Improved solubility and oral bioavailability of apigenin via Soluplus/Pluronic F127 binary mixed micelles system

The aim of this study was to develop a novel mix micelles system composing of two biocompatible copolymers of Soluplus^® and Pluronic F127 to improve the solubility, oral bioavailability of insoluble drug apigenin (AP) as model drug. The AP-loaded mixed micelles (AP-M) were prepared by ethanol thin-film hydration method. The formed optimal formulation of AP-M were provided with small size (178.5?nm) and spherical shape at ratio of 4:1 (Soluplus^®:Pluronic F127), as well as increasing solubility of to 5.61?mg/mL in water which was about 3442-fold compared to that of free AP. The entrapment efficiency and drug loading of AP-M were 95.72 and 5.32%, respectively, and a sustained release of AP-M was obtained as in vitro release study indicated. Transcellular transport study showed that the cell uptake of AP was increased in Caco-2 cell transport models. The oral bioavailability of AP-M was 4.03-fold of free AP in SD rats, indicating the mixed micelles of Soluplus^® and Pluronic F127 is an industrially feasible drug delivery system to promote insoluble drug oral absorption in the gastrointestinal tract.     

Preparation and irradiation of Pluronic F127-based thermoreversible and mucoadhesive hydrogel for local delivery of naproxen

To improve physical properties and modulate the mucoadhesive hydrogel formulation via cross-linking by radiation, hydrogels were prepared using thermoreversible polymer Pluronic F127 (PF127) and mucoadhesive polymer carbopol 934P (C934P). As a model drug, naproxen was loaded in the hydrogel formulation. Sol-gel transition temperatures of hydrogels were measured by the tube-inversion method. The mucoadhesive potential of each formulation was determined by measuring the force required to detach the formulation from oral mucosal tissue. To strengthen the mechanical properties, the formulations were irradiated using an electronic beam. Drug release from the hydrogels and the cytotoxicity of each formulation were investigated. Sol-gel transition temperatures of the formulations were decreased by the addition of carbopol and were close to body temperature. The mucoadhesive force of the PF127 formulation was increased by addition of carbopol. In vitro release was sustained and the release rate was reduced by the addition of carbopol. After irradiation, the mucoadhesive force was increased about five-fold especially in the case of PF127 23% (9.7 kPa) and in vitro release was not sustained further. In conclusion, the use of a PF127 formulation incorporating a mucoadhesive polymer could effectively and safely improve oral residence time and absorption of naproxen. Irradiated formulations showed permanent cross-linking and improved properties.     

Controlled Release Camptothecin Tablets based on Pluronic and Poly(acrylic acid) Copolymer. Effect of Fabrication Technique on Drug Stability,Tablet Structure,and Release Mode

ABSTRACT

Poly(ethylene oxide)-b-poly(propylene oxide)-b-(polyethylene oxide)-g-poly(acrylic acid), a graft-comb copolymer of Pluronic® 127 and poly(acrylic acid) (Pluronic-PAA), was explored as an excipient for tablet dosage form of camptothecin (CPT). The tablets were prepared by either direct compression of the drug-polymer physical blend, suspension in ethanol followed by evaporation, or compression after kneading and characterized with respect to their physical structures, drug stability, and release behavior. Porosity and water uptake rate were strongly dependent on the fabrication procedure, ranking in the order: direct compression of physical blend > compression after suspension/evaporation in ethanol > compression after kneading. Tablets prepared by compression of physical blends swelled in water with a rapid surface gel layer formation that impeded swelling and disintegration of the tablets core. These tablets were able to sustain the CPT release for a period of time longer than those observed with the tablets made by either suspension/evaporation or kneading, which disintegrated within a few minutes. Despite the tablet disintegration, the CPT release was impeded for at least 6 hr, which was attributed to the ability of the Pluronic-PAA copolymers to form micellar aggregates at the hydrated surface of the particles. Physical mixing did not alter the fraction of CPT being in the pharmaceutically active lactone form, whilst the preparation of the tablets by the other two methods caused a significant reduction in the lactone form content. Tablets prepared from the physical blends demonstrated CPT release rates increasing with the pH due to the PAA ionization leading to the increase in the rate and extent of the tablet swelling. The results obtained demonstrate the potential of the Pluronic-PAA copolymers for the oral administration of chemotherapeutic agents.     

