Young-Hee Shin

Long-acting injectable formulations of antipsychotic drugs for the treatment of schizophrenia

Antipsychotic drugs have been used to treat patients with schizophrenia and other psychotic disorders. Long-acting injectable antipsychotic drugs are useful for improving medication compliance with a better therapeutic option to treat patients who lack insight or adhere poorly to oral medication. Several long-acting injectable antipsychotic drugs are clinically available. Haloperidol decanoate and fluphenazine decanoate are first-generation depot drugs, but the use of these medicines has declined since the advent of second-generation depot agents, such as long-acting risperidone, paliperidone palmitate, and olanzapine pamoate. The second-generation depot drugs are better tolerated and have fewer adverse neurological side effects. Long-acting injectable risperidone, the first depot formulation of an atypical antipsychotic drug, was prepared by encapsulating risperidone into biodegradable microspheres. Paliperidone palmitate is an aqueous suspension of nanocrystal molecules, and olanzapine pamoate is a microcrystalline salt of olanzapine and pamoic acid suspended in aqueous solution. This review summarizes the characteristics and recent research of formulations of each long-acting injectable antipsychotic drug.

Development of a Novel Soft Hydrogel for the Transdermal Delivery of Testosterone

Abstract A soft hydrogel formulation for the transdermal delivery of testosterone (TS) was developed, and the effect of various skin-permeation enhancers was studied in vitro and in vivo. Testosterone was incorporated into a polyvinyl alcohol (PVA)-based soft hydrogel with polyisobutylene (PIB) and various skin-permeation enhancers (dodecylamine, HPE101, oleic acid, or lauric acid). In vitro rat-skin permeation of TS from the soft hydrogel was investigated using Keshary-Chien diffusion cells for 24 hr at 37°C. In vivo plasma-concentration profiles of TS after applying the soft hydrogel on the dorsal skin of rat were determined using a commercial radioimmunoassay kit. The formulated soft hydrogel formed a thin film on the skin within 2 to 3 min after application and remained in a dried-film state for at least 24 hr. Addition of PIB into the hydrogel to increase the adhesion resulted in a negligible reduction in the skin-permeation rate of TS. However, rat-skin permeation of TS increased with the addition of permeation enhancers both in vitro and in vivo. Dodecylamine at the concentration of 3% was the most effective among tested. Plasma concentration of TS significantly increased for at least 24 hr with the addition of dodecylamine. These results suggest the feasibility of the development of a soft hydrogel formulation for the transdermal delivery of TS.

Evaluation of dextran-flufenamic acid ester as a polymeric colon-specific prodrug of flufenamic acid, an anti-inflammatory drug, for chronotherapy

Dextran-flufenamic acid ester (Dex-FFA) with varied degree of substitution (DS) was prepared by imidazolide method. Dex-FFA was stable in pH 1.2 or pH 6.8 buffer. The depolymerization degree of Dex-FFA by dextranase decreased as DS increased. Dex-FFA with DS of 13 or 20 released FFA up to 70% or 21% of the dose, respectively, on 24 h-incubation with the 10% cecal contents. FFA was liberated up to 29% of the dose on 24 h-incubation of dextranase pre-treated Dex-FFA with the homogenates of the upper intestine, whereas no FFA was detected devoid of dextranse-pretreatment. Upon oral administration of Dex-FFA (DS 13, 20 mg equivalent of FFA/kg) or FFA (10 mg/kg) to rats, tmax for FFA with Dex-FFA administration delayed approximately 6 h compared with that of free FFA administration, while Cmax for FFA was similar. The plasma level for FFA became greater around 6 h after administration of Dex-FFA than free FFA and it was maintained throughout the period of 24 h-experiment. Dex-FFA markedly attenuated gastric ulcerogenicity of FFA. Taken together, Dex-FFA could be useful as a colon-specific prodrug which possesses anti-inflammatory properties and offers opportunities as a chronotherapeutic approach for the treatment of arthritis.

Further evidence of bradykinin involvement in septic shock: reduction of kinin production in vivo and improved survival in rats by use of polymer tailored SBTI with longer t1/2

Involvement of bradykinin in septic shock and its therapeutic endeavor using soybean trypsin inhibitor (SBTI, Kunitz type) were investigated in an in vivo model of septic shock induced by pseudomonal elastase. Pseudomonal elastase injection at 0.5 mg/kg i.v. to guinea pigs resulted in elevation level of bradykinin in the blood from < 1 ng/ml to 25 ng/ml which was accompanied by a drop of mean arterial blood pressure (MABP) (about 45 mmHg). When native soybean trypsin inhibitor (SBTI, Kunitz type, 20 kDa) was injected, into this model, induction of bradykinin generation and hypotension by the bacterial protease treatment was completely obliterated as judged by the both levels of bradykinin and MABP. Specifically, by the treatment with SBTI, bradykinin levels did not increase and the drop of the blood pressure was minimal (< 10 mmHg) in this time frame (< 30 min). We designed and prepared succinylated gelatin-conjugated SBTI (suc-gel SBTI) with enlarged molecular mass (M(r) approximately 110,000) and higher area under the curve of the plasma concentration, which exhibits about 6 times longer plasma half-life (t1/2) and about 4 times larger area under the curve of plasma concentration. Suc-gel-SBTI suppressed the pseudomonal protease-induced shock much more effectively than native SBTI, the conjugate exhibited its effect for more than 3 h, while the native SBTI showed the effect only within 2 h after i.v. injection.

