Production of haloperidol-loaded PLGA nanoparticles for extended controlled drug release of haloperidol

This study developed an emulsion-solvent evaporation method for producing haloperidol-loaded PLGA nanoparticles with up to 2% (wt/wt. of polymer) drug content, in vitro release duration of over 13 days and less than 20% burst release. The free haloperidol is removed from the nanoparticle suspension using a novel solid phase extraction technique. This leads to a more accurate determination of drug incorporation efficiency than the typical washing methods. It was discovered that PLGA end groups have a strong influence on haloperidol incorporation efficiency and its release from PLGA nanoparticles. The hydroxyl-terminated PLGA (uncapped) nanoparticles have a drug incorporation efficiency of more than 30% as compared to only 10% with methyl-terminated PLGA (capped) nanoparticles. The in vitro release profile of nanoparticles with uncapped PLGA has a longer release period and a lower initial burst as compared to capped PLGA. By varying other processing and materials parameters, the size, haloperidol incorporation and haloperidol release of the haloperidol-loaded PLGA nanoparticles were controlled.     

Controlling the in vitro release profiles for a system of haloperidol-loaded PLGA nanoparticles

We have used a systematic methodology to tailor the in vitro drug release profiles for a system of PLGA/PLA nanoparticles encapsulating a hydrophobic drug, haloperidol. We applied our previously developed sonication and homogenization methods to produce haloperidol-loaded PLGA/PLA nanoparticles with 200-1000 nm diameters and 0.2-2.5% drug content. The three important properties affecting release behavior were identified as: polymer hydrophobicity, particle size and particle coating. Increasing the polymer hydrophobicity reduces the initial burst and extends the period of release. Increasing the particle size reduces the initial burst and increases the rate of release. It was also shown that coating the particles with chitosan significantly reduces the initial burst without affecting other parts of the release profile. Various combinations of the above three properties were used to achieve in vitro release of drug over a period of 8, 25 and >40 days, with initial burst <25% and a steady release rate over the entire period of release. Polymer molecular weight and particle drug content were inconsequential for drug release in this system. Experimental in vitro drug release data were fitted with available mathematical models in literature to establish that the mechanism of drug release is predominantly diffusion controlled. The average value of drug diffusivities for PLGA and PLA nanoparticles was calculated and its variation with particle size was established.     

Paclitaxel-loaded polyester nanoparticles prepared by spray-drying technology: in vitro bioactivity evaluation

Paclitaxel (PTX), an antimicrotubular agent used in the treatment of ovarian and breast cancer, was encapsulated in nanoparticles (NPs) of poly(lactide-co-glycolide) (PLGA) and poly(ε-caprolactone) (PCL) polymers using the spray-drying technique. Morphology, size distribution, drug encapsulation efficiency, thermal degradation and drug release were characterized. MCF7 cells were employed to evaluate the efficacy of the systems on cell cycle and cytotoxicity. The particle size was in the range 0.8–1?µm. The incorporation efficiency of PTX was more than 80% in all NPs obtained. In vitro drug release took place during 35 days, and drug release rates were in the order PCL?>?PLGA 50:50?>?PLGA 75:25. Unloaded NPs showed to be cytocompatible at MCF7 cells. PTX-loaded NPs demonstrated the release of the drug block cells in the G2/M phase. All PTX-loaded formulations showed their efficacy in killing MCF7 cells, mainly PTX-loaded PLGA 50:50 and PLGA 75:25 that cause a decrease in cell viability lower than 20%.     

