Formulation In Healthy Volunteers Research Articles

Inhalation of a Dry Powder Tobramycin PulmoSphere Formulation in Healthy Volunteers

To evaluate the efficiency and reproducibility of pulmonary delivery of an investigational tobramycin PulmoSphere formulation (PStob) [Inhale Therapeutic Systems; San Carlos, CA] by a passive dry powder inhaler, and to compare serum concentrations and whole-lung deposition with a commercial nebulized tobramycin product (TOBI; Chiron Corporation; Seattle, WA). A five-period, open-label, nonrandomized crossover study. Fourteen healthy volunteers were studied, and 12 completed the study. PStob powder was manufactured using lipid-based PulmoSphere technology, producing highly dispersible porous particles. PStob was radiolabeled with (99m)Tc, and in vitro experiments confirmed it as a valid drug marker. To identify whole-lung distribution via scintigraphy, subjects inhaled contents of a single capsule (72 L/min) containing 25 mg of (99m)Tc-labeled PStob (13.5 mg of tobramycin free base) in periods 1 to 3. In period 4, subjects received (99m)Tc nebulized tobramycin, approximately 2.5 mL of 300 mg/5 mL. Deposition and blood samples were obtained. In period 5, six 25-mg doses of unlabeled PStob (81 mg of tobramycin base) were inhaled and blood samples were collected. Mean whole-lung deposition of PStob was 34 +/- 6% and nebulized tobramycin was 5 +/- 2%. Peak tobramycin concentration in serum (Cmax) values were 0.6 microg/mL with PStob and 0.28 microg/mL after nebulized tobramycin. Serum area under the curve was 4.4 microg x h/mL vs 2.1 micro g x h/mL for nebulized tobramycin. Median time to Cmax for PStob was comparable to nebulized tobramycin. The aerosol doses of PStob (25 mg and 150 mg) were well dispersed and tolerated. Serum drug concentrations matched scintigraphy data and were roughly twice that of the comparator. Intrasubject dose variability for three equivalent periods did not exceed 18% relative SD. PStob Cmax (0.6 microg/mL) was well below the toxic threshold (2 micro g/mL).

Bioequivalence study of two brands of enalapril tablets after single oral administration to healthy volunteers

To compare the relative bioavailability and bioequivalence of 2 enalapril tablet formulations in healthy volunteers under fasting conditions. An open-label, single-dose, randomized, two-period, crossover trial with a 1-week washout period in 24 healthy volunteers. The 2 enalapril 20 mg tablet formulations used were Antiprex (Elpen, Greece) as test and Renitec (Vianex, Greece) as reference preparation. Serial blood samples were collected at 19 points for 36 h. Plasma samples were analyzed for enalaprilat, the pharmacologically active metabolite of enalapril, by a validated GC/MS assay. Pharmacokinetic parameters, such as AUC(0-infinity), AUC(0-t), C(max) T(max), t1/2 and MRT were calculated from plasma concentrations for both formulations. Statistical comparisons (ANOVA and 90% confidence intervals) of AUC(0-infinity), AUC(0-t) and C(max) data were evaluated after logarithmic transformation, and differences of T(max) were tested non-parametrically. The parametric 90% confidence intervals of the geometric mean values of the test/reference ratios were 88.0 - 117.6% (point estimate: 101.8%) for AUC(0-infinity), 88.7 - 118.9% (point estimate: 102.7%) for AUC(0-t), and 91.0% - 123.4% (point estimate: 106.0%) for C(max) No statistically significant differences were found between the 2 preparations for T(max) t1/2 and MRT values. From the results of the present study, it is concluded that the test and reference tablet formulations of enalapril are bioequivalent for both the extent and the rate of absorption and therefore the 2 products can be considered to be interchangeable in clinical practice.