Development and characterization of a ricinoleic acid poloxamer gel system for transdermal eyelid delivery

Objective: This study deals with the preparation and evaluation of a pluronic lecithin organogel (PLO gel) containing ricinoleic acid for the transdermal eyelid delivery of dexamethasone and tobramycin.

Methods: Five different PLO gel formulations (F1, F2, F3, F4 and F5) containing tobramycin (0.3%) and dexamethasone (0.1%) were prepared and compared to a conventional PLO gel (light mineral oil PLO gel, F6) with respect to physical appearance and viscosity. The optimized ricinoleic acid PLO gel formulation (F2) was further characterized for pH, gelation temperature, morphology and drug content. Ex vivo permeability of dexamethasone and bactericidal activity of tobramycin from formulation F2 was tested, and values were compared to the marketed Tobradex® eye ointment.

Results: No apparent changes in the physical appearance and consistency were observed when ricinoleic acid was used as the oil phase. The pH of the optimized ricinoleic acid PLO gel (formulation F2) was found to be 6.54 with a gelation temperature of 31?°C. The drug content of tobramycin and dexamethasone were found to be 102.8% and 100.14%, respectively. The penetration profile of dexamethasone from formulation F2 was found to be much higher than the marketed Tobradex® eye ointment. F2 showed a better antimicrobial activity and higher zones of inhibition when compared to the marketed Tobradex® eye ointment.

Conclusion: The findings of this investigation indicate that the ricinoleic acid PLO gel has the potential for use as a transdermal eyelid delivery system.     

Polysialic acid and pluronic F127 mixed polymeric micelles of docetaxel as new approach for enhanced antitumor efficacy

In our previous study, polysialic acid-octadecyl dimethyl betaine (PSA-BS18) was synthesized and modified to liposomal EPI. Preliminary experiments revealed that the PSA-BS18 was a potential material for targeting tumor site with superior curative effects. In this study, PSA-BS18 and Pluronic F127 (F127) mixed polymeric micelles encapsulated docetaxel (DTX) (FP/DTX) were prepared by a self-assembly method. The FP/DTX was found to have a diameter of 34.83?±?0.50?nm with a narrow polydispersity, the entrapment efficiency was 99.12?±?1.17%, and the drug loading efficiency of 1.40?±?0.01%. The storage and dilution stability of FP/DTX was fine. In vitro release studies demonstrated that FP/DTX had delayed the drug release from the micelles. In vitro cytotoxicity assay on B16 cells presented that FP/DTX led to a stronger cytotoxic activity in comparison to F127 micelles based DTX (F127/DTX) and Tween80-based DTX (Taxotere^®). The in vivo imaging study showed that the accumulation of FP/DTX at tumor sites was more than F127/DTX. The in vivo antitumor activity of FP/DTX against B16 tumor xenograft model showed a significant higher inhibition and a lower toxicity compared with F127/DTX and Taxotere^®. Taken together, the results obtained above showed that PSA-BS18 and F127 mixed polymeric micelles may be a promising strategy for antitumor delivery of DTX.     

Preparation and in vitro characterization of pluronic-attached polyamidoamine dendrimers for drug delivery

Context: Polyamidoamine (PAMAM) dendrimers have attracted lots of interest as drug carriers. And little study about whether pluronic-attached PAMAM dendrimers could be potential drug delivery systems has been carried on.

Objective: Pluronic F127 (PF127) attached PAMAM dendrimers were designed as novel drug carriers.