Design and Development of a Novel Controlled Release PLGA Alginate-Pectinate Polyspheric Drug Delivery System

A 23 full factorial design was employed to evaluate and optimize the drug entrapment efficiency and in vitro drug release from PLGA microparticles encapsulated in a complex crosslinked alginate-pectinate matrix (polysphere). The independent formulation variables included the volume of internal and external phases, and concentration of PLGA. Surface morphology and internal structure of PLGA microparticles and polyspheres were examined by scanning electron microscopy which revealed spherical PLGA microparticles with highly porous surfaces that accounted for the rapid burst effect of this system. Texture analysis was used to profile the matrix resilience, tolerance, and energy absorbed. In vitro drug release was assessed in buffer media on PLGA microparticles and polyspheres. Polyspheres exhibited ideal zero-order release while PLGA microparticles had a burst effect followed by lag phase. Kinetic modeling of in vitro drug release data indicated that formulations were not highly dependent on polymeric erosion as a mechanism for drug release but rather diffusion. A close correlation existed between the matrix tolerance and energy absorbed. Formulations with decreased tolerance absorbed less energy, thus led to rapid surface erosion, lower matrix integrity and hence a burst effect. The converse was true for an increased matrix tolerance, which led to zero-order release supported by superior matrix integrity and a significantly reduced burst effect. The rat subcutaneous model validated in vitro release data and demonstrated that the polyspheres provided flexible yet superior rate-modulated drug delivery.     

葫芦素B-聚乳酸-羟基乙酸共聚物载药纳米粒的构建与药效学评价

目的 以聚乳酸-羟基乙酸共聚物（PLGA）作为纳米制剂载体材料将葫芦素B制备成纳米粒,并考察其对HepG2肝癌细胞的抑制效果。方法 使用乳化溶剂蒸发法制备葫芦素B-PLGA载药纳米粒,以PLGA浓度（X₁）、PVA浓度（X₂）和药物浓度（X₃）作为考察因素,以载药纳米粒的粒径大小（Y₁）和包封率（Y₂）作为评价指标,应用中心复合设计-效应面法优化葫芦素B-PLGA载药纳米粒处方;测定了纳米粒的粒径分布和Zeta电位值,通过透射电镜观察其微观形态,并考察了葫芦素B-PLGA载药纳米粒的体外药物释放特性;比较了葫芦素B与葫芦素B-PLGA载药纳米粒对HepG2肝癌细胞的抑制效果。结果 葫芦素B-PLGA载药纳米粒的最优处方组成为：PLGA浓度为9.0%,PVA浓度为2.0%,药物浓度为4.5%,制备的纳米粒粒径为（145.4±15.8） nm,Zeta电位值为（-7.6±0.8） mV;透射电镜下可观察到纳米粒表面光滑,分布均匀;葫芦素B-PLGA载药纳米粒释药前期出现突释,后期平缓,48 h药物释放达到86%;葫芦素B-PLGA载药纳米粒对HepG2肝癌细胞的抑制作用显著高于葫芦素B。结论 葫芦素B-PLGA载药纳米粒可延缓药物释放,提高对HepG2肝癌细胞的抑制活性,为进一步临床研究奠定实验基础。     

Haloperidol-loaded PLGA nanoparticles: systematic study of particle size and drug content

We have produced haloperidol-loaded PLGA/PLA nanoparticles by using two emulsification-solvent evaporation methods: homogenization and sonication. We have established how five independent processing parameters and two materials characteristics control the particle size and drug content. The interdependencies between processing and materials parameters and the subsequent nanoparticle characteristics are discussed in terms of underlying scientific principles that are broadly applicable to the production of drug-loaded polymer nanoparticles. This level of understanding should quicken the pace of designing protocols for making new drug-PLGA nanoparticles. It was determined that the particle size of haloperidol-loaded PLGA/PLA nanoparticles is effectively controlled by the amount of shear stress transferred from the energy source to the organic phase, which is strongly correlated to the following parameters: type of applied energy, aqueous phase volume, and polymer concentration in the organic solvent. The drug content of these nanoparticles is controlled by reducing the diffusion of the drug from the organic to the aqueous phase during the solvent evaporation stage of the preparation and by increasing the drug-polymer interactions. The following significantly inhibit drug diffusion: large particle size, higher polymer concentration and polymer molecular weight, and reducing the drug solubility in the aqueous phase by adjusting the pH. Specific drug-polymer interactions are engineered by optimizing the lactide to glycolide ratio (L:G ratio) and including specific polymer end groups. When optimized, the drug-loaded PLGA/PLA nanoparticles contain as much as 2.5% haloperidol.     

