Influence of a standard meal on the absorption of a controlled release pseudoephedrine suspension.

The influence of a standard meal on the extent and rate of absorption of pseudoephedrine from a liquid controlled release (CR) formulation (Pennkinetic System) was studied in 16 normal male volunteers. Equivalent single doses of an immediate release reference syrup (IR-Sudafed) and the CR suspension were each studied under both fasted and postprandial conditions. AUC results showed no significant influence of food or formulation, indicating that the CR formulation was absorbed to the same extent as the IR product under all conditions. CMAX and TMAX tabulations under fasted conditions indicated that the CR preparation peaked at a lower level at a later time. Food diminished IR CMAXs but the CR suspension's CMAXs and TMAXs were apparently unaffected by food. This study indicates that this CR pseudoephedrine suspension releases drug independently of food intake.

Bioavailability evaluation of a controlled-release dextromethorphan liquid.

A randomized, two-way, steady-state crossover study was performed in 24 healthy male volunteers to evaluate the bioavailability of a controlled-release (CR) dextromethorphan (DM) suspension. Only slow and intermediate DM metabolizers were allowed to participate in the study; determination of metabolizer status was performed before study enrollment. Each volunteer was administered 30 mg of an immediate-release (IR) DM solution qid or 60 mg DM as a CR suspension bid for two weeks, for a total daily dose of 120 mg. After a two-week washout period, the subjects were administered the alternate treatment. Blood samples were collected over a 12-hour dosing period on the last day of each treatment and analyzed for DM and its active metabolite, dextrorphan (DP). In addition, urine was collected over the 12-hour steady-state dosing interval and measured for DM and two metabolites. Pharmacokinetic determinations were made from plasma DM and DP data, and total urinary excretion was determined. All comparisons made between the two formulations indicated that the CR DM suspension was bioequivalent to the IR DM solution at steady state, while producing a prolonged release of the drug over time.

Influence of a standard meal on the absorption of controlled-release pseudoephedrine capsules.

The influence of a standard meal on the extent and rate of absorption of pseudoephedrine from a controlled-release (CR) capsule formulation (Pennkinetic System) was studied in 16 normal male volunteers. Equivalent single doses of an immediate-release (IR) pseudoephedrine reference syrup and the CR capsules were each studied under both fasted and postprandial conditions. Pharmacokinetic analysis evaluated the fraction of drug absorbed over time as determined by the Wagner-Nelson method. The area under the drug concentration versus time curve (AUC) results were not influenced by food or formulation, indicating that the CR formulation was absorbed to the same extent as the IR syrup. The maximum plasma concentration (Cmax) and the time to maximum concentration (tmax) tabulations under fasted conditions indicated that the CR preparation peaked at a lower level and a later time than the IR syrup. Food minimally affected the Cmax of the IR formulation, but did not affect that of the CR formulation. Food delayed the tmax of both the IR and CR preparations by less than 1 h, but only the delay of the CR formulation was statistically significant. Neither delay was considered clinically meaningful. The results of this study strongly suggest that the pharmacokinetic profile of the CR pseudoephedrine capsules was minimally affected by the presence of food.

Pharmacokinetic evaluation of two doxepin products.

The pharmacokinetics of two marketed formulations of doxepin HCl administered as a single 100-mg oral dose were compared. Sixteen healthy volunteers between the ages of 21 and 50 years participated in this crossover study. A one-week washout period intervened between doses. Blood samples were drawn before drug administration and at various times up to 48 hours after dosing. The concentrations of doxepin (DOX) and desmethyldoxepin (DDOX), the major active metabolite, were determined. Bioequivalence was determined by statistical comparisons of the area under the curve and maximum concentrations of DOX and DDOX. Statistical comparisons indicated no difference between the two formulations with respect to any of the parameters. The results of this study demonstrate that the two formulations of doxepin HCl are bioequivalent and would be expected to have similar clinical efficacy.

