Drug delivery to inflamed colon by nanoparticles: Comparison of different strategies

For inflammatory bowel disease (IBD) treatment, local delivery of molecules loaded in nanoparticles to the inflamed colon could be a promising strategy. The aim of this study was to investigate how drug-loaded polymeric nanoparticles target the site of inflammation and to analyse the influence of different colon-specific delivery strategies. Three different polymeric nanoparticles were formulated using ovalbumin (OVA) as a model drug. pH-sensitive nanoparticles were made with Eudragit^® S100. Mucoadhesive nanoparticles were created with trimethylchitosan (TMC). A mix of polymers, PLGA, PEG-PLGA and PEG-PCL, were used to obtain a sustained drug delivery. Furthermore, ligands targeting immune cells (i.e. mannose) or the inflamed colon (i.e. a specific peptide) were grafted on the PEG chain of PCL. Interaction of nanoparticles with the intestinal epithelium was explored using Caco-2 monolayers designed to mimic an inflamed epithelium and then visualized using confocal laser microscopy. TMC nanoparticles had the highest apparent permeability for OVA in the untreated model. However, in the inflamed model, there were no difference between TMC, PLGA-based and Eudragit^® nanoparticles. The uptake of nanoparticles in the inflamed mouse colon was assessed in a horizontal diffusion chamber. Mannose-grafted PLGA nanoparticles showed the highest accumulation of OVA in inflamed colon. Based on these results, active targeting of macrophages and dendritic cells may be a promising approach for targeting the colon in IBD.     

Drug delivery to the nasal cavity: in vitro and in vivo assessment

Drugs are given intranasally for both local and systemic applications, and the use of the intranasal route is predicted to rise dramatically in the next 10 years. Nasal drug delivery may be assessed by a variety of means, but high reliance is often placed upon in vitro testing methodology (emitted dose, droplet or particle size distribution, spray pattern, and plume geometry). Spray pattern and plume geometry define the shape of the expanding aerosol cloud, while droplet size determines the likelihood of deposition within the nasal cavity by inertial impaction. Current FDA guidance recommends these methods as a means of documenting bioavailability (BA) and bioequivalence (BE) for topically acting solution formulations, because they can be performed reproducibly and are more discriminating among products. Nasal drug delivery in vivo may be determined by several radionuclide imaging methods: the two-dimensional imaging technique of gamma scintigraphy has been used most widely, but the three-dimensional method of positron emission tomography (PET) is being used increasingly often. In some situations a good in vitro/in vivo correlation (IVIVC) exists; for instance, negligible penetration into the lungs has been demonstrated in the case of nasal pump sprays delivering large droplets, while a clear difference may be shown in intranasal deposition between two aerosols with markedly different size distributions. However, recent studies have shown a poorer IVIVC for two similar nasal pump sprays, where significant differences in in vitro parameters were not reflected in differences in nasal deposition in vivo. It is suggested that radionuclide imaging data may have an important role to play as an adjunct to in vitro testing in BA and BE assessments and may provide a clearer understanding of the changes in in vitro parameters that are important for predicting differences in in vivo performance.     

In vitro and in vivo evaluation of Triptolide-loaded pluronic P105 polymeric micelles

Thin film method was applied successfully to prepare Triptolide (TP)-loaded micelles system. With a dynamic light scattering sizer and a transmission electron microscopy, it was shown that the TP-loaded micelles had a mean size of 84.3±6.4 nm with a spherical shape. The in vitro release profiles indicated that the release of TP from the micelles exhibited a sustained release behavior. A similar phenomenon was also observed in a pharmacokinetic study in rats, in which AUC of the micelles formulation were 4.7-fold higher than that of TP injection. The biodistribution study in rats showed that the TP-loaded micelles not only decreased drug uptake by liver, but also increased distribution of drug in ovary. The present work demonstrated the feasibility of controlled delivery of TP utilizing micelles system.     