Ethyl acetate as a dispersing solvent in the production of poly(DL-lactide-co-glycolide) microspheres: effect of process parameters and polymer type

This study deals with the production of poly(DL-lactide-co-glycolide) (PLGA) microspheres using ethyl acetate as a dispersing solvent, a partially water soluble and less toxic solvent, by using emulsification and solvent diffusion/evaporation techniques. PLGA 50 : 50 was used, having molecular weights, 12 000 and 34 000 with the end group capped (RG502, 503) and uncapped (RG502H, 503H) biodegradable polymers. The microspheres were loaded with nifedipine (NFD) as a model drug. Solvent removal from the embryonic microspheres was manipulated by adopting different techniques. These methods have shown a significant effect on the physicochemical and release characteristics of the microspheres. Rapid removal of the solvent resulted in microspheres with a loose matrix and large size. Use of higher molecular weight polymers increased the size of the microspheres as well as delayed release of the drug. The uncapped polymer has given a higher rate of diffusion when compared to the capped polymers. Thermal analyses showed a uniform molecular distribution of the drug in the polymer matrix. The mechanism of drug release from the PLGA microspheres followed the Fickian diffusion.     

Ethyl acetate as a dispersing solvent in the production of poly(DL-lactide-co-glycolide) microspheres: effect of process parameters and polymer type

This study deals with the production of poly(DL-lactide-co-glycolide) (PLGA) microspheres using ethyl acetate as a dispersing solvent, a partially water soluble and less toxic solvent, by using emulsification and solvent diffusion/ evaporation techniques. PLGA 50 : 50 was used, having molecular weights, 12000 and 34000 with the end group capped (RG502, 503) and uncapped (RG502H, 503H) biodegradable polymers. The microspheres were loaded with nifedipine (NFD) as a model drug. Solvent removal from the embryonic microspheres was manipulated by adopting different techniques. These methods have shown a significant effect on the physicochemical and release characteristics of the microspheres. Rapid removal of the solvent resulted in microspheres with a loose matrix and large size. Use of higher molecular weight polymers increased the size of the microspheres as well as delayed release of the drug. The uncapped polymer has given a higher rate of diffusion when compared to the capped polymers. Thermal analyses showed a uniform molecular distribution of the drug in the polymer matrix. The mechanism of drug release from the PLGA microspheres followed the Fickian diffusion.     

Nanoparticle-based topical ophthalmic formulation for sustained release of stereoisomeric dipeptide prodrugs of ganciclovir

Poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles (NP) of Val-Val dipeptide monoester prodrugs of ganciclovir (GCV) including L-Val-L-Val-GCV (LLGCV), L-Val-D-Val-GCV (LDGCV) and D-Val-L-Val-GCV (DLGCV) were formulated and dispersed in thermosensitive PLGA-PEG-PLGA polymer gel for the treatment of herpes simplex virus type 1 (HSV-1)-induced viral corneal keratitis. Nanoparticles containing prodrugs of GCV were prepared by a double-emulsion solvent evaporation technique using various PLGA polymers with different drug/polymer ratios. Nanoparticles were characterized with respect to particle size, entrapment efficiency, polydispersity, drug loading, surface morphology, zeta potential and crystallinity. Prodrugs-loaded NP were incorporated into in situ gelling system. These formulations were examined for in vitro release and cytotoxicity. The results of optimized entrapment efficiencies of LLGCV-, LDGCV- and DLGCV-loaded NP are of 38.7?±?2.0%, 41.8?±?1.9%, and 45.3?±?2.2%; drug loadings 3.87?±?0.20%, 2.79?±?0.13% and 3.02?±?0.15%; yield 85.2?±?3.0%, 86.9?±?4.6% and 76.9?±?2.1%; particle sizes 116.6?±?4.5, 143.0?±?3.8 and 134.1?±?5.2?nm; and zeta potential ?15.0?±?4.96, ?13.8?±?5.26 and ?13.9?±?5.14?mV, respectively. Cytotoxicity studies suggested that all the formulations are non-toxic. In vitro release of prodrugs from NP showed a biphasic release pattern with an initial burst phase followed by a sustained phase. Such burst effect was completely eliminated when NP were suspended in thermosensitive gels with near zero-order release kinetics. Prodrugs-loaded PLGA NP dispersed in thermosensitive gels can thus serve as a promising drug delivery system for the treatment of anterior eye diseases.     