Comparison of the bioavailability of unequal doses of divalproex sodium extended-release formulation relative to the delayed-release formulation in healthy volunteers

Valproate formulations, divalproex sodium extended-release (ER) and the traditional divalproex sodium delayed-release (DR) formulations, are not bioequivalent. This study evaluated if ER QD regimens with 14 and 20% higher daily doses were equivalent to the corresponding DR BID regimens with respect to exposure (AUC) while achieving lower maximum concentration ( C max) and higher minimum concentration ( C min) values. This was a Phase I, multiple-dose, fasting, randomized, open-label, crossover design study in healthy adult volunteers ( n=36). The two crossover comparisons of unequal total daily doses were: 1000 mg ER versus 875 mg DR and 1500 mg ER versus 1250 mg DR. For each of 14 and 20% higher ER versus DR dose comparisons, the ER and DR regimens were equivalent with respect to AUC. Furthermore, the ER formulation achieved a lower C max central value and a higher C min mean than the corresponding values for the DR formulation. The mean peak-to-trough fluctuations of valproic acid plasma concentrations were 42–48% lower for the ER formulation compared with the DR. The higher ER doses were as well tolerated as DR, with a small number of adverse events that were non-serious in nature and mild in intensity. Therefore, increasing the once-daily ER dose 14–20% while converting from a total daily DR dose given twice-daily results in equivalent exposure with lower C max and higher C min values.

Pulmonary distribution and clearance of two beclomethasone liposome formulations in healthy volunteers

The pulmonary distribution and clearance of 99mTc-labelled beclomethasone dipropionate (Bec) dilauroylphosphatidylcholine (DLPC) and dipalmitoylphosphatidylcholine (DPPC) liposomes were compared in 11 healthy volunteers using gamma scintigraphy. As delivered by using the Aerotech jet nebulizer both liposome aerosols had a suitable droplet size (mass median aerodynamic diameter 1.3 μm) allowing deep pulmonary deposition. However, in the total drug output during the inhalation there was a relatively large difference between DLPC and DPPC of 11.4 and 3.1 μg, respectively. In a gamma camera study no significant differences existed in the central/peripheral lung deposition between the DLPC and DPPC formulations. Progressive clearance of both Tc-labelled Bec liposomes was seen: 24 h after inhalation, 79% of the originally deposited radioactivity of DLPC liposomes and 83% of that of DPPC liposomes remained in the lungs. Thus there was slightly slower clearance of inhaled liposomes using DPPC instead of DLPC. We conclude that both liposome formulations are suitable for nebulization, although aerosol clouds were more efficiently made from the DLPC liposome suspension. Our results support the view that liposome encapsulation of a drug can offer sustained release and drug action in the lower airways.

Comparison of Two Cyclosporine Formulations in Healthy Volunteers: Bioequivalence of the New Sang‐35 Formulation and Neoral

This study was conducted to establish bioequivalence between a newly developed oral cyclosporine formulation, Sang‐35 (SangStat Medical Corp., Menlo Park, CA), and the microemulsion formulation Neoral (Novartis Pharmaceuticals, East Hanover, NJ). In a randomized, open‐label, two‐way crossover study, 36 fasted, healthy male volunteers received a single 500‐mg cyclosporine dose formulated either as Sang‐35 or Neoral. Mean are under the concentration‐time curve to infinity (AUC0‐∞) for Sang‐35 was 13,900 µg‐hr/L compared with 14,000 µg‐hr/L for Neoral, with a 90% confidence interval (CI) of 96% to 103% for the geometric mean ratio of the two formulations. Mean maximum concentration (Cmax) was 1,690 µg/L for Sang‐35 and 1,700 µg/L for Neoral, with a 90% CI of 96% to 103%. Geometric mean ratios for both AUC0‐∞ and Cmax were within the acceptance criteria for bioequivalence (80‐125%). Additional studies showed no differences between Sang‐35 and Neoral after high‐fat meals (n = 19), in female volunteers (n = 25) and in black volunteers (n = 7). It is concluded that single doses of the oral cyclosporine formulations Sang‐35 and Neoral are bioequivalent in healthy fasted subjects, after high‐fat meals, in women, and in blacks.

