ABSTRACT
Repeated oral administration of mexazolam, an anti-anxiety agent, may cause adverse effects such as gastric disturbance, drowsiness, and ataxia due to transiently high blood levels. Transdermal administration would avoid the systemic side effects and gastric disorders after oral administration. We have developed a matrix using ethylene-vinyl acetate [EVA], a heat-processible and flexible material, for transdermal delivery of mexazolam. Drug solubility was highest at 40% PEG-400 volume fraction. The release and permeation profiles through the rat skin were determined for 24 h using a modified Keshary-Chien diffusion cell. The drug release was increased by increasing the concentration with a linear relationship between the release rate and the square root of loading dose. Increasing temperature increased drug release from the EVA matrix. The activation energy [E[a]], which was measured from a slope of log P versus 1000/T plot, was 8.64 Kcal/mol for a 1.5% loading dose. To reduce the brittleness and increase the pore of the EVA matrix, diffrent plasticizers were used. Among the plasticizers, including the citrates or the phthalate groups, diethyl phthalate showed the highest effect on the release of mexazolam. To increase the skin permeation of mexazolam from the EVA matrix, enhancers such as the fatty acids, the pyrrolidones, the propylene glycol derivatives, the glycerides, and the non-ionic surfactants were added to the EVA matrix, respectively, and skin permeation was evaluated using a modified Keshary-Chien diffusion cell fitted with intact excised rat skin. Among the several enhancers used, N-methyl-2-pyrrolidone showed the best enhancement factor. In conclusion, enhanced transdermal delivery of mexazolam through an EVA matrix containing plasticizer and a permeation enhancer could be useful in the development of a transdermal drug delivery system
ABSTRACT
Topical drug dosage forms such as ointments and creams can be easily removed through wetting, movement and contact. The new bioadhesive formulations with enhanced local anesthetic effects are needed for topical administration. The adhesive capacity of hydroxypropyl methylcellulose [HPMC] was determined by measuring the maximum detachment force and the adhesion work with an auto peeling tester. The release of drug from a HPMC gel was studied according to the drug concentration. Permeation study through the rat skin was performed at 37°C using phosphate buffer solution [pH = 7.4] as a receptor medium. To increase the skin permeation of bupivacaine from the HPMC gels, penetration enhancer such as the saturated and unsaturated fatty acids, the pyrrolidones, the propylene glycol derivatives, the glycerides, and the non-ionic surfactants were incorporated in the bupivacaine-HPMC gels. The local anesthetic effect of the formulated gel preparation was examined using a tail-flick analgesimeter. As the concentration of HPMC increased, the bioadhesive force and viscosity were increased. The rate of drug release was increased with increasing the drug concentration. Among the enhancers used, polyoxyethylene 2-oleyl ether showed the most enhancing effects on drug permeation through the skin. In the rat tail flick test, the area under the efficacy curve of bupivacaine gel containing polyoxyethylene 2-oleyl ether and tetrahydrozoline showed a 2.36-fold increase in anesthetic activity compared to control gel without any additives. The bupivacaine gels containing both penetration enhancer and vasoconstrictor showed enhancement and prolonged efficacy compared to the control gel. To enhance the local anesthetic effects of bupivacaine, the transdermal bupivacaine gel formulation containing penetration enhancer and vasoconstrictor could be developed
ABSTRACT
