Bioavailability, Pharmacokinetics, and Transepidermal Water Loss of Short Contact Tazarotene Lotion 0.1% Versus Tazarotene (Tazorac®) Cream 0.1.

Objective: Two clinical studies were conducted to 1) assess the pharmacokinetic (PK) properties of tazarotene and tazarotenic acid in DFD-03 lotion (a 1-minute, short-contact formulation for the topical treatment of acne vulgaris) and tazarotene cream 0.1% and 2) to evaluate transepidermal water loss (TEWL) with DFD-03 lotion, tazarotene gel (0.1%), or vehicle. Design: The PK study included a single-center, randomized, multiple-dose, laboratory-blinded, open-label, parallel-design, and the TEWL study included a multiple-dose, within-subject comparison design. Participants: The PK study included healthy adult men aged 18 to 40 years (n=43), and the TEWL study included healthy adults, male or female, aged 18 to 40 years (n=24). Measurements: PK was assessed via Cmax, AUC0-12, AUC0-24, Tmax, Cmin, Tmin, and fluctuation. TEWL was assessed via evaporimetry. Results: Tazarotene levels were very low due to rapid esterase hydrolysis to the primary active metabolite, tazarotenic acid. Tazarotenic acid AUC0-24 ratios (%) were at least two times higher when the test product was applied twice daily (Treatment-1) versus once daily (Treatment-2) on Days 7 and 14 (268.73% and 254.42%, respectively). Tazarotenic acid AUC0-24 ratios (%) were nearly 100 percent for Treatment-1 versus once-daily tazarotene cream 0.1% (Treatment-3) (99.36% and 83.21%, on Days 7 and 14, respectively). Starting on Day 7, DFD-03 lotion TEWL readings were significantly greater than vehicle (p≤0.05), except for on one study day. DFD-03 lotion TEWL readings were numerically greater (nonsignificant) than tazarotene gel. Conclusion: DFD-03 lotion was well-tolerated, increased TEWL when applied twice daily for one minute, and had a PK profile with similar overall exposure as compared with commercially available tazarotene formulations applied once daily for 12 hours.

Rational Vehicle Design Ensures Targeted Cutaneous Steroid Delivery.

Objective: To design a topical vehicle that provided the optimal balance of betamethasone dipropionate penetration and retention in the skin, with minimal systemic absorption. Design: Six test formulations of betamethasone dipropionate 0.05% in vehicles contained the following penetration enhancers: elaidyl alcohol (Formulation-1), hexanol (Formulation-2), dodecanol (Formulation-3), octadecanol (Formulation-4), docosanol (Formulation-5), or oleyl alcohol (Formulation-6). Test agents were applied to human cadaver skin in static Franz-cell chambers containing receptor fluid. Measurements: Betamethasone absorption into the receptor fluid was measured over 24 hours. The distribution of betamethasone and its metabolites in the stratum corneum, epidermis, and dermis was analyzed using LC-MS/MS. The formulation with the optimal balance of penetration, permeation, retention, and minimal absorption was selected for a similar study comparing its penetration and absorption versus several commercially available betamethasone formulations. Results: Formulation-3 resulted in the highest retention of betamethasone in the skin as well as the highest steroid levels in the receptor fluid at 12 and 24 hours. Formulation-6 had the second highest retention of betamethasone in total skin, with relatively low absorption into the receptor fluid. All other variants had both lower steroid retention in the skin and lower absorption into the receptor fluid, with the exception of Formulation-2 which had higher absorption at 24 hours. Formulation-6/DFD-01 was selected for further development. Comparison of Formulation-6/DFD-01 with commercially available formulations of betamethasone dipropionate showed it had the highest steroid levels in the epidermis and dermis combined, with relatively low levels in the receptor fluid. Conclusion: Formulation-6/DFD-01 had the optimal balance of betamethasone retention in the skin, with low systemic absorption. This designed vehicle ensured retention of the corticosteroid in skin layers to maximize local efficacy while minimizing potential for hypothalamic-pituitary-adrenal suppression.

Safety and pharmacokinetics of single and multiple intravenous bolus doses of diclofenac sodium compared with oral diclofenac potassium 50 mg: A randomized, parallel-group, single-center study in healthy subjects.