Novel oral delivery system of indomethacin by solidified mPEG-PDLLA micelles: in vivo study

To administer indomethacin (IND) orally using polymeric micelles, IND loaded solidified polymeric micelles (IND-SPM) were prepared and evaluated for their in vitro and in vivo characteristics. IND and methoxy-poly(ethylene glycol) poly(d, l-lactide) copolymer (mPEG-PDLLA) were dissolved in acetone followed by the addition of an equivalent amount of polyplasdone XL-10 and stirred to obtain a suspension. Afterwards, acetone was completely evaporated. It was found that IND-SPM generates small polymeric micelles of 18.1 nm. Moreover, the solubility of IND at pH 6.8 increased 4.6-folds, and more than 90% of IND in 20 mg of IND-SPM was dissolved in 250 mL SIF pH 6.8 within 30 min. Pharmacokinetic parameters in fasted rats showed that IND-SPM 1:3 resulted in 3-folds increase of AUC and C(max) compared to commercial IND. mPEG-PDLLA micelles were found to be efficient carriers for oral administration of IND as solid dosage forms by adsorption on polyplasdone XL-10.     

Novel oral delivery system of indomethacin by solidified mPEG-PDLLA micelles: in vivo study

To administer indomethacin (IND) orally using polymeric micelles, IND loaded solidified polymeric micelles (IND-SPM) were prepared and evaluated for their in vitro and in vivo characteristics. IND and methoxy-poly(ethylene glycol) poly(d, l-lactide) copolymer (mPEG-PDLLA) were dissolved in acetone followed by the addition of an equivalent amount of polyplasdone XL-10 and stirred to obtain a suspension. Afterwards, acetone was completely evaporated. It was found that IND-SPM generates small polymeric micelles of 18.1 nm. Moreover, the solubility of IND at pH 6.8 increased 4.6-folds, and more than 90% of IND in 20 mg of IND-SPM was dissolved in 250 mL SIF pH 6.8 within 30 min. Pharmacokinetic parameters in fasted rats showed that IND-SPM 1:3 resulted in 3-folds increase of AUC and C_max compared to commercial IND. mPEG-PDLLA micelles were found to be efficient carriers for oral administration of IND as solid dosage forms by adsorption on polyplasdone XL-10.     

Exploiting gastrointestinal bacteria to target drugs to the colon: an in vitro study using amylose coated tablets

The bacterial substrate amorphous amylose, in the form of a film coating, provides a means of delivering drugs to the colon. This coating has traditionally been applied to multi-unit systems, in part because of the small size and divided nature of this type of dosage form, which provides a large surface area for enzymatic attack and drug release. The present study was conducted to explore the utility of the coating for colonic targeting of single unit tablet systems. Amylose was combined with the water-insoluble polymer ethylcellulose, which acts as a structuring agent, in different proportions to produce film coatings of various thicknesses for application to mesalazine (mesalamine or 5-aminosalicylic acid)-containing tablets. Drug release from the coated products was assessed under pH dissolution conditions resembling the stomach and small intestine, and also in conditions simulating the colon using a batch culture fermenter inoculated with human faecal bacteria. The rate and extent of drug release was related to the ratio of amylose to ethylcellulose in the film and the thickness of the coating. Increasing the proportion of ethylcellulose in the film and/or the thickness of the coating depressed the rate of drug release in the conditions of the upper gastrointestinal tract. Drug release from the coated products was accelerated in the fermentation environment of the colon. This is attributed to bacterial digestion of the amylose component of the film coat producing pores for drug diffusion. This work indicates that amylose coated tablet formulations are promising vehicles for drug delivery to the colon.     