Sophoridine-loaded PLGA microspheres for lung targeting: preparation,in vitro,and in vivo evaluation

Lung-targeting sophoridine-loaded poly(lactide-co-glycolide) (PLGA) microspheres were constructed by a simple oil-in-oil emulsion-solvent evaporation method. The obtained microspheres were systematically studied on their morphology, size distribution, drug loading, encapsulation efficiency, in vitro release profile, and biodistribution in rats. The drug-loaded microparticles showed as tiny spheres under SEM and had an average size of 17?μm with 90% of the microspheres ranging from 12 to 24?μm. The drug loading and encapsulation efficiency were 65% and 6.5%, respectively. The in vitro drug release behavior of microspheres exhibited an initial burst of 16.6% at 4?h and a sustained-release period of 14 days. Drug concentration in lung tissue of rats was 220.10?μg/g for microspheres and 6.77?μg/g for solution after intraveneous injection for 30?min, respectively. And the microsphere formulation showed a significantly higher drug level in lung tissue than in other major organs and blood samples for 12 days. These results demonstrated that the obtained PLGA microspheres could potentially improve the treatment efficacy of sophoridine against lung cancer.     

In vitro phagocytosis and monocyte-macrophage activation with poly(lactide) and poly(lactide-co-glycolide) microspheres.

Treatment of many intracellular infections in the mononuclear phagocytic system (MPS), requires targeting of antibiotics by a drug delivery system. The objective of this study was to examine whether the particular nature of microspheres, made of end-group capped and uncapped poly(lactide) [PLA] and poly(lactide-co-glycolide) [PLGA 50:50 and PLGA 75:25], affect the uptake into and also the activation of monocyte-macrophages. Placebo and gentamicin sulfate containing microspheres were incubated with J774 murine monocyte-macrophages and fresh human blood monocytes. Phagocytosis became more efficient with increasing polymer hydrophobicity, whereas opsonization of the particles in serum exerted inconsistent effects. Monocyte activation was determined by flow cytometry and measured as oxidative burst. The cellular oxidative burst induced by the particles was higher for end-group uncapped polymers. Opsonization increased significantly the oxidative activity of J774 monocytes, but affected inconsistently that of human blood monocytes. The results demonstrate that PLA and PLGA microspheres loaded with gentamicin sulfate were efficiently phagocytosed in vitro. The end-group uncapped polymer-type microspheres promoted significantly cell activation, which may be of importance for drug delivery and targeting to intracellular infections.     

Self-assembled nanoparticles of reduction-sensitive poly (lactic-co-glycolic acid)-conjugated chondroitin sulfate A for doxorubicin delivery: preparation,characterization and evaluation

In this study, reduction-sensitive self-assembled polymer nanoparticles based on poly (lactic-co-glycolic acid) (PLGA) and chondroitin sulfate A (CSA) were developed and characterized. PLGA was conjugated with CSA via a disulfide linkage (PLGA-ss-CSA). The critical micelle concentration (CMC) of PLGA-ss-CSA conjugate is 3.5?µg/mL. The anticancer drug doxorubicin (DOX) was chosen as a model drug, and was effectively encapsulated into the nanoparticles (PLGA-ss-CSA/DOX) with high loading efficiency of 15.1%. The cumulative release of DOX from reduction-sensitive nanoparticles was only 34.8% over 96?h in phosphate buffered saline (PBS, pH 7.4). However, in the presence of 20?mM glutathione-containing PBS environment, DOX release was notably accelerated and almost complete from the reduction-sensitive nanoparticles up to 96?h. Moreover, efficient intracellular DOX release of PLGA-ss-CSA/DOX nanoparticles was confirmed by CLSM assay in A549 cells. In vitro cytotoxicity study showed that the half inhibitory concentrations of PLGA-ss-CSA/DOX nanoparticles and free DOX against A549 cells were 1.141 and 1.825?µg/mL, respectively. Therefore, PLGA-ss-CSA/DOX nanoparticles enhanced the cytotoxicity of DOX in vitro. These results suggested that PLGA-ss-CSA nanoparticles could be a promising carrier for drug delivery.     

