Enhanced transdermal delivery of low molecular weight heparin by barrier perturbation.

The purpose of this work was to investigate the in vitro transdermal delivery of low molecular weight heparin (LMWH). Hairless rat skin was mounted on Franz diffusion cells and treated with various enhancement strategies. Passive flux was essentially zero and remained low even after iontophoresis (0.065 U cm(-2) h(-1)) or application of ultrasound (0.058 U cm(-2) h(-1)). A significant increase in flux across tape stripped skin (4.0 U cm(-2) h(-1)) suggests the interaction of stratum corneum (SC) with LMWH which was confirmed using Differential Scanning Calorimetry and Fourier Transform-Infrared spectrophotometry. Maltose microneedles were then employed as a means to locally disrupt and bypass the SC. Transepidermal water loss (TEWL) and transcutaneous electrical resistance (TER) were measured to confirm the barrier disruption. Microneedles breached the SC resulting in increased TEWL, decreased TER and enhanced LMWH permeability (0.175 U cm(-2) h(-1)). Microneedles when used in conjunction with iontophoresis had a synergistic effect on LMWH delivery resulting in enhancement of flux by 14.7-fold as compared to iontophoresis used alone. Confocal laser scanning microscopy substantiated the evidence about LMWH interaction with SC. In conclusion, LMWH was shown to interact with SC and therefore tape stripping or microneedles dramatically increased its delivery due to disruption of the SC skin barrier.

Enhancement of transdermal delivery of heparin by various physical and chemical enhancement techniques.

Conventional anticoagulants such as unfractionated heparin and warfarin have numerous limitations compared with low-molecular-weight heparin (LMWH). However, the need for repetitive parenteral administration is still a major disadvantage of LMWH, and the absorption of macromolecules such as LMWH across the gastrointestinal tract is very poor. Due to these problems with oral delivery of LMWH, transdermal delivery can be considered as an alternate route of administration. However, overcoming the skin barrier is necessary for the transport of larger molecules across the stratum corneum. This review focuses on the transdermal delivery of LMWH, providing a brief overview of heparin delivery via invasive and oral routes and discusses the advantages of using LMWH rather than heparin for transdermal delivery, and the primary reasons for poor permeability of LMWH. Various strategies employed for transdermal delivery of heparin are summarized, and chemical and physical enhancement techniques or suitable formulations that can be used to improve transcutaneous penetration and various chemical enhancers that act on the skin by different modes of action are discussed. We also consider physical approaches such as iontophoresis, electroporation, and ultrasound, as well as combination strategies to deliver heparin. The developments in physical and chemical enhancement strategies over the past decade are summarized. In addition, recent novel approaches such as microneedles employed for the transdermal delivery of LMWH are also discussed.

Zaleplon: a pyrazolopyrimidine sedative-hypnotic agent for the treatment of insomnia.

BACKGROUND: Insomnia is the subjective complaint of poor sleep or an inadequate amount of sleep that adversely affects daily functioning. For the past 4 decades, treatment of insomnia has shifted away from the use of barbiturates toward the use of hypnotic agents of the benzodiazepine class. However, problems associated with the latter (eg, next-day sedation, rebound insomnia, dependence, and tolerance) have prompted development of other agents. OBJECTIVE: This review describes the recently approved nonbenzodiazepine agent, zaleplon. METHODS: Studies of zaleplon were identified through a search of English-language articles listed in MEDLINE and International Pharmaceutical Abstracts, with no limitation on year. These were supplemented by educational materials from conferences. RESULTS: The efficacy and tolerability of zaleplon have been documented in the literature. Zaleplon has been shown to improve sleep variables in comparison with placebo. Like most hypnotic agents, zaleplon can be used for problems of sleep initiation at the beginning of the night, but its short duration of clinical effect may also allow patients to take it later in the night without residual effects the next morning. Zaleplon can be taken < or = 2 hours before awakening without "hangover" effects. It is generally well tolerated, with headache being the most commonly reported adverse event in clinical trials (15%-18%). Compared with flurazepam, a long-acting benzodiazepine sedative-hypnotic agent, zaleplon causes significantly less psychomotor and cognitive impairment (P < 0.001). Zaleplon has not been studied in pregnant women or children. The dose of zaleplon should be individualized; the recommended daily dose for most adults is 10 mg. CONCLUSIONS: Insomnia has a substantial impact on daily functioning. If pharmacologic treatment is indicated for insomnia, the choice of an agent should be guided by individual patient characteristics.

Effect of ciprofloxacin on the pharmacokinetics of multiple-dose phenytoin serum concentrations.

