Local drug delivery using poly(lactic-co-glycolic acid) nanoparticles in thermosensitive gels for inner ear disease treatment

Intratympanic (IT) therapies have been explored to address several side effects that could be caused by systemic administration of steroids to treat inner ear diseases. For effective drug delivery to the inner ear, an IT delivery system was developed using poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and thermosensitive gels to maintain sustained release. Dexamethasone (DEX) was used as a model drug. The size and zeta potential of PLGA NPs and the gelation time of the thermosensitive gel were measured. In vitro drug release was studied using a Franz diffusion cell. Cytotoxicity of the formulations was investigated using SK-MEL-31 cells. Inflammatory responses were evaluated by histological observation of spiral ganglion cells and stria vascularis in the mouse cochlea 24 h after IT administration. In addition, the biodistribution of the formulations in mouse ears was observed by fluorescence imaging using coumarin-6. DEX-NPs showed a particle size of 150.0 ± 3.2 nm in diameter and a zeta potential of −18.7 ± 0.6. The DEX-NP-gel showed a gelation time of approximately 64 s at 37 °C and presented a similar release profile and cytotoxicity as that for DEX-NP. Furthermore, no significant inflammatory response was observed after IT administration. Fluorescence imaging results suggested that DEX-NP-gel sustained release compared to the other formulations. In conclusion, the PLGA NP-loaded thermosensitive gel may be a potential drug delivery system for the inner ear.     

Preparation,characterization and pharmacological evaluation of tolterodine hydrogels for the treatment of overactive bladder

In this study, transdermal gel formulations for tolterodine were developed to investigate the effects of gel matrix and chemical enhancers on drug skin permeation from tolterodine hydrogels. In vitro permeation studies of tolterodine through excised mouse skin were carried out using Franz-type diffusion cells. In the optimum gel formulation, Carbopol 940 was selected as the gel matrix. Compared to gels without enhancer, tolterodine hydrogels with N-methyl pyrrolidone (NMP) showed significant enhancing effect on transdermal permeation of tolterodine (p < 0.05). The results of in vitro percutaneous delivery experiment showed that the relationship of the steady accumulative percutaneous amount (Q, μg cm⁻²) of tolterodine hydrogels and time was Q_4–12h = 770.19t^1/2 − 966.99. Tolterodine permeated at the steady-state speed of 770.19 μg cm⁻² h⁻¹ and its release coincided with Higuchi Equation. The pharmacokinetic properties of the optimized tolterodine formulation were studied in rabbits. The absolute bioavailability of tolterodine was 11.47%. Since the absence of hepatic first-pass metabolism, only a single active compound-tolterodine was detected in the plasma. A skin irritation study was also carried out on rabbits, and the results showed tolterodine hydrogels had no skin irritation. In the pharmacodynamic study, the significant effects of tolterodine hydrogels on the inhibition of pilocarpine-induced rat urinary bladder contraction were last to 12 h, indicating that tolterodine hydrogels could produce prolonged pharmacological responses. In conclusion, tolterodine hydrogels were formulated successfully using Carbopol 940 and NMP and these results helped in finding the optimum formulation for percutaneous drug release. It is quite evident that tolterodine hydrogels may offer a possibility to avoid the first-pass effect, resulting in a single active compound of tolterodine in plasma, which may profit on the patient under the dose control and the reduction of potential adverse effect from two active compounds in the body.     

Characterisation and stability studies of a hydrophilic decapeptide in different adjuvant drug delivery systems: a comparative study of PLGA nanoparticles versus chitosan-dextran sulphate microparticles versus DOTAP-liposomes

Poly[lactic-co-glycolide] (PLGA) nanoparticles, chitosan-dextran sulphate microparticles, and DOTAP-liposomes were prepared as vaccine adjuvants and drug carriers for a small hydrophilic model peptide, and their different physico-chemical properties (size, PDI, zeta-potential, pH-value and peptide loading) were investigated. The model peptide's encapsulation efficiency (EE) in PLGA particles amounted to 15%, for DOTAP-liposomes to 20% and for chitosan particles up to 90%. The structural appearance of the particles was visualized by SEM and TEM. The stability of the aqueous formulations and the corresponding lyophilisates was monitored for 12 weeks (stored at T = 2-8 °C). The freeze-drying process and the addition of an appropriate cryoprotective agent (sucrose) proved to be essential for all carrier systems. As a result of this study, three different peptide-loaded drug delivery systems with different properties were successfully manufactured and showed sufficient product stability of their freeze-dried formulations over 12 weeks of storage.     