Ciprofloxacin-encapsulated poly(DL-lactide-co-glycolide) nanoparticles and its antibacterial activity

The aim of this study was to prepare ciprofloxacin HCl (CIP)-encapsulated poly(dl-lactide-co-glycolide) (PLGA) copolymer nanoparticles and its antibacterial potential was evaluated with pathogenic bacteria, Escherichia coli (E. coli), in vitro and in vivo. CIP-encapsulated nanoparticles of PLGA were prepared by multiple emulsion solvent evaporation method. PLGA nanoparticles showed spherical shapes with particle sizes around 100-300 nm. Loading efficiency was lower than 50% (w/w) because of water-solubility properties of CIP. At drug release study, CIP showed initial burst effect for 12 h and then continuously released for 2 weeks. At in vitro antibacterial activity test, CIP-encapsulated nanoparticles showed relatively lower antibacterial activity compared to free CIP due to the sustained release characteristics of nanoparticles. However, CIP-encapsulated PLGA nanoparticles (doses: 25 mg CIP/kg of mice) effectively inhibited the growth of bacteria due to the sustained release characteristics of nanoparticles, while free CIP was less effective on the inhibition of bacterial growth. These results indicated that CIP-encapsulated PLGA nanoparticles have superior effectiveness to inhibit the growth of bacteria in vivo.     

Design of a Multifunctional PLGA Nanoparticulate Drug Delivery System: Evaluation of its Physicochemical Properties and Anticancer Activity to Malignant Cancer Cells

Purpose  Several individual approaches were combined to fabricate a novel nanoparticulate drug delivery system to achieve targeting and anticancer effects in various malignant cancer cells. Methods  Doxorubicin was conjugated to Poly(lactic-co-glycolic acid) (PLGA), which was formulated into nanoparticle via solvent-diffusion method. The surface of the nanoparticles was subsequently linked with Poly(ethylene glycol) (PEG) and Arg-Gly-Asp (RGD) peptide to realize both passive and active targeting functions. The multifunctional nanoparticles were then tested against several malignant cancer cell lines. Results  The conjugation increased loading efficiency of doxorubicin to PLGA nanoparticles (the encapsulation efficiency was over 85%) and alleviated the drug burst release effect substantially. The drug was released from the polymeric matrix in a sustained release manner over a period of 12 days. The resultant nanoparticles were spherically uniform and well-dispersed. The nanoparticle targeting ability was proven through strong affinity to various integrin-expressing cancer cells, and much less affinity to the low integrin expression cancer cells. The nanoparticles also showed high efficacy in inducing apoptosis in specific malignant cancer cell. Conclusion  The developed multifunctional nanoparticles hold potential to treat malignant integrin-expressing cancers.     

Self-Assembled Biodegradable Nanoparticles Developed by Direct Dialysis for the Delivery of Paclitaxel