还原响应型透明质酸抗肿瘤胶束的构建及其体外性质研究

目的合成透明质酸-胱胺-硬脂酸(HA-CYS-SA)两亲性聚合物,并研究其所制备胶束的理化性质、还原敏感性以及体外抑瘤效果。方法以碳二亚胺作为偶联剂,使胱胺、硬脂酸先后与透明质酸发生酰胺偶联反应,制得载体聚合物并通过核磁共振波谱法确定其结构。采用改进的探头超声法制备载多西他赛的聚合物胶束,以芘荧光法测定其临界胶束浓度,动态光散射法测定胶束的粒径分布,透射电镜观察胶束的微观形态;通过对载药胶束在不同谷胱甘肽浓度下的粒径变化与药物释放行为的考察,验证胶束的还原敏感性;通过激光共聚焦显微镜研究载药胶束的细胞摄取能力,并对载药胶束的体外抑瘤效果进行考察。结果成功制得两亲性聚合物材料,胶束粒子呈规则的球形,粒径为(186.7±5.3)nm;制备的载药胶束具有良好的还原敏感响应性,在无谷胱甘肽或10μmol·L~(-1)谷胱甘肽存在时,胶束的粒径在24 h内无明显变化;而在10及20 mmol·L~(-1)谷胱甘肽存在时,24 h后胶束的粒径分别增大了1.53倍和1.89倍,多西他赛的释放量分别提升了约43%及84%。包载荧光染料香豆素6的HA-CYS-SA胶束组的荧光强度明显高于游离香豆素6组,证明其具有更好的细胞摄取能力;载药胶束对4T1细胞的半数抑制浓度为0.304μg·m L~(-1),说明其具有显著的体外抗肿瘤效果。结论所构建的还原敏感型胶束具有良好的理化性质、还原敏感响应性、细胞摄取能力以及抑瘤效果,是极具应用潜力与发展前景的药物载体。     

In vivo and in vitro release of macromolecules from polymeric drug delivery systems

In vivo release rates of a macromolecule from an ethylene-vinyl acetate copolymer have been shown to be indistinguishable from those of identical implants tested in vitro. The studies were conducted for approximately 2 months, and two different techniques were used to assess release rates. One of these techniques, using [3H]inulin as a marker, may be particularly useful in future studies assessing in vivo release rates from drug delivery systems. The appearance of [3H]inulin in the urine of rats bearing implants allowed continuous monitoring of release. A histological evaluation of tissue sections surrounding polymer implanted for 7 months showed no inflammatory cell reaction.     

Stearic acid-g-chitosan polymeric micelle for oral drug delivery: in vitro transport and in vivo absorption

Stearic acid-g-chitosan (low molecular weight chitosan CS-SA) with different amino-substituted degrees was synthesized and evaluated as an oral delivery vehicle in this paper. Synthesized CS-SA with 4.47%, 24.36% and 40.36% amino-substituted degree (SD) could form micelles by self-aggregation in aqueous medium. The critical micelle concentration (CMC) ranged from about 0.16 to 0.25 mg/mL, which decreased with the increased SD of CS-SA. The CS-SA micelles had 33.4-130.9 nm size and 22.9- 48.4 mV zeta potential. CS-SA with higher SD had the smaller size and the higher zeta potential. The permeability and possible transport route of CS-SA micelles across the gastrointestinal tract was investigated by in vitro model Caco-2 cells. The results exhibited that the CS-SA micelles had good permeability, and the permeability enhanced with increasing SD of the CS-SA. The transport of the micelles showed energy, pH and concentration dependent transcytosis process, mainly through macropinocytosis and partly via fluid-phase transcytosis and caveolar route. The reversible decrease in transepithelial electrical resistance (TEER) by treatment of micelles suggested that paracellular transport pathway was another route of the micelles crossing the gastrointestinal tract. Using doxorubicin (DOX) as a model drug, the permeation results further demonstrated that the DOX transport mediated by CS-SA micelles could avoid efflux via P-glycoprotein. In vivo study demonstrated that the micelles could significantly improve the bioavailability of encapsulated drug. The results presented that the CS-SA with higher SD was a promising vehicle for oral drugs.     

