dynamic light scattering (mean particle size < 300 nm). In vitro studies showed a controlled dexamethasone release from hydrogels containing the drug associated to the nanocapsules following the Higuchi's squared root model (k = 20.21 ± 2.96 mg/cm²/h^1/2) compared to the hydrogels containing the free drug (k = 26.65 ± 2.09 mg/cm²/h^1/2). Conclusion: Taking all these results together, the hydrogel containing D-NC represent a promising approach to treat antiproliferative-related dermatological disorders.     

聚乳酸类可生物降解材料在缓控释药物制剂中的应用

综述了用聚乳酸类可生物降解型高分子材料制备缓控释药物载体的研究现状.分别介绍了该类材料在微粒给药载体、凝胶制剂、缓释支架和埋植制剂的应用及其制备方法.阐述了目前聚乳酸类生物降解材料在缓控释药物制剂中的主要问题,展望了其发展前景.     

制备方法对高分子载药涂层结构和体外释放动力学的影响

分别采用浸涂法和喷涂法在316L不锈钢基体表面制备含雷帕霉素的丙烯酸树脂缓释涂层,并使用FTIR、SEM及DSC对涂层中雷帕霉素的物化状态进行了测试和分析,测试了上述两种方法制备的药物洗脱支架的体外药物释放动力学曲线,并分析了两种制备方法之间的差异.结果表明上述两种方法制备的含药涂层药物分布状态存在一定差异,药物释放速率有所不同,以浸涂法制备的含药涂层释放速率更快.     

Double-walled microspheres loaded with meglumine antimoniate: preparation,characterization and in vitro release study

Objective: The objective of this study was to fabricate double-walled poly(lactide-co-glycolide) (PLGA) microspheres to increase encapsulation efficiency and avoid rapid release of hydrophilic drugs such as meglumine antimoniate.

Methods: In this study, double-walled and one-layered microspheres of PLGA were prepared using the emulsion solvent evaporation technique to better control the release of a hydrophilic drug, meglumine antimoniate (Glucantime®), which is the first choice treatment of cutaneous leishmaniasis. The effect of hydrophobic coating on microspheres' size, morphology, encapsulation efficiency and drug release characteristics was evaluated. Furthermore, the presence of antimony in meglumine antimoniate made it possible to observe the drug distribution within the microspheres' cross section by means of energy dispersive X-ray spectroscopy.

Results: Drug distribution images confirmed accumulation of the drug within the inner core of double-walled microspheres. In addition, these microspheres encapsulated the drug more efficiently up to 87% and demonstrated reduced initial burst and prolonged release compared to one-layered microspheres. These superiorities make double-walled microspheres an optimum candidate for sustained delivery of hydrophilic drugs.

Conclusion: Double-walled microspheres provide some advantages over traditional microspheres overcoming most of their limitations. Double-walled microspheres were found to be more efficient than their corresponding one-layered microspheres in terms of encapsulation efficiencies and release characteristics.     

Design and in vitro characterization of buccoadhesive tablets of timolol maleate

Objective: The purpose of this work was to develop and evaluate buccoadhesive tablets of timolol maleate (TM) due to its potential to circumvent the first-pass metabolism and to improve its bioavailability.

Methods: The tablets were prepared by direct compression using two release modifying polymers, Carbopol 974P (Cp-974p) and sodium alginate (SA). A 3² full factorial design was employed to study the effect of independent variables, Cp-974p and SA, in various proportions in percent w/w, which influences the in vitro drug release and bioadhesive strengths. Physicochemical properties of the drug were evaluated by ultraviolet, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and powder X-ray diffraction (P-XRD). Tablets were evaluated for hardness, thickness, weight variation, drug content, surface pH, swelling index, bioadhesive force and in vitro drug release.

Results: The FTIR and DSC studies showed no evidence of interactions between drug, polymers and excipients. The P-XRD study revealed that crystallinity of TM remain unchanged in optimized formulation tablet. Formulation F9 achieves an in vitro drug release of 98.967%?±?0.28 at 8?h and a bioadhesive force of 0.088 N?±?0.01211.

Conclusion: We successfully developed buccal tablet formulations of TM and describe a non-Fickian-type anomalous transport as the release mechanism.     

