Sangkil Lee

A retinyl palmitate-loaded solid lipid nanoparticle system: Effect of surface modification with dicetyl phosphate on skin permeation in vitro and anti-wrinkle effect in vivo

Surface-modified solid lipid nanoparticles (SLNs) containing retinyl palmitate (Rpal) were prepared by the hot-melt method using Gelucire 50/13(®) and Precirol ATO5(®). Dicetyl phosphate (DCP) was added to negatively charge the surfaces of the SLNs and thereby enhance the skin distribution properties of Rpal. In vitro skin permeation and in vivo anti-aging studies were performed using SLNs dispersed in a hydrogel. The SLNs were under 100 nm in size with an even polydispersity index (PDI), and the high absolute zeta-potential value was sufficient to maintain the colloidal stability of the SLNs. DCP-modified negative SLNs (DCPmod-SLNs) enhanced the skin distribution of Rpal 4.8-fold and delivered Rpal to a greater depth than did neutral SLNs. The in vivo anti-wrinkle effect of the DCPmod-SLN formulation was Rpal dose-dependent. However, the anti-wrinkle effects of the DCPmod-SLN formulations were significantly different from that of the negative control and effectively prevented the reduction of elastin and superoxide dismutase by UV irradiation. In conclusion, the DCPmod-SLN system presented is a good candidate for topical Rpal delivery.

Nanostructured lipid carrier-loaded hyaluronic acid microneedles for controlled dermal delivery of a lipophilic molecule

Nanostructured lipid carriers (NLCs) were employed to formulate a lipophilic drug into hydrophilic polymeric microneedles (MNs). Hyaluronic acid (HA) was selected as a hydrophilic and bioerodible polymer to fabricate MNs, and nile red (NR) was used as a model lipophilic molecule. NR-loaded NLCs were consolidated into the HA-based MNs to prepare NLC-loaded MNs (NLC-MNs). A dispersion of NLCs was prepared by high-pressure homogenization after dissolving NR in Labrafil and mixing with melted Compritol, resulting in 268 nm NLCs with a polydispersity index of 0.273. The NLC dispersion showed a controlled release of NR over 24 hours, following Hixson–Crowell’s cube root law. After mixing the NLC dispersion with the HA solution, the drawing lithography method was used to fabricate NLC-MNs. The length, base diameter, and tip diameter of the NLC-MNs were approximately 350, 380, and 30 μm, respectively. Fluorescence microscopic imaging of the NLC-MNs helped confirm that the NR-loaded NLCs were distributed evenly throughout the MNs. In a skin permeation study performed using a Franz diffusion cell with minipig dorsal skin, approximately 70% of NR was localized in the skin after 24-hour application of NLC-MNs. Confocal laser scanning microscopy (z-series) of the skin at different depths showed strong fluorescence intensity in the epidermal layer, which appeared to spread out radially with the passage of time. This study indicated that incorporation of drug-loaded NLCs into MNs could represent a promising strategy for controlled dermal delivery of lipophilic drugs.

Surface modification of lipid-based nanocarriers for cancer cell-specific drug targeting

Targeted drug delivery systems using nanocarriers for anticancer drugs have been investigated for over several decades. Among the many nanocarrier systems, lipid-based nanocarriers such as liposomes, solid lipid nanoparticles, and nanostructured lipid carriers have afforded attention as a carrier system to improve the efficacy of anticancer drugs. Recent efforts have focused on cancer cell-specific drug delivery through the functionalization of the surface of lipid-based nanocarriers with various ligands such as targeting moieties, cell-penetrating peptides, and cell-penetrating homing peptides to overcome non-selectivity, minimize side effects, and enhance antitumor efficacy. However, the use of ligand modification has been limited because the nanocarriers were easily recognized by the mononuclear phagocyte system and thus rapidly removed from the blood circulation. To achieve prolonged systemic circulation, nanocarriers were further modified with protective polymers such as polyethylene glycol (PEG). Unexpectedly, this presented a PEG dilemma, as the interaction of ligands with the target was hindered and induced poor cellular uptake. Recently, stimuli-sensitive cleavage of the PEG coat, following recognition of the cancer cell microclimate, such as low pH, redox-potential, and over-expressed enzymes, was established to solve this problem. This review presents a comprehensive overview on the current state of surface-modified lipid-based nanocarriers for the improved delivery of anticancer drugs.

