Preparation of alginate microspheres by water-in-oil emulsion method for drug delivery: Effect of Ca2+ post-cross-linking

Alginate microspheres were prepared by a water-in-oil emulsion solvent diffusion method. The alginate microspheres were post-cross-linked with Ca²⁺ ions. Influence of Ca²⁺ concentration on the characteristics and drug release behaviors of alginate microspheres was evaluated. Blue dextran was used as a water-soluble model drug. The non-cross-linked alginate microspheres were less than 100 μm in size and had a spherical shape. The cross-linked alginate microspheres were also spherical in shape with a rougher surface but their particle sizes were larger than 100 μm. The drug encapsulation efficiency of the non-cross-linked alginate microspheres was very high (82%). The drug encapsulation efficiency of alginate microspheres cross-linked with 5% and 10% Ca²⁺ concentrations were similar to the non-cross-linked microspheres. The in vitro drug releases of the cross-linked alginate microspheres showed prolong release profiles. The cumulative release of blue dextran decreased as the Ca²⁺ concentration increased. Thus, Ca²⁺-post-cross-linked alginate microspheres show possibility for use as controlled-release drug carriers.     

pH-Sensitive oral insulin delivery systems using Eudragit microspheres

In this paper, we present in vitro and in vivo release data on pH-sensitive microspheres of Eudragit L100, Eudragit RS100 and their blend systems prepared by double emulsion-solvent evaporation technique for oral delivery of insulin. Of the three systems developed, Eudragit L100 was chosen for preclinical studies. Insulin was encapsulated and in vitro experiments performed on insulin-loaded microspheres in pH 1.2 media did not release insulin during the first 2?h, but maximum insulin was released in pH 7.4 buffer media from 4 to 6?h. The microspheres were characterized by scanning electron microscopy to understand particle size, shape and surface morphology. The size of microspheres ranged between 1 and 40?µm. Circular dichroism spectra indicated the structural integrity of insulin during encapsulation as well as after its release in pH 7.4 buffer media. The in vivo release studies on diabetic-induced rat models exhibited maximum inhibition of up to 86%, suggesting absorption of insulin in the intestine.     

Preparation and characterization of fenofibrate-loaded PLA–PEG microspheres

A series of biodegradable block copolymer of poly(lactide)(PLA)/poly(ethylene glycol) (PEG) were prepared by Ring-Opening polymerization of D, L-lactide, using stannous octoate as a catalyst. By nanoprecipitation method, the PLA-PEG can be made into microspheres containing fenofibrate, which is a kind of important cholesterol-lowering drugs. The purpose of this study is to investigate the effect of the copolymer composition on the size, the entrapment and the release behavior of the fenofibrate loaded microspheres. The microspheres can be achieved with small size below 100 nm, better encapsulation efficiencies of more than 55.3% and slower release rates. The release of fenofibrate from microsphere would reach the balance first, when the microsphere prepared by high proportion of hydrophilic PEG block. And the release property of fenofibrate/PLA-PEG microsphere was better than Lipanthyl (a commercial capsule of fenofibrate). It was observed that the composition of PLA-PEG copolymer played a major role in encapsulation efficiency of microspheres and release rates.     

Formulation and characterization of naked DNA and complexed DNA loaded polymer films

Sustained release of DNA from polymeric films is of considerable interest for enhanced and prolonged gene therapy. This report describes the detailed studies of the formulation of naked plasmid DNA (pDNA) and complexed DNA-incorporated polymer films and in vitro release of the DNA. The effect of hydrophilic polymers (PEG, HA) also studied to modulate the release of pDNA and complexed DNA (lipoplex) from slow biodegradable polymer (PCL) films. The polymer system consists of a biodegradable semi-crystalline polymer (PCL) blended with a hydrophilic polymer such as poly (ethylene glycol) (PEG) or hyaluronic acid (HA). For the release of pDNA (naked DNA), a burst effect was always seen, and the addition of HA and PEG did not suppress the burst release of pDNA from PCL films. For complexed pDNA (lipoplex), the release was slow, but it could be accelerated using additives such as PEG or HA. The transfection efficiency of the complexed DNA and the naked pDNA was determined in vitro using COS 7 cells to evaluate the bioactivity of the released DNA. Transfection was observed from released lipoplexes samples from PCL/HA film. Overall, this work suggested that these polymeric DNA delivery systems are promising for the local sustained release of DNA from implanted films.     