Two high-performance liquid chromatographic methods for quantitation of theophylline in plasma.

Two high-performance liquid chromatographic methods are described for the assay of theophylline in plasma. Both allowed the separation of theophylline from the caffeine metabolites, theobromine and 1,7-dimethylxanthine. Method A, using 8-chlorotheophylline as internal standard, involved back extraction of theophylline from organic extract with 0.1 M sodium hydroxide. Method B used generally accepted solvent extraction followed by evaporation and beta-hydroxyethyltheophylline as internal standard. High-performance liquid chromatographic analyses were performed on reversed-phase phenyl columns (25 X 0.46 and 25 X 0.41 cm) using 20% methanol in 20 mM phosphate buffer at pH 5.6 for Method A and 2% acetonitrile and 8% methanol in 20 mM phosphate buffer for Method B. The column effluent was monitored at UV 273 nm. Standard curves for both Methods A and B were fitted by linear regression (r greater than 0.999) in the concentration range of 0.05-50 micrograms/ml. Either method was selective, accurate and reproducible over the concentration range 0.08-26 micrograms/ml. However, compared with Method B, Method A provided significant advantages in terms of simplicity, speed and efficiency.

Bioavailability assessment of a new liquid controlled-release pseudoephedrine product.

Development of a liquid controlled-release pseudoephedrine product is described. Two bioequivalence studies were conducted. In a single-dose study involving 20 subjects, the bioavailabilities of five controlled-release suspensions with a broad range of drug-release rates were compared with an immediate-release form of pseudoephedrine hydrochloride in a four-way crossover, incomplete block, sequence-randomized study. Serial blood sampling up to 36 hours after drug ingestion provided area-under-the-curve (AUC), maximum plasma concentration (Cmax), and time to peak (tmax). In the multiple-dose study, involving 18 subjects, the bioavailability of the optimal formulation determined from the single-dose study was compared with a reference pseudoephedrine hydrochloride syrup. Serial blood sampling up to 12 hours after drug ingestion was performed to determine AUC, Cmax, and tmax. The single-dose investigation showed that all formulations were bioequivalent except the product with the slowest release rate, which had lower AUC and Cmax values. The results of the multiple-dose study confirmed these findings with the reference syrup. The use of a series of drug formulations with a wide range of release rates permitted selection of an optimal product in addition to providing the information needed to ensure continuous production of bioequivalent products.

Quantitative determination of dextromethorphan and three metabolites in urine by reverse-phase high-performance liquid chromatography.

A high-performance liquid chromatographic (HPLC) method for the quantitation of dextromethorphan (I) and its three metabolites, dextrorphan (II), 3-hydroxy-9 alpha,13 alpha,14 alpha-morphinan (III), and 3-methoxy-9 alpha,13 alpha,14 alpha-morphinan (IV), in urine was developed. For the analysis of nonconjugated compounds, urine samples at pH 11-11.5, containing 3-methoxy-17-methyl-10-oxo-9 alpha,13 alpha,14 alpha-morphinan as an internal standard, were applied to an extraction column, and the compounds were eluted with 10% n-butyl alcohol-hexane. The organic eluant was extracted with 0.1 M HCl, and an aliquot of the acidic extract was analyzed by HPLC utilizing a 5-micron phenyl column (25 X 0.46-cm i.d.) with a mobile phase of 10 mM potassium phosphate-acetonitrile (45:55, pH 4.0); the column effluent was monitored by UV detection at 280 nm. Free and conjugated metabolites in the enzyme-treated urine were analyzed by selective extraction of I and IV with hexane from urine samples at pH greater than 12 and extraction of II and III with 10% n-butyl alcohol-hexane from urine samples at pH 11-11.5. The minimum quantifiable levels of I-IV ranged from 0.017 to 0.09 micrograms of base/mL and from 0.11 to 0.21 micrograms of base/mL in nonhydrolyzed and hydrolyzed urine, respectively.

