An evaluation of the pharmacokinetics of tiotropium following a single-dose inhalation in healthy subjects using an ultra-sensitive bioanalytical method

Abstract

Objective and significance: The systemic bioavailability of tiotropium following administration via inhalation is known to be very low. A validated ultra-sensitive bioanalytical method with the lowest lower limit of quantitation (LLOQ) was developed and used to evaluate the complete pharmacokinetic profile of tiotropium.

Methods: This was a pharmacokinetic study performed in 18 healthy subjects. Each subject was administered a dose of 18?mcg of tiotropium from a dry powder inhaler (DPI). The subjects’ plasma tiotropium concentrations were assayed with LLOQ of 0.1?pg/mL.

Results: The results showed a mean C_max of 4.98 ± 3.55?pg/mL, and a median (t_max) of 3.6?minutes (range: 1.8–12?minutes). The means for area under the concentration–time curve (AUC) from time zero hours to infinity (AUC_inf) and AUC from time zero hours to the time of the last measurable tiotropium concentration (AUC_t) were 51.11 ± 27.4?pg*h/mL and 37.37 ± 23.38?pg*h/mL, respectively. The mean apparent elimination half-life (t_1/2) was 68.02 ± 24.55?hours. This calculated half-life is longer than what others have reported where a less sensitive LLOQ was used.

Conclusion: The lower LLOQ enabled further insight into the pharmacokinetics of tiotropium that was not possible with other analytical methods. With this method, we were able to quantify tiotropium concentrations as early as one minute following drug administration and up to 144?hours after dosing. The application of this method will allow for studies to be designed properly and enable further investigations into the pharmacokinetics of tiotropium.     

Development and Characterization of an Oral Controlled-Release Delivery System for Melatonin

Abstract

Sugar spheres loaded with melatonin (MT) were coated with Aquacoat® to control the release rate of MT. Dissolution of MT was evaluated using the USP basket method. With 18-20 mesh beads, T_50% (time to release 50% of drug) for 5%, 10%. and 20% coatings was 10 min, 35 min, and 60 min, respectively. A desired release pattern over 8 hours was obtained with 20% coating on 8-10 mesh beads. T_50% for 5%, 10%, and 20% coatings was about 1, 2, and 4 hours, respectively. MT in 20% coated beads was quite stable during storage at room temperature with less than 5% MT degraded during 6 months of storage. Dissolution profiles from 8-10 mesh beads with a 20% coating were unchanged after 6 months of storage at room temperature, Administration of the dosage form to human subjects maintained MT plasma concentrations over 100 pg/ml for approximately 8 hours.     

Pharmacokinetics of Lignocaine in Humans After Peri-Oral Injections

Serum levels of lignocaine in ten healthy volunteers were determined after peri-oral injection of 36 mg lignocaine hydrochloride. Rapid absorption from injection site occured with a mean peak serum level of 46 ug/ml at 10 minutes.

In addition, lignocaine pharmacokinetics following peri-oral administration were studied. The serum concentration-time data were found to obey the one-compartment open model adequately with first-order absorption and elimination rates.     

Pharmacokinetics of Lignocaine in Humans After Peri-Oral Injections

Abstract

Serum levels of lignocaine in ten healthy volunteers were determined after peri-oral injection of 36 mg lignocaine hydrochloride. Rapid absorption from injection site occured with a mean peak serum level of 46 ug/ml at 10 minutes.

In addition, lignocaine pharmacokinetics following peri-oral administration were studied. The serum concentration-time data were found to obey the one-compartment open model adequately with first-order absorption and elimination rates.     

Comparative oral bioavailability of conventional propranolol tablets and a new controlled-absorption propranolol capsule

Abstract

The relative bioavailabilities of a new once-a-day propranolol formulation (Duranol) and conventional propranolol tablets (Inderal) were evaluated in six healthy male volunteers in a randomized balanced cross-over study. During the first treatment period, subjects were administered either a single 160 mg Duranol capsule at 9 a.m. or 80 mg Inderal at 9 a.m. and 9 p.m. Plasma propranolol concentrations were measured at 0, 2, 3, 4, 5, 6, 8, 10, 12, 13, 14, 15, 16, 24 and 36 hours after the 9 a.m. dose.

