Drug Dev Ind Pharm [journal]
- Two steps modification for improvement of cyclobenzaprine transdermal delivery: releasing from patch and penetrating through skin. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2016 Jul 19.:1-8.
The aim of this study was to improve the transdermal delivery of cyclobenzaprine (CBZ) from drug-in-adhesive patch which showed less side effects and better compliance. CBZ base was prepared and then characterized using differential scanning calorimetry (DSC). The interaction between CBZ and pressure-sensitive adhesive (PSA) was determined by Fourier Transform Infrared Spectroscopy (FT-IR). The influences of PSAs, penetration enhancers, patch thickness and drug content on the transdermal delivery of CBZ were studied thoroughly in vitro. Both CBZ releasing from patch and penetrating through the skin showed very great effect on the transdermal delivery of CBZ. The percentage of drug released from patch was increased with the decreasing of patch thickness, and so did the permeation percentage. The stratum corneum (SC) contributed approximately 57% resistance of total skin permeation resistance, and Span 20 increased the transdermal permeation by approximately 1.59-fold. The pharmacokinetic parameters were obtained through in vivo experiments of the optimized formulation using rabbit. Furthermore, the in vitro skin permeation results of CBZ patch correlated well with the in vivo absorption results in rabbit.
- Preparation of polymer-blended quinine nanocomposite particles by spray drying and assessment of their instrumental bitterness-masking effect using a taste sensor. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2016 Jul 12.:1-37.
The development of taste-masking technologies for foods and drugs is essential because it would enable people to consume and receive healthy and therapeutic effect without distress.In current study, in order to develop a novel method to prepare nanocomposite particles (microparticles containing bitter nanoparticles) in only one step by using spray drying, a two-solution mixing nozzle-equipped spray dryer that we previously reported was used. The nanocomposite particles with or without poorly water-soluble polymers prepared using our spray drying technique were characterized.1) The organic solution containing quinine, a model of bitter compound and poorly water-soluble polymers and 2) sugar alcohol (mannitol) aqueous solution were separately flown in tubes and two solutions were spray dried through two-solution type spray nozzle to prepare polymer-blended quinine nanocomposite particles. Mean diameters of nanoparticles, taste masking effect, and dissolution rate of quinine were evaluated.The results of taste masking by taste sensor suggested that the polymer (Eudragit EPO, Eudragit S100 or Ethyl cellulose)-blended quinine nanocomposite particles exhibited marked masking of instrumental quinine bitterness compared with the quinine nanocomposite particles alone. Quinine nanocomposite formulations altered the quinine dissolution rate, indicating that they can control intestinal absorption of quinine.These results suggest that polymer-blended quinine composite particles prepared using our spray drying technique are useful for masking bitter tastes in the field of food and pharmaceutical industry.
- Solubility and dissolution performances of spray-dried solid dispersion of Efavirenz in Soluplus. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2016 Jul 17.:1-13.
Efavirenz (EFV), a first-line anti-HIV drug largely used as part of antiretroviral therapies, is practically insoluble in water and belongs to BCS class II (low solubility/high permeability). The aim of this study was to improve the solubility and dissolution performances of EFV by formulating an amorphous solid dispersion of the drug in polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus(®)) using spray-drying technique. To this purpose, spray-dried dispersions of EFV in Soluplus(®) at different mass ratios (1:1.25, 1:7, 1:10) were prepared and characterized using particle size measurements, SEM, XRD, DSC, FTIR and Raman microscopy mapping. Solubility and dissolution were determined in different media. Stability was studied at accelerated conditions (40 °C/75% RH) and ambient conditions for 12 months. DSC and XRD analyses confirmed the EFV amorphous state. FTIR spectroscopy analyses revealed possible drug-polymer molecular interaction. Solubility and dissolution rate of EFV was enhanced remarkably in the developed spray-dried solid dispersions, as a function of the polymer concentration. Spray-drying was concluded to be a proper technique to formulate a physically stable dispersion of amorphous EFV in Soluplus(®), when protected from moisture.
- Antifungal ME1111 in vitro human onychopharmacokinetics. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2016 Jul 4.:1-8.