Purpose The main objective of this study was to obtain self-assembled biodegradable nanoparticles by a direct dialysis method for the delivery of anticancer drug. The in vitro cellular particle uptake and cytotoxicity to C6 glioma cell line were investigated. Methods Self-assembled anticancer drugs—paclitaxel-loaded poly(d,l-lactic-co-glycolic acid) (PLGA) and poly(l-lactic acid) (PLA) nanoparticles—were achieved by direct dialysis. The physical and chemical properties of nanoparticles were characterized by various state-of-the-art techniques. The encapsulation efficiency and in vitro release profile were measured by high-performance liquid chromatography. Particle cellular uptake was studied using confocal microscopy, microplate reader, and flow cytometry. In addition, the cytotoxicity of this drug delivery system was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on C6 glioma cell line to predict the possible dose response of paclitaxel-loaded PLGA and PLA nanoparticles. Results PLGA and PLA nanoparticles with or without vitamin E tocopherol polyethylene glycol succinate (TPGS) as an additive were obtained, in which the sustained release of paclitaxel of more than 20 days was achieved. The coumarin6-loaded PLGA and PLA nanoparticles could penetrate the C6 glioma cell membrane and be internalized. The cytotoxicity of paclitaxel-loaded nanoparticles seemed to be higher than that of commercial Taxol? after 3 days incubation when paclitaxel concentrations were 10 and 20 μg/ml. Conclusions Direct dialysis could be employed to achieve paclitaxel-loaded PLGA and PLA nanoparticles, which could be internalized by C6 glioma cells and enhance the cytotoxicity of paclitaxel because of its penetration to the cytoplasm and sustained release property.     

Paclitaxel-loaded polyester nanoparticles prepared by spray-drying technology: in vitro bioactivity evaluation

Paclitaxel (PTX), an antimicrotubular agent used in the treatment of ovarian and breast cancer, was encapsulated in nanoparticles (NPs) of poly(lactide-co-glycolide) (PLGA) and poly(ε-caprolactone) (PCL) polymers using the spray-drying technique. Morphology, size distribution, drug encapsulation efficiency, thermal degradation and drug release were characterized. MCF7 cells were employed to evaluate the efficacy of the systems on cell cycle and cytotoxicity. The particle size was in the range 0.8-1?μm. The incorporation efficiency of PTX was more than 80% in all NPs obtained. In?vitro drug release took place during 35 days, and drug release rates were in the order PCL?>?PLGA 50:50?>?PLGA 75:25. Unloaded NPs showed to be cytocompatible at MCF7 cells. PTX-loaded NPs demonstrated the release of the drug block cells in the G2/M phase. All PTX-loaded formulations showed their efficacy in killing MCF7 cells, mainly PTX-loaded PLGA 50:50 and PLGA 75:25 that cause a decrease in cell viability lower than 20%.     

Brain targeted delivery of paclitaxel using endogenous ligand

The objective of the present investigation was to formulate nanoparticles constructed using PLGA polymer for the effective targeted delivery to brain via nasal route. The PLGA nanoparticles were optimized using novel design of experiment technique by 2³ full factorial design. Drug: polymer ratio (X₁), surfactant concentration (X₂) and stirring speed (X₃) were identified as critical process parameters, and its impact on particle size (Y₁) and % entrapment efficiency (Y₂) was studied. The optimized nanoparticle formulation was conjugated with glutathione as an endogenous ligand by using carbodiimide chemistry using (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide) (EDAC) as linker molecule. From Ellman's assay, it was found that a total of 691.27 ± 151 units of glutathione were conjugated upon each PLGA nanoparticle. The in vitro release studies as well as ex vivo studies revealed biphasic pattern of drug release with initial burst release followed by slow exponential release of drug over a period of 24 h. The in vivo biodistribution studies were conducted on rat following nasal administration of the nanoparticle formulation (conjugated and unconjugated) and were compared with plain paclitaxel suspension. The results clearly demonstrated that the brain targeting efficiency was enhanced with the glutathione conjugated formulation (387.474%) as compared to the unconjugated nanoparticle formulation (224.327%). Further, the in vitro in vivo correlation studies revealed good relationship (R² > 0.95) as obtained from the levy plot. Glutathione proves to be an efficient vector for the successful transport of poor bioavailable drug to the brain.     