Enantioselective pharmacokinetics and bioavailability of different racemic α-lipoic acid formulations in healthy volunteers

The pharmacokinetics and the absolute bioavailability of the enantiomers of α-lipoic acid (α-LA) from different dosage forms have been studied for the first time in twelve healthy volunteers using a specific enantioselective HPLC assay. Single doses of 200 mg racemic α-LA were administered orally (four tablets each containing 50 mg, 200 mg tablet and oral solution) and intravenously (4 min constant rate infusion), in random order. The IV infusion resulted in mean peak plasma levels (C max) of 13.0 μg ml −1 (range 8.45–21.06 μg ml −1) for the R(+)- and 11.6 μg ml −1 (range 6.40–19.64 μg ml −1) for the S(−) form ( P<0.001). Plasma concentrations of both α-LA-enantiomers declined with mean terminal half lives ( t 1/2) of 0.37±0.25 h for R(+)- and 0.32±0.14 h for S(−)-α-LA. The areas under the curve (AUC) calculated were 1.82 μg·h ml −1 (range 1.20–2.66 μg·h ml −1) and 1.44 μg·h ml −1 (range 0.83–2.16 μg·h ml −1) for R(+)- and S(−)-α-LA, respectively ( P<0.001). The mean total plasma clearance of 12.24±2.62 ml min −1 kg −1 for R(+)- and 15.64±4.18 ml min −1 kg −1 for S(−)-α-LA differed also significantly ( P<0.001), but was closely related to the normal plasma flow of the liver for both enantiomers. The apparent volume of distribution ( V t ) of both enantiomers, in contrast, was not significantly different from each other ( R(+)-: 419±369 ml kg −1; S(−)-: 471±338 ml kg −1; P=0.424). After oral dosage C max was observed at 0.21±0.07 h for the oral solution (OS), at 0.70±0.41 h for the 50 mg tablet and at 0.90±0.74 h for the 200 mg tablet formulation, with apparently no differences between the enantiomers within each formulation. The t 1/2 for all oral dosage forms was comparable to the IV administration. Highest C max values were observed for the OS with 1.95 μg ml −1 for R(+)- (range 0.87–4.76 μg ml −1) and 1.17 μg ml −1 for S(−)-α-LA (range 0.52–2.76 μg ml −1; P<0.001). The AUC of the OS showed similar differences between both enantiomers with 0.65 μg·h ml −1 for the R(+)- (range 0.36–1.15 μg·h ml −1) and 0.37 μg·h ml −1 (range 0.20–0.64 μg·h ml −1) for the S(−)-form ( P<0.001). The absolute bioavailability ( F abs) of the enantiomers from the OS was calculated to be 38±15 and 28±14% for R(+)- and S(−)-α-LA, respectively ( P<0.001). The results of both tablet forms with respect to the pharmacokinetic behaviour of both enantiomers were in accordance with the results of the OS. From both solid dosage forms F abs was calculated to be about 25 and 20% for the R(+)- and S(−)-enantiomer, respectively. In conclusion, the F abs of the R(+)-enantiomer of α-LA was shown tò be significantly higher compared to the values which could be achieved for S(−)-α-LA. This observation was in general applicable and independent from the galenical formulations used.

Iron-ovotransferrin preparation does not interfere with ciprofloxacin absorption*