This study determined ME1111 onychopharmacokinetics and possible topical antifungals' clinical efficacy in human great toenails using an in vitro finite dose model. ME1111 topical formulations in 1, 5, 10 or 15% for 3 days observation and 1, 5 or 10% for 14 days observation, respectively, were used to determine ME1111 penetration rate and transungual kinetics. ME1111 concentrations in the deeper nail (ventral/intermediate layers) and a cotton pad/nail bed, were several orders of magnitude greater than MIC90 and MFC90 for three major dermatophytes. ME1111 concentrations 3 days after a single and 14 days after multiple dosing of 10% formulation were 253 and 7991 μg/g nail, respectively, and superior to those of 8% ciclopirox control. ME1111 concentration (μg equivalent/cm(3)) in the cotton pad following 10% ME1111 multiple applications increased linearly throughout the 336 h experiment and was significantly greater than that of 8% ciclopirox. Flux rate of ME1111 averaged as 50.9 μg/cm(3)/day, which was ca. two orders of magnitude greater than the MIC90 values. The novel antifungal ME1111 penetrated well into human nail plate and its concentrations in the deeper nail and cotton pad after application of 10% formulation were significantly greater than those of ciclopirox.
- The 12-3-12 cationic gemini surfactant as a novel gastrointestinal bioadhesive material for improving the oral bioavailability of coenzyme Q10 naked nanocrystals. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2016 Jul 3.:1-11.
To improve the oral bioavailability of nanocrystalline drug preparations, the cationic 12-3-12 quaternary ammonium surfactant gemini was introduced into nanocrystals as a novel gastrointestinal bioadhesive material. Coenzyme Q10 (CoQ10), a typical Biopharmaceutics Classification System (BCS) class II drug, was used as a model drug. The 12-3-12 gemini surfactant was added to the preparation at a low concentration and imbued the particles with abundant positive charges. In vitro and in vivo gastrointestinal adhesion tests confirmed that the gemini-modified nanocrystals were prone to adhere to the upper gastrointestinal tract (GIT), thereby prolonging retention time in the GIT and enhancing absorption. In the distribution study in rats, the use of nanocrystals modified with gemini led to greater drug distribution to the heart and the liver than that achieved with the naked nanocrystals. A pharmacokinetic study in beagle dogs showed that the gemini-modified CoQ10 nanocrystals improved the oral bioavailability of CoQ10 in a dose-dependent manner, and the smaller size produced a much better effect with the same gemini modification. These results demonstrate that the cationic surfactant gemini is a promising oral bioadhesive material with applications in nanoscale drug delivery systems.
- Appropriate selection of an aggregation inhibitor of fine particles used for inhalation prepared by emulsion solvent diffusion. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2016 Jul 12.:1-12.
Dry powder inhaler (DPI) formulations have been developed to deliver large amounts of drugs to the lungs.Fine particles of a poorly water-soluble drug, the model drug ONO-2921, were prepared by the emulsion solvent diffusion (ESD) method for use in a DPI.The effects of additives on the fine particle formation of ONO-2921 were estimated when droplets of an ethanolic drug solution were dispersed into aqueous media containing various additives. Subsequently, the suspensions were freeze-dried to create powdered samples to estimate the inhalation properties using a twin impinger and an Andersen cascade impactor.This simple ESD method produced submicron-sized ONO-2921 particles (approximately 600 nm) in combination with suitable additives. In addition, the freeze-dried powder produced using additives exhibited superior in vitro inhalation properties. Among these methods, the freeze-dried powder produced with 0.50% weight/volume one type of polyvinyl alcohol (PVA-205) displayed the most efficient features in the fine particle fraction (FPF). These results could be explained by the stabilization of the ONO-2921 suspension by PVA-205, indicating that PVA-205 acts as an aggregation inhibitor of fine particles.The ESD method, in combination with appropriate types and amounts of additives, may be useful for preparing a DPI suitable for delivering drugs directly to the lungs without the assistance of carrier particles.
- Influences of copolymers (Copovidone, Eudragit RL PO and Kollicoat MAE 30 DP) on stability and bioactivity of spray-dried and freeze-dried lysozyme. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2016 Jun 26.:1-11.
