Sustained release nanoparticulate formulation containing antioxidant-ellagic acid as potential prophylaxis system for oral administration

The aim of the present work was to develop ellagic acid (EA) loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles for oral administration. PLGA nanoparticles were prepared by a method based on the concept of emulsion-diffusion-evaporation by using polyethylene glycol (PEG) 400 as a cosolvent for solubilizing the drug. While developing this method, didodecyldimethylammomium bromide (DMAB) and polyvinyl alcohol (PVA), alone and in combination with chitosan (CS) were employed. DMAB stabilized particles were the smallest of all the formulations with a particle size of 148.5 nm. PVA alone gave particles of 269.7 nm but a blend with CS (80:20) resulted in an increase in particle size (359.6 +/- 23.6 nm). Initial release of EA from nanoparticles in pH 7.4 phosphate buffer was rapid, followed by a slower sustained release. Release rates followed the order PVA > PVA-CS > DMAB. Release rate from the PLGA-DMAB particles was slowest, which is attributed to higher hydrophobicity of DMAB as compared to PVA, preventing diffusion of drug out of polymeric matrix. Insolubility of CS at alkaline pH could have retarded the release in case of PVA-CS system. In situ intestinal permeability study of pure drug and the drug encapsulated in nanoparticles prepared using PVA, PVA-CS blend and DMAB as stabilizer in rats showed 66, 75, 73 and 87% permeation, respectively. EA showed good free radical scavenging effect in a yeast cell culture model as well as in a cell free system.     

Sustained release docetaxel-incorporated lipid nanoparticles with improved pharmacokinetics for oral and parenteral administration

The aim of this study was to develop docetaxel-incorporated lipid nanoparticles (DTX-NPs) to improve the pharmacokinetic behaviour of docetaxel (DTX) after oral and parenteral administration via sustained release. DTX-NPs were prepared by nanotemplate engineering technique with palmityl alcohol as a solid lipid and Tween-40/Span-40/Myrj S40 as a surfactants mixture. Spherical DTX-NPs below 100?nm were successfully prepared with a narrow particle size distribution, 96% of incorporation efficiency and 686 times increase in DTX solubility. DTX-NPs showed a sustained release over 24?h in phosphate-buffered saline and simulated gastric and intestinal fluids, while DTX-micelles released DTX completely within 12?h. The half-maximal inhibitory concentration (IC₅₀) of DTX-NPs against human breast cancer MCF-7 cells was 1.9 times lower than that of DTX-micelles and DTX solution. DTX-NPs demonstrated 3.7- and 2.8-fold increase in the area under the plasma concentration–time curve compared with DTX-micelles after oral and parenteral administration, respectively.     

Formulation and evaluation of carnosic acid nanoparticulate system for upregulation of neurotrophins in the brain upon intranasal administration

To develop formulations of carnosic acid nanoparticles and to assess their in vivo efficacy to enhance the expression of neurotrophins in rat model. Carnosic acid loaded chitosan nanoparticles were prepared by ionotropic gelation technique using central composite design. Response surface methodology was used to assess the effect of three factors namely chitosan concentration (0.1–1% w/v), tri-poly phosphate concentration (0.1–1% w/v) and sonication time (2–10?min) on the response variables such as particle size, zeta potential, drug encapsulation efficiency and drug release. The neurotrophins level in the rat brain upon intranasal administration of optimized batch of carnosic acid nanoparticles was determined. The experimental values for the formulation were in good agreement with those predicted by the mathematical models. A single intranasal administration of the optimized formulation of carnosic acid nanoparticles was sufficient to result in comparable levels of endogenous neurotrophins level in the brain that was almost on par with four, once a day intranasal administration of solution in rats. The results clearly demonstrated the fact that nanoparticulate drug delivery system for intranasal administration of carnosic acid would require less number of administrations to elicit the required pharmacological activity owing to its ability to localize on the olfactory mucosal region and provide controlled delivery of carnosic acid for prolonged time periods.     