Iron supplements can interfere with the bioavailability of a number of drugs, including thyroxine, tetracycline derivatives, penicillamine, methyldopa, levodopa, carbidopa, ciprofloxacin, and the newer fluoroquinolones. A new iron formulation was tested in which iron ions are bound to ovotransferrin, a protein that shares more than an 80% similarity with the sequence of human transferrin and apparently is less likely than the commonly used iron salts to reduce drug absorption. Ciprofloxacin was taken as a model drug, of wide use and restricted range of therapeutic levels, and its absorption was evaluated after the administration of the iron-ovotransferrin complex versus an iron-gluconate formulation in healthy volunteers. At variance with the iron gluconate formulation, which led to a reduction of about 50% of peak serum ciprofloxacin levels (Cmax; 1.0 +/- 0.2 versus 2.4 +/- 0.3 micrograms/ml; p < 0.01) and of the area under the serum concentration-time curve from time 0 to infinity [AUC(0 - infinity); 10.1 +/- 1.1 versus 18.3 +/- 1.0 mg.L-1.hr; p < 0.01], the iron-ovotransferrin complex caused only modest, non significant changes in absorption with a minimal reduction of the AUC[0 - infinity) (17.3 +/- 1.0 versus 18.3 +/- 1.0 mg.L-1.hr; difference not significant) and a nonsignificant decrease in the Cmax (2.2 +/- 0.3 versus 2.4 +/- 0.3 microgram/ml; difference not significant). Iron was also well absorbed from the formulation in the presence of a fatty meal. The very common drug interactions with oral iron preparations can be effectively prevented by the use of the iron-ovotransferrin complex interacting to a minimal extent with a sensitive drug with a reduced margin of efficacy, such as ciprofloxacin.

Determination of the maximal tolerated dose of a new acute oral caffeine formulation in healthy volunteers.

Clinical Pharmacology & Therapeutics (1996) 59, 179–179; doi: 10.1038/sj.clpt.1996.215

Study of the bioavailability of four indomethacin suppository formulations in healthy volunteers

The bioavailability of four different 100 mg indomethacin suppository formulations was determined in healthy male volunteers. Two marketed formulations, Indocid ® and Dolcidium ®, and a triglyceride (Witepsol H 15) supplemented with 5% monoglycerides (Dim. LS) or 9% fatty acids and 1% fatty acid methyl esters (FA/FAME) were included in the study. The AUC 0−12h (μg h ml −1) was (mean ± S.D.) 9.51 ± 4.06 8.96 ± 2.55, 10.78 ± 5.64 and 11.01 ± 5.07 for the Indocid ®, Dolcidium ®, Dim. LS and FA/FAME formulations, respectively. The bioavailability parameters for the marketed formulations were comparable to those reported for similar formulations in the literature. The values of the two supplemented triglyceride formulations were not significantly different from those obtained from the reference formulation, Indocid ®. As the addition of monoglycerides and fatty acid-fatty acid methyl esters to a triglyceride suppository base not only enhances rectal absorption but also reduces rectal mucosal irritation in rabbits, these additives might be useful for rectal drug administration. However, further experiments with larger groups of volunteers or patients, using multiple applications, are necessary in order to reveal the suitability and safety of these excipients as alternatives for those presently used in suppository formulations.

Bioavailability of four oral Coenzyme Q 10 formulations in healthy volunteers

The bioavailability of four different Coenzyme Q 10 (CoQ) formulations was compared in ten healthy volunteers in a four-way randomised cross-over trial. The included formulations were: A hard gelatine capsule containing 100 mg of CoQ and 400 mg of Emcompress ®. Three soft gelatine capsules containing: 100 mg of CoQ with 400 mg of soy bean oil (Bioquinon ®); 100 mg of CoQ with 20 mg of polysorbate 80, 100 mg of lecithin and 280 mg of soy bean oil; and 100 mg of CoQ with 20 mg of polysorbate 80 and 380 mg of soy bean oil, respectively. The result suggests that the soya bean oil suspension of CoQ (Bioquinon ® has the highest bioavailability. A difference in basic AUC and AUC after p.o.administration of CoQ was observed with respect to sex. A characteristic two peak-pattern was observed at the concentration-time profile.