Evaluation of taste-masking effects of pharmaceutical sweeteners with an electronic tongue system.

Abstract Electronic tongue systems have been developed for taste measurement of bitter drug substances in accurate taste comparison to development palatable oral formulations. This study was to evaluate the taste masking effect of conventional pharmaceutical sweeteners such as neohesperidin dihydrochalcone, sucrose, sucralose and aspartame. The model drugs were acetaminophen, ibuprofen, tramadol hydrochloride, and sildenafil citrate (all at 20 mM). The degree of bitterness was measured by a multichannel taste sensor system (an electronic tongue). The data was collected by seven sensors and analyzed by a statistical method of principal components analysis (PCA). The effect of taste masking excipient was dependent on the type of model drug. Changing the concentration of taste masking excipients affected the sensitivity of taste masking effect according to the type of drug. As the excipient concentration increased, the effect of taste masking increased. Moreover, most of the sensors showed a concentration-dependent pattern of the taste-masking agents as higher concentration provided higher selectivity. This might indicate that the sensors can detect small concentration changes of a chemical in solution. These results suggest that the taste masking could be evaluated based on the data of the electronic tongue system and that the formulation development process could be performed in a more efficient way.

Characteristics of indomethacin-saccharin (IMC-SAC) co-crystals prepared by an anti-solvent crystallization process

The creation of co-crystals of various insoluble drug substances has been extensively investigated as a promising approach to improve their pharmaceutical performance. In this study, co-crystal powders of indomethacin and saccharin (IMC-SAC) were prepared by an anti-solvent (water) addition and compared with co-crystals by evaporation method. No successful synthesis of a pharmaceutical co-crystal powder via an anti-solvent approach has been reported. Among solvents examined, methanol was practically the only one that resulted in the formation of highly pure IMC-SAC co-crystal powders by anti-solvent approach. The mechanism of a preferential formation of IMC-SAC co-crystal to IMC was explained with two aspects: phase solubility diagram and solution complexation concept. Accordingly, the anti-solvent approach can be considered as a competitive route for producing pharmaceutical co-crystal powders with acceptable properties.

Development and optimization of a self-microemulsifying drug delivery system for atorvastatin calcium by using D-optimal mixture design

In this study, we developed and optimized a self-microemulsifying drug delivery system (SMEDDS) formulation for improving the dissolution and oral absorption of atorvastatin calcium (ATV), a poorly water-soluble drug. Solubility and emulsification tests were performed to select a suitable combination of oil, surfactant, and cosurfactant. A d-optimal mixture design was used to optimize the concentration of components used in the SMEDDS formulation for achieving excellent physicochemical characteristics, such as small droplet size and high dissolution. The optimized ATV-loaded SMEDDS formulation containing 7.16% Capmul MCM (oil), 48.25% Tween 20 (surfactant), and 44.59% Tetraglycol (cosurfactant) significantly enhanced the dissolution rate of ATV in different types of medium, including simulated intestinal fluid, simulated gastric fluid, and distilled water, compared with ATV suspension. Good agreement was observed between predicted and experimental values for mean droplet size and percentage of the drug released in 15 minutes. Further, pharmacokinetic studies in rats showed that the optimized SMEDDS formulation considerably enhanced the oral absorption of ATV, with 3.4-fold and 4.3-fold increases in the area under the concentration-time curve and time taken to reach peak plasma concentration, respectively, when compared with the ATV suspension. Thus, we successfully developed an optimized ATV-loaded SMEDDS formulation by using the d-optimal mixture design, that could potentially be used for improving the oral absorption of poorly water-soluble drugs.