Evaluation of hydrophobic nanoparticulate delivery system for insulin

Insulin loaded hydrophobic nanoparticles were prepared by solvent diffusion followed by lyophilization. Nanoparticles were characterized for mean size by dynamic laser scattering and for shape by scanning electron microscopy. Insulin encapsulation efficiency, in vitro stability of nanoparticles in presence of proteolytic enzymes and in vitro release were determined by high pressure liquid chromatography analysis. The biological activity insulin from the nanopraticles was estimated by enzyme-linked immunosorbant assay and in vivo using Wister diabetic rats. Nanoparticles ranged 0.526±0.071 μm in diameter. Insulin encapsulation efficiency was 95.7±1.2%. Insulin hydrophobic nanoparticles suppressed insulin release promoted sustained release in pH 7.4 phosphate buffer and shown to protect insulin from enzymatic degradation in vitro in presence of chymotripsin. Nanoencapsulated insulin was bioactive, demonstrated through both in vivo and in vitro.     

Development of a new solid lipid nanoparticle formulation containing retinoic acid for topical treatment of acne

The development of solid lipid nanoparticles (SLN) containing all-trans retinoic acid (RA) is an interesting approach to topical treatment of acne. SLN has potential for controlled release and follicular penetration, which can reduce adverse effects in comparison with conventional formulations. However, the encapsulation efficiency (EE) of RA in SLN is usually low, unless a high surfactant/lipid ratio is used. The aim of this work was to develop SLN with high EE using a low surfactant/lipid ratio. Different formulations of RA-loaded SLN were prepared using glyceryl behenate as lipid matrix. The particle size, EE, zeta potential and differential scanning calorimetry (DSC) were investigated. High EE in SLN was obtained with addition of amines. These results indicate that the utilization of amines is an interesting approach to improve the EE of RA in SLN using a low surfactant/lipid ratio.     

口服胸腺五肽乳酸-羟基乙酸共聚物纳米粒的制备及物理性质考察

目的制备供口服给药的胸腺五肽乳酸-羟基乙酸共聚物(thymopentin-poly lactic-co-glycolicacid;TP5-PLGA)纳米粒,并对纳米粒的物理性质进行考察。方法用复乳-溶剂挥发法制备TP5-PLGA纳米粒,以包封率为评价指标,用L16(45)正交设计优选纳米粒制备的处方工艺条件,用HPLC法测定胸腺五肽的含量,用激光粒度仪测定纳米粒的粒径,用透射电镜观察纳米粒的形态,用动态透析法考察纳米粒的体外释药特征。结果正交设计确定纳米粒制备的最优处方工艺条件为胸腺五肽质量浓度50 g.L-1,载体材料PLGA质量浓度100 g.L-1,乳化剂PVA质量浓度20 g.L-1;优化处方与工艺制备的纳米粒为规整的圆球形,平均粒径为(150.3±9.6)nm,载药量与包封率分别为(2.403±0.066)%与(28.12±0.60)%;体外释药结果表明,前5 h药物释放(31.27±1.5)%,存在一定突释,4 d累积释药量为(43.60±2.3)%。结论以乳酸-羟基乙酸共聚物为载体材料制备胸腺五肽纳米粒工艺简便,制剂具有良好的物理性质和体外释药特征。     

口服胰岛素聚乳酸纳米粒的胃肠道吸收与药效学研究

目的　考察口服胰岛素聚乳酸纳米粒 (INS PLA NP)在胃肠道不同部位的吸收以及吸收促进剂脱氧胆酸 (DOC)对吸收的影响。方法　在正常大鼠胃肠道不同部位 (胃、小肠、结肠 )分别给予含与不含吸收促进剂DOC的INS PLA NP后 ,观察降血糖效果。结果　大鼠灌胃给药后未能显示降血糖效果 ,添加DOC后仍基本无效。小肠直接给药后表现出和缓持久的降血糖效果 ,而DOC在小肠给药中能明显加快INS PLA NP的吸收并增强药效 ,但这一促进吸收作用存在一定的限度。结肠给药也基本无效 ,添加DOC后可产生强度不大的降血糖作用。结论　INS PLA NP主要在小肠吸收 ,DOC对于这一吸收具有促进作用     