Methods: Two conjugation ratios of PF127-attached PAMAM dendrimers were synthesized. ¹H nuclear magnetic resonance (¹H-NMR), Fourier transform infrared spectrum (FTIR), element analysis and ninhydrin assay were used to characterize the conjugates. Size, zeta potential and critical micelle concentrations (CMC) were also detected. And DOX was incorporated into the hydrophobic interior of the conjugates. Studies on their drug loading and drug release were carried on. Furthermore, hemolysis and cytotoxicity assay were used to evaluate the toxicity of the conjugates.

Results and discussion: PF127 was successfully conjugated to the fifth generation PAMAM dendrimer at two molar ratios of 19% and 57% (PF127 to surface amine per PAMAM dendrimer molecular). The conjugates showed an increased size and a reduced zeta potential. And higher CMC values were obtained than pure PF127. Compared with unconjugated PAMAM dendrimer, PF127 conjugation significantly reduced the hemolytic toxicity and cytotoxicity of PAMAM dendrimer in vitro. The encapsulation results showed that the ability to encapsulate DOX by the conjugate of 19% conjugation ratio was better than that of 57% conjugation ratio. And the maximum is ～12.87 DOX molecules per conjugate molecule. Moreover, the complexes showed a sustained release behavior compared to pure DOX.

Conclusion: Findings from the in vitro study show that the PF127-attached PAMAM dendrimers may be potential carriers for drug delivery.     

高稳自组装PEG-PMMA-HDMA载药胶团的制备及其性能研究

以PEG2000-Br为引发剂,甲基丙烯酸甲酯(MMA)为单体,1,6-己二醇二甲基丙烯酸酯(HDMA)为交联剂,采用原子转移自由基聚合( ATRP)制备了两亲交联聚合物PEG-PMMA-HDMA以及作为对照样的线性聚合物PEG-PMMA.由GPC、1 H-NMR研究可知,PEG-PMMA为线性分子,而PEG-PMMA...     

Development and characterization of stabilized double loaded mPEG-PDLLA micelles for simultaneous delivery of paclitaxel and docetaxel

Objective: Double loaded micelles (DLM) in which paclitaxel (PTX) and docetaxel (DTX) were co-solubilized with monomethoxy poly(ethylene glycol)-block-poly(d,l-lactide) (mPEG-PLA) copolymer were prepared and evaluated in an aim to investigate the effect of a combination of PTX and DTX on the stability of mPEG-PLA micelles compared to single drug-loaded micelles (SDM), especially that recent clinical anticancer formulations are limited by the existence of toxic excipients and stability issues.

Materials and methods: The SDM and DLM of PTX and DTX were prepared by a solvent evaporation method. Micellar size, size distribution, drug loading content and drug release were investigated. Transmission electron microscopy was used to investigate the stabilization mechanism.

Results: The drug loading efficiency of both PTX and DTX in DLM and SDM were 25% and 10%, respectively. ¹H NMR showed a successful encapsulation of both drugs in the polymeric micelle. DLM showed better physical stability at drug concentrations higher than 1?mg/mL compared to SDM. Moreover, DLM, SDM-PTX and SDM-DTX were stable for 24, 9 and 1?h, respectively. The stabilization mechanism of DLM was investigated, a network structure of DLM was observed in TEM graphs. Furthermore, DLM showed complete and faster drug release compared to SDM. mPEG-PLA double loaded micelles can deliver two poorly water soluble anticancer drugs at clinically relevant doses. The obtained results offer a promising alternative for double drug therapy without any formulation associated undesirable effects and encourage further in vivo development and optimization of the DLM as a drug delivery system for anticancer drugs.     