Development of biodegradable in situ implant and microparticle injectable formulations for sustained delivery of haloperidol

The objective of this study is to formulate injectable, biodegradable sustained release in situ implant (ISI), and in situ microparticle (ISM) formulations of haloperidol. Factors affecting the in vitro drug release, pharmacokinetics, and stability of the formulations were investigated. The concentration of the polymer, poly(lactide-co-glycolide) acid (PLGA), and the type of solvents showed a pronounced effect on the in vitro drug release from the ISI and ISM formulations. The ISM formulation [20% PLGA in N-methyl-2-pyrrolidone (NMP)–peanut oil, 1:4] showed reduced maximum plasma concentration (60 versus 44 ng/mL) and longer release (30 days, plasma concentration of 8 ng/mL versus 20 days, plasma concentration of 6 ng/mL) compared with the ISI formulation (20% PLGA in NMP) after intramuscular injection in rats. The delivery of haloperidol can be extended further by changing the concentration, molecular weight, and lactide-to-glycolide ratio of the PLGA. These formulations can be easily administered by both intramuscular and subcutaneous injections. The shelf lives of both systems were found to be 2 years when stored at 4°C. Haloperidol can be formulated as an injectable ISI or ISM systems suitable for 1 month or longer release. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:3753–3762, 2012     

Novel hyperbranched polyamidoamine nanoparticle based gene delivery: transfection, cytotoxicity and in vitro evaluation

In this study, hyperbranched polyamidoamine (hPAMAM) was developed as a novel non-viral gene vector for the first time. The hPAMAM was synthesized using a modified “one-pot” method. DNA was then bound to hPAMAM at different weight ratios (w_hPAMAM/w_DNA). The higher weight ratio could bring larger particle size and higher zeta potential of hPAMAM-DNA complexes. The encapsulated DNA was protected by hPAMAM from degradation for over 3 h. Under the optimal condition, high gene transfection efficiency could be achieved in COS7 (47.47 ± 1.42%) and HEK293 (40.8 ± 0.98%) cell lines. And hPAMAM showed rather minor cytotoxicity in vitro (cell viability = 91.38 ± 0.46% in COS7 and 92.38 ± 0.61% in HEK293). The hPAMAM mediated human vascular endothelial growth factor 165 (hVEGF₁₆₅) gene transfected cells could express hVEGF₁₆₅ stably for 14 days, with the peak expression at day 2. In conclusion, hPAMAM based gene delivery was economical, effective and biocompatible, and may serve as a promising non-viral vehicle for gene therapy.     

Formulation and Characterization of Injectable Poly(<Emphasis Type="SmallCaps">dl</Emphasis>-lactide-<Emphasis Type="BoldItalic">co</Emphasis>-glycolide) Implants Loaded with N-Acetylcysteine,a MMP Inhibitor