Sustained release spherical agglomerates of polymethacrylates containing mefenamic acid: in vitro release,micromeritic properties and histological studies

Mefenamic acid (MA) spherical agglomerates (SAs) were prepared with various polymethacrylates having different permeability characteristics (Eudragit RS 100, Eudragit RL 100 and Eudragit L 100) and also with combination of Eudragit RS 100 and Eudragit L 100 in different ratios. SAs were prepared by spherical crystallization method using ethanol/dichloromethane solvent (crystallization) system. The influence of various formulation factors on the encapsulation efficiency, as in vitro drug release, and micromeritic properties was investigated. Target release profile of MA was also drawn. The yields of preparation and the encapsulation efficiencies were high for all formulations. The shape and surface characteristics of SAs were observed by a scanning electron microscope. The particle sizes are in the range of 0.219?±?0.1 to 0.482?±?0.25?mm (mean ± confidence interval t_95%). In addition, histological studies showed that the administration of MA in SAs containing Eudragit RS/L provided a distinct tissue protection in the stomach and duodenum. Differential scanning calorimetry and X-ray diffraction of powder studies showed that MA particles crystallized in the presence of polymethacrylates did not undergo structural modifications.     

Brimonidine formulation in polyacrylic acid nanoparticles for ophthalmic delivery

In ocular drug delivery, a major problem is providing an adequate concentration of a therapeutic agent in the precorneal area. Mucoadhesive carriers such as polyacrylic acid in sub-colloidal, nanoparticulate form, have a strong potential for ophthalmic drug delivery. A formulation of brimonidine loaded in polyacrylic acid nanoparticles has been prepared for potential delivery in ophthalmic therapy. The particles were prepared by a reverse microemulsion polymerization technique and their sizes were in the range of 50 nm. In a preliminary biocompatibility test, Caco-2 cells (human primary colonic tumour adenocarcinoma) and human corneal epithelial cells incubated with polyacrylic acid nanoparticles were found to retain their viability over varying times. The loading efficiency of the drug brimonidine in the particles was shown to be between 80–85% and pH dependent. The bioadhesive polyacrylic hydrogel nanoparticles, used in the present study, exhibited superior loading properties for brimonidine, and the formulation was stable for more than 5 weeks. When the drug-loaded nanoparticles were dispersed in a phosphate buffer saline (pH = 7.4), the drug was slowly released over several hours. Two-photon laser scanning microscopic studies of dye-conjugated polyacrylic acid nanoparticles demonstrated the accumulation of the particles on the surface and intercellular spaces of Caco-2 cells.     

Pharmacokinetics and in vivo biodistribution of optimized PLGA nanoparticulate drug delivery system for controlled release of emtricitabine

Abstract

The objective of this study was to develop systematically optimized (OPT) nanoparticles (NPs) providing a controlled release using PLGA of emtricitabine (FTC) employing Formulation by Design (FbD), and evaluate their in vitro and in vivo performance. FTC generates severe adverse effects with risks of toxicity. Thus, NPs were prepared to reduce these drawbacks in this study. The NPs were prepared by water-in-oil-in-water (w/o/w) emulsion method, followed by high-pressure homogenization. The FTC NPs were systematically OPT using 3² central composite design and the OPT formulation located using overlay plot. The pharmacokinetics and in vivo biodistribution of OPT-FTC NPs were investigated in male Wistar rats via the oral administration. Transmission electron microscopy studies on OPT-FTC NPs demonstrated uniform shape and size of particles. In vitro release was sustained up to 15 days in PBS pH 7.4. Augmentation in the values of C_max (1.63 fold) and AUC_0-∞ (5.39 fold) indicated significant enhancement in the rate and extent of bioavailability by the OPT-FTC NPs compared to pure drug. OPT-FTC NPs showed 2.325 fold increase in the values of FTC concentrations in liver. The OPT-FTC NPs was found to be quite stable during 6 months of study period. Hence, the developed OPT-FTC NPs can be used as drug carrier for sustained/prolonged drug release and/or to reduce toxic effects.     