In vitro cytotoxicity and bioavailability of solid lipid nanoparticles containing tamoxifen citrate

Abstract

The objective of this study was to evaluate the influence of solid lipid nanoparticles (SLN) loaded with the poorly water-soluble drug tamoxifen citrate (TC) on the in vitro antitumor activity and bioavailability of the drug. TC-loaded SLN were prepared by solvent injection method using glycerol monostearate (GMS) or stearic acid (SA) as lipid matrix. Poloxamer 188 or tween 80 were used as stabilizers. TC-loaded SLN (F3 and F4) prepared using GMS and stabilized by poloxamer 188 showed highest entrapment efficiency % (86.07?±?1.74 and 90.40?±?1.22%) and reasonable mean particle sizes (130.40?±?9.45 and 243.80?±?12.33?nm), respectively. The in vitro release of TC from F3 and F4 exhibited an initial burst effect followed by a sustained drug release. In vitro cytotoxicity of F3 against human breast cancer cell line MCF-7 showed comparable antitumor activity to free drug. Moreover, the results of bioavailability evaluation of TC-loaded SLN in rats compared to free TC indicated that 160.61% increase in the oral bioavailability of TC. The obtained results suggest that incorporation of the poorly water-soluble drug TC in SLN preserves the in vitro antitumor activity and significantly enhance oral bioavailability of TC in rats.     

Development of composite PLGA microspheres containing exenatide-encapsulated lecithin nanoparticles for sustained drug release

This study aimed to prepare poly (D, L-lactic-co-glycolic acid) microspheres (PLGA-Ms) by a modified solid-in-oil-in-water (S/O/W) multi-emulsion technique in order to achieve sustained release with reduced initial burst and maintain efficient drug concentration for a prolonged period of time. Composite PLGA microspheres containing exenatide-encapsulated lecithin nanoparticles (Ex-NPs-PLGA-Ms) were obtained by initial fabrication of exenatide-loaded lecithin nanoparticles (Ex-NPs) via the alcohol injection method, followed by encapsulation of Ex-NPs into PLGA microspheres. Compared to Ms prepared by the conventional water-in-oil-in-water (W/O/W) technique (Ex-PLGA-Ms), Ex-NPs-PLGA-Ms showed a more uniform particle size distribution, reduced initial burst release, and sustained release for over 60 d in vitro. Cytotoxicity studies showed that Ms prepared by both techniques had superior biocompatibility without causing any detectable cytotoxicity. In pharmacokinetic studies, the effective drug concentration was maintained for over 30 d following a single subcutaneous injection of two types of Ms formulation in rats, potentially prolonging the therapeutic action of Ex. In addition, administration of Ex-NPs-PLGA-Ms resulted in a more smooth plasma concentration-time profile with a higher area under the curve (AUC) compared to that of Ex-PLGA-Ms. Overall, Ex-NPs-PLGA-Ms prepared by the novel S/O/W method could be a promising sustained drug release system with reduced initial burst release and prolonged therapeutic efficacy.     

Encapsulation of low lipophilic and slightly water-soluble dihydroartemisinin in PLGA nanoparticles with phospholipid to enhance encapsulation efficiency and in vitro bioactivity

Context: PLGA nanoparticles have been widely utilised to encapsulate lipophilic drugs for sustained release.

Objective: This study was to enhance encapsulation efficiency and drug loading for the poorly lipophilic drug dihydroartemisinin (DHA) in PLGA nanoparticles, where amphiphilic phospholipid was employed as the intermediate. Materials and methods: DHA-phospholipid complex formulation was optimised using the response surface method. DHA-phospholipid complex-nanoparticles (DHA-PLC-NPs) were prepared using the solvent evaporation method. Results: The particle size, zeta potential, entrapment efficiency and drug loading of the nanoparticles were 265.3?±?7.9?nm, ?21.4?±?6.3?mV, 74.2?±?6.5% and 2.80?±?0.35%, respectively. Compared with the rapidly released free form, DHA underwent sustained release from the nanoparticles. DHA-PLC-NPs presented stronger cell proliferative inhibition than DHA treatment alone and apoptosis was obviously induced after DHA-PLC-NPs treatment. Conclusion: Phospholipid complexes are useful intermediate to improve the lipophilicity of drugs, the interaction with the hydrophobic core of PLGA and the encapsulation efficiency of poorly lipophilic drugs in polymeric nanoparticles.