Mean peak plasma propranolol concentrations (Cmax) of 92.7 ng/ml at 2 hours and 53.9 ng/ml at 2.8 hours were recorded after administration of the first and second Inderal doses, respectively. After Duranol dosing, the Cmax of 85 ng/ml was not significantly different than the Inderal values; however, Duranol's tmax of 8 hours was significantly greater (p < 0.05) than either tmax recorded for Inderal. Compared to data obtained after administration of conventional propranolol tablets, mean propranolol concentrations were significantly lower at 2, 3 and 4 hours (p < 0.01) and significantly higher at 8, 10 and 12 hours (p < 0.05) after Duranol administration. The lengths of time plasma levels remained at 5, 10, 20, 30, 40, 50, 60, 70 and 80 ng/ml were not significantly different between the two products. In addition, the mean AUCs for Inderal and Duranol after 12 hours (380.2 vs 434.0 ng ml<^?1h, respectively), 24 hours (728.0 vs 728.8 ng ml^?1h, respectively), 36 hours (813.0 vs 826.8 ng ml^?1h, respectively), or from time 0 to infinity (838.6 vs 860.4 ng ml^?1h, respectively) were not significantly different.

These results indicate no loss in bioavailability despite a significantly prolonged absorption time for Duranol relative to conventional propranolol tablets. These results suggest that in the treatment of cardiovascular disorders an equivalent single dose of Duranol can be substituted for the daily requirements of conventional propranolol administered in divided doses.     

Disposition of 14C-Quinelorane in Dogs Following Oral or Intravenous Dosing and Transdermal Patch Application

A transdermal patch was developed to circumvent the emesis associated with the oral and intravenous administration of a dopamine agonist, quinelorane, to dogs.

Approximate steady-state plasma concentrations were achieved following the daily application of a transdermal patch for 7 days. Each dog received between 0.1 and 0.2 mg/kg per day from the transdermal patch.

At steady-state conditions, dogs received either a single oral dose of ¹⁴C-quinelorane at 0.1 mg/kg, a bolus intravenous dose of 0.03 mg/kg or had a transdermal patch containing the radioactive free base, ¹⁴C-quinelorane, applied to their abdomens for 24 hours; the approximate dose was 0.18 mg/kg.

The plasma pharmacokinetics were measured by liquid scintillation counting and ELISA.

The systemic bioavailability of quinelorane, as measured by the ELISA, was 30%, indicative of first-pass metabolism.

The radioactive urinary metabolite profile was similar for all three routes of administration. Principal entities in the urine were quinelorane, the N-despropyl- and the hydroxy-lactam- metabolites, accounting for 29, 25 and 3% of the dose, respectively. The major route of excretion of radioactivity was via. the urine, irrespective of the route by which the drug was administered.     

Topical oleo-hydrogel preparation of ketoprofen with enhanced skin permeability.