Design and synthesis of mixed micellar system for enhanced anticancer efficacy of Paclitaxel through its co-delivery with Naringin

Emergence of multidrug resistance (MDR) has limited the success of chemotherapeutic agents. Reversal of drugs efflux systems through combination therapy has got wider attention for increasing anticancer drugs efficacy. This study aims at co-encapsulation of Paclitaxel with Naringin in mixed polymeric micelles for enhanced anticancer activity of the drug. Drug-loaded micelles were prepared using two different amphiphilic block co-polymers and were characterized for morphology, size, zeta potential, drug encapsulation, in vitro release and stability using atomic force microscope (AFM), zetasizer, UV spectrophotometer, and FT-IR. MTT assay and fluorescence microscopy were used for in vitro cytotoxicity and cellular uptake studies. Nano-size micelles with spherical morphology and negative charge encapsulated 76.52?±?0.94% and 32.87 0.61% Paclitaxel and Naringin, respectively. The micelles were thermally stable and retained 87.05?±?0.69% and 92.88?±?2.17% Paclitaxel and Naringin upon one-month storage. Maximum drug release was achieved at fourth hour of the study for both the loaded drugs. Paclitaxel co-encapsulation with Naringin synergistically improved its intracellular uptake and 65% in vitro cytotoxicity against breast cancer cells was achieved at its lower dose of 15?µg/mL. Results suggest that co-encapsulation of Paclitaxel with Naringin in mixed micelles is an effective strategy for achieving its higher anticancer activity.     

Perturbation and stability analysis of strong form collocation with reproducing kernel approximation

Solving partial differential equations using strong form collocation with nonlocal approximation functions such as orthogonal polynomials and radial basis functions offers an exponential convergence, but with the cost of a dense and ill‐conditioned linear system. In this work, the local approximation functions based on reproducing kernel approximation are introduced for strong form collocation method, called the reproducing kernel collocation method (RKCM). We perform the perturbation and stability analysis of RKCM, and estimate the condition numbers of the discrete equation. Our stability analyses, validated with numerical tests, show that this approach yields a well‐conditioned and stable linear system similar to that in the finite element method. We also introduce an effective condition number where the properties of both matrix and right‐hand side vector of a linear system are taken into consideration in the measure of conditioning. We first derive the effective condition number of the linear systems resulting from RKCM, and show that using the effective condition number offers a tighter estimation of stability of a linear system. The mathematical analysis also suggests that the effective condition number of RKPM does not grow with model refinement. The numerical results are also presented to validate the mathematical analysis. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis and characterization of amphiphilic star-shaped copolymers based on β-cyclodextrin for micelles drug delivery

Purpose: A series of β-CD amphiphilic star-shaped copolymers with exceptional characteristics were synthesized and their potential as carriers for micelles drug delivery was investigated.

Methods: A series of amphiphilic copolymers based on β-CD were synthesized by introducing poly (acrylic acid)-co-poly(methyl methacrylate)-poly (vinyl pyrrolidone) or poly (acrylic acid)-co-poly(methyl methacrylate)-co-poly(monoacylated-β-CD)-poly (vinyl pyrrolidone) blocks to the primary hydroxyl group positions of β-CD. The micellization behavior of the copolymers, the synthesis conditions, characteristics, drug release in vitro and tissue distribution of vinpocetine (VP) micelles in vivo were investigated.

Results: Around 60 types of β-CD amphiphilic star-shaped copolymers were successfully synthesized and the critical micelle concentration ranged from 9.80?×?10^?4 to 5.24?×?10^?2g/L. The particle size, drug loading and entrapment efficiency of VP-loaded β-CD-P₄ micelles prepared with optimal formulation were about 65?nm, 21.44?±?0.14%, and 49.05?±?0.36%, respectively. The particles had good sphericity. The cumulative release rates at 72?h of VP-loaded β-CD-P₄ micelles in pH 1.0, pH 4.5, pH 6.5, or pH 7.4 media were 93%, 69%, 49%, and 43%, respectively. And, the lung targeting efficiency of VP-loaded β-CD-P₄ micelles was 8.98 times higher than that of VP injection.

Conclusion: The VP-loaded β-CD-P₄ micelles exhibited controlled-release property, pH-induced feature and lung targeting capacity compared with VP injection, suggesting that the β-CD-P₄ copolymers are an excellent candidate for micelles drug delivery.     