A pH-sensitive nanocomposite microsphere based on chitosan and montmorillonite with in vitro reduction of the burst release effect

Objective: The aim of this study was to prepare pH-sensitive ofloxacin (OFL)/montmorillonite (MMT)/chitosan (CTS) nanocomposite microspheres that improve the burst release effect of the drug by the solution intercalation technique and emulsification cross-linking techniques. Methods: First, OFL/MMT hybrids were prepared through the solution intercalation technique. Then, OFL/MMT-intercalated OFL/MMT/CTS nanocomposite microspheres were obtained through emulsification cross-linking technology. The intercalated nanocomposite was confirmed by Fourier-transform infrared spectroscopy and X-ray diffraction. Finally, in vitro release of OFL from the microspheres was performed in simulated gastric fluids and simulated intestinal fluids. The effect of MMT content on drug encapsulation efficiency and the drug release of the nanocomposite microspheres were investigated. Results: The results showed that the release rate of OFL from the nanocomposite microspheres at pH 7.4 was higher than that at pH 1.2. Compared with pure CTS microspheres, the incorporation of certain amount of MMT in the nanocomposite microspheres can enhance the drug encapsulation efficiency and reduce the burst release. Conclusion: A sustained release particulate system can be obtained by incorporating MMT into the nanocomposite microspheres and can improve the burst release effect of the drug.     

In vitro evaluation of the effects of various additives and polymers on nerve growth factor microspheres

Objective: To evaluate the effects of various additives or polymers on the in vitro characteristics of nerve growth factor (NGF) microspheres.

Materials and methods: NGF microspheres were fabricated using polyethylene glycol (PEG), ovalbumin (OVA), bovine serum albumin (BSA) or glucose as protein protectors, and poly(lactide-co-glycolide) (PLGA) or poly(lactic acid) (PLA)/PLGA blends as encapsulation materials.

Results: Encapsulation efficiencies of the NGF microspheres with various additives or polymers were not more than 30%. A comparative study revealed that OVA was somewhat superior over others, and was thus chosen as the protective additive in subsequent experiments. Polymer analysis showed that NGF release from 1:1 PLA (η?=?0.8):PLGA (75/25, η?=?0.45) microspheres lasted for 90?d with a burst release rate of 12.7%. About 40% of the original bioactivity was retained on the 28th day, while 10% was left on the 90th day.

Discussion and conclusion: The combination of OVA as an additive and the PLA/PLGA blend as the coating matrix is suitable for encapsulation of NGF in microspheres for extended release.     

Study of physicochemical properties of flutamide-loaded Ocimum basilicum microspheres with ex vivo mucoadhesion and in vitro drug release

Drug which shows extensive first pass effect is difficult task that, needs to be solved by formulators in the pharmaceutical science. The low oral bioavailability (49%) of flutamide may be due to poor wettability, low aqueous solubility and extensive first pass effect. The aim of present investigation was to prepare flutamide loaded microspheres and incorporate it into suppositories for rectal delivery to avoid first pass effect and enhance residence time. Flutamide loaded mucoadhesive microspheres of Ocimum Basilicum mucilage (OBM) were prepared using spray drying and characterized by percent production yield, encapsulation efficiency, particle size, zeta potential, polydispersity index, DSC, SEM, XRPD, in vitro drug release and stability studies. Moreover, ex vivo mucoadhesion was investigated using falling liquid film technique to determine the adhesion of microspheres to sheep rectal mucosa. The microspheres had nearly spherical shape and size about 2.53?μm. The encapsulation efficiency and mucoadhesion of optimized formulation MBF10 were found to be 69.6?±?2.3% and 89.01?±?2.18%, respectively. Percent CDR of optimized flutamide loaded mucoadhesive microspheres was found to be 88.7?±?1.3 at 7?h. In conclusion, OBM microparticles based suppository could be used to deliver drug through rectal delivery.     