In an attempt to improve the skin penetration of ketoprofen, various transdermal formulations were prepared, and their in vitro skin permeability and in vivo percutaneous absorption were evaluated. In vitro permeation studies were performed using a modified Franz cell diffusion system in which permeation parameters such as cumulative amount at 8 hr Q8hr, steady-state flux Jss, or lag time tL were determined. In the in vivo percutaneous absorption study using the hairless mouse, maximum concentration Cmax and area under the curve at 24 hr AUC24h were measured. The optimal transdermal formulation (oleo-hydrogel formulation) of ketoprofen showed a Q8hr value of 227.20 micrograms/cm2, a Jss value of 29.61 micrograms/cm2/hr, and a tL value of 0.46 hr. The Q8hr and Jss values were about 10-fold (p < .01) higher than those (Q8hr = 19.61 micrograms/cm2; Jss = 2.66 micrograms/cm2/hr) from the K-gel and about 3.5-fold (p < .01) than those (Q8hr = 60.00 micrograms/cm2; Jss = 7.99 micrograms/cm2/hr) of the K-plaster. In the in vivo percutaneous absorption, the Cmax (6.82 micrograms/ml) and AUC24h (55.74 micrograms.hr/ml) values of the optimal formulation were significantly (p < .01) higher than those of K-gel and K-plaster. The relative bioavailability of the oleo-hydrogel following transdermal administration in reference to oral administration was about 37%, and the Cmax value (4.73 micrograms/cm2) in the hypodermis following topical administration was much higher than those from the conventional products (Cmax of K-gel and K-plaster were 0.92 +/- 0.19 microgram/cm2 and 1.27 +/- 0.37 microgram/cm2, respectively). These data demonstrate that the oleo-hydrogel formulation of ketoprofen was more beneficial than conventional products (K-gel and K-plaster) in enhancing transdermal permeation and skin absorption of ketoprofen. Furthermore, there was a good correlation between in vitro permeation parameters and in vivo percutaneous absorption parameters.     

Disposition of 14C-Quinelorane in Dogs Following Oral or Intravenous Dosing and Transdermal Patch Application

Abstract

A transdermal patch was developed to circumvent the emesis associated with the oral and intravenous administration of a dopamine agonist, quinelorane, to dogs.

Approximate steady-state plasma concentrations were achieved following the daily application of a transdermal patch for 7 days. Each dog received between 0.1 and 0.2 mg/kg per day from the transdermal patch.

At steady-state conditions, dogs received either a single oral dose of ¹⁴C-quinelorane at 0.1 mg/kg, a bolus intravenous dose of 0.03 mg/kg or had a transdermal patch containing the radioactive free base, ¹⁴C-quinelorane, applied to their abdomens for 24 hours; the approximate dose was 0.18 mg/kg.

The plasma pharmacokinetics were measured by liquid scintillation counting and ELISA.

The systemic bioavailability of quinelorane, as measured by the ELISA, was 30%, indicative of first-pass metabolism.

The radioactive urinary metabolite profile was similar for all three routes of administration. Principal entities in the urine were quinelorane, the N-despropyl- and the hydroxy-lactam- metabolites, accounting for 29, 25 and 3% of the dose, respectively. The major route of excretion of radioactivity was via. the urine, irrespective of the route by which the drug was administered.     

Garenoxacin pharmacokinetics in patients undergoing maintenance hemodialysis

Introduction: Studies on the pharmacokinetics of the antibiotic garenoxacin (GRNX) in patients with renal insufficiency are lacking. In this study, we attempted to ascertain the appropriate dose of GRNX in patients undergoing maintenance hemodialysis (MH) based on pharmacokinetic parameters and clinical outcomes. Methods: Six male patients with infections who were undergoing MH received 200 mg GRNX once daily. Blood samples were taken before and at 1, 2, 4, 6, 12, and 24 hours after GRNX administration. Plasma GRNX concentrations were measured using high‐performance liquid chromatography. Findings: The mean maximum plasma concentration (C_max) was 3.00 ± 1.12 µg/mL, time to maximum plasma concentration (T_max) was 3.0 ± 2.0 hours, and area under the curve for 24 hours (AUC_0–24) was 40.7 ± 16.7 µg·h/mL. The half‐life (T_1/2) of GRNX could not be calculated because plasma concentrations remained high 24 hours after administration. C_max was strongly associated with the GRNX dose per kilogram body weight (r = 0.85, P = 0.03). Clinically, fever resolved within 3 days of GRNX administration and C‐reactive protein levels returned to normal 14 days after administration. One patient experienced temporary increases in serum transaminase levels. Discussion: MH patients receiving 200 mg GRNX once daily for infection showed a reduced C_max but similar AUC_0–24 compared with healthy individuals. While this study evaluated the effect of GRNX treatment, further research is needed to assess the accumulation of GRNX and the impact of continuous administration on its pharmacokinetics, as well as to prevent the development of resistant mutants.     