齐墩果酸固体脂质纳米粒口服给药系统的制备与表征(英文)

采用改良的乳化-溶剂挥发法制备齐墩果酸-固体脂质纳米粒(OA-SLNs)并对其性质进行评价。其粒径,zeta电位,包封率和载药率分别为(104.5±11.7)nm,(-25.5±1.8)mV,(94.2±3.9)%,和(4.71±0.15)%。透射电子显微镜下,可见球形实心纳米粒。X-粉末衍射和差示扫描量热(DSC)图谱证实药物分子均匀分散在脂质骨架中。体外释放实验表明,OA-SLNs以每小时4.88%速率缓慢释放药物,符合零级释放动力学模型。OA-SLNs在人工胃液和肠液中具有良好的稳定性。本文研究为OA-SLNs口服给药系统的应用进一步研究提供了可能。     

Studies on lactoferrin nanoparticles of gambogic acid for oral delivery

Abstract

Purpose: Lactoferrin (Lf), a mammalian cationic iron-binding glycoprotein belonging to the transferrin (Tf) family, has been widely used in a variety of fields ranging from treating infant diarrhea and supporting newborn growth to food and pharmaceutical applications. In this study, Lf nanoparticles were firstly used as carriers of gambogic acid (GA) to enhance oral absorption and anti-cancer activity, hence reducing the related toxic effect.

Methods: Gambogic acid-lactoferrin nanoparticles (GL-NPs) were prepared by the nanoparticle albumin-bound (NAB) technology. The formed nanoparticles were characterized by DSC, TEM, etc. In situ intestinal perfusion experiment was performed to clarify the absorption mechanism of GL-NPs. Furthermore in vivo and in vitro anti-tumor activities of GL-NPs were also investigated.

Results: GL-NPs was successfully prepared with about 150?nm mean size, +20?mV ζ potential, 92.3?±?7.2% encapsulation efficiency and 9.04?±?0.7% DL; GL-NPs also exhibited a better stability and a desirable slow release in vitro experiment. The results of in situ intestinal perfusion showed a transformation of GA absorption from passive diffusion into active transport or facilitated diffusion by GL-NPs. MTT assay of GL-NPs showed almost an equal anti-proliferative effect with arginine solution of GA (Arg-GA) in HepG2 cell. The inhibitory rate against S180 tumor mice after oral administration of GL-NPs was up to 86.01% which was1.39-folds of intravenous injection of Arg-GA.

Conclusion: The in vitro results showed that the NAB technology was feasible for industrial production of Lf nanoparticles and the in vivo results proved that the effective GL-NPs is a promising approach for the oral delivery of GA. These obtained research works have also paved the preliminary way for the study of Lf as an oral drug delivery carrier.     

Development of potent oral nanoparticulate formulation of coenzyme Q10 for treatment of hypertension: can the simple nutritional supplements be used as first line therapeutic agents for prophylaxis/therapy?

Coenzyme Q10 (CoQ10) is an antioxidant with well-established pharmacological activities against several chronic diseases; however, it is marketed only as a nutritional supplement without any claims of its therapeutic activity and one of the reasons for this could be the poor oral bioavailability rendering difficulties in administering this molecule to achieve therapeutic concentrations. Therefore, the present investigation was aimed at improving the oral bioavailability of CoQ10 by delivering it as nanoparticulate formulation. Biodegradable nanoparticulate formulations based on poly(lactide-co-gylcolide) (PLGA) were prepared by emulsion technique using quaternary ammonium salt didodecyldimethylammonium bromide (DMAB) as a stabilizer. The effect of initial CoQ10 loading on entrapment efficiency and the particle size was studied using 5-75% initial load resulting in good entrapment efficiency (61-83%) without any appreciable increase in the particle size for 5-30% loading (107-110 nm). However, 50% and 75% led to increase in particle size with no appreciable changes in entrapment efficiency. The intestinal uptake of CoQ10 as a suspension in carboxymethylcellulose (CMC), a commercial formulation and the developed nanoparticulate formulation was studied in male Sprague-Dawley (SD) rats and found to be 45%, 75% and 79%, respectively, suggesting that solubility and permeability related problems of CoQ10 were overcome by nanoparticulate formulation. Furthermore, the developed nanoparticulate formulation was evaluated for its therapeutic potential in renal hypertensive animals (Goldblatt 2K1C model), demonstrating improved efficacy at a 60% lowered dose as compared to CoQ10 suspension and superior efficacy than the commercial formulation at an equal dose. Together, these results indicate the potential of nanotechnology in improving the therapeutic value of molecules like CoQ10, facilitating its usage as first line therapeutic agent thus revolutionizing its role in current medical therapy.     