In a randomized, parallel-group, single-center study in 42 healthy adults, the safety and pharmacokinetic parameters of an intravenous formulation of 18.75 and 37.5 mg diclofenac sodium (DFP-08) following single- and multiple-dose bolus administration were compared with diclofenac potassium 50 mg oral tablets. Mean AUC0-inf values for a 50-mg oral tablet and an 18.75-mg intravenous formulation were similar (1308.9 [393.0]) vs 1232.4 [147.6]). As measured by the AUC, DFP-08 18.75 mg and 37.5 mg demonstrated dose proportionality for extent of exposure. One subject in each of the placebo and DFP-08 18.75-mg groups and 2 subjects in the DFP-08 37.5-mg group reported adverse events that were considered by the investigator to be related to the study drug. All were mild in intensity and did not require treatment. Two subjects in the placebo group and 1 subject in the DFP-08 18.75-mg group reported grade 1 thrombophlebitis; no subjects reported higher than grade 1 thrombophlebitis after receiving a single intravenous dose. The 18.75- and 37.5-mg doses of intravenous diclofenac (single and multiple) were well tolerated for 7 days. Additional efficacy and safety studies are required to fully characterize the product.

Sustained delivery of human growth hormone from a novel gel system: SABER.

PURPOSE: The purpose of this study was to evaluate the release of recombinant human growth hormone (rhGH) from a novel non-polymeric sustained release system, SABER. METHODS: The SABER system consists of sucrose acetate isobutryate, a solvent and a polymeric release modifier. Spray dried formulations of zinc complexed rhGH in sodium bicarbonate containing sucrose and polysorbate 20 were homogenized with various SABER systems (10% w/v rhGH) and assessed in vitro and in vivo (rat studies). The effect of protein to sucrose ratio in the spray dried formulation and a release modifier, poly-D,L-lactic acid (PLA), in the SABER system, on the initial release was investigated along with the effect of dose volume. RESULTS: The in vitro release studies with rhGH SABER suspensions indicate that increasing the sucrose content from 2 to 5 mg/ml in the rhGH formulations increased the initial release (24 h) from 78.0% to 93.5%. When the protein formulation was held constant and 1.0% w/w PLA was added to the solvent phase, the initial release was reduced from 78.0% to less than 5.0%. The initial release in vivo after subcutaneous administration (SC) in rats (15 mg/kg rhGH) decreased with increasing PLA content (1.0% w/w PLA, Cmax = 342.8 ng/ml; 10% w/w PLA, Cmax = 35.4 ng/ml), while increased sucrose content increased both the initial release (AUC(0-2) days) and persistence (AUC(2-7) days) over the 7 days from 64.2 to 228.4 ng day/ml (total AUC). A linear dose response (rhGH serum levels) was observed after SC administration of different rhGH SABER volumes greater than 100 microl. Histological examination of the injection sites indicated a mild inflammatory response similar to that observed after injection of PLA microspheres. CONCLUSIONS: The addition of PLA reduced the initial release rate of protein release from SABER, while increasing the sucrose content of the protein formulation yielded increased rhGH persistence. These results demonstrate that the SABER delivery system allows weight-based dosing at volumes greater than 100 microl to achieve sustained release of intact rhGH in vivo for at least 7 days.

Evaluation of the AERx pulmonary delivery system for systemic delivery of a poorly soluble selective D-1 agonist, ABT-431.

PURPOSE: ABT-431 is a chemically stable, poorly soluble prodrug that rapidly converts in vivo to A-86929, a selective dopamine D-1 receptor agonist. This study was designed to evaluate the ability of the AERx pulmonary delivery system to deliver ABT-431 to the systemic circulation via the lung. METHODS: A 60% ethanol formulation of 50 mg/mL ABT-431 was used to prepare unit dosage forms containing 40 microL of formulation. The AERx system was used to generate a fine aerosol bolus from each unit dose that was collected either onto a filter assembly to chemically assay for the emitted dose or in an Andersen cascade impactor for particle size analysis. Plasma samples were obtained for pharmacokinetic analysis after pulmonary delivery and IV dosing of ABT-431 to nine healthy male volunteers. Doses from the AERx system were delivered as a bolus inhalation(s) (1, 2, 4, and 8 mg) and intravenous infusions were given over 1 hr (5 mg). Pharmacokinetic parameters of A-86929 were estimated using noncompartmental analysis. RESULTS: The emitted dose was 1.02 mg (%RSD = 11.0, n = 48). The mass median aerodynamic diameter of the aerosol was 2.9 +/- 0.1 microm with a geometric standard deviation of 1.3 +/- 0.1 (n = 15). Tmax (mean +/- SD) after inhalation ranged from 0.9 +/- 0.6 to 11.5 +/- 2.5. The mean absolute pulmonary bioavailibility (as A-86929) based on emitted dose ranged from 81.9% to 107.4%. CONCLUSIONS: This study demonstrated that the AERx pulmonary delivery system is capable of reproducibly generating fine nearly monodisperse aerosols of a small organic molecule. Aerosol inhalation utilizing the AERx pulmonary delivery system may be an efficient means for systemic delivery of small organic molecules such as ABT-431.