Binders for colon specific drug delivery: an in vitro evaluation

In order to screen out an optimum complex for reducing the nephrotoxicity of cisplatin (CDDP), we investigated and compared CDDP–chondroitin sulfate complexes to CDDP in terms of in vivo pharmacokinetics and in vitro cytotoxicity. The polymeric carriers used in the study were chondroitin sulfate A (CSA, 4-sulfate) with mean molecular weights of 10 kDa (CSA-1) and 23 kDa (CSA-2), and chondroitin sulfate C (CSC, 6-sulfate) with mean molecular weights of 8 kDa (CSC-1) and 25 kDa (CSC-2). The resultant complexes (CDDP–CSA-1, CDDP–CSA-2, CDDP–CSC-1 and CDDP–CSC-2) were administered intravenously to rats. The obtained plasma concentration–time curves during the 3 h period studied for all complexes are biphasic. The plasma dispositions of complexes were dependent on the molecular sizes with urinary excretion as main elimination pathway. CDDP–CSA-1 and CDDP–CSC-1 were unable to effectively increase the plasma retention of platinum due to rapid renal excretion. Furthermore, CDDP–CSA-1 disappeared from plasma more quickly than CDDP–CSC-1. CDDP–CSA-2 and CDDP–CSC-2, with similar urinary excretion as CDDP, gave rise to approximately five and four-fold increase in AUC_{0–3 h} values, respectively, than that was achieved with native CDDP treatment. Biodistribution was compared between CDDP–CSA-2 and CDDP–CSC-2. Both complexes effectively suppressed the extensive distribution of CDDP into most tissues, especially kidney. However, CDDP–CSC-2 showed less reduction effect than CDDP–CSA-2. In addition, a significantly higher accumulation in tumor tissue was found with the administration of CDDP–CSA-2 than CDDP. Moreover, CSA complexes displayed an IC₅₀ of 6 μM Pt-equivalents against SW4800 human colon cancer cells, similar to that of CDDP, whereas CSC complexes were less active than CDDP. These studies indicate that the complex prepared with CSA, which is greater than 20 kDa of molecular size, is superior to that of CSC, exhibiting improved pharmacokinetics and similar pharmacological activity to the native drug.     

Tachykinin NK(2) receptors and enhancement of cholinergic transmission in the inflamed rat colon: an in vivo motility study

In the gastrointestinal tract, tachykinin NK(2) receptors are localized both on smooth muscle and nerve fibres. NK(2) receptor antagonists reduce exaggerated intestinal motility in various diarrhoea models but the site of action contributing to this effect is unknown. In this study we investigated the effects of atropine (1.4 micromol kg(-1), i.v.), hexamethonium (13.5 micromol kg(-1), i.v.), and nepadutant (0.1 micromol kg(-1), i.v.), a selective tachykinin NK(2) receptor antagonist, on distension (0.5 and 1 ml)-, or irritation (acetic acid, 0.5 ml of 7.5% v v(-1))-induced motility in the rat distal colon in vivo. The effects of atropine, hexamethonium or N(omega)-nitro-L-argininemethylester (L-NAME, 1.85 micromol kg(-1), i.v.) on [betaAla(8)]NKA(4-10) (10 nmol kg(-1), i.v.)-induced colonic contractions were also investigated. When the colonic balloon was filled with a subthreshold volume (0.5 ml), the intraluminal instillation of acetic acid triggered a high-amplitude phasic colonic motility which was partially reduced by nepadutant and suppressed by either hexamethonium or atropine. Filling of the balloon with 1 ml evoked reflex (hexamethonium-sensitive), atropine-sensitive phasic colonic motility: nepadutant had no significant effect on the distension-evoked motility. Neither hexamethonium nor atropine significantly reduced [betaAla(8)]NKA(4-10)-induced colonic contractions, whereas nepadutant suppressed them. Following L-NAME pretreatment, [betaAla(8)]NKA(4-10)-induced colonic contractions were inhibited by both atropine and hexamethonium. In hexamethonium-pretreated animals, an atropine-sensitive component of [betaAla(8)]NKA(4-10)-induced colonic contractions was also evident. These results indicate that the application of irritants onto the colonic mucosa induces the release of endogenous tachykinins which enhance excitatory cholinergic mechanisms through the stimulation of NK(2) receptors.     