Drug release testing methods of polymeric particulate drug formulations

The long-term controlled delivery of drugs has been successfully achieved by biodegradable polymeric particulate systems. The drug release testing method is important for the characterization of dosage form performance under in vitro standardized conditions and can provide insight into the in vivo performance of the drug product. In vitro drug release testing methods for polymeric particulate systems are classified into sample and separate (SS), dialysis, and continuous flow (CF) methods. In the SS method, the drug-loaded microparticles are suspended in a vessel and the samples for the analysis are obtained by separating the particles using filtration or centrifugation. The dialysis method physically separates microparticles from the release media by a membrane, which eliminates the undesired loss of particles during sample preparation and handling. The CF method uses apparatus consisted of flow-through cell that holds the sample, pump and water bath in closed or open ends system. In this method, the release media is continuously circulated through a cell containing drug-loaded microparticles. This review summarizes the principles of the drug release testing methods and discusses their characteristics with the recent research results.

Effect of glycyrrhizic acid on protein binding of diltiazem, verapamil, and nifedipine

The effects of glycyrrhizic acid (GLZ) on protein binding of diltiazem, verapamil, and nifedipine were investigated. Protein binding studies (human serum, human serum albumin (HSA) and α1-acid glycoprotein (AAG)) were conducted using the equilibrium dialysis method with and without addition of GLZ. The binding parameters, such as the number of moles of bound drug per mole of protein, the number of binding sites per protein molecule, and the association constant, were estimated using the Scatchard plot. The serum binding of nifedipine, verapamil, and diltiazem was displaced with addition of GLZ, and the decreases of Ks for serum were observed. GLZ decreased the association constants of three drugs for HSA and AAG, while the binding capacity remained similar with addition of GLZ. Although the characteristics of interaction were not clear, GLZ seemed to mainly affect HSA binding of nifedipine rather than AAG binding, while GLZ seemed to affect both AAG- and HSA-bindings of verapamil and diltiazem resulting in a serum binding displacement.

Liquid chromatography–tandem mass spectrometry to determine the stability of collagen pentapeptide (KTTKS) in rat skin

The objective of this study was to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to determine the stability of collagen pentapeptide (KTTKS), which is a subfragment of collagen and has been proved to promote the extracellular release of collagen in skin fibroblast, in rat skin. The chromatographic condition was optimized on an Acclaim C-18 column (2.1 mm × 150 mm, 3 μm) under isocratic elution using a mobile phase consisting of deionized water and acetonitrile (87:13, v/v) mixture containing 5mM pentafluoropropionic acid as an ion-pairing reagent. The quantitation of KTTKS was performed on a triple quadrupole mass spectrometer in multiple reaction monitoring mode. The calibration curve showed good linearity in the concentration range of 0.05-10.0 μg/mL (r(2)>0.999). The intra- and inter-day precisions were 0.8-6.5% and 2.4-5.8%, respectively, and the intra- and inter-day accuracies were 96.3-102.7% and 92.8-98.5%, respectively. The developed LC-MS/MS method was successfully applied to investigate the degradation rate and sites of KTTKS in rat skin homogenate. KTTKS was found to be very susceptible to the peptide bond cleavage by aminopeptidases present in the skin.

Efficacy of Hydrogel Patch in Wound Rat Model

Sodium polyacrylate based hydrogel patch was prepared and its wound healing efficacy in comparison with control groups was evaluated in thermal burn wound (, 10 sec burn) and excision wound rat model. Cytotoxicity of gamma irradiated (25 kGy) hydrogel patch was investigated in human fibroblasts and showed no significant cytotoxicity. Wound closure rates (H50%) in hydrogel patch group and BAND- treated group were faster than that of control group (uncovered open wound). Hydrogel patch showed an enhancement in wound healing process.

Effects of calcium channel blockers on human erythrocyte ghost membranes

The effects of calcium channel blockers (CAB’s), verapamil, diltiazem and nicardipine, on erythrocyte ghost membranes have been studied. Using the fluorospectroscopic method, it was observed that the fluidity of the inner layer of ghost membranes was increased with an increase of drug concentrations but did not any changes in the fluidity of the outer layer. These drugs showed protective effect against hypotonic hemolysis of erythrocytes. Thus, the expansion of surface area in response to corpuscular volume of erythrocytes in the presence of CAB’s is seemed to play an important role in protecting hypotonic hemolysis of erythrocytes.

Liquid chromatography-mass spectrometric method for the sensitive determination of niflumic acid in human plasma and its application to pharmacokinetic study of talniflumate tablet.

A sensitive LC-MS method was developed and validated for the determination of niflumic acid (NFA), the active metabolite of the talniflumate formulation, in human plasma. The analyses were performed on C(18) column using acetonitrile-ammonium acetate buffer (pH 5.7, 40:60) as a mobile phase with quadrupole MS detection of NFA at m/z 281 in a negative ion-monitoring mode. Calibration curve was linear in the concentration range of 1-1000ng/mL in human plasma. The higher sensitivity of LC-MS allowed low concentrations of NFA to be determined at initial drug absorption and terminal elimination phases following oral administration of talniflumate tablet.