Purpose The objective of this study was to develop poly(lactic-co-glycolic acid) (PLGA) injectable implants (i.e., millicylinders) with microencapsulated N-acetylcysteine (NAC) for site-specific controlled NAC release, for potential chemopreventive applications in persons with previously excised head and neck cancers. Methods PLGA 50:50 (i.v. = 0.57 dl/g) implants with 1–10 wt% NAC free acid or 10 wt% NAC salts (NAC–Na⁺, NAC–Mg²⁺ and NAC–Ca²⁺) were prepared by solvent extrusion and/or fluid energy micronization (FEM) methods. X-ray diffraction (XRD), scanning electron microscopy (SEM), and differential scanning calorimetry (DSC) studies were performed to evaluate the physical mixing of NAC with PLGA. PLGA implant degradation was studied by kinetics of polymer molecular weight decline (gel permeation chromatography) and mass loss. Release studies were conducted in N₂ purged PBS (pH 7.4) at 37°C in evacuated and sealed ampoules. NAC was quantified by HPLC at 210 nm. Results XRD, SEM and DSC studies indicated that NAC had dissolved in the polymer phase at 1–3.5% w/w loading, but became discretely suspended in the polymer at 6–10% w/w. Initial burst and long-term release rate increased with increased drug loading, and release was uncharacteristically rapid at higher loading (6–10% w/w). The cause of the rapid release was linked to extensive plasticization, matrix porosity and general acid catalysis of PLGA degradation caused by the NAC free acid. PLGA millicylinders loaded with 10% w/w NAC–Ca²⁺ and NAC–Mg²⁺salts exhibited reduced burst (34 vs 13–22% release within a day of incubation for NAC free acid vs NAC–Ca²⁺ and NAC–Mg²⁺salts, respectively) and slow and continuous complete release over 4 weeks without significant NAC-catalyzed degradation of PLGA. Release of NAC from NAC–Ca²⁺/PLGA implant was slower than that of NAC–Mg²⁺/PLGA consistent with the lower solubility of the former salt. NAC with its free thiol was rapidly converted to its cystine dimer in the presence of molecular oxygen. PLGA released samples in sealed and evacuated ampoules indicated >80% parent NAC remaining after the 1 month release analysis irrespective of initial NAC free acid and salt forms. Conclusion By encapsulating the NAC–Mg²⁺ and NAC–Ca²⁺ salts in PLGA implants, the high initial burst, short release duration, and the general acid catalysis caused by the NAC free acid were each prevented and 1-month slow and continuous release was attained with minimal instability of the free thiol group.     

Preparation,Characterization, and In Vitro Evaluation of 1- and 4-Month Controlled Release Orntide PLA and PLGA Microspheres

Purpose. To prepare, characterize and evaluate in vitro sustained delivery formulations for a novel LHRH antagonist, Orntide acetate, using biodegradable microspheres (ms). Methods. Poly(d,l-lactide) (PLA) and poly(d,l-lactide-co-glycolide) (PLGA) were characterized for molecular weight (M_w, M_n) using gel permeation chromatography (GPC) and content of free end carboxyl groups (acid number, AN) by a titration method. 1- and 4-month Orntide ms were prepared by a dispersion / solvent extraction / evaporation process and characterized for drug content (HPLC), bulk density (tapping method), particle size (laser diffraction method), surface morphology (scanning electron microscopy, SEM), and structural integrity of encapsulated peptide by Fourier Transform Matrix Assisted Laser Desorption mass spectrometry (FT-MALDI). Peptide binding to PLA and PLGA and non-specific adsorption to blank ms was studied in 0.1 M phosphate buffer pH 7.4 (PB) and 0.1 M acetate buffer pH 4.0 (AB). In vitro release of peptide was assessed in PB and AB. Results. M_w for the PLGA copolymers varied from 10,777 to 31,281 Da and was 9,489 Da for PLA. AN was between 4.60 and 15.1 for the hydrophilic resomers and 0.72 for the hydrophobic 50:50 PLGA copolymer. Spherical ms (3.9 μ to 14 μ in diameter) with mostly non-porous surface and varying degree of internal porosity were prepared. FT-MALDI mass spectra of the extracted peptide showed that the encapsulation process did not alter its chemical structure. Peptide binding to PLGA and PLA and non-specific adsorption to blank PLGA ms were dependent upon pH and were markedly higher in PB than in AB. The initial in vitro release in PB varied from 0.5 to 26%/24 h but due to substantial binding of the peptide to the polymeric matrix the long-term release in PB could not be determined. Application of a dialysis method allowed for a more accurate determination of in vitro release and a good total drug recovery. Conclusions. Orntide acetate was successfully incorporated into PLA and PLGA ms and the 1- and 4-month in vitro release profiles were achieved by polymer selection and optimization of the manufacturing parameters.     

Cytotoxicity and apoptotic signalling cascade induced by chelidonine-loaded PLGA nanoparticles in HepG2 cells in vitro and bioavailability of nano-chelidonine in mice in vivo