Cell penetrating peptides as an innovative approach for drug delivery; then, present and the future

With the rapid development of biotechnology, various macromolecules as therapeutic agents have made drug delivery an important field of research. However, these are being commercialized as injection form. Due to low patient compliance, various non-invasive routes emerge as a promising strategy. Cell penetrating peptides (CPPs) have shown to assist in efficient and non-toxic manner. They provide ample evidence to deliver of many cargoes ranging from small molecules to proteins and even nanocarriers for various applications. This review briefly discusses about introduction of CPPs, history, cellular uptake mechanisms and various possible alternative routes for CPP-conjugated drug delivery system. It also aims to give a perspective on present status of CPP-mediated research, clinical development, possible obstacles as well as future opportunities. Thus, development of novel CPPs that are safe, tissue-specific and highly efficient will be exemplified and become ideal vehicles for therapeutic delivery in near future.

Formulation of a modified-release pregabalin tablet using hot-melt coating with glyceryl behenate

A modified-release (MR) tablet of the anti-anxiety drug pregabalin (PRE) was prepared by hot-melt coating PRE with glyceryl behenate (GB) as a release retardant and compressing to form a matrix with microcrystalline cellulose (MCC) as a hydrophilic diluent. GB-coated PRE had a size in the range of 177-290 μm with good to acceptable flowability. Tablet hardness decreased slightly as GB content increased. PRE release from the tablet matrices was successfully modified by altering the ratio of MCC and GB, and it was found that dissolution- or diffusion-controlled release depended on the amount of GB used. Drug release was pH-independent. An accelerated stability test on the most promising MR tablet at 40°C and 75% relative humidity for 6 months showed no significant changes in PRE content, and the occurrence of total impurities--including PRE-lactam--was within acceptable limits. After oral administration of the selected MR tablet or a commercial IR capsule (Lyrica) to healthy human volunteers, pharmacokinetic parameters including Tmax, Cmax, AUC0-24, and T1/2 were compared. The confidence interval of AUC0-24 was within the adequate range, but that of Cmax was inadequate. This study demonstrated the potential use of GB for PRE-containing MR formulations.

Use of laryngeal mask airway and its removal in a deeply anaesthetized state reduces emergence agitation after sevoflurane anaesthesia in children.

This study investigated the effect of laryngeal mask airway (LMA) and removal while in a deeply anaesthetized state (deep removal) compared with endotracheal tube and extubation when awake or deeply anaesthetized on the incidence of emergence agitation in children after sevoflurane anaesthesia for subumbilical surgery. Patients (2 – 7 years) were randomly assigned to one of three groups: ET-A group (n = 56, endotracheal tube and extubation whilst awake); ET-D group (n = 56, endotracheal tube and deep extubation); LMA-D group (n = 56, experienced LMA and deep removal). The incidence of postoperative emergence agitation was significantly lower in the LMA-D patients compared with patients in the ET-A group (21.4% and 41.1%, respectively). Patients in the LMA-D group required a significantly shorter stay in the postanaesthetic care unit (PACU) than ET-A patients. There were no significant differences in the incidence of postoperative emergence agitation or length of stay in the PACU between the ETA and ET-D groups, or between the ET-D and LMA-D groups. In conclusion, using an LMA and deep removal decreased postoperative emergence agitation compared with using an endotracheal tube and awake extubation after paediatric sevoflurane anaesthesia.

Delivery of biopharmaceuticals using combination of liposome and iontophoresis: a review

Non-invasive route for the delivery of biopharmaceuticals is one of the interesting areas in drug delivery systems. Since stratum corneum is regarded as an effective physical barrier to permeation of high molecular weight biopharmaceuticals, several methods have been studied for overcoming this problem and enhancing their permeation. The one technique for better transdermal delivery is to use drug carriers such as microemulsions, nanoemulsions, solid lipid nanoparticles and liposomes. These carriers can facilitate the permeation of drugs by modifying physicochemical characteristics of entrapped ingredient. Liposomes are used as potential drug carriers to enhance the percutaneous absorption of various biopharmaceuticals. Iontophoresis is another enhancing method to increase the biomembrane permeability of ionic or charged compounds using electric potential. The new strategies combining liposomes and iontophoresis technique are increasing rapidly in the field of drug delivery and possess additional benefits. It is possible to deliver neutral drugs by entrapping them in charged vehicle and their flux can be enhanced by iontophoresis. Thus, combination of liposome and iontophoresis can be effective means for transdermal permeation of biopharmaceuticals in a non-invasive and sustainable fashion.