5-Fluorouracil encapsulated HA/PLGA composite microspheres for cancer therapy

5-Fluorouracil (5FU) was successfully entrapped within poly(lactide-co-glycolide) (PLGA) and hydroyapatite (HA) composite microspheres using the emulsification/solvent extraction technique. The effects of HA to PLGA ratio, solvent ratio as well as polymer inherent viscosity (IV) on encapsulation efficiency were investigated. The degradation and drug release rates of the microspheres were studied for 5?weeks in vitro in phosphate buffered solution of pH 7.4 at 37?°C. The drug release profile followed a biphasic pattern with a small initial burst followed by a zero-order release for up to 35?days. The initial burst release decreased with increasing HA content. The potential of HA in limiting the initial burst release makes the incorporation of HA into PLGA microspheres advantageous since it reduces the risk of drug overdose from high initial bursts. The linear sustained drug release profile over the course of 5?weeks makes these 5-FU-loaded HA/PLGA composite microparticles a promising delivery system for the controlled release of chemotherapy drugs in the treatment of cancer.     

Dual cross-linked chitosan microspheres formulated with spray-drying technique for the sustained release of levofloxacin

Objective: This study was aimed to develop sustained drug release from levofloxacin (LF)-loaded chitosan (CS) microspheres for treating ophthalmic infections.

Significance: Dual cross-linked CS microspheres developed by the spray-drying technique displays significantly higher level of sustained drug release compared with non-cross-linked CS microspheres.

Methods: LF-loaded CS microspheres were prepared using the spray-drying technique, and then solidified with tripolyphosphate and glutaraldehyde as dual cross-linking agents. The microspheres were characterized by surface morphology, size distribution, zeta potential, encapsulation efficiency, and drug release profiles in vitro. The drug quantification was verified and analyzed by high-performance liquid chromatography (HPLC). The structural interactions of the CS with LF were studied with Fourier transform infrared spectroscopy. The effect of various influencing excipients in the formulation of the dual cross-linked CS microspheres on drug encapsulation efficiency and the drug release profiles were extensively investigated.

Result: The microspheres demonstrated high encapsulation efficiency (72.4?～?98.55%) and were uniformly spherical with wrinkled surface. The mean particle size was between 1020.7?±?101.9 and 2381.2?±?101.6?nm. All microspheres were positively charged (zeta potential ranged from 31.1?±?1.32 to 42.81?±?1.55?mV). The in vitro release profiles showed a sustained release of the drug and it was remarkably influenced by the cross-linking process.

Conclusion: This novel spray-drying technique we have developed is suitable for manufacturing LF-loaded CS microspheres, and thus could serve as a potential platform for sustained drug release for effective therapeutic application in ocular infections.     

Peculiar effect of polyethylene glycol in comparison with triethyl citrate or diethyl phthalate on properties of ethyl cellulose microcapsules containing propranolol hydrochloride in process of emulsion-solvent evaporation