Poor oral bioavailability of chelidonine, a bio-active ingredient of Chelidonium majus, showing anti-cancer potentials against cancer cells with multidrug resistance, makes its optimal use rather limited. To address this problem, we encapsulated chelidonine in biodegradable poly(lactide-co-glycolide) (PLGA) polymers and evaluated nano-chelidonine's (NCs) anti-cancer efficacy vis-à-vis free chelidonine (FC) against HepG2 cells and also evaluated its bioavailability in mice. Physicochemical characteristics indicated that stable spherical NC were formed in nanometer size range (123 ± 1.15 nm) with good yield (86.34 ± 1.91%), better encapsulation efficiency (82.6 ± 0.574%), negative surface charge (−19.6 ± 2.48 mV) and ability of prolonged and sustained release of chelidonine. Fourier transform infrared analysis revealed that NC resembled similar peaks as that of FC suggesting effective encapsulation in PLGA. NC exhibited rapid cellular uptake and stronger apoptotic effect (∼46.6% reduced IC₅₀ value) than FC, blocking HepG2 cells at G2/M phase. p53, cyclin-D1, Bax, Bcl-2, cytochrome c, Apaf-1, caspase-9 and caspase-3 expressions also corroborated well to suggest greater anticancer potentials of NC. Our in vivo studies demonstrated NC to be more bio-available than FC and showed a better tissue distribution profile without inducing any toxicity (100 mg/kg bw) in mice. Unlike FC, NC could permeate into brain tissue, indicating thereby NC's better potentials for use in therapeutic oncology.     

Improvement of survival in C6 rat glioma model by a sustained drug release from localized PLGA microspheres in a thermoreversible hydrogel

A local drug delivery system based on sustained drug release is an attractive approach to treat brain tumors. We have developed a novel device using drug-incorporated poly(lactic-co-glycolic acid) (PLGA) microspheres embedded in thermoreversible gelation polymer (TGP) formulation (drug/PLGA/TGP formulation). TGP forms a gel at body temperature but sol at room temperature. Therefore, when this formulation is injected into the brain tumor, the PLGA microspheres in TGP gel are localized at the injection site and do not diffuse throughout the brain tissue; eventually, sustained drug release from PLGA microspheres is achieved at the target site. In this study, two chemotherapeutic drugs (camptothecin (CPT) or vincristine (VCR)) were incorporated into PLGA microspheres to prepare drug/PLGA/TGP formulations. VCR/PLGA microspheres exhibited the higher encapsulation efficiency than CPT/PLGA microspheres (70.1% versus 30.1%). In addition, VCR/PLGA microspheres showed a higher sustained release profile than CPT/PLGA microspheres (54.5% versus 72.5% release, at 28 days). Therapeutic effect (mean survival) was evaluated in the C6 rat glioma model (control group, 18 days; CPT/PLGA/TGP treatment group, 24 days; VCR/PLGA/TGP treatment group, 33 days). In particular, the VCR/PLGA/TGP formulation produced long-term survivors (>60 days). Therefore, this formulation can be therapeutically effective formulation for the glioma therapy.     

The design of flexible ciprofloxacin-loaded PLGA implants using a reversed phase separation/coacervation method

The purpose of this research is to design and characterize flexible PLGA-based implants for the controlled release of ciprofloxacin hydrochloride for up to 6 weeks in vitro. This research uses a reversed phase separation/coacervation method to fabricate flexible PLA and PLGA: excipient implants with dichloromethane/mineral oil as solvent/non-solvent. Physical characterization was performed using thermal and mechanical analyses. Drug loading and release studies were performed with ciprofloxacin HCl as the model drug. Release kinetics was modeled to elucidate possible mechanisms of drug release. Four polymer-excipient combinations with glass transition temperatures less than 20 °C and representing a wide range of Young’s moduli were shown to entrap up to 8% of ciprofloxacin HCl that could be released at a controlled rate for 65 days in vitro. The release rate could consistently fit a ternary Gaussian pattern with an R² > 0.99. It was postulated that these release patterns could be related to ciprofloxacin that was loosely or poorly bound (burst release), trapped within the polymer matrix, or encapsulated by the polymer. These studies show that flexible implants can be fabricated from PLGA-based polymers for the controlled release of ciprofloxacin hydrochloride for up to 6 weeks in vitro.     