We performed this study to determine if an interaction exists during the co-administration of ciprofloxacin with phenytoin. Seven healthy volunteers received oral phenytoin, 200 mg/day, as a single dose for 10 days. On day 9, phenytoin blood sampling was performed at times 0, 1, 2, 4, 6, 8, 10, 12, and 24 h. On day 10, oral ciprofloxacin, 500 mg, b.i.d. was initiated. On day 14, blood samples were collected as previously described. Pharmacokinetic analysis was performed to determine if there were differences between the area under the concentration time curve (AUC), maximum serum concentration, Cmax, and time of maximum serum concentration, Tmax, of phenytoin before and during co-administration of ciprofloxacin. Four subjects completed the study. Results of the analysis showed no significant differences between AUC, Cmax, and Tmax of phenytoin before and during ciprofloxacin administration. However, one subject showed marked reductions in both AUC and Cmax. Similar reductions in plasma concentrations have also been reported, resulting in breakthrough seizures. In conclusion, ciprofloxacin was not shown to increase phenytoin plasma concentrations or AUC in healthy volunteers. The potential for decreasing plasma phenytoin concentrations may exist and warrants close monitoring of levels when these two agents are given simultaneously.

Effect of urine pH and ascorbic acid on the rate of conversion of methenamine to formaldehyde.

The kinetics of conversion of methenamine to the active form formaldehyde were studied in pooled urine samples at 37 degrees in the pH range 4.9-6.5. Using a method for the determination of both formaldehyde and unhydrolyzed methenamine, the rate of formaldehyde formation in urine was found to be apparent first order and was pH dependent. Bactericidal concentrations of formaldehyde (> 28 micrograms ml-1) were achieved in 3 h in urine of pH 6.0 containing methenamine at 750 micrograms ml-1. There was no difference in the in vitro rate of conversion of methenamine to formaldehyde between the urine collected from normal subjects and the urine from subjects administered ascorbic acid. The rates of degradation of the mandelate and hippurate salts in buffer systems of various pH values did not differ significantly from those of methenamine base in urine adjusted to the same pH. The half-life of methenamine conversion to formaldehyde increased approximately 20 times from 20 h at pH 5.0 to about 400 h at pH 6.5. The data suggest that unless the urine is maintained below pH 6 only a small fraction of methenamine would be converted daily to formaldehyde and, thus, may explain the need for large doses of this drug in patients.

A statewide survey of pharmacokinetic service provision in Georgia.

A survey of pharmacokinetic service (PKS) provision and characteristics of the service was conducted in Georgia's 223 hospitals. The survey's questionnaire, returned by 133 (59.6%) institutions, showed that 23.3% currently had a PKS and that 47% of those without a PKS had plans to establish one in the future. Services were primarily provided by pharmacists (93%) who were certified to provide the consultations in only 40% of the institutions and the PKS was run through either the pharmacy (93%) or pathology laboratory. All services used calculators and/or computers with a variety of software programs to assist in pharmacokinetic evaluations. Patients were charged for the service in 38% of the institutions.

Stability and compatibility of methylprednisolone sodium succinate and cimetidine hydrochloride in 5% dextrose injection.

The stability and compatibility of methylprednisolone sodium succinate in admixtures with cimetidine hydrochloride in 5% dextrose injection were determined. Admixtures containing methylprednisolone sodium succinate, in concentrations equivalent to methylprednisolone 0.4 or 1.25 mg/mL, and cimetidine 3 mg/mL (as the hydrochloride salt) were prepared in 5% dextrose injection 100 mL. Control solutions containing each drug alone at the same concentrations were also prepared. The admixtures were prepared in triplicate and were kept in polyvinyl chloride infusion containers at controlled room temperature (24 degrees C). Immediately after mixing and at 2, 4, 8, 12, and 24 hours, samples were removed and visually inspected, measured for pH, and assayed by stability-indicating high-performance liquid chromatography to determine the concentrations of methylprednisolone 21-succinate ester and cimetidine. No visual evidence of incompatibility was noted either with the unaided eye or a microscope. No substantial changes in pH occurred over the study period. The addition of cimetidine decreased the pH of the methylprednisolone sodium succinate control solutions from about 7.3 to about 5.6. The concentrations of methylprednisolone 21-succinate ester and cimetidine in both test and control solutions did not change significantly over the 24-hour study period. Methylprednisolone sodium succinate, in concentrations equivalent to methylprednisolone 0.4 and 1.25 mg/mL, was chemically stable and visually compatible in admixtures with cimetidine 3 mg/mL (as the hydrochloride salt) in 5% dextrose injection 100 mL at 24 degrees C for 24 hours.

Stability of drugs with enteral nutrient formulas.