Plasticizers play a crucial role in various process of microencapsulation. In this study, the effect of incorporation of plasticizer in process of emulsion solvent evaporation was investigated on properties of ethyl cellulose (EC) microcapsules containing propranolol hydrochloride. The effect of plasticizer type and concentration were investigated on characteristics of microcapsules prepared from different viscosity grades of EC. Product yield, encapsulation efficiency, mean particle size, shape, surface characteristics, solid state of drug, and drug release profiles were evaluated. Product yield and encapsulation efficiency were not dependent on plasticizer type and concentration. However, encapsulation efficiency decreased with increase in EC viscosity grade in the most of the cases. The mean particle size was in the range of 724–797?μm and was not dependent on plasticizer type. Microcapsules formed in the presence of PEG had a very smooth surface with few pores. XRD and DSC studies revealed a reduction of drug crystallinity after microencapsulation especially in presence of PEG. The results showed that the presence of TEC and DEP with different concentrations had no marked effect on drug release from microcapsules containing different viscosity grades of EC. This was not the case when PEG was used, and despite its water solubility it reduced the drug release rate noticeably. The reduction in the drug release in the presence of PEG was concentration-dependent. The use of PEG as a plasticizer in process of emulsion solvent evaporation highly improved the EC microcapsule structure and retarded the drug release rate and therefore is recommended.     

Sustained release of piroxicam from solid lipid nanoparticle as an effective anti-inflammatory therapeutics in vivo

Abstract

This study aims to investigate the solid lipid nanoparticle (SLN) as a novel vehicle for the sustained release and transdermal delivery of piroxicam, as well as to determine the anti-inflammation effect of piroxicam-loaded SLN. SLN formulation was optimized and the particle size, polydispersity index, zeta potential (ZP), encapsulation efficiency, drug release, and morphological properties were characterized. The transdermal efficiency and mechanism of the piroxicam-loaded SLNs were investigated in vitro. With the inflammation induced edema model in rat, the anti-inflammatory efficiency of piroxicam-enriched SLNs (Pir-SLNs) was evaluated. The SLN formulation was optimized as: lecithin 100?mg, glycerin monostearate 200?mg, and Tween (1%, w/w). The particle size is around 102?±?5.2?nm with a PDI of 0.262. The ZP is 30.21?±?2.05?mV. The prepared SLNs showed high entrapment efficiency of 87.5% for piroxicam. There is no interaction between piroxicam and the vehicle components. The presence of polymorphic form of lipid with higher drug content in the optimized Pir-SLNs enables the Pir-SLNs to release the drug with a sustained manner. Pir-SLNs with oleic acid as enhancer can radically diffuse into both the stratum corneum and dermal layer, as well as penetrate through the hair follicles and sebaceous glands with significantly higher density than the other control groups. Pir-SLNs promptly inhibited the inflammation since the 3rd hour after the treatment by decreasing the PGE₂ level. SLN was demonstrated to be a promising carrier for encapsulation and sustained release of piroxicam. Pir-SLN is a novel topical preparation with great potential for anti-inflammation application.     

BSA-PLGA微球的优化制备及特性

目的:优化BSA-PLGA微球制备工艺,并对其包封率、形态、体外释放药物及微球包裹前后BSA的稳定性进行评价。方法:以PLGA为载体,采用复乳溶剂挥发法制备BSA-PLGA微球。Micro BCA法测定微球的包封率和载药量,扫描电子显微镜观察微球的形态,激光粒度仪测定粒度及分布,聚丙烯酰胺凝胶电泳(SDS-PAGE)研究微球包裹前后BSA分子结构的完整性,同时考察体外释药性能。结果:根据优化工艺制备的微球外观圆整,平均粒径(2275.8±256.9)nm,包封率(82.59±2.92)%,载药量(13.76±0.49)×10-2%,包裹前后BSA结构稳定,体外释放28天以上,释放曲线符合Higuchi方程。结论:本研究获得了较优化的BSA-PLGA微球制备工艺,所制备的微球具有较高的包封率和明显的缓释效果。     

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.     