人血清白蛋白注射用凝胶的处方工艺研究

目的：制备人血清白蛋白（HSA）可注射用凝胶,使用星点设计-效应面优化法对处方工艺进行优化筛选。方法：以聚乳酸-羟基乙酸共聚物（PLGA）为载体材料N-甲基-2-吡咯烷酮（NMP）和苯甲酸苄酯（BB）为共溶剂制备载HSA可注射用凝胶;以PLGA的用量及共溶剂的组成为考察因素,体外释放为评价指标,用线性方程和二次及三次多项式描述体外释放和两个影响因素之间的数学关系,根据最佳数学模型描绘效应面,选择最佳处方,并进行预测分析。结果：各指标的三项式拟合方程均优于多元线形回归方程,建立的数学模型的预测值与实际值符合较好。结论：用星点设计-效应面法优化处方工艺预测性良好。     

Transferrin-conjugated lipid-coated PLGA nanoparticles for targeted delivery of aromatase inhibitor 7α-APTADD to breast cancer cells

Transferrin (Tf)-conjugated lipid-coated poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles carrying the aromatase inhibitor, 7α-(4′-amino)phenylthio-1,4-androstadiene-3,17-dione (7α-APTADD), were synthesized by a solvent injection method. Formulation parameters including PLGA-to-lipid, egg PC-to-TPGS, and drug-to-PLGA ratios and aqueous-to-organic phase ratio at the point of synthesis were optimized to obtain nanoparticles with desired sizes and drug loading efficiency. The optimal formulation had a drug loading efficiency of 36.3 ± 3.4%, mean diameter of 170.3 ± 7.6 nm and zeta potential of −18.9 ± 1.5 mV. The aromatase inhibition activity of the nanoparticles was evaluated in SKBR-3 breast cancer cells. IC₅₀ value of the Tf-nanoparticles was ranging from 0.77 to 1.21 nM, and IC₅₀ value of the nanoparticles was ranging from 1.90 to 3.41 nM (n = 3). The former is significantly lower than the latter (p < 0.05). These results suggested that the aromatase inhibition activity of the Tf-nanoparticles was enhanced relative to that of the non-targeted nanoparticles, which was attributable to Tf receptor (TfR) mediated uptake. In conclusion, Tf-conjugated lipid-coated PLGA nanoparticles are potential vehicles for improving the efficiency and specificity of therapeutic delivery of aromatase inhibitors.     

Controlled delivery of aspirin: effect of aspirin on polymer degradation and in vitro release from PLGA based phase sensitive systems

The objective of this study was to develop poly (d,l-lactide-co-glycolide) (PLGA) based injectable phase sensitive in situ gel forming delivery system for controlled delivery of aspirin, and to characterize the effect of drug/polymer interaction on the in vitro release of aspirin and polymer degradation. Aspirin was dissolved into PLGA solution in 1-methyl-2-pyrrolidone. Poly(ethylene glycol)400 was used as plasticizer to reduce initial burst release. The solution formulation was injected into aqueous release medium to form a gel depot. Released samples were withdrawn periodically and assayed for aspirin content by high performance liquid chromatography. The effect of aspirin on the degradation of PLGA matrix was evaluated using Proton Nuclear Magnetic Resonance and Gel Permeation Chromatography. PLGA based in situ gel forming formulations controlled the in vitro release of aspirin for 7 days only. Analysis of PLGA matrix residuals revealed that PLGA in aspirin loaded formulations exhibited a significantly (p < 0.05) faster degradation compared to blank formulations. These findings suggest that aspirin causes an unusually faster degradation of PLGA. Such faster degradation of PLGA has not been noticed for any other drugs reported in the literature.     

Electrospun Micro- and Nanofibers for Sustained Delivery of Paclitaxel to Treat C6 Glioma in Vitro

Purpose The present study aims to develop electrospun PLGA-based micro- and nanofibers as implants for the sustained delivery of anticancer drug to treat C6 glioma in vitro.Methods PLGA and an anticancer drug—paclitaxel-loaded PLGA micro- and nanofibers were fabricated by electrospinning and the key processing parameters were investigated. The physical and chemical properties of the micro- and nanofibers were characterized by various state-of-the-art techniques, such as scanning electron microscope and field emission scanning electron microscope for morphology, X-ray photoelectron spectroscopy for surface chemistry, gel permeation chromatogram for molecular weight measurements and differential scanning calorimeter for drug physical status. The encapsulation efficiency and in vitro release profile were measured by high performance liquid chromatography. In addition, the cytotoxicity of paclitaxel-loaded PLGA nanofibers was evaluated using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide MTT) assay on C6 glioma cell lines.Results PLGA fibers with diameters of around several tens nanometers to 10 μm were successfully obtained by electrospinning. Ultrafine fibers of around 30 nm were achieved after addition of organic salts to dilute polymer solution. The encapsulation efficiency for paclitaxel-loaded PLGA micro- and nanofibers was more than 90%. DSC results suggest that the drug was in the solid solution state in the polymeric micro- and nanofibers. In vitro release profiles suggest that paclitaxel sustained release was achieved for more than 60 days. Cytotoxicity test results suggest that IC50 value of paclitaxel-loaded PLGA nanofibers (36 μg/ml, calculated based on the amount of paclitaxel) is comparable to the commercial paclitaxel formulation-Taxol?.Conclusions Electrospun paclitaxel-loaded biodegradable micro- and nanofibers may be promising for the treatment of brain tumour as alternative drug delivery devices.     

