Changshan Sun

Mechanism of Dissolution Enhancement and Bioavailability of Poorly Water Soluble Celecoxib by Preparing Stable Amorphous Nanoparticles

PURPOSE Nanoparticle engineering offers promising methods for the formulation of poorly water soluble drug compounds. The aim of the present work was to enhance dissolution and oral bioavailability of poorly water-soluble celecoxib (CXB) by preparing stable CXB nanoparticles using a promising method, meanwhile, investigate the mechanism of increasing dissolution of CXB. METHODS CXB nanoparticles were produced by combining the antisolvent precipitation and high pressure homogenization (HPH) approaches in the presence of HPMC E5 and SDS (2:1, w/w). Then the CXB nanosuspensions were converted into dry powders by spray-drying. The effect of process variables on particle size and physical state of CXB were investigated. The physicochemical properties of raw CXB and CXB nanoparticles were characterized by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), X-ray photoelectron spectra (XPS), fourier transform infrared (FT-IR) spectroscopy, diffrential scanning calorimetry (DSC), as well as, measuring the particle size and contact angle. Additionally, the studies of in-vitro drug dissolution and oral bioavailability in beagle dogs of nanoparticles were performed. RESULTS The images of SEM revealed spherical CXB nanoparticles. The DSC and XRPD results indicated that the antisolvent precipitation process led to the amorphization of CXB. Under storage, the amorphous CXB nanoparticles showed promising physical stability. The XPS data indicated the amorphous CXB nanoparticles exhibited different surface property compared to raw CXB. Hydrogen bonds were formed between the raw CXB and HPMC E5 as proven by the FT-IR spectra. CXB nanoparticles increased the saturation solubility of CXB fourfold. CXB nanoparticles completely dissolved in the dissolution medium of phosphate buffer (pH 6.8, 0.5% SDS) within 5 min, while there was only 30% of raw CXB dissolved. The C(max) and AUC(0-24h) of CXB nanoparticles were approximately threefold and twofold greater than those of the Celecoxib Capsules, respectively. CONCLUSIONS The process by combining the antisolvent precipitation under sonication and HPH was a promising method to produce small, uniform and stable CXB nanoparticles with markedly enhanced dissolution rate and oral bioavailability due to an increased solubility that is attributed to a combination of amorphization and nanonization with increased surface area, improved wettability and reduced diffusion pathway.

Dual-stimuli responsive hyaluronic acid-conjugated mesoporous silica for targeted delivery to CD44-overexpressing cancer cells.

In this paper, a redox and enzyme dual-stimuli responsive delivery system (MSN-SS-HA) based on mesoporous silica nanoparticles (MSN) for targeted drug delivery has been developed, in which hyaluronic acid (HA) was conjugated on the surface of silica by cleavable disulfide (SS) bonds. HA possesses many attractive features, including acting as a targeting ligand and simultaneously a capping agent to achieve targeted and controlled drug release, prolonging the blood circulation time, and increasing the physiological stability and biocompatibility of MSN. The anticancer drug doxorubicin (DOX) was chosen as a model drug. In vitro drug release profiles showed that the release of DOX was markedly restricted in pH 7.4 and pH 5.0 phosphate buffer solution (PBS), while it was significantly accelerated upon the addition of glutathione (GSH)/hyaluronidases (HAase). In addition, the release was further accelerated in the presence of both GSH and HAase. Confocal laser scanning microscopy (CLSM) and fluorescence-activated cell sorting (FACS) showed that MSN-SS-HA exhibited a higher cellular uptake via cluster of differentiation antigen-44 (CD44) receptor-mediated endocytosis compared with thiol (SH)-functionalized MSN (MSN-SH) in CD44 receptor over-expressed in human HCT-116 cells. The DOX-loaded MSN-SS-HA was more cytotoxic against HCT-116 cells than NIH-3T3 (CD44 receptor-negative) cells due to the enhanced cellular uptake of MSN-SS-HA. This paper describes the development of an effective method for using a single substance as multi-functional material for MSN to simultaneously regulate drug release and achieve targeted delivery.