Experiments were performed to determine the chemical stability and compatibility of cephalexin, cimetidine, diazepam, or propranolol with full-strength and half-strength Isocal, Sustacal, and Sustacal HC (Mead Johnson). The enteral nutrient formulas (ENFs) containing the solid or liquid dosage forms were stored at 24 degrees C and samples were taken at times 0, 1.5, 3, 6, 8, 10, and 24 hours. At each sampling time, the mixtures were visually examined for signs of incompatibilities such as precipitation, viscosity changes, and phase separation. Samples from each time period were analyzed by a stability-indicating high-performance liquid chromatography (HPLC) method. The drugs mixed with half-strength ENFs were also passed through ultrafiltration membranes to separate complexed from uncomplexed drug. Neither visual changes nor variations in pH were observed in any formula. With the exception of cephalexin suspension in half-strength ENFs, none of the drug concentrations changed appreciably throughout the study period. The assays performed for undecomposed drug at each sampling time for the various full- or half-strength ENF-solid drug mixtures stored at 24 degrees C for 24 hours ranged from 92.3 to 103.4 percent for cephalexin, 96.2 to 103.0 percent for cimetidine, 93.9 to 106.2 percent for diazepam, and 95.5 to 102.2 percent for propranolol. For the liquid drugs, the concentration ranged from 86.5 to 102.0 percent for cephalexin, 97.0 to 101.1 percent for cimetidine, 98.2 to 103.0 percent for diazepam, and 97.4 to 104.8 percent for propranolol. Ultrafiltration studies showed varying percent binding dependent on the drug studied.

Formulation and stability of diazepam suspension compounded from tablets.

The stability of diazepam in an extemporaneous suspension compounded from tablets was studied. A diazepam 1 mg/mL suspension was prepared by levigating diazepam 10-mg tablets with ethanol and propylene glycol and incorporating them into a suspension vehicle containing magnesium aluminum silicate and carboxymethylcellulose sodium with flavoring and sweetening agents. Samples of the suspension were stored in amber glass bottles at 5, 22, and 40 degrees C. At various times during the 60-day study period, samples were inspected visually for signs of caking or color change and evaluated for ease of pouring and redispersion. Also at those times, the concentration of diazepam in each sample was determined by a stability-indicating, high-performance liquid chromatography procedure. The concentration of diazepam in each sample was at least 90% of the initial concentration throughout the 60-day storage period. All samples remained homogeneous and showed no signs of caking or settling. A diazepam suspension compounded from tablets was found to be pharmaceutically acceptable and easily pourable and redispersible. The suspension is stable for at least 60 days at room or refrigerated temperature.

Separation and quantitation of methenamine in urine by ion-pair extraction.

An ion-pair extraction technique is described for separating methenamine, a urinary tract antibacterial agent, from formaldehyde in human urine samples. Separation conditions are developed from extraction constants for the methenamine-bromocresol green ion-pair. The technique involves adsorption of the ion-pair onto a silica cartridge and elution with methylene chloride:1-pentanol (95:5). Methenamine is freed from the ion-pair by the addition of excess tetrabutylammonium iodide and converted to formaldehyde (determined spectrophotometrically) by reaction with ammonia and acetylacetone. Linear standard plots were obtained from urine containing methenamine which was diluted to 10-160 micrograms/mL. The lower limit of detection was 6 micrograms/mL of methenamine. Absolute recovery from urine was greater than or equal to 94.5%. The precision (CV) of detection of methenamine in the presence of formaldehyde was less than 2%, and less than or equal to 4.5% for the detection of formaldehyde in the presence of methenamine. No interferences were noted. The applicability of the method was demonstrated by analysis of human urine levels of both methenamine and formaldehyde following oral administration of a methenamine salt to a volunteer.

Kinetics of hydrolysis of methenamine.

The kinetics of degradation of methenamine were studied in citrate--phosphate buffers between pH 2.0 and 7.4 at 37.5 degrees. GLC was used to monitor the rate of hydrolysis. The conversion of methenamine to formaldehyde was found to be pH dependent in the buffers of constant ionic strength, with the reaction half-life decreasing from 13.8 hr at pH 5.8 to 1.6 hr at pH 2.0. The kinetics of degradation also were measured at 47, 57, and 67 degrees, and the reaction obeyed the Arrhenius relationship. At pH 2.0, the activation energy was calculated to be 23.5 kcal/mole; at pH 5.1, it was 12.0 kcal/mole.

GLC determination of methenamine in tablets.

A rapid and sensitive GLC method was developed for the quantitative determination of methenamine in tablets. The method was shown to possess several advantages over the official NF assay. After dissolution of the whole tablet in absolute ethanol and addition of an internal standard (pentylenetetrazol), an aliquot was injected into the gas chromatograph for analysis. The sample was chromatographed using a stainless steel column packed with 10% OV-17 on Chromosorb W-HP. Quantitation was achieved by measuring peak heights. The simplicity, directness, extreme rapidity, and accuracy of the method represents an improvement over the official method and the other proposed assays.