In vivo uptake and acute immune response to orally administered chitosan and PEG coated PLGA nanoparticles

Nanoparticulate drug delivery systems offer great promise in addressing challenges of drug toxicity, poor bioavailability and non-specificity for a number of drugs. Much progress has been reported for nano drug delivery systems for intravenous administration, however very little is known about the effects of orally administered nanoparticles. Furthermore, the development of nanoparticulate systems necessitates a thorough understanding of the biological response post exposure. This study aimed to elucidate the in vivo uptake of chitosan and polyethylene glycol (PEG) coated Poly, dl, lactic-co-glycolic Acid (PLGA) nanoparticles and the immunological response within 24 h of oral and peritoneal administration. These PLGA nanoparticles were administered orally and peritoneally to female Balb/C mice, they were taken up by macrophages of the peritoneum. When these particles were fluorescently labelled, intracellular localisation was observed. The expression of pro-inflammatory cytokines IL-2, IL-6, IL-12p70 and TNF-α in plasma and peritoneal lavage was found to remain at low concentration in PLGA nanoparticles treated mice as well as ZnO nanoparticles during the 24 hour period. However, these were significantly increased in lipopolysaccharide (LPS) treated mice. Of these pro-inflammatory cytokines, IL-6 and IL-12p70 were produced at the highest concentration in the positive control group. The anti-inflammatory cytokines IL-10 and chemokines INF-γ, IL-4, IL-5 remained at normal levels in PLGA treated mice. IL-10 and INF-γ were significantly increased in LPS treated mice. MCP-1 was found to be significantly produced in all groups in the first hours, except the saline treated mice. These results provide the first report to detail the induction of cytokine production by PLGA nanoparticles engineered for oral applications.     

Preparation and characterization of poly(dl-lactide-co-glycolide) nanoparticles for siRNA delivery

Synthetic short interfering RNA (siRNA) is promising for specific and efficient knockdown of disease-related genes. However, in vivo application of siRNA requires an effective delivery system. Commonly used siRNA carriers are based on polycations, which form electrostatic complexes with siRNA. Such poly- or lipoplexes are of limited use in vivo due to severe problems associated with toxicity, serum instability and non-specific immune-responses. The aim of the present study was to prepare uniformly sized nanoparticles (NPs) with a high load of siRNA by use of the safe and biodegradable poly-(dl-lactide-co-glycolide) (PLGA) polymer without including polycations. The siRNA was encapsulated in the core of NPs by the double emulsion solvent evaporation method. To optimize the NP formulation, the effects of important formulation and processing parameters were investigated systematically. Generally, spherical siRNA-loaded NPs (<300 nm, PDI < 0.2, zeta potential −40 mV) were obtained. An encapsulation efficiency of up to 57% was achieved by adjusting the inner water phase volume, the PLGA concentration, the first emulsification sonication time, and stabilization of the water–oil interface with serum albumin. The integrity of siRNA was preserved during the preparation. Preparation of core-loaded siRNA-NPs based on PLGA and no cationic excipient seems possible and promising for delivery of siRNA.     

替硝唑原位固化缓释凝胶的处方研究

目的:应用Box-Behnken法设计并优化替硝唑原位固化缓释凝胶处方.方法:通过体外释放度的单因素影响试验确定考察因素与水平,以凝胶粘度、遇水固化时间、释放时间为响应变量,应用Box-Behnken法进行处方筛选与优化.结果:优化处方为35.3%(w/w)单甲氧基聚乙二醇-聚乳酸(mPEG-PDLLA 10/90),5.9% (w/w)替硝唑和58.8% (w/w)N-甲基-2-吡咯烷酮(NMP).该凝胶体外释放时间达192 h,无突释现象.结论:通过Box-Behnken法成功实现了替硝唑原位固化缓释凝胶的处方筛选.     