Uniform mesoporous carbon as a carrier for poorly water soluble drug and its cytotoxicity study

In this study, uniform mesoporous carbon spheres (UMCS) with 3-D pore system and fibrous ordered mesoporous carbon (FOMC) with 2-dimensional hexagonal mesoporous structure were studied as drug carriers for oral drug delivery system. Lovastatin (LOV), which has low water solubility, was chosen as a model drug. Drug release rate and degree of drug loading of UMCS and FOMC were compared. The effects of different pore channel structures and pore sizes on LOV uptake and release were systematically investigated. Cytotoxicity of UMCS and FOMC on human colon carcinoma (Caco-2) cells were also studied. The results indicate that UMCS has a higher degree of drug loading (up to 36.26% drug weight/total weight) compared with FOMC. The dissolution rate of LOV from UMCS was found to be markedly increased compared with pure crystalline LOV, and the dissolution rate of LOV from FOMC was relatively sustained compared with UMCS, and both UMCS and FOMC exhibited a weak cytotoxicity at tested concentrations (10-800 μg/ml).

Novel Chitosan-Functionalized Spherical Nanosilica Matrix As an Oral Sustained Drug Delivery System for Poorly Water-Soluble Drug Carvedilol

A novel spherical nanosilica matrix (SNM) together with chitosan (CTS) encapsulated SNM (CTS-SNM) was developed in order to investigate the feasibility of using chitosan to regulate drug release rate from porous silica and obtain an oral sustained drug delivery system. To achieve this goal, we synthesized a spherical nanosilica matrix (SNM) and incorporated chitosan chains on the SNM surface. Solvent evaporation method was adopted to load the model drug carvedilol into SNM and CTS-SNM. The physicochemical properties of the drug carriers and drug-loaded composites were systematically studied using scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen adsorption, X-ray diffraction (XRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The structural changes in CTS-SNM in simulated gastrointestinal fluid as well as the relationships between swelling effect of chitosan and in vitro drug release behaviors were investigated. Pharmacokinetic and bioavailability aspects were also discussed. The results showed that the powerful dispersing effect of SNM and the blocking action due to the swelling of chitosan were the two main factors contributing to the sustained drug release behavior. The swelling effect of chitosan in an acidic environment together with the shrinking effect in a relatively alkaline environment allowed regulation of drug release behavior in simulated gastrointestinal fluid. An in vivo study showed that the bioavailability of CAR was improved 182% compared with that of the commercial capsule when SNM was used as the drug carrier. As for CAR-CTS-SNM, the T(max) of CAR was delayed by about 3.4 h and the bioavailability was slightly increased in comparison with the commercial capsule. We believe that SNM and CTS-SNM developed in this study will help increase the use of polymers and inorganic materials in pharmaceutical applications and stimulate the design of oral drug delivery systems for immediate or sustained release of poorly water-soluble drugs.

Inclusion of celecoxib into fibrous ordered mesoporous carbon for enhanced oral bioavailability and reduced gastric irritancy

Fibrous ordered mesoporous carbon (FOMC) was developed as a new drug delivery system for loading an insoluble drug, designed to be orally administered, and then to enhance the drug loading capacity, improve the dissolution rate, enhance the oral bioavailability and reduce the gastric damage. Celecoxib (CEL) was chosen as a model drug. The nanostructures and effect of different pore sizes (4.4-7.0 nm) on drug loading and release properties were studied. The results showed that FOMC has a high drug loading capacity (0.599 g/g, drug weight/carrier weight) and the dissolution rate of CEL from FOMC was much faster than pure crystalline CEL using buffer (pH 6.8) as a dissolution medium. Moreover, the oral bioavailability of CEL loaded into FOMC was significantly improved compared with that of CEL capsules and the gastric damage caused by CEL which was loaded in FOMC was also reduced, demonstrating the protective effect of FOMC.

Mesoporous carbon as a novel drug carrier of fenofibrate for enhancement of the dissolution and oral bioavailability.

