Current developments using emerging transdermal technologies in physical enhancement methods.

Transdermal drug delivery using patches offers many advantages, but is limited primarily by the stratum corneum barrier. Amongst the various methods to overcome this barrier, physical methods are gaining in popularity and commercial devices development. Macroflux, MTS and Silex are based on microporation, involving use of microneedles that pierce thereby bypassing the stratum corneum. Intraject , Powderject and Helios are based on needleless jet injectors wherein very fine, solid particulate drug, is fired directly into the skin, using high-pressure gas. Med- Tats incorporate use of modified drug-containing tattoos, which bind to the skin, wherein the drug is absorbed. CHADD is based on use of heat, which increases skin - permeation of drugs. High-power, pulsed lasers transmit positive mechanical forces to the skin and create intercellular channels into the skin transiently. Sonophoresis involves use of ultrasound, which transiently disrupts the stratum corneum barrier. This technique offers a non-invasive transdermal extraction of interstitial fluids of sampling body fluids. Modified Liposomes include Ethosomes (containing alcohol) and Transferosomes (containing surfactants), which have enhanced skin permeability. Pulsed magnetic fields may create transient pores in cell membranes, including skin, resulting in increased permeation. Iontophoresis is based on application of electric potential for enhancing the movement of substances to and from the body. Dupel, Ionzyme, Liposite, ETrans, Phoresor and Drionic are based on iontophoresis. GlucoWatch offers non-invasive blood glucose monitoring, based on reverse iontophoresis. This review outlines recent commercial developments in physical transdermal drug delivery technology and the specific devices and applications being targeted by the pharmaceutical industry.

Liquid chromatographic assay of nifedipine in human plasma and its application to pharmacokinetic studies.

A highly sensitive, selective and reproducible reversed-phase high-performance liquid chromatographic method has been developed for the determination of nifedipine in human plasma with minimum sample preparation. The method is sensitive to 3 ng/ml in plasma, with acceptable within- and between-day reproducibilities and linearity (r2 > 0.99) over a concentration range from 10-200 ng/ml. Acidified plasma samples were extracted using diethyether containing diazepam as internal standard and chromatographic separation was accomplished on C18 column using a mobile phase consisting of acetonitrile, methanol and water (35:17:48, v/v). The within-day precision ranged from 2.22 to 4.64% and accuracy ranged from 102.4-106.4%. The day-to-day precision ranged from 2.34-7.07% and accuracy from 95.1-100.1%. The relative recoveries of nifedipine from plasma ranged from 91.0-107.3% whereas extraction recoveries were 88.6-93.3%. Following eight 6-week freeze-thaw cycles, nifedipine in plasma samples proved to be stable with accuracy ranging from 0.64 to 3.0% and precision ranging from 3.6 to 4.15%. Nifedipine was also found to be photostable for at least 120 min in plasma, 30 min in blood and for 60 min in aqueous solutions after exposure to light. The method is sensitive and reliable for pharmacokinetic studies and therapeutic drug monitoring of nifedipine in humans after the oral administration of immediate-release capsules and sustained-release tablets to five healthy subjects.

Influence of piperacillin on the pharmacokinetics of methotrexate and 7-hydroxymethotrexate.

The influence of concomitant administration of piperacillin (PIP) on the pharmacokinetic parameters of methotrexate (MTX) and 7-hydroxymethotrexate (7-OH-MTX) was studied in rabbits. Six rabbits received an initial i.v. bolus (0.21 mg kg(-1)) followed by a constant-rate i.v. infusion of the drug (5 microg min(-1) kg(-1)) for 240 min. The PIP dose (30 mg kg(-1)) was repeated every 30 min until the end of the infusion period. The control group consisted of four rabbits treated the same way except for the addition of PIP. There were significant increases in the mean residence times found for MTX (MRTinf) and 7-OH-MTX (MRTm,inf) following PIP administration. Concomitant administration of PIP with MTX also produced significant 1.5- and 2.8-fold increases in the area under the curve of MTX and 7-OH-MTX, respectively. The total body clearance of MTX and the operative total body clearance of 7-OH-MTX significantly decreased, but in a less than proportional manner. The study demonstrates that the interaction between MTX and PIP is mainly due to the reduced clearance of both MTX and 7-OH-MTX combined with a slight increase in the formation clearance of the metabolite.

Hypoglycemic effect of oral insulin in diabetic rabbits using pH-dependent coated capsules containing sodium salicylate without and with sodium cholate.

The hypoglycemic effect of oral insulin (20 U and 40 U) capsules coated with a pH-dependent soluble polymer (Eudragit S100) and containing sodium salicylate (50 mg) without and with sodium cholate (50 mg) was studied in alloxan-hyperglycemic rabbits and compared with that of s.c. insulin injection (20 U). The capsules containing 20 U insulin + sodium salicylate (50 mg) produced a significant reduction in plasma glucose level to 82 and 73% of initial values at 2 and 3 hr after administration, respectively. The blood glucose level slowly returned to normal values at 5 hr. The AUC0-5 hr was 73.7 +/- 43.5 mg.hr/dl compared to 242 +/- 70.5 mg.hr/dl for insulin (20 U, s.c.) with a relative hypoglycemia of 30.4%. A higher dose of oral insulin (40 U) + sodium salicylate (50 mg) was more effective in reducing plasma glucose level which steadily decreased and reached 56% of the initial value by 5 hr (AUC0-5 hr = 132 +/- 41.5 mg.hr/dl and relative hypoglycemia = 27.3%). Sodium cholate (50 mg), however, slightly improved sodium salicylate effect producing an AUC0-5 hr of 139 +/- 37.3 mg.hr/dl with relative hypoglycemia of 28.7%. The relative hypoglycemia of pH-dependent coated capsules reached in the present experiment is the highest found so far.

Promotion of oral insulin absorption in diabetic rabbits using pH-dependent coated capsules containing sodium cholate.

The hypoglycemic effect of oral insulin (40 U) capsules coated with a pH-dependent soluble polymer (Eudragit S100) and containing various doses of sodium cholate (20, 50, 100 mg) was studied in alloxan-hyperglycemic rabbits and compared with that of s.c. insulin injection (20 U). Sodium cholate (20 and 50 mg/capsule) produced a dose-related enhancement of an insulin-induced decrease in the blood glucose level. Insulin capsules containing sodium cholate (50 mg/capsule) produced a steady reduction of the blood glucose level reaching 69% of the initial values (P < 0.01) by 3 h and 48% (P < 0.001) by 5 h after administration. This capsule produced an AUC0-5 h of 125 +/- 14.8 mg.h/dl with relative hypoglycemia (R.H.) of 25.8% compared with insulin s.c. The capsules containing sodium cholate (100 mg), however, did not significantly (P > 0.05) improve the hypoglycemic effect of insulin more than the smaller dose (50 mg/capsule) producing an AUC and R.H. of 135 +/- 12.3 mg.h/dl and 27.9%, respectively. The capsule coated with Eudragit S100 and containing insulin mixed with sodium cholate seems to be a promising formulation to overcome the unavailability of oral insulin.