Pharmacokinetic evaluation of a transdermal anastrozole-in-adhesive formulation

Abstract

Background and objective: Anastrozole is a well-established active pharmaceutical ingredient (API) used for the treatment of hormone-sensitive breast cancer (BC) in postmenopausal women. However, treatment with the only available oral formulation is often associated with concentration-dependent serious side effects such as hot flashes, fatigue, muscle and joint pain, nausea, diarrhea, headache, and others. In contrast, a sustained-release system for the local application of anastrozole should minimize these serious adverse drug reactions.

Methods: Anastrozole-in-adhesive transdermal drug delivery systems (TDDS) were developed offering efficient loading, avoidance of inhomogeneity or crystallization of the drug, the desired controlled release kinetics, storage stability, easy handling, mechanical stability, and sufficient stickiness on the skin. In vitro continuous anastrozole release profiles were studied in Franz diffusion cells. In vivo, consecutive drug plasma kinetics from the final anastrozole transdermal system was tested in beagle dogs. For drug analysis, a specific validated liquid chromatography- mass spectrometry method using fragment ion detection was developed and validated.

Results: After efficient drug loading, a linear and sustained 65% drug release from the TDDS over 48 h was obtained. In vivo data showed a favorable anastrozole plasma concentration-time course, avoiding side effect-associated peak concentrations as obtained after oral administration but matching therapeutic plasma levels up to 72 h.

Conclusion: These results provide the basis for establishing the transdermal application of anastrozole with improved pharmacokinetics and drug safety as novel therapeutic approach and promising option to treat human BC by decreasing the high burden of unwanted side effects.

Keywords: Franz diffusion cells; anastrozole; breast cancer; pharmacokinetics; transdermal drug delivery system.

Figure 1

Scheme of steps of the pharmaceutical TDDS build up. Abbreviations: API, active pharmaceutical ingredient; TDDS, transdermal drug delivery systems.

Figure 2

Effects of incorporation of anastrozole without and with prior solvation into the TDDS polymer matrix. Notes: Microscopic pictures of anastrozole aggregate formation in TDDS without solvent (A). Absence of crystallization (B) when using EtOH as solvent (the faint structures seen are air bubbles, and green color is filter) but crystal formation upon drying of the TDDS loaded with anastrozole dissolved in EA (C). Table: lower right: compilation of results, demonstrating the absence of crystal