The purpose of this study was to develop mesoporous carbon loaded with a poorly watersoluble drug to enhance the drug dissolution and improve the oral bioavailability. Mesoporous carbon was synthesized using Pluronic 127 triblock polymer (F127), TEOS and phenolic resins. Fenofibrate (FFB) was chosen as a model drug and loaded onto mesoporous carbon using three different loading methods involving incipient wetness impregnation, and the solvent and melting methods. The effect of the physical state and the specific surface area were investigated using nitrogen adsorption, transmission electron microscopy (TEM), powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC). It was found that the physicochemical properties of the drug as well as the drug loading methods had critical effects on the drug release rate. In vitro drug release studies showed that incorporation of FFB in mesoporous carbon greatly enhanced the dissolution rate in comparison with that of the pure crystalline drug. Moreover, the oral bioavailability of the drug from mesoporous carbon was higher than that of FFB commercial capsules. Furthermore, mesoporous carbon produced no irritation of the mucosa of the gastrointestinal tract as shown by gastric mucosa irritation test.

The investigation of MCM-48-type and MCM-41-type mesoporous silica as oral solid dispersion carriers for water insoluble cilostazol.

Abstract Objective: To explore the suitable application of MCM-41 (Mobil Composition of Matter number forty-one)-type and MCM-48-type mesoporous silica in the oral water insoluble drug delivery system. Methods: Cilostazol (CLT) as a model drug was loaded into synthesized MCM-48 (Mobil Composition of Matter number forty-eight) and commercial MCM-41 by three common methods. The obtained MCM-41, MCM-48 and CLT-loaded samples were characterized by means of nitrogen adsorption, thermogravimetric analysis, ultraviolet-visible spectrophotometry, scanning electron microscopy, transmission electron microscopy, differential scanning calorimetry and powder X-ray diffractometer. Results: It was found that solvent evaporation method was preferred according to the drug loading efficiency and the maximum percent cumulative drug dissolution. MCM-48 with 3D cubic pore structure and MCM-41 with 2D long tubular structure are nearly spherical particles in 300–500 nm. Nevertheless, the silica carriers with similar large specific surface areas and concentrating pore size distributions (978.66 m2/g, 3.8 nm for MCM-41 and 1108.04 m2/g, 3.6 nm for MCM-48) exhibited different adsorption behaviors for CLT. The maximum percent cumulative drug release of the two CLT/silica solid dispersion (CLT-MCM-48 and CLT-MCM-41) was 63.41% and 85.78% within 60 min, respectively; while in the subsequent 12 h release experiment, almost 100% cumulative drug release were both obtained. In the pharmacokinetics aspect, the maximum plasma concentrations of CLT-MCM-48 reached 3.63 mg/L by 0.92 h. The AUC0–∞ values of the CLT-MCM-41 and CLT-MCM-48 were 1.14-fold and 1.73-fold, respectively, compared with the commercial preparation. Conclusion: Our findings suggest that MCM-41-type and MCM-48-type mesoporous silica have great promise as solid dispersion carriers for sustained and immediate release separately.

Uniform nano-sized valsartan for dissolution and bioavailability enhancement: Influence of particle size and crystalline state

The central purpose of this study was to evaluate the impact of drug particle size and crystalline state on valsartan (VAL) formulations in order to improve its dissolution and bioavailability. VAL microsuspension (mean size 22 μm) and nanosuspension (30-80nm) were prepared by high speed dispersing and anti-solvent precipitation method and converted into powders through spray drying. Differential scanning calorimetry studies indicated amorphization of VAL in the spray-dried valsartan nanosuspension (SD-VAL-Nano) but recrystallization occurred after 6 months storage at room temperature. The spray-dried valsartan microsuspension (SD-VAL-Micro) conserved the crystalline form. The VAL dissolution rate and extent were markedly enhanced with both SD-VAL-Micro and SD-VAL-Nano as compared to crude VAL crystals over the pH range of 1.2-6.8. Pharmacokinetic studies in rats demonstrated a 2.5-fold increase in oral bioavailability in the case of SD-VAL-Nano compared with the commercial product while the SD-VAL-Micro provided a much less desirable pharmacokinetic profile. In conclusion, reducing particle size to the nano-scale appears to be a worthwhile and promising approach to obtain VAL products with optimum bioavailability. In addition, the impact of crystalline state on the bioavailability of nano-sized VAL might be not as big as that of particle size.

