Physiologically Based Pharmacokinetic Model Development and Verification for Bioequivalence Testing of Bempedoic Acid Oral Suspension and Reference Tablet Formulation.

The bioequivalence of bempedoic acid oral suspension and commercial immediate release (IR) tablet formulations were assessed using a physiologically based pharmacokinetic (PBPK) model. The mechanistic model, developed from clinical mass balance results and in vitro intrinsic solubility, permeability, and dissolution data, was verified against observed clinical pharmacokinetics (PK) results. Model inputs included a fraction of a dose in solution (0.01%), viscosity (118.8 cps), and median particle diameter (50 µm) for the suspension and particle diameter (36.4 µm) for IR tablets. Dissolution was determined in the relevant media (pH 1.2-6.8) in vitro. Model simulations of bioequivalence predicted oral suspension (test) to IR tablet (reference) geometric mean ratio estimates of 96.9% (90% confidence interval [CI]: 92.6-101) for maximum concentration and 98.2% (90% CI: 87.3-111) for the area under the concentration-time curve. Sensitivity analyses showed gastric transit time had a minor impact on model predictions. Oral suspension biopharmaceutical safe space was defined by extremes of particle size and the percent of bempedoic acid in solution. PBPK model simulations predicted that the rate and extent of bempedoic acid absorption are unlikely to exhibit clinically meaningful differences when dosed as an oral suspension compared with an IR tablet without requiring a clinical bioequivalence study in adults.

Effects of growth conditions on the barrier properties of a human skin equivalent.

PURPOSE: Development of transdermal and topical formulations requires extensive skin permeation testing and the availability of reproducible test models. We have worked on development of a Human Skin Equivalent (HSE) by culture with a combination of additives, including the PPAR-alpha agonist clofibrate, in order to simulate the cutaneous barrier of human skin. METHODS: HSEs were constructed by culturing human keratinocytes on dermal matrices consisting of human fibroblasts and collagen and cultured in specific growth conditions (combination of clofibrate, ascorbic acid and fatty acids). The resulting HSEs were characterized for their morphology, lipid composition and permeability profile and compared to human skin and EpidermFT. RESULTS: The unique media growth additives combination normalized the lipid profile and significantly increased the permeability barrier of the HSEs to caffeine and hydrocortisone (p < 0.05). The HSEs overestimated the permeation of most compounds by 2-7 fold as compared to human skin. The permeability profiles obtained though were very similar and not significantly different (p < 0.05) from those of EpidermFT. CONCLUSIONS: Culture with the growth media additives combination produced a pronounced effect on the permeability barrier of the HSEs. Further validation of permeability with additional agents could comprise the first step toward their use in skin permeability screening.

Percutaneous permeation modifiers: enhancement versus retardation.

BACKGROUND: The use of permeation enhancers to compromise the barrier properties of skin has been ongoing for decades. However, toxicity associated with certain xenobiotics has led to the development of permeation retardants. Since both enhancers and retardants modify the surface layer of the skin, they can be collectively referred to as penetration modifiers. OBJECTIVE: This review attempts to outline a comparison of two types of penetration modifiers: enhancers and retardants. METHODS: In addition to reports of enhancement and retardation by modifiers, we also provide evidence as to why we should group these compounds together, since we have found that retardants can become enhancers in different formulation environments. CONCLUSION: Since modifiers influence drug delivery, further exploration of these compounds is required to understand their modifying action on the properties of skin.

Transdermal iontophoresis.

Iontophoresis is a technique used to enhance the transdermal delivery of compounds through the skin via the application of a small electric current. By the process of electromigration and electro-osmosis, iontophoresis increases the permeation of charged and neutral compounds, and offers the option for programmed drug delivery. Interest in this field of research has led to the successful delivery of both low (lidocaine) and high molecular drugs, such as peptides (e.g., luteinising hormone releasing hormone, nafarelin and insulin). Combinations of iontophoresis with chemical enhancers, electroporation and sonophoresis have been tested in order to further increase transdermal drug permeation and decrease possible side effects. In addition, rapid progress in the fields of microelectronics, nanotechnology and miniaturisation of devices is leading the way to more sophisticated iontophoretic devices, allowing improved designs with better control of drug delivery. Recent successful designing of the fentanyl E-TRANS iontophoretic system have provided encouraging results. This review will discuss basic concepts, principles and applications of this delivery technique.

Topical drug delivery by a polymeric nanosphere gel: Formulation optimization and in vitro and in vivo skin distribution studies.

Tyrosine-derived nanospheres have demonstrated potential as effective carriers for the topical delivery of lipophilic molecules. In this investigation, a gel formulation containing nanospheres was developed for effective skin application and enhanced permeation. Carbopol and HPMC hydrophilic gels were evaluated for dispersion of these nanospheres. Sparingly water soluble diclofenac sodium (DS) and lipophilic Nile Red were used as model compounds. DS was used to determine the optimum polymer type, viscosity and release properties of the gel while fluorescent Nile Red was used in in vitro and in vivo skin distribution studies. In addition, the effect of a penetration enhancer, Azone, on the skin delivery was investigated. Dispersion of Nile Red-loaded nanospheres in 1% w/v HPMC gel produced a uniform and stable dispersion with suitable rheological properties for topical application, without any short-term cellular toxicity or tissue irritation. In vitro permeation studies using human cadaver skin revealed that the deposition of Nile Red via the nanosphere gel in the upper and lower dermis was 1.4 and 1.8 fold higher, respectively, than the amount of Nile Red deposited via an aqueous nanosphere formulation. In vivo, the HPMC gel containing Nile Red-loaded nanospheres significantly enhanced (1.4 fold) the permeation of Nile Red to the porcine stratum corneum/epidermis compared to the aqueous Nile Red-loaded nanospheres. An additional increase (1.4 fold) of Nile Red deposition in porcine stratum corneum/epidermis was achieved by incorporation of Azone (0.2M) into the nanosphere gel formulation. Therefore, tyrosine-derived nanospheres dispersed in gels offer promise for the topical delivery of lipophilic drugs and personal care agents to skin for treatment of cancers, psoriasis, eczema, and microbial infections.