Encapsulation and characterization of controlled release flurbiprofen loaded microspheres using beeswax as an encapsulating agent

The aim of the present study was to extend the use of flurbiprofen in clinical settings by avoiding its harmful gastric effects. For this purpose, we designed the controlled release solid lipid flurbiprofen microspheres (SLFM) by emulsion congealing technique. Drug was entrapped into gastro resistant biodegradable beeswax microspheres which were prepared at different drug/beeswax ratios 1:1, 1:2 and 1:3 using gelatin and tween 20 as emulsifying agents. The effect of emulsifiers and the effect drug/beeswax ratios were studied on hydration rate, encapsulating efficiency, micromeritic properties, scanning electron microscopy (SEM), fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray diffraction (X-RD) analysis and in vitro drug release at pH 1.2 for 2 h and at pH 6.8 for 10 h. SEM revealed that microspheres made with tween 20 were smooth while microspheres made with gelatin showed porous morphology, however, they were all spherical in nature. The practical yield (recovery) showed a dependence on drug-beeswax ratio and it was variable from 53 to 84%. High loading encapsulating efficiency of flurbiprofen from 8 to 94% was achieved. FTIR and DSC analysis confirmed the absence of any drug polymer interaction indicating drug stability during microencapsulation. X-RD of pure flurbiprofen shows sharp peaks, which decreases on encapsulation, indicating decrease in the crystallinity of drug in microspheres. The micromeritic studies confirmed the presence of excellent and good flow properties of microspheres. Entrapment efficiency, morphology, practical yield, hydration rate, flow properties demonstrated their dependence on the HLB value of emulsifiers and emulsifiers with higher HLB were found more appropriate for effective microencapsulation of flurbiprofen. The release kinetics followed zero order mechanism of drug release at pH 6.8. Release pattern depends on the morphology of flurbiprofen microspheres and amount of beeswax used in the microspheres preparation. The microspheres prepared with high HLB values i.e., tween 20 showed effective control of drug release from microspheres. The absence of drug release at pH 1.2 proved the suitability of beeswax for its use as a gastro resistant material.     

pH-Sensitive oral insulin delivery systems using Eudragit microspheres

In this paper, we present in vitro and in vivo release data on pH-sensitive microspheres of Eudragit L100, Eudragit RS100 and their blend systems prepared by double emulsion-solvent evaporation technique for oral delivery of insulin. Of the three systems developed, Eudragit L100 was chosen for preclinical studies. Insulin was encapsulated and in vitro experiments performed on insulin-loaded microspheres in pH 1.2 media did not release insulin during the first 2 h, but maximum insulin was released in pH 7.4 buffer media from 4 to 6 h. The microspheres were characterized by scanning electron microscopy to understand particle size, shape and surface morphology. The size of microspheres ranged between 1 and 40 μm. Circular dichroism spectra indicated the structural integrity of insulin during encapsulation as well as after its release in pH 7.4 buffer media. The in vivo release studies on diabetic-induced rat models exhibited maximum inhibition of up to 86%, suggesting absorption of insulin in the intestine.     

Preparation,characterization, in vitro bioactivity and protein loading/release property of mesoporous bioactive glass microspheres with different compositions

Mesoporous bioactive glass microspheres (MBGMs) with large mesopores have attracted considerable attention in the field of bone tissue regeneration and drug delivery systems due to their excellent bioactivity, biocompatibility and high specific area. In this study, a loose structure of MBGMs with adjustable chemical compositions was synthesized by the combination of sol-gel and water-in-oil (W/O) microemulsion. All the prepared MBGMs possessed a large mesopore diameter that increased with CaO content, a high surface area and good apatite-inducing formation ability. In vitro protein absorption and release assays demonstrated that the MBGMs exhibited decreased loading efficiency and burst release behavior as the CaO content increased. Additionally, an enhanced BSA-loading amount and prolonged release curve were obtained after the surfaces of MBGMs were modified by amine groups. Furthermore, the preliminary in vitro cell experiments showed that MBGMs exhibited good biocompatibility. The results indicated that MBGMs could be a promising candidate as a drug/protein carrier for bone tissue regeneration.     