Disposition of the flavonoid quercetin in rats after single intravenous and oral doses

The pharmacokinetic and mean time tissue distribution parameters, after a single 50-mg/kg dose of quercetin administered as intravenous bolus, oral solution, and oral suspension, were determined using rat as an animal model. Following intravenous administration, the elimination rate constant and the elimination half-life were found to be 0.0062 min^-1 and 111 min, respectively. Examining the mean time tissue distribution parameters reflected a strong binding affinity of the drug molecules to both plasma and tissue proteins. In addition, the low permeability rate of drug molecules in the peripheral system was demonstrated. Following the oral administration of the drug, the extent of absorption was greater from solution than from suspension. Moreover, the solution showed a shorter T_max and a higher C_max than suspension. The absolute bioavailability for the solution was 0.275 and that for suspension was 0.162. The mean residence time (MRT) and the mean absorption time (MAT) were higher for suspension, reflecting the need for dissolving the drug in order to be absorbed. The mean (in-vivo) dissolution time (MDT_in-vivo) was 34.5 min. Thus, an oral quercetin formulation that can readily form a drug solution in the gastrointestinal tract may enhance the absorption of the drug.     

Interleukin-6 collection through long-term implanted microdialysis sampling probes in rat subcutaneous space

Microdialysis sampling is a method that has promise for collection of important signaling proteins such as cytokines that are involved in every aspect of the immune response. The objective of this study was to determine the role of membrane and tissue alterations on the reduction of interleukin-6 (IL-6) relative recovery of microdialysis probes implanted for 3 and 7 days versus probes implanted on day 0 (acute implant or control probe). Lipopolysaccharide (LPS), a bacterial endotoxin, was used to elicit IL-6 production in the animals. Within the same animal, the recovery of IL-6 through control probes implanted the day of sample collection was compared to the 3- or 7-day implanted probes. Two hours post-LPS administration, the IL-6 concentrations obtained from either the 3-day or 7-day implanted probe were reduced by more than 8-fold when compared to the control probe. The IL-6 concentrations obtained for the 3-day versus control probes 2-h post-LPS injection were 730 +/- 310 and 6440 +/- 1550 pg/mL (mean +/- SD, n = 3), respectively. For the 7-day implant, the IL-6 concentration in the dialysis probe obtained at 2-h post-LPS injection was 990 +/- 590 versus 5520 +/- 1430 pg/mL (mean +/- SD, n = 3) for the control. In vitro recovery experiments and scanning electron microscopy images combined with the in vivo data suggest that the decreased IL-6 content in the dialysate was caused principally by tissue alterations or tissue encapsulation rather than membrane blockage with biological components (membrane biofouling).     

Disposition of the Flavonoid Quercetin in Rats After Single Intravenous and Oral Doses

Abstract

The pharmacokinetic and mean time tissue distribution parameters, after a single 50-mg/kg dose of quercetin administered as intravenous bolus, oral solution, and oral suspension, were determined using rat as an animal model. Following intravenous administration, the elimination rate constant and the elimination half-life were found to be 0.0062 min^?1 and 111 min, respectively. Examining the mean time tissue distribution parameters reflected a strong binding affinity of the drug molecules to both plasma and tissue proteins. In addition, the low permeability rate of drug molecules in the peripheral system was demonstrated. Following the oral administration of the drug, the extent of absorption was greater from solution than from suspension. Moreover, the solution showed a shorter T_max and a higher C_max than suspension. The absolute bioavailability for the solution was 0.275 and that for suspension was 0.162. The mean residence time (MRT) and the mean absorption time (MAT) were higher for suspension, reflecting the need for dissolving the drug in order to be absorbed. The mean (in-vivo) dissolution time (MDT_in-vivo) was 34.5 min. Thus, an oral quercetin formulation that can readily form a drug solution in the gastrointestinal tract may enhance the absorption of the drug.     