Bioinequivalence of Four 100mg Oral Aspirin Formulations in Healthy Volunteers

The single dose pharmacokinetics of 4 commercially available 100 mg oral aspirin formulations were studied in 6 healthy men and 6 healthy women. Two of the formulations were rapid release ('Cardiprin' 100, 'Platelin') and the other 2 were enteric coated formulations ('Astrix' 100, 'Cartia'). There were marked differences in the plasma concentration-time profiles between the rapid release and the enteric coated formulations. There were no significant differences (p greater than 0.05) in the mean time to achieve maximum aspirin concentrations between 'Cardiprin' 100 (0.48 h) and 'Platelin' (0.35 h), but this was significantly prolonged (p less than 0.001) for 'Astrix' 100 (3.73 h) and even more prolonged for 'Cartia' (6.84 h). Similar between-formulation differences were seen in the areas under the plasma concentration-time curves, for which the rank order was 'Cardiprin' 100 (1.60 mg/L.h) = 'Platelin' (1.54 mg/L.h) greater than 'Astrix' 100 (0.73 mg/L.h) greater than 'Cartia' (0.56 mg/L.h). For 'Cardiprin' 100, 'Platelin' and 'Astrix' 100 plasma aspirin concentrations were below 5 micrograms/L by 7 h after ingestion, whereas for 'Cartia' aspirin was detectable for up to 16 h, giving the appearance of sustained release. The enteric coated formulations produced the greatest variability in the plasma aspirin concentration vs time profiles. The urinary recovery of salicylate was greater than 80% of the administered dose for all 4 formulations. The clinical significance of the marked pharmacokinetic differences observed with these 4 low-dose aspirin formulations is not known.

Bioequivalence of two atenolol formulations in healthy volunteers. Evaluation by ergometric exercise, gas liquid chromatography and radioreceptor assay

Bioequivalence of two atenolol formulations in healthy volunteers. Evaluation by ergometric exercise, gas liquid chromatography and radioreceptor assay

Comparative bioavailability of a cisapride suppository and tablet formulation in healthy volunteers

The comparative bioavailability of cisapride as a 30 mg suppository and three 5 mg oral tablets was investigated in 12 non-smoking, healthy male volunteers. The two formulations were administered on two separate occasions following an overnight fast, according to a randomized cross-over design. The plasma concentration of cisapride was measured over 48 h after drug administration. The 30 mg suppository exhibited a mean time to the peak plasma concentration of 3.8 h, while the tablets showed a significantly earlier peak time of 1.5 h. The maximum plasma concentration of cisapride after the 30 mg suppository (50.3 ng.ml-1) was significantly lower than after the tablets (74.3 ng.ml-1). The AUCs following the two treatments did not differ significantly from each other. The comparative bioavailability of the 30 mg cisapride suppository in relation to the three 5 mg oral tablets was 85%, with a 95%-confidence interval of 67% to 102% (not adjusted for dose). Normalizing the mean AUC by dose, the relative bioavailability of the suppository was 43% of that of the tablet. The elimination half-life of cisapride was not significantly different following the administration of the two formulations (9.3 h for the suppository and 9.8 h for the tablet).

Delayed release peppermint oil capsules (Colpermin) for the spastic colon syndrome: a pharmacokinetic study.

Excretion of menthol (as glucuronide) from orally ingested peppermint oil contained in Colpermin was compared with oil contained in two soft gelatine capsules. Total 24 h urinary excretion of menthol was similar in the two formulations in healthy volunteers, but peak menthol excretion levels were lower and excretion delayed with Colpermin. Menthol excretion was reduced in ileostomy patients who took Colpermin and moderate amounts of unmetabolised menthol were recovered from the ileostomy effluent. This is consistent with Colpermin being a delayed-release form of peppermint oil.

Influence of alcohol on the pharmacokinetics of diazepam controlled-release formulation in healthy volunteers.

Twelve normal volunteers were empanelled in an open-label, three-way crossover study to evaluate the influence of alcohol on the pharmacokinetics of controlled-release diazepam capsules. Each volunteer received one 15-mg diazepam controlled-release capsule alone, concomitantly with alcohol or followed by alcohol 2 hours later. The mean plasma concentration-time profiles following both alcohol treatments were superimposable on the profile from the control. The mean plateau concentrations were observed to endure from 2 through 12 hours in all cases. The mean +/- S.D. areas under the plasma concentration-time curves from time zero to infinity were similar indicating no difference in the extent of absorption of diazepam in the presence of alcohol. The harmonic mean elimination half-lives were also similar. Overall, the pharmacokinetics and the release properties of controlled-release diazepam capsule were not influenced by alcohol in normal volunteers.