Comparison of lidocaine and 2-chloroprocaine in paracervical block: clinical effects and drug concentrations in mother and child.

2-Chloroprocaine (CP) has recently been recommended as a less toxic alternative to amide-type local anesthetics due to its rapid metabolism. A double-blind, randomized study comparing CP to lidocaine when used for paracervical block was carried out. Twenty-nine patients received CP, while 31 received lidocaine. None of the 60 mothers developed adverse side effects. Adequate pain relief was achieved in 28 cases in each group, with a mean duration of 40 min regardless of the anesthetic. No change in uterine activity was observed. In the CP group one fetus had mild bradycardia, while two in the lidocaine group had severe, and three mild bradycardia within 5-7 min after the block. Low concentrations of CP were detected in the venous blood of 2 of 29 mothers and in the umbilical venous blood of their babies. Measurable amounts of its metabolite, 2-chloro-4-aminobenzoic acid (CABA), were found in all 13 samples of maternal blood 5 min after PCB and in 6 of 27 maternal samples at birth. Traces of CABA were found in umbilical venous blood in three neonates; in a fourth, a level of 1,000 ng/ml was found. In contrast, unmetabolized lidocaine was found in all maternal samples and in all but one of the cord samples at birth. Concentration of lidocaine in cord blood at delivery ranged from less than 100 to 4,000 ng/ml and were similar for both arterial and venous samples. No correlation could be demonstrated between levels of local anesthetics in the cord samples and the frequency or severity of fetal bradycardia regardless of the anesthetic.

Sustained-release drug delivery system I: Coated ion-exchange resin system for phenylpropanolamine and other drugs.

Ion-exchange resin-drug complexes have been used to formulate sustained-release products of acidic and basic drugs. However, sustained release may be difficult to achieve due to many variables. A novel technique is reported that minimizes these variables by providing a polymeric film coating to the ion-exchange resin-drug complex particles, making drug release from these particles diffusion controlled. Direct application of an atomized polymer solution to the fluidized ion-exchange resin-drug complex particles was ineffective in controlling drug release since the coating came off in the dissolution medium due to swelling and fracturing of the particles. Pretreatment of the ion-exchange resin-drug complex particles with an agent such as polyethylene glycol was essential for the particles to retain their geometry and coating during dissolution. With divinylbenzenesulfonic acid resin complexed with phenylpropanolamine as a model, mixtures of ethylcellulose-coated and uncoated resin-drug complex particles were prepared. These mixtures gave varying drug release profiles that showed rank-order correlation with plasma concentration profiles obtained in bioavailability studies with suspension dosage forms.

Metabolism and measurement of chloroprocaine, an ester-type local anesthetic.

Blood levels of intact chloroprocaine were determined using a GLC procedure capable of detecting as little as 10 ng of chloroprocaine/ml of blood. It was necessary to detective plasma cholinesterases in collected samples by adding echothiophate iodide to blood sampling tubes. An extraction procedure, followed by a TLC separation and spectrodensitometric assay, was developed for measurement of the metabolite 2-chloro-4-aminobenzoic acid in plasma and urine. With these procedures, data were obtained showing that chloroprocaine is hydrolyzed rapidly by plasma cholinesterases. No unchanged drug could be detected in any blood samples obtained from volunteers who received chloroprocaine by intravenous infusion or from obstetric patients who had epidural anesthesia during labor and delivery. Blood levels of 2-chloro-4-amino-benzoic acid rose promptly with the administration of chloroprocaine and declined rapidly after drug administration. Most of the metabolite was recovered in urine.

GLC determination of doxepin plasma levels.

A procedure is described for extracting doxepin, a tricyclic antidepressant, from plasma and subsequently measuring its concentration by GLC. The developed technique permits the resolution and quantitative determination of the cis- and trans-isomers of doxepin as well as its desmethyl metabolite. The method allows precise, reliable measurement of the drug and one of its metabolities in concentrations as low as 10 ng/ml of plasma.