Interspecies Comparison of Pharmacokinetic Parameters of an Oral Sustained Release Preparation of Iloprost

Abstract

Iloprost is a chemically stable, pharmacologically highly potent PGl₂-mimetic for which therapeutic efficacy was proven after iv infusion treatment in PAOD-patients. The development of an oral, therapy facilitating preparation was mainly based on the imitation of plasma levels as obtained after iv to provide an equieffective dosage form. Due to the short half-life in plasma a modified release preparation was formulated. In the present set of experiments the pharmacokinetics of sustained release iloprost in animals and man was investigated after species specifically different dosages. After normalization for the bioavailable fraction of a 150 μg dose several mean pharmacokinetic parameters were similar in all species with peak plasma levels of 162, 223 and 160 pg/ml (pig, dog, man), t_max-values of 1.5, 1.9 and 1.6 h, AUC-values of 651, 730 and 763 pg-h/ml. The half-value duration, representing the time of half-maximal plasma levels and thus describing retardation, accounted for 2.8, 2.5 and 2.4 h. For all species a correlation between in-vitro liberation data of the dosage form and drug amount absorbed in-vivo could be shown. Despite differences in gastrointestinal conditions pharmacokinetics was able to demonstrate an interspecies comparability of systemic iloprost levels after intragastric treatment with an extended release preparation of iloprost, which helped to select an optimal formulation variant and to extrapolate toxicological tolerability data for the administration to man. By this strategy a promising oral dosage form could be selected which might be therapeutically equivalent to iv infusion after individual dose titration in patients.     

Development of a sustained release dosage form for alpha-lipoic acid. II. Evaluation in human volunteers

Within this study an oral sustained release dosage form of alpha-lipoic acid (thioctic acid) has been generated and evaluated in healthy volunteers. A granulate comprising 56.8% alpha-lipoic acid and 43.2% chitosan acetate was compressed to tablets (weight: 0.45 g; diameter: 10.0 mm; thickness: 4 mm). Three of these tablets were administered at once orally to each volunteer. Prior to administration and then every hour for 12 hours blood samples were taken from the antebrachial vein. alpha-Lipoic acid concentrations in plasma were quantified via precolumn derivatization and reversed-phase high-performance liquid chromatography (HPLC). Results demonstrated that an increased plasma level of alpha-lipoic acid can be achieved by this formulation for at least 12 hours. Within this time period at least two maximum plasma concentrations were reached. The first one is based on the release of alpha-lipoic acid, which is not ionically and therefore only loosely bound to chitosan, whereas a second maximum is based on the release of the drug during the enzymatic degradation of the chitosan matrix in the colon. The AUC(0-12) was determined to be 183.8 +/- 101.4 microg x min/mL (mean +/- SD; n = 8). Because of the pulsed sustained release of alpha-lipoic acid, the dosage form described here seems to be highly beneficial in order to stimulate the glucose uptake in the case of diabetes type II.     

Interspecies Comparison of Pharmacokinetic Parameters of an Oral Sustained Release Preparation of Iloprost