Folate-polyethyleneimine functionalized mesoporous carbon nanoparticles for enhancing oral bioavailability of paclitaxel.

Polymer-functionalized carbon nanoparticles hold great promise for their use in enhancing the oral absorption of drugs with poor oral bioavailability. And since the abundant expression of folate receptors in intestinal tract, folic acid (FA) modified uniform mesoporous carbon spheres (UMCS) was used to improve oral absorption of paclitaxel, a chemotherapeutic drug with poor oral bioavailability. In this research, folate-polyethyleneimine (FA-PEI) was grafted onto acid-treated uniform mesoporous carbon spheres through one-step electrostatic attraction. PTX was loaded into mesopores of nanoparticles through solvent evaporation, present as amorphous. The release of PTX from the FA-PEI-UMCS nanoparticles exhibited an initial rapid release, followed by a sustained release. And release rate could be regulated by changing amount of FA-PEI complex on the UMCS. The uptake of PTX-encapsulated nanoparticles was studied exploiting Caco-2 cells as an in vitro model. The results of confocal microscopy and flow cytometry demonstrated that folate functionalization enhanced internalization of nanoparticles by the cells. Moreover, PTX loaded in FA-PEI-UMCS nanoparticles resulted in a 5.37-fold increase in apparent permeability (Papp) across Caco-2 cell monolayers compared to Taxol(®). And the in vivo results showed that FA-PEI-UMCS nanoparticles did not only improve the oral bioavailability of PTX, but also decrease the gastrointestinal toxicity of PTX. In conclusion, the FA-PEI-UMCS nanoparticles might be a potentially applicable system to improve oral absorption of drugs with poor oral bioavailability.

Investigation of Nanosized Crystalline Form to Improve the Oral Bioavailability of Poorly Water Soluble Cilostazol

PURPOSE The aim of this study was to develop cilostazol (CLT) nanocrystals intended to improve its dissolution rate and enhance its bioavailability. METHODS In this study, CLT nanosuspension was prepared by the anti-solvent and high-pressure homogenization method. The effects of the production parameters, such as the stabilizer concentration, pressure and number of cycles, were investigated. Characterization of the product was performed by scanning electron microscopy (SEM), Nitrogen adsorption, differential scanning calorimetry (DSC), X-ray powder diffraction analysis (XRPD), X-ray Photoelectron Spectroscopy (XPS), particle size analysis and dissolution testing. Additionally, the comparison studies of oral bioavailability in beagle dogs of three type tables were performed. RESULTS The images of SEM showed a spherical smooth CLT powder, and Nitrogen adsorption test revealed spray dried powder were porous with high BET surface area compared with that of raw CLT. DSC and XRPD results demonstrated that the combination of preferred polymorph B and C of CLT were prepared successfully, the saturation solubility of the nanosized crystalline powder is about 5 fold greater than that of raw CLT, and the dissolution rate was enhanced 4 fold than that of raw CLT. The Cmax and AUC0-48h of CLT nanosized crystalline tablets were 2.1 fold and 1.9 fold, and 3.0 fold and 2.3 fold compared with those of the nanosized tablets and commercial tablets, respectively. CONCLUSION The anti-solvent-high-pressure homogenization technique was employed successfully to produce cilostazol nanosuspensions. The bioavailability of CLT tablets prepared using spray dried nanosized crystalline powder after oral administration to dogs was markedly increased compared with that produced by nanosized tablets and commercial tablets, because of its greater dissolution rate owing to its transition of the crystalline state to form C and form B, reduced particle size and porous structure with increased surface area.