A nanoparticulate drug-delivery system for 20(S)-protopanaxadiol: formulation,characterization, increased oral bioavailability and anti-tumor efficacy

As with many other hydrophobic anticancer agents, 20(S)-protopanaxadiol (PPD) has a very low oral bioavailability. In this study, a precipitation-combined ultrasonication technique was used to prepare PPD nanosuspensions. The mean particle size of the nanosuspensions was approximately 222?±?12?nm, the drug payload achieved 50% after lyophilization and the maximum PPD concentration can reach 100?mg/ml, which is over 30?000 times the solubility of PPD in aqueous solution (3?μg/ml). After oral administration, the C_max and AUC_last values of PPD nanosuspensions were approximately 3.66-fold and 3.48-fold as those of PPD coarse suspensions, respectively. In contrast to the free drug solution, PPD nanosuspensions showed higher in vitro anti-tumor activity against HepG-2 cells (an IC₅₀ value of 1.40 versus 5.83?μg/ml at 24?h, p?<?0.01). The in vivo study in H22-tumor-bearing mice demonstrated that PPD nanosuspensions showed good anti-tumor efficacy with an inhibition rate of 79.47% at 100?mg/kg, while 50?mg/kg of cyclophosphamide was displayed as positive control, and the inhibition rate was 87.81%. Considering the highest drug payload, oral bioavailability reported so far, significant anti-tumor efficacy and excellent safety of encapsulated drugs, PPD nanosuspensions could be used in potential effective strategies for anticancer therapy; further investigation is ongoing.     

Preparation of a solid-in-oil nanosuspension containing L-ascorbic acid as a novel long-term stable topical formulation

l-Ascorbic acid (AA, vitamin C) easily decomposes into inactive compounds in aqueous solutions and this has limited its topical use. This work reports the preparation of a solid-in-oil nanosuspension (SONS) containing AA and validation of its basic storage stability. Although AA itself is water-soluble, it can readily be nanosuspended in squalane via complex formation involving a combination of sucrose erucate (i.e. lipophilic surfactant) and sucrose monolaureate (i.e. hydrophilic surfactant) to yield SONS with a very low moisture content (<500 ppm). To extract encapsulated AA, a lipase-based enzymatic degradation technique was used to degrade a formulation phase making it easier for AA to distribute into an extraction solution. Our results demonstrate that almost all the encapsulated AA (95.3%) was readily extracted from the SONS upon addition of medium-chain triglyceride, which offers the possibility of degrading the formulation phase using lipase. Finally, its storage stability study was investigated at 25 °C over 90 days under protection from light. An aqueous solution containing AA was used as a control. Compared with the control, the SONS markedly increased the stability of AA due to its low moisture content and, thus, the potential usefulness SONSs as a novel long-term stable topical formulation of AA has been proved.     

Development and in vivo evaluation of a new oral nanoparticulate dosage form for leuprolide based on polyacrylic acid

It was the aim of this study to develop a nanoparticulate oral drug delivery system for leuprolide based on polyacrylic acid (PAA). In order to achieve formation of nanoparticles in a mild, aqueous environment, two different techniques were combined, namely hydrophobic ion pairing between leuprolide and sodium dodecyl sulphate in a first step, followed by encapsulation into nanoparticles gained by interpolymer complexation between polyacrylic acid and Pluronic F68. The obtained nanoparticles were characterized regarding particle size distribution, drug encapsulation efficiency and in vitro release profile. Additionally, the pharmacokinetic profiles of leuprolide after oral administration of PAA-nanoparticulate and PAA-control tablets to male Sprague-Dawley rats were assessed and compared. It could be shown, that hydrophobic ion pairing increased encapsulation efficacy of leuprolide and leads to a slowed drug release of nanoparticulate suspensions. Relative oral bioavailability of leuprolide could be increased by nanoparticulate tablets up to 4.2-fold. Results verify that the suggested approach is a promising strategy for the design of oral delivery systems for oral administration of peptide drugs.     