Iloprost is a chemically stable, pharmacologically highly potent PGl₂-mimetic for which therapeutic efficacy was proven after iv infusion treatment in PAOD-patients. The development of an oral, therapy facilitating preparation was mainly based on the imitation of plasma levels as obtained after iv to provide an equieffective dosage form. Due to the short half-life in plasma a modified release preparation was formulated. In the present set of experiments the pharmacokinetics of sustained release iloprost in animals and man was investigated after species specifically different dosages. After normalization for the bioavailable fraction of a 150 μg dose several mean pharmacokinetic parameters were similar in all species with peak plasma levels of 162, 223 and 160 pg/ml (pig, dog, man), t_max-values of 1.5, 1.9 and 1.6 h, AUC-values of 651, 730 and 763 pg-h/ml. The half-value duration, representing the time of half-maximal plasma levels and thus describing retardation, accounted for 2.8, 2.5 and 2.4 h. For all species a correlation between in-vitro liberation data of the dosage form and drug amount absorbed in-vivo could be shown. Despite differences in gastrointestinal conditions pharmacokinetics was able to demonstrate an interspecies comparability of systemic iloprost levels after intragastric treatment with an extended release preparation of iloprost, which helped to select an optimal formulation variant and to extrapolate toxicological tolerability data for the administration to man. By this strategy a promising oral dosage form could be selected which might be therapeutically equivalent to iv infusion after individual dose titration in patients.     

Improved efficacy of a microencapsulated macrophage colony stimulating factor and methotrexate in melanoma

This study examines the effects of a combination therapy of both methotrexate (MTX) and albumin microspheres containing recombinant human macrophage colony-stimulating factor (rhM-CSF) in melanoma tumors. Melanoma tumors were induced in C57BL/6 male mice with subcutaneous injection of B-16 tumor cells. Therapy started once the tumor size reached 0.5 cm in diameter. Mice were divided into several groups, and dosing was carried out daily until death. Group I received MTX solution (2 mg/kg or 15 mg/kg), group II received rhM-CSF solution (100 micrograms), group III received albumin rhM-CSF microspheres (100 micrograms), and groups V-XV received different combinations of both agents daily. The weight, tumor size, and survival time (in days) were recorded. From the results, the control (no rhM-CSF administered) group survived for 11.8 +/- 1.92 days, and the group that received MTX solution survived for 19.4 +/- 5.03 days. However, the group that received both the MTX solution (15 mg/kg) and albumin rhM-CSF microspheres (100 micrograms/kg) demonstrated a significant increase (p < .05) in the survival time (30.4 +/- 3.27 days). The concentrations of cytokines (tumor necrosis factor alpha [TNF-alpha] and interleukin-1 beta [IL-1 beta]) in the different treatment groups were monitored to determine the effect of rhM-CSF on the immune system. The TNF-alpha concentration was significantly higher in the group that received the combination therapy (204 +/- 54.6 pg/ml) versus the control group (31.5 +/- 7.02 pg/ml). The IL-1 beta concentration was significantly higher (p < .05) in the rhM-CSF microsphere (100 micrograms/kg) treated group (62 +/- 17.2 pg/ml) versus the rhM-CSF solution (29.1 +/- 8.7 pg/cc).     

Biological half-life of iodine in adults with intact thyroid function and in athyreotic persons

A joint project between the Human Monitoring Laboratory (HML) and the Ottawa Hospital has measured the retention of 131I in patients who have received the radioiodine diagnostically. Thirty-nine subjects with intact thyroid glands and nine athyreotic subjects were measured in the HML's whole-body/thyroid counter to determine the retention of 131I following its medical administration. The average biological half-life of 131I in 26 euthyroid subjects was found to be 66.1+/-6.3 days which may he statistically significantly lower than the ICRP recommended value of 80 days. Nine hyperthyroid patients had a mean biological half-life of 38.2+/-8.6 days and in three hypothyroid patients the corresponding value was 29.3+/-8.8 days. Thyroid 131I uptake was measured in a conventional clinical fashion at the Ottawa Hospital Civic campus 24 h after oral administration of the radioiodine using a collimated thick sodium iodide detector placed over the neck anteriorly. Measured values were 10.144+/-0.009, 0.314+/-0.035 and 0.045+/-0.010 of the administered dose in euthyroid, hyperthyroid and hypothyroid patients respectively. The euthyroid range at the hospital is 0.06 - 0.22. Uptake was significantly lower for the euthyroid group than the ICRP value of 0.3. The radioiodine retention in athyreotic subjects followed a two compartment model with biological half-lives of 1.0+/-1.2 days and 18.4+/-1.1 days.     