Mepivacaine, an amide-type local anesthetic, has been used to relieve local pain. Among the many drug delivery systems, transdermal drug delivery has some advantages, as it provides controlled drug delivery for an extended period of time. To develop new gel formulations that have suitable bioadhesion, the bioadhesive force of hydroxypropyl methylcellulose [HPMC] was assessed using an auto-peeling tester. The effect of drug concentration on drug release from 2% HPMC gel was studied using synthetic cellulose membrane at 37 +/- 0.5°C. The drug concentrations tested were 0.5, 1, 1.5, 2, and 2.5%. The effect of temperature on drug release from the 2% drug gel was evaluated at 27, 32, 37 and 42°C. To increase the skin permeation of mepivacaine from HPMC gel, enhancers such as saturated and unsaturated fatty acids, pyrrolidones, propylene glycol derivatives, glycerides, and non-ionic surfactants were incorporated into the mepivacaine-HPMC gels. The enhancing effect of the enhancer on drug permeation was then examined in the modified Keshary-Chien cell. For the efficacy study, the anesthetic action of the formulated mepivacaine gel containing enhancer and vasoconstrictor was evaluated with the tail-flick analgesimeter. Among the various kinds of HPMC, HPMC-K100M gel showed the highest viscosity and bioadhesive force. As the viscosity of the HPMC gels increased, the bioadhesive forces increased. Increasing the drug concentration or temperature increased the drug release rate. Among the enhancers used, polyoxyethylene 2-oleyl ether showed the greatest enhancement of permeation. Based on the area under the efficacy curve of the rat tail flick test curve, mepivacaine gel containing polyoxyethylene 2-oleyl ether and tetrahydrozoline showed prolonged and increased local anesthetic action compared to the control. For bioadhesive mepivacaine gels with enhanced local anesthetic action, mepivacaine gels containing penetration enhancer and vasoconstrictor could be developed with the bioadhesive polymer, HPMC
Subject(s)
Anesthesia, Local , Drug Delivery Systems , Surface-Active Agents , Methylcellulose/analogs & derivatives , Reaction Time/drug effectsABSTRACT
PURPOSE: To compare the effectiveness of embolization of the bronchial artery embolization for the management of hemoptysis in pulmonary tuberculosis cases with the severity of lung parenchymal injury and pleural infiltration, as seen on plain chest radiographs, and with the findings of angiography of the bronchial artery. MATERIALS AND METHODS: Among 265 patients with hemoptysis due to pulmonary tuberculosis, the findings of plain chest radiography and angiography of the bronchial artery were comparatively analyzed in the 206 for whom the results of follow up were available. The chest radiographic findings were lassified as follows: Type I refers to simple pulmonary tuberculosis; Type II includes cases in which pulmonary tuberculosis is complicated by bronchiectasis, aspergillosis, or cavitation; Type III is either Types I or II accompanied by pleural infiltrates limited to the lung apex, and Type IV includes cases in which pleural infiltrates have extended beyond the apex in the whole of the lung. Bronchial angiographic findings were divided into four groups : Group I consists of cases which show abnormalities of only the bronchial artery; Group II includes those in which abnormalities are seen in the bronchial artery and either the internal mammary or an ntercostal artery; Group III comprises cases which belong to Group I or II and in which a branch of the subclavian artery is abnormal, and Group IV includes those in which abnormalities occur in at least two branches of the subclavian artery, or there is direct visualization of hypervascularity of this vessel. The initial post-embolic hemostatic effect and the results of follow up were studied over a six-month period. RESULTS: As compared with simple pulmonary tuberculosis (Type I), we found that as the severity of pleural infiltration and complications revealed by plain chest radiographs increased (Type II, III, IV), so did the severity of the manifestation of systemic collateral arteries other than the bronchial artery, as depicted by increase on bronchial angiography. Early post-embolic hemostasis occurred in 96% of Type-I cases (47/49), 82% of Type II (36/44), 70% of Type III (28/40), and 55% of Type IV (40/73). The average success rate was 74% (151/205). During the six month follow-up period, continued hemostasis was found in 80% of Type-I patients (36/45), 75% of Type II (30/40), 59% of Type III (20/34), and 48% of Type IV (20/42). The average long-term hemostasis rate was 66% (106/161). CONCLUSION: Bronchial angiography shows that in systemic collateral arteries circulation increases very substantially, and in cases in which plain chest radiographs depict extensive pleural infiltration or complications associated with pulmonary tuberculosis, it is therefore difficult to expect good hemostatic results after embolization. In such instances we thus recommend aggressive treatment such as surgical intervention.