The PLGA nanoparticles for sustainable release of CGRP to ameliorate the inflammatory and vascular disorders in the lung of CGRP-deficient rats

The calcitonin gene-related peptide (CGRP) has been demonstrated relating to vascular and inflammatory regulations not only the nerve systems. As the anti-inflammation factor and the most potent vasodilator, the CGRP holds therapeutic potentials for the treatment of cardiovascular diseases which was, however, limited by its peptide nature and short half-life. With advantages in improving the stability, circulation time and protection from degradation, the nanoparticles were promising as delivery carriers for the peptide. Nevertheless, few nanoparticulate systems were developed to deliver the CGRP peptide for the modulation of vascular or inflammatory functions instead of neural regulation. In this study, the CGRP was encapsulated into the poly (lactic-co-glycolic acid) (PLGA) nanoparticle for sustained release of CGRP in vivo. The nanoparticles recovered the systemic level of CGRP and the vascular inflammatory factors in the CGRP^+/− rats comparing to the administration of (Dulbecco''s Phosphate Buffered Saline) DPBS or peptide only. With the decrease of vascular wall thickness and the attenuation of the T cell infiltration in the lung, the polymer based CGRP delivery system showed potentials to facilitate the therapeutic effects of the CGRP which may help for the development of CGRP-based therapy in vascular and inflammatory disorder related diseases.     

Preparation and In Vitro/Ex Vivo Evaluation of Moxifloxacin-Loaded PLGA Nanosuspensions for Ophthalmic Application

The aim of the present investigation was to prepare a colloidal ophthalmic formulation to improve the residence time of moxifloxacin. Moxifloxacin-loaded poly(dl-lactide-co-glycolide) (PLGA) nanosuspensions were prepared by using the solvent evaporation technique. The nanosuspensions were characterised physically by using different techniques like particle size, zeta potential, FTIR, DSC, and XRD analysis. In vitro and ex vivo studies of nanosuspensions were carried out using a modified USP dissolution apparatus and all-glass Franz diffusion cells, respectively. The antibacterial activities of the nanosuspension and marketed formulations were performed against S. aureus and P. aeroginosa. The moxifloxacin-loaded PLGA nanosuspensions showed uniform particle size, ranging between 164–490 nm with negative zeta potential for all batches. The percentage entrapment efficiency of the drug-loaded nano-suspension was found to be between 84.09 to 92.05%. In vitro drug release studies suggest that all of the formulations showed extended drug release profiles and follow Korsemeyer-Peppas release kinetics. In vitro corneal permeability was found to be comparable with that of the marketed formulation across isolated goat cornea, indicating the suitability of the nanosuspension formulation in the ophthalmic delivery of moxifloxacin. The optimised nano-suspension was found to be more active against S. aureus and P. aeruginosa compared to the marketed eye drops.     

Antitumor Efficacy and Toxicity of 5-Fluorouracil-Loaded Poly(Lactide Co-glycolide) Pellets

The aim of this study was to formulate a biodegradable implant capable of imparting local antitumor activity through the sustained release of the chemotherapeutic agent, 5-fluorouracil (5-FU). Thus, injectable pellets (<1.2 mm diameter) made from poly(lactide co-glycolide) (PLGA) and loaded with 5-FU at varying drug:polymer ratios were fabricated using hot-melt extrusion and tested for their ability to provide sustained release of 5-FU in in vitro and in vivo settings. In addition, these formulations were compared against soluble 5-FU for their antitumor activity in vivo as well as for their toxicity. It was demonstrated that the release rate of 5-FU from PLGA pellets was directly related to the percentage of 5-FU in the pellets. PLGA pellets loaded with 50% w/w 5-FU exhibited comparable, and significantly enhanced, antitumor activity (as measured by tumor volumes and survival) in vivo in a thymoma and colon cancer model, respectively, when compared to an equivalent bolus dose (120 mg/kg) of soluble 5-FU. We concluded that 5-FU-loaded PLGA pellets were more effective and specifically less erythrotoxic than 5-FU bolus injections and therefore may prove to be of benefit as an intraoperative adjunct therapy for patients with cancers that are sensitive to 5-FU and who are undergoing tumor resection.