Protein stability is the most crucial factor in protein pharmaceutical preparations. Various techniques were applied for producing stable protein formulations such as spray-drying and freeze-drying. However, heating and freezing stresses are disadvantages for proteins using these methods, respectively. Accordingly, excipients have been used to preserve therapeutic effects of proteins during processing and for long period of time. Therefore, influences of Copovidone, Eudragit(®) RL-PO and Kollicoat(®) MAE-30 DP (as excipients) on stability and integrity of lysozyme (as a model protein) in spray-dried and freeze-dried forms were investigated. Protein formulations in both dried forms were prepared without and with the addition of mentioned excipients at different concentrations. Protein formulations were characterized for yield determination, morphology using scanning electron microscopic (SEM), thermal analysis by Differential Scanning Calorimetry (DSC), secondary structure stability using Fourier transform infrared (FT-IR) spectroscopy and biological activity. All protein formulations were subjected to a stability study as solid protein formulations for 3 weeks at 24 °C/76% relative humidity and aqueous protein samples were stored at 50 °C for 30 min in a water bath. Results showed that Copovidone successfully preserved integrity and biological activity of lysozyme before and after storage in both spray-dried and freeze-dried forms with more advantage for using higher concentration of the same excipient. Smooth spheres of spray-dried lysozyme formulations with Copovidone were smaller than spray-dried lysozyme without and with Kollicoat(®) MAE-30 DP, which affected %yield produced. Copovidone has demonstrated valuable protection ability for lysozyme.
- In vitro and in vivo evaluation of puerarin-loaded PEGylated mesoporous silica nanoparticles. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2016 Jun 9.:1-7.
Puerarin, which is extracted from Chinese medicine, is widely used in China and mainly used as a therapeutic agent for the treatment of cardiovascular diseases. Owing to its short elimination half-life in human beings, frequently intravenous administration of high doses of puerarin may be needed, which possibly leads to severe and acute side effects. The development of an effective sustained-release drug delivery system is urgently needed. In this study, PEGylated mesoporous silica nanoparticles (PEG-MSNs) had become a preferred way to prolong the half-life and improve the bioavailability of drugs. The release of puerarin from PEG-MSNs was pH dependent, and the release rate was much faster at lower pH than that at higher pH. Moreover, the PEG-MSNs exhibited improved blood compatibility over the MSNs in terms of low hemolysis, and it could also reduce the side effect of hemolysis induced by PUE. Compared with puerarin, PUE-loaded PEG-MSNs showed a 2.3-fold increase in half-life of puerarin and a 1.47-fold increase in bioavailability. Thus, the PEG-MSNs hold the substantial potential to be further developed as an effective sustained-release drug delivery system.
- Synchronized and controlled release of metformin hydrochloride/glipizide from elementary osmotic delivery. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2016 Jun 29.:1-9.
The combination of metformin hydrochloride (MTF) and glipizide (GLZ) is second-line medication for diabetes mellitus type 2 (DMT2). In the present study, elementary osmotic pump ( EOP) tablet is designed to deliver the combination of MTF and GLZ in a sustained and synchronized manner. By analyzing different variables of the formulation, sodium hydrogen carbonate is introduced as pH modifier to improve the release of GLZ, while ethyl cellulose acts as release retardant to reduce the burst release phase of MTF. A two-factor, three-level face-centered central composite design (FCCD) is applied to investigate the impact of different factors on drug release profile. Compared with conventional tablets, the EOP tablet demonstrates a controlled release behavior with relative bioavailability of 99.2% for MTF and 99.3% for GLZ. Data also shows EOP tablet is able to release MTF and GLZ in a synchronized and sustained manner both in vitro and in vivo.
- Co-delivery of pemetrexed and miR-21 antisense oligonucleotide by lipid-polymer hybrid nanoparticles and effects on glioblastoma cells. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2016 Jun 29.:1-10.
Combination therapy using anticancer drugs and nucleic acid is a more promising strategy to overcome multidrug resistance in cancer and to enhance apoptosis. In this study, lipid-polymer hybrid nanoparticles (LPNs), which contain both pemetrexed and miR-21 antisense oligonucleotide (anti-miR-21), have been developed for treatment of glioblastoma, the most aggressive type of brain tumor. Prepared LPNs have been well characterized by particle size distribution and zeta potential measurements, determination of encapsulation efficiency, and in vitro release experiments. Morphology of LPNs was determined by transmission electron microscopy. LPNs had a hydrodynamic size below 100 nm and exhibited sustained release of pemetrexed up to 10 h. Encapsulation of pemetrexed in LPNs increased cellular uptake from 6% to 78%. Results of confocal microscopy analysis have shown that co-delivery of anti-miR-21 significantly improved accumulation of LPNs in the nucleus of U87MG cells. Nevertheless, more effective cytotoxicity results could not be obtained due to low concentration of anti-miR-21, loaded in LPNs. We expect that the effective drug delivery systems can be obtained with higher concentration of anti-miR-21 for the treatment of glioblastoma.