Biodegradable polymeric microspheres for nalbuphine prodrug controlled delivery: in vitro characterization and in vivo pharmacokinetic studies

The objective of this work was to study the in vitro characteristics as well as in vivo pharmacokinetic performance of a series nalbuphine (NA) prodrug-loaded microspheres. An oil-in-water solvent evaporation method was used to incorporate the various NA prodrugs into poly(D,L-lactide-co-glycolide) (PLGA)-based microspheres. The morphology of microspheres under the scanning electron microscopy (SEM) revealed a spherical shape with smooth surface. Drug release rates for the microspheres were found to be a function of prodrug hydrophilicity, with higher drug release rates for microspheres loaded with more hydrophilic prodrugs. The release profiles fit well to the Baker and Lonsdale's spherical matrix model, suggesting the drug release from microspheres was consistent with a diffusion mechanism. The in vivo pharmacokinetic studies after s.c. injection of microspheres into rabbits showed sustained plasma NA-time profiles, with approximately 104.7, 67.2, and 41.0% relative bioavailability for microspheres loaded with nalbuphine propionate (NAP), nalbuphine pivalate (NPI), and nalbuphine decanoate (NDE), respectively. The in vitro release characteristics correlated well with the in vivo pharmacokinetic profiles. The results indicated that the prodrug hydrophilicity had significant effects on the in vitro as well as in vivo drug release kinetics. The present study demonstrates the feasibility of using biodegradable polymeric microspheres for controlled delivery of NA prodrugs.     

Assessment of the recovery of three lipophilic psoralens by microdialysis: an in vitro study

The microdialysis method is extensively developed in neuropharmacological experiments. It is a non-invasive technique with promising applications in biological research. The aim of this work was to establish and to optimize a process to microdialyse chemicals. Three lipophilic molecules used in dermatology were tested: 5-methoxypsoralen (5-MOP), 8-methoxypsoralen (8-MOP) and trimethylpsoralen (TMP). These psoralens have the same basic chemical structure (furocoumarin). The different radical substitutions are responsible for their different lipophilicities. In this work, different microdialysis parameters were studied: the relative recovery and the equilibrium time in relation to the perfusion rate and to the drug lipophilicity. The equipment was composed of a CMA/100® microinjection pump, CMA/20® microdialysis probes (membrane length of 10 mm, cut off 20 and 100 kDa) and a CMA/140® microcollector. The perfusate was a phosphate buffer 0.06 M (pH 7.4). The psoralen dialysates were assessed by high performance liquid chromatography. The relative recovery of psoralens increased with the decreasing perfusion rates and with the drug lipophilicity. The equilibrium time decreased with the increasing perfusion rates. TMP was not detected under these experimental conditions. This work defines the optimal parameters for in vivo studies and shows the limit of this technique for the investigation of lipophilic drugs.     

Enhanced oral bioavailability of paclitaxel in pluronic/LHR mixed polymeric micelles: preparation, in vitro and in vivo evaluation

In order to enhance paclitaxel oral bioavailability, mixed polymeric micelles that comprised of pluronic copolymers and low molecular weight heparin-all-trans-retinoid acid (LHR) conjugate were developed. PTX-loaded mixed polymeric micelles (MPMs) were prepared by dialysis method with high drug loading 26.92 ± 2.08% and 25.82 ± 1.9% for F127/LHR and P188/LHR MPMs respectively, and were found to be spherical in shape with an average size of around 140 nm and a narrow size distribution. In vitro release study showed that pluronic/LHR MPMs exhibited delayed release characteristics compared to Taxol and faster drug release profile compared to LHR plain polymeric micelles (PPMs). The cytotoxic activity of PTX-loaded pluronic/LHR MPMs was slightly higher than LHR PPMs in MCF-7 cells (p<0.01). In situ effective permeability of PTX through rat small intestine was 5- to 6-fold higher with mixed micelles than that of Taxol. Moreover, pluronic/LHR MPMs achieved significantly higher AUC and C(max) level than both of LHR PPMs and Taxol. This enhancement might be due to the inhibition of both P-glycoprotein efflux system and cytochrome P450 metabolism by pluronic copolymers. The current results encourage further development of paclitaxel mixed polymeric micelles as an oral drug delivery system.     