Triptolide loaded solid lipid nanoparticle hydrogel for topical application

Triptolide (TP) has been shown to have anti-inflammatory, antifertility, antineoplastic, and immunosuppressive activity. However, its clinical usage is limited to some extent due to its poor water solubility and toxicity. In order to use innovative ways to administer TP and to overcome or alleviate its disadvantages, controlled-release delivery systems such as solid lipid nanoparticle(SLN(s)) have been developed. In the present paper we describe the preparation and some characterization of specialized delivery systems for TP. The transdermal delivery and anti-inflammatory activity were also evaluated. The results indicated that SLN could serve as an efficient promoter of TP penetrating into skin. Furthermore, different formulations were optimized in this study. The best formulation of SLN, consisted of tristearin glyceride, soybean lecithin, and PEG400MS, with a particle size of 123 ± 0.9 nm, polydispersity index (PI) of 0.19, and zeta potential of - 45 mV. When this SLN dispersion was incorporated into hydrogel, the nanoparticulate structure was maintained, and aggregation and gel phenomena of the particle could be avoided. The cumulative transdermal absorption rate in 12 h was 73.5%, whereas the conventional TP hydrogel was 45.3%. The anti-inflammatory effect is over two-fold higher than that of conventional TP hydrogel. Moreover, this SLN hydrogel consists of pharmaceutically acceptable ingredients, such as soybean lecithin and lipid, and the nanoparticle can improve safety and minimize the toxicity induced by TP.     

Preparation and characterization of marine sponge collagen nanoparticles and employment for the transdermal delivery of 17β-estradiol-hemihydrate

Background: Transdermal administration of estradiol offers advantages over oral estrogens for hormone replacement therapy regarding side effects by bypassing the hepatic presystemic metabolism. Aim: The objective of this study was to develop nanoparticles of Chondrosia reniformis sponge collagen as penetration enhancers for the transdermal drug delivery of 17β-estradiol-hemihydrate in hormone replacement therapy. Method: Collagen nanoparticles were prepared by controlled alkaline hydrolysis and characterized using atomic force microscopy and photon correlation spectroscopy. Estradiol-hemihydrate was loaded to the nanoparticles by adsorption to their surface, whereupon a drug loading up to 13.1% of sponge collagen particle mass was found. After incorporation of drug-loaded nanoparticles in a hydrogel, the estradiol transdermal delivery from the gel was compared with that from a commercial gel that did not contain nanoparticles. Results: Saliva samples in postmenopausal patients showed significantly higher estradiol levels after application of the gel with nanoparticles. The area under the curve (AUC) for estradiol time–concentration curves over 24 hours was 2.3- to 3.4-fold higher and estradiol levels 24 hours after administration of estradiol were at least twofold higher with the nanoparticle gel. Conclusions: The hydrogel with estradiol-loaded collagen nanoparticles enabled a prolonged estradiol release compared to a commercial gel and yielded a considerably enhanced estradiol absorption. Consequently, sponge collagen nanoparticles represent promising carriers for transdermal drug delivery.     

Pharmacokinetics of Nilvadipine After Multiple Oral Dosing to Steady-State

Forty-four healthy male volunteers were randomly assigned to receive one of four dosing regimens: placebo or a dose of 6, 8, 10 or 12 mg of nilvadipine administered at 0, 7 and 14 hr each day for 19 doses over seven days. There was a proportional relationship between the maximum plasma concentration of nilvadipine after the first dose and the last dose and the dose administered. There was also a proportional relationship between the area under the plasma concentration-time curve during the last dosing interval and the administered dose. Results showed that there was no accumulation of drug in plasma at steady-state. In addition, there was no dose-dependency in the oral clearance, elimination rate constant or terminal elimination half-life values. The pharmacokinetics of nilvadipine are linear upon multiple dosign over the dosing range studied