A potential new therapeutic system for glaucoma: solid lipid nanoparticles containing methazolamide

Methazolamide (MTA) is an antiglaucoma drug; however, there are many side effects of its systemic administration with insufficient ocular therapeutic concentrations. The aim of this study was to formulate MTA-loaded solid lipid nanoparticles (SLNs) and evaluate the potential of SLNs as a new therapeutic system for glaucoma. SLNs were prepared by a modified emulsion–solvent evaporation method and their physicochemical characteristics were evaluated. The pharmacodynamics was investigated by determining the percentage decrease in intraocular pressure. The ocular irritation was studied by Draize test. Despite a burst release of SLNs, the pharmacodynamic experiment indicated that MTA–SLNs had higher therapeutic efficacy, later occurrence of maximum action, and more prolonged effect than drug solution and commercial product. Formulation of MTA–SLNs would be a potential delivery carrier for ocular delivery, with the advantages of a more intensive treatment for glaucoma, lower in doses and better patient compliance compared to the conventional eye drops.     

Evaluation of poly(lactic acid) as a biodegradable drug delivery system for parenteral administration

Poly(lactic acid) (PLA) microspheres of 1–10 μm diameter prepared by emulsion deposition and containing entrapped prednisolone released the drug rapidly into an aqueous medium. Similarly sized microparticles prepared by a fusion process exhibited a more prolonged drug release profile and may have potential as a long-acting parenteral delivery system. Both methods of fabricating the polymer produced material which was cytotoxic when phagocytosed by mouse peritoneal macrophages. The intracellular toxicity and hence potential irritancy in vivo was only partially overcome by incorporating anti-inflammatory drug. Compressed implants of the same polymers containing prednisolone 10% w/w (100 mg·cm⁻³) and weighing 12 mg were readily administered and sustained the delivery of the drug for over 30 days without complications at the implantation site.     

Thiolated polycarbophil/glutathione: Defining its potential as a permeation enhancer for oral drug administration in comparison to sodium caprate

Thiolated polyacrylates were shown to be permeation enhancers with notable potential. The aim of this study was to evaluate the permeation enhancing properties of a thiolated polycarbophil/glutathione (PCP-Cys/GSH) system for oral drug application in comparison to a well-established permeation enhancer, namely sodium caprate. In vitro permeation studies were conducted in Ussing-type chambers with sodium fluoresceine (NaFlu) and fluoresceine isothiocyanate labeled dextran (molecular mass 4?kDa; FD4) as model compounds. Bioavailability studies were carried out in Sprague Dawley rats with various formulations. Moreover, cytotoxic effects of both permeation enhancers were compared. Permeation enhancement ratios of 1% sodium caprate were found to be 3.0 (FD4) and 2.3 (NaFlu), whereas 1% PCP-Cys/0.5% GSH displayed enhancement ratios of 2.4 and 2.2. Both excipients performed at a similar level in vivo. Sodium caprate solutions increased oral bioavailability 2.2-fold (FD4) and 2.3-fold (NaFlu), while PCP-Cys hydrogels led to a 3.2-fold and 2.2-fold enhancement. Cell viability experiments revealed a significantly higher tolerance of Caco-2 cells towards 0.5% PCP-Cys (81% survival) compared to 0.5% sodium caprate (5%). As PCP-Cys is not absorbed from mucosal membranes due to its comparatively high molecular mass, systemic side-effects can be excluded. In conclusion, both systems displayed a similar potency for permeation enhancement of hydrophilic compounds. However, PCP-Cys seems to be less harmful to cultured cells.