Finite sample corrections for average equivalence testing.

Average (bio)equivalence tests are used to assess if a parameter, like the mean difference in treatment response between two conditions for example, lies within a given equivalence interval, hence allowing to conclude that the conditions have "equivalent" means. The two one-sided tests (TOST) procedure, consisting in testing whether the target parameter is respectively significantly greater and lower than some pre-defined lower and upper equivalence limits, is typically used in this context, usually by checking whether the confidence interval for the target parameter lies within these limits. This intuitive and visual procedure is however known to be conservative, especially in the case of highly variable drugs, where it shows a rapid power loss, often reaching zero, hence making it impossible to conclude for equivalence when it is actually true. Here, we propose a finite sample correction of the TOST procedure, the α $$ \alpha $$ -TOST, which consists in a correction of the significance level of the TOST allowing to guarantee a test size (or type-I error rate) of α $$ \alpha $$ . This new procedure essentially corresponds to a finite sample and variability correction of the TOST procedure. We show that this procedure is uniformly more powerful than the TOST, easy to compute, and that its operating characteristics outperform the ones of its competitors. A case study about econazole nitrate deposition in porcine skin is used to illustrate the benefits of the proposed method and its advantages compared to other available procedures.

Influence of Molecular Structure and Physicochemical Properties of Immunosuppressive Drugs on Micelle Formulation Characteristics and Cutaneous Delivery.

The aim of this study was to investigate whether subtle differences in molecular properties affected polymeric micelle characteristics and their ability to deliver poorly water-soluble drugs into the skin. D-α-tocopherol-polyethylene glycol 1000 was used to prepare micelles containing ascomycin-derived immunosuppressants-sirolimus (SIR), pimecrolimus (PIM) and tacrolimus (TAC)-which have similar structures and physicochemical properties and have dermatological applications. Micelle formulations were prepared by thin-film hydration and extensively characterized. Cutaneous delivery and biodistribution were determined and compared. Sub-10 nm micelles were obtained for the three immunosuppressants with incorporation efficiencies >85%. However, differences were observed for drug loading, stability (at the highest concentration), and their in vitro release kinetics. These were attributed to differences in drug aqueous solubility and lipophilicity. Differences between the cutaneous biodistribution profiles and drug deposition in the different skin compartments pointed to the impact of differences in thermodynamic activity. Therefore, despite their structural similarities, SIR, TAC and PIM did not demonstrate the same behaviour either in the micelles or when applied to the skin. These outcomes indicate that polymeric micelles should be optimized even for closely related drug molecules and support the hypothesis that drugs are released from micelles prior to skin penetration.

Polymeric micelle formulations for the cutaneous delivery of sirolimus: A new approach for the treatment of facial angiofibromas in tuberous sclerosis complex.

Facial angiofibromas are benign tumors characteristic of tuberous sclerosis complex. The disease involves the mTOR pathway and the cutaneous manifestation responds to topical treatment with sirolimus (SIR). However, there are no approved topical SIR products and extemporaneous formulations have been sub-optimal. The aims of this study were (i) to develop aqueous formulations of SIR loaded in polymeric micelles prepared using D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and (ii) to use the cutaneous biodistribution method, in conjunction with a new statistical approach, to investigate the feasibility of SIR delivery to the viable epidermis. Optimized micelle solutions and hydrogels (0.2%) were developed and stable at 4 °C for at least 6 and 3 months, respectively. Cutaneous delivery experiments (infinite and finite dose) using porcine skin demonstrated that both formulations increased SIR cutaneous bioavailability as compared to the control (ointment 0.2%). Moreover, studies with the micellar hydrogel 0.2% demonstrated SIR deposition in the viable epidermis with no transdermal permeation. These encouraging results confirmed that polymeric micelles enabled development of aqueous SIR formulations capable of targeted epidermal delivery. Furthermore, the cutaneous biodistribution provided a detailed insight into drug bioavailability in the different skin compartments that could complement/explain clinical observations of formulation efficacy.