Influence of surface interaction between drug and excipient in binary mixture for dry powder inhaler applications

The present study documents the drug-excipient incompatibility in the physical mixtures and its influence on bulk homogeneity and flowability for dry powder inhalers (DPI) applications. Binary mixtures with the model drugs (aceclofenac; salbutamol sulphate) and lactose monohydrate were prepared separately at varied drug loading (1–33 wt.%), and their physicochemical properties were assessed using various characterization techniques. The DSC, P-XRD and FT-IR studies show a significant shift in the signature peak of drug and excipient while ss-NMR, LC-MS show the absence of peaks. In contrast, new peaks are observed in LC-MS and GC studies. The insights are comprehended through a series of XPS studies. The findings indicated the formation of condensed or addition compound. This is attributed to an interaction between polar protic groups (-NH-, -COOH, -OH) and hemiacetal carbon (HO-C-OR) of drug and excipient in the solid-state. It induces crystal strain and alters bulk properties related to mixing (relative standard deviation, %RSD), cohesion and flow function coefficient (FFC). However, surface modification of excipient using MgSt and aerosil R972 (model nano-particle) eliminates such inter-particle interactions, crystal level changes. It improves the bulk properties of binary mixtures pivotal for DPI performance.     

Tailoring morphological and interfacial properties of diatom silica microparticles for drug delivery applications

Diatomaceous earth (DE), naturally available silica, originated from fossilized diatoms has been explored for use in drug delivery applications as a potential substitute for synthetic silica materials. The aim of this study is to explore the influence of particle size, morphology and surface modifications of diatom silica microparticles on their drug release properties. Raw DE materials was purified and prepared to obtain high purity DE silica porous particles with different size and morphologies. Comparative scanning electron microscope and particle characterization confirmed their particle size including irregularly shaped silica particles (size 0.1–1 μm, classified as “fine”), mixed fractions (size 1–10 μm, classified as “mixture”) and pure, unbroken DE structures (size 10–15 μm, classified as “entire”). Surface modification of DE with silanes and phosphonic acids was performed using standard silanization and phosphonation process to obtain surface with hydrophilic and hydrophobic properties. Water insoluble (indomethacin) and water soluble (gentamicin) drugs were loaded in DE particles to study their drug release performances. In vitro drug release studies were performed over 1–4 weeks, to examine the impact of the particle size and hydrophilic/hydrophobic functional groups. The release studies showed a biphasic pattern, comprising an initial burst release for 6 h, followed by near-zero order sustained release. This study demonstrates the potential of silica DE particles as a natural carrier for water soluble and insoluble drugs with release controlled by their morphological and interfacial properties.     

Design of polymeric nanoparticles and its applications as drug delivery systems for acne treatment

Objective: The aim of this study was to evaluate a formulation made of poly(lactide-co-glycolide) (PLGA) nanoparticles containing azelaic acid for potential acne treatment.

Methods: Azelaic acid-loaded PLGA nanoparticles were prepared by spontaneous emulsification processes using poloxamer 188 as stabilizer. Several manufacturing parameters such as stirring rate, concentration of stabilizer and different recovery methods were investigated. Nanoparticles were evaluated in terms of size, zeta potential, encapsulation efficiency, release kinetics and permeation kinetics in vitro. Furthermore, in vitro toxicological studies were performed in Saccharomyces cerevisiae model.

Results: The results showed that by adjusting some formulation conditions it was possible to obtain nanoparticles with high loading and a controlled drug release. Freeze-dried recovery altered the nanoparticles structure by enhancing porous structures and mannitol was required to control the mean particle size. The centrifugation recovery was found to be the best approach to nanoparticles recovery. Similar toxicity profiles were observed for both drug-free and azelaic acid-loaded nanoparticles, with concentration-dependent decreases in cell viability.

Conclusion: These results indicate a potential formulation for controlled release delivery of azelaic acid to the follicular unit.     