The role of fillers and sodium metabisulfite on drug release from aged polyox tablets

Polyethylene oxides (PEOs) are extensively used to control the release rate of drugs from matrices. Unfortunately, polyox polymers are prone to oxidation under high temperature and relative humidity. The aim of this study was to investigate the effect of sodium metabisulfite as an antioxidant to overcome the drug release changes from polyox matrices (PEO 301 and 303) when stored at 40?°C. The effect of different types of fillers (lactose, mannitol and dicalcium phosphate dihydrate) on stability of diltiazem HCl release profiles was also investigated. Generally, the presence of sodium metabisulfite stabilized the release of drug from PEO matrices stored at 40?°C for 8 weeks. Whilst the absence of metabisulfite caused an increase in drug release from polyox matrices when stored at 40?°C. The results indicate that all three concentrations (0.25, 0.5 and 1% w/w) of sodium metabisulfite were able to overcome structural changes of polyox samples hence stabilizing the drug release. The results also showed that the incorporation of fillers in polyox matrices reduced the sensitivity of drug release when stored at elevated temperature. This indicates that when these excipients were used there was no need to incorporate additional antioxidant. DSC results showed that there was no difference in the melting points of fresh polyox samples and aged polyox samples containing sodium metabisulfite, whereas the melting point of aged polyox samples without sodium metabisulfite were lower than fresh polyox samples. This indicates that the presence of metabisulfite is essential to stabilize polyox samples.     

Comparative in vitro Study on Pure Metals(Fe,Mn,Mg,Zn and W) as Biodegradable Metals

Five pure metals including Fe,Mn,Mg,Zn and W have been investigated on their corrosion behavior and in vitro biocompatibility by electrochemical measurement,static immersion test,contact angle measurement, cytotoxicity and hemocompatibility tests.It is found that the sequence of corrosion rate of five metals in Hank’s solution from high to low is:Mg > Fe > Zn > Mn > W.Fe,Mg and W show no cytotoxicity to L929 and ECV304 cells,Mn induces significant cytotoxicity to both L929 and ECV304 cells,and Zn has almost no inhibition effect on the metabolic activities of ECV304 while largely reduces the cell viability of L929 cells. The hemolysis percentage of five pure metals is lower than 5%except for Mg and platelets adhered on Zn has been activated and pseudopodia-like structures can be observed while platelets on the other four metals keep normal.     

Ketoprofen 1-alkylazacycloalkan-2-one esters as dermal prodrugs: in vivo and in vitro evaluations

Six new 1-alkylazacycloalkan-2-one esters of ketoprofen (1-6) were synthesized and evaluated as potential dermal prodrugs of ketoprofen. Their lipophilicity by both experimental lipophilicity indices (log k') and calculated ClogP was also determined. In vitro experiments were carried out to evaluate the chemical and enzymatic stability and permeation through excised human skin of these new ketoprofen derivatives. Furthermore, we investigated the in vivo topical anti-inflammatory activity of ester 5, which showed the best in vitro profile, evaluating the ability of this compound to inhibit methyl nicotinate-induced skin erythema on healthy human volunteers. Esters 1-6 showed increased lipophilicity compared with the parent drug (ketoprofen), good stability in phosphate buffer pH 7.4, and were readily hydrolyzed by porcine esterase. Results from in vitro percutaneous absorption studies showed that, among all esters synthesized, only for esters 1 and 5 did a higher cumulative amount of drug penetrate through the skin, compared with that obtained after topical application of ketoprofen. In vivo results showed an interesting delayed and sustained activity of ester 5, compared with the parent drugs.     

The structure and properties of materials used in advanced drug delivery systems

The various requirements placed on materials that might serve as suitable components in drug delivery systems are discussed. Special attention is paid to the interactions between the drug delivery constructs and the biological environment, using the interactions in the vascular compartment of the body as an example. Two alternative general approaches are compared: (a) “controlled drug release”, which aims to reduce or eliminate side effects by producing a steady therapeutic concentration of drug in the body; (b) “site-selective drug delivery”, which aims to ensure that the drug is delivered to the site of its biochemical and disease-related site of action, at the same time maintaining the drug inactive elsewhere in the body. It is concluded that materials for delivering drugs to selected sites of disease within the body must be designed to utilise the unique features (structure, function, rhythm) of the main elements involved in the disease. Equally important is to design drug carriers that do not interact non-specifically within the body so that their specific action would be prevented. It is difficult to see how this could be achieved using materials entirely “foreign” to the body. Utilising the primary structures used by the biological systems (proteins, glycoproteins, carbohydrates) and creating novel higher structures (secondary, tertiary, quartenary) that mimic the native material is the logical way forward in the search for new drug delivery systems, and we need to turn more and more to the molecular basis of biology for guidance and inspiration.     

Emulsion/solvent evaporation as an alternative technique in pellet preparation

Paracetamol/Eudragit RS, paracetamol/ethylcellulose, and paracetamol/cellulose acetate pellets of different drug/polymer ratios (w/w) were prepared by the dissolution/solvent evaporation technique. These pellets were then characterized by particle size distribution analysis, ultraviolet (UV) spectroscopy, differential thermal analysis, and scanning electron microscopy (SEM). Hard gelatin capsules were filled with each particle size fraction of these pellets, and in vitro dissolution studies were performed to verify the capability of each series of pellets to control drug release. Pellets were spherical, presented a polynucleated microcapsule structure, and under certain experimental conditions, the yield of the preparation process reached very high values. The dissolution studies pointed out the slow paracetamol release from these pellets.