茶多酚/壳聚糖/海藻酸钠纳米微球的制备

目的探讨各因素对制备茶多酚/壳聚糖/海藻酸钠纳米微球载药率、包埋率的影响,研究纳米微球体外释放行为,为后期缓释抗菌膜的制备提供基础。方法采用单因素实验、正交实验考察海藻酸钠溶液浓度、壳聚糖溶液浓度、CaCl_2溶液浓度、茶多酚溶液浓度对纳米微粒载药率、包封率的影响,并考察其体外释放率。结果当海藻酸钠溶液、壳聚糖溶液、CaCl_2溶液、茶多酚溶液的质量浓度分别为15,10,15,0.8 mg/m L时,该工艺条件下制备的纳米微粒载药率为22.71%,包封率为61.38%,且粒径集中在500 nm左右,有较好的缓释效果。结论所得的最佳工艺制备条件为后期做缓释抗菌膜打下良好基础。     

基于凝固浴剪切法制备多孔实心聚(乳酸-羟基乙酸)共聚物载药微球

以聚(乳酸-羟基乙酸)为基质材料,采用一种新颖的流动凝固浴剪切法制备包载盐酸万古霉素的载药微球,并研究微球的形貌结构、粒径、包封率、载药率、体外释放性能及其影响因素。结果表明,所制备的载药微球平均粒径在15~29μm范围,微球呈现内部实心表面多孔的复合结构;微球的包封率及载药可分别在15%~75%和1.5%~9.3%范围内调控。微球制备过程中的工艺条件对微球结构形貌、包封率、载药率及释放性能有重要影响,通过调整微球的粒径,可有效减缓释药过程中的突释现象。     

Evaluation of biodegradable polyester-co-lactone microparticles for protein delivery

Poly(glycerol adipate-co-ω-pentadecalactone) (PGA-co-PDL) was previously evaluated for the colloidal delivery of α-chymotrypsin. In this article, the effect of varying polymer molecular weight (M_W) and chemistry on particle size and morphology; encapsulation efficiency; in vitro release; and the biological activity of α-chymotrypsin (α-CH) and lysozyme (LS) were investigated. Microparticles were prepared using emulsion solvent evaporation and evaluated by various methods. Altering the M_W or monomer ratio of PGA-co-PDL did not significantly affect the encapsulation efficiency and overall poly(1,3-propanediol adipate-co-ω-pentadecalactone) (PPA-co-PDL) demonstrated the highest encapsulation efficiency. In vitro release varied between polymers, and the burst release for α-CH-loaded microparticles was lower when a higher M_W PGA-co-PDL or more hydrophobic PPA-co-PDL was used. The results suggest that, although these co-polyesters could be useful for protein delivery, little difference was observed between the different PGA-co-PDL polymers and PPA-co-PDL generally provided a higher encapsulation and slower release of enzyme than the other polymers tested.     

Development and gamma-scintigraphy study of Hibiscus rosasinensis polysaccharide-based microspheres for nasal drug delivery

Objective: This work describes the application of natural plant polysaccharide as pharmaceutical mucoadhesive excipients in delivery systems to reduce the clearance rate through nasal cavity.

Methods: Novel natural polysaccharide (Hibiscus rosasinensis)-based mucoadhesive microspheres were prepared by using emulsion crosslinking method for the delivery of rizatriptan benzoate (RB) through nasal route. Mucoadhesive microspheres were characterized for different parameters and nasal clearance of technetium-99m (^99mTc)-radiolabeled microspheres was determined by using gamma-scintigraphy.

Results: Their Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) studies showed that the drug was stable during preparation of microspheres. Aerodynamic diameter of microspheres was in the range 13.23?±?1.83–33.57?±?3.69?µm. Change in drug and polysaccharide ratio influenced the mucoadhesion, encapsulation efficiency and in-vitro release property. Scintigraphs taken at regular interval indicate that control solution was cleared rapidly from nasal cavity, whereas microspheres showed slower clearance (p?Conclusion: Natural polysaccharide-based microspheres achieved extended residence by minimizing effect of mucociliary clearance with opportunity of sustained delivery for longer duration.