Development of porous ceramic bodies for applications in tissue engineering and drug delivery systems

Hydroxyapatite (OHAp) particles with a specific surface area of 9 m²/g were obtained through a thermal treatment at 900 °C followed by deagglomeration by ball milling in ethanol for 20 h. Slurries with a 50-vol.% solids loading were prepared by mixing the particles with water. Organic inclusions with particles sizes from 55 to 750 μm were added and ceramic bodies were consolidated by slip casting. Dense and porous ceramic bodies were obtained with densities as low as 30% and as high as 94% and pore sizes up to 750 μm. The possibility of manufacturing ceramic bodies with porosity gradients designed according to the features of the porous ceramic bodies was studied in order to adapt them to the severe requirements of tissue engineering scaffolds.     

Dissolution rate and stability study of flavanone aglycones,naringenin and hesperetin,by drug delivery systems based on polyvinylpyrrolidone (PVP) nanodispersions

Objective: To study the dissolution behavior, the release mechanism and the stability of nanodispersion system of aglycones with PVP. Methods: The nanodispersion system of polyvinylpyrrolidone (PVP)/naringenin–hesperetin was prepared using the solvent evaporation method. The chemical stability (compatibility) of naringenin and hesperetin in the prepared dispersions was studied under accelerated conditions for 3 months. The evaluation of physical stability was performed by X-ray diffraction analysis (XRD) and by comparing the dissolution profile before and after storage at high temperature and moisture (40ºC, RH 75%). Results: The dissolution rate of naringenin and hesperetin released was dramatically increased in the nanodispersion system of PVP/naringenin–hesperetin (80/20, w/w). The release mechanism of both flavanone aglycones was better described by the diffusion model (Higuchi model). Also it was found that the rate-limiting step that controlled the release of naringenin and hesperetin in the nanodispersion system was dissolution of the carrier (PVP). Conclusions: During accelerated degradation analysis, for 3 months at high temperature and moisture, PVP nanodispersion system showed enhanced chemical compatibility and physical stability. The physical evaluation (obtained from XRD analysis) of PVP/naringenin–hesperetin (80/20, w/w) in the selected storage conditions did not show any crystallization of flavanone aglycones in the PVP nanodispersion system or any change in their release profile.     

BA-MMA-AA三元共聚物和TPT复合改性纳米Si3N4粉体研究

采用自制的BA-MMA-AA三元共聚物和四异丙氧基钛（TPT）对纳米Si3N4进行表面包覆处理,利用红外光谱分析、TEM、粒径分布、接触角等手段进行表征,结果表明：在纳米Si3N4粉体的表面包覆了有机物,并与其发生了化学作用,有效地阻止了纳米Si3N4粉体的团聚;处理过的Si3N4粉体粒径明显减小,在有机溶剂中的分散稳定性显著增加,表面自由能明显降低,改善了纳米Si3N4粉体在聚合物基体中的分散。     

Physicochemical studies of binary eutectic of ibuprofen and ketoprofen for enhanced transdermal drug delivery

Methods: The thermodynamic, eutectic, and crystalline properties of ibuprofen and ketoprofen binary mixtures were investigated using differential scanning calorimetry (DSC) and X-ray powder diffractometry (XRPD). Results: The DSC studies showed that melting point (61°C), enthalpy (11.3 kJ/mol), and entropy of fusion (33.7 J/K/mol) of the binary eutectic were significantly lower than those of the individual anti-inflammatory drugs (NSAIDs). Due to the melting-point depression and enhanced skin lipid solubility, the steady-state flux of ibuprofen and ketoprofen from preparations of the binary eutectic increased as compared to pure NSAIDs using shed snakeskin as a model membrane. The NSAID membrane flux values were calculated by flux ratio equations based on drug thermodynamic data, and compared to experimental values obtained from permeation studies. Conclusion: The proposed flux ratio equations correctly predicted flux increase.