Novel microemulsion in situ electrolyte-triggered gelling system for ophthalmic delivery of lipophilic cyclosporine A: in vitro and in vivo results

The objective of the present study was to design a novel microemulsion in situ electrolyte-triggered gelling system for ophthalmic delivery of a lipophilic drug, cyclosporine A (CsA). A CsA-loaded microemulsion was prepared using castor oil, Solutol HS 15 (surfactant), glycerol and water. This microemulsion was then dispersed in a Kelcogel solution to form the final microemulsion in situ electrolyte-triggered gelling system. In vitro, the viscosity of the CsA microemulsion Kelcogel system increased dramatically on dilution with artificial tear fluid and exhibited pseudo-plastic rheology. In vivo results revealed that the AUC(0-->32 h) of corneal CsA for the microemulsion Kelcogel system was approximately three-fold greater than for a CsA emulsion. Moreover, at 32 h after administration, CsA concentrations delivered by the microemulsion Kelcogel system remained at therapeutic levels in the cornea. This CsA microemulsion in situ electrolyte-triggered gelling system might provide an alternative approach to deliver prolonged precorneal residence time of CsA for preventing cornea allograft rejection.     

Stimulation of inflammatory responses in vitro and in vivo by lipophilic HMG-CoA reductase inhibitors

The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase catalyses the rate limiting step in cholesterol biosynthesis and is markedly inhibited by the statin family of drugs. The effect of statins on lipid lowering is clearly defined, but the ability of the drugs to directly regulate inflammatory functions has not been well explored. In this report, we show that there are differences among the statins in their capacity to induce proinflammatory responses both in human monocytes in vitro, and in leukocytes in mice in vivo. Treatment of human monocytes with lipophilic statins alone stimulated the production of MCP-1, IL-8, TNF-alpha and IL-1 beta and markedly sensitized the cells to subsequent challenge with inflammatory agents. Lipophilic statins also increased the production of reactive oxygen species in monocytes. In contrast, pretreatment of cells with the hydrophilic pravastatin did not induce these heightened inflammatory responses. Furthermore, treatment of mice with lipophilic statins caused a markedly higher influx of leukocytes into the inflamed peritoneal cavity following challenge with thioglycollate. Overall, these results demonstrate that the lipophilic statins influence a regulatory pathway in monocytes that controls cytokine production and that the statins induce different pro-inflammatory responses both in vitro and in vivo.     

Lipid nanoparticles for prolonged topical delivery: an in vitro and in vivo investigation

Dermal therapy is still a challenge due to the difficulties in controlling the active pharmaceutical ingredient (API) fate within the skin. Recently, lipid nanoparticles have shown a great potential as vehicle for topical administration of active substances, principally owing to the possible targeting effect and controlled release in different skin strata. Ketoprofen and naproxen loaded lipid nanoparticles were prepared, using hot high pressure homogenization and ultrasonication techniques, and characterized by means of photo correlation spectroscopy and differential scanning calorimetry. Nanoparticle behavior on human skin was assessed, in vitro, to determine drug percutaneous absorption (Franz cell method) and, in vivo, to establish the active localization (tape-stripping technique) and the controlled release abilities (UVB-induced erythema model). Results demonstrated that the particles were able to reduce drug penetration increasing, simultaneously, the permeation and the accumulation in the horny layer. A prolonged anti-inflammatory effect was observed in the case of drug loaded nanoparticles with respect to the drug solution. Direct as well as indirect evidences corroborate the early reports on the usefulness of lipid nanoparticles as carriers for topical administration, stimulating new and deeper investigations in the field.     

In vitro and in vivo evaluation of pectin beads for the colon delivery of beta-lactamases

The aim of the present study was to provide a "proof of concept" of colon delivery of beta-lactamases by pectin beads aiming to degrade residual beta-lactam antibiotics, in order to prevent the emergence of resistant bacterial strains.Pectin beads were prepared according to ionotropic gelation method using CaCl2 as a gelling agent. Particles were then washed and soaked in polyethylenimine (PEI). Coating beads with PEI considerably improved their stability in simulated intestinal medium. In vitro studies showed that beta-lactamases were released from pectin beads in colonic medium due to the action of pectinolytic enzymes. When ampicillin was added to this medium, the release of beta-lactamases induced, as expected, the antibiotic inactivation. Finally, after oral administration of loaded-beads to CD1 mice, beta-lactamases were retrieved in high concentrations in faeces. Observation by SEM of beads extracted from mice intestinal tracts concluded the core degradation of beads without any modification of the PEI coating layer.This study demonstrates that a multiparticulate system with suitable characteristics for site-specific colonic delivery can be prepared. This system could be used to target beta-lactamases to the colon in order to hydrolyse antibiotic residues during treatment and prevent their impact on colonic microflora.     

Poly-lactide-co-glycolide nanoparticles containing voriconazole for pulmonary delivery: in vitro and in vivo study

Poly-lactide-co-glycolide nanoparticles (207–605 nm) containing voriconazole (VNPs) were developed using a multiple-emulsification technique and were also made porous during preparation in presence of an effervescent mixture for improved pulmonary delivery. Pulmonary deposition of the particles was studied using a customized inhalation chamber. VNPs had a maximum of 30% (w/w) drug loading and a zeta potential (ZP) value around ? 20 mV. In the initial 2 hours, 20% of the drug was released from VNPs, followed by sustained release for 15 days. Porous particles had a lower mass median aerodynamic diameter (MMAD) than nonporous particles. Porous particles produced the highest initial drug deposition (~ 120 μg/g of tissue). The drug was detectable in lungs until 7 days and 5 days after administration, for porous and nonporous particles, respectively. VNPs with improved drug loading were successfully delivered to murine lungs. Porous nanoparticles with lower MMADs showed better pulmonary deposition and sustained presence in lungs.From the Clinical EditorIn this paper, voriconazole-containing porous nanoparticles were studied for inhalational delivery to lung infections in a murine model, demonstrating prolonged half-life and improved pulmonary deposition.     

Development of biodegradable polymeric paste formulations for taxol: An in vitro and in vivo study

Biodegradable polymeric paste formulations (‘surgical pastes’) for local delivery of taxol were developed and characterized. Taxol was mixed into melted poly(D,L-lactide)-block-poly(ethylene glycol)-block-poly(D,L-lactide) (PDLLA-PEG-PDLLA) copolymers and blends of low molecular weight poly(D,L-lactic acid) and poly-ϵ-caprolactone (PDLLA:PCL) to obtain the paste formulations. The release of taxol into PBS albumin buffer was measured by HPLC. The polymers and pastes were characterized by gel permeation chromatography (GPC), differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR) and scanning electron microscopy (SEM). Taxol was released in a sustained manner from the PDLLA-PEG-PDLLA paste over a period of 2 months by diffusion and polymer erosion. The release from the blend was mainly erosion controlled and consisted of a burst followed by a period of slow release. Efficacy of the pastes in inhibiting tumor growth in mice was evaluated. Molten, taxol loaded paste formulations were placed at subcutaneous tumor sites in mice (pastes harden at 37°C). After 16 days, the reduction in tumor weight was measured. Both the taxol loaded copolymer and 90:10 PDLLA:PCL blend formulations significantly inhibited tumor growth in mice. The pastes with faster in vitro release rates resulted in greater efficacy in inhibiting tumor growth. The results showed that biodegradable polymeric surgical pastes are promising formulations for the local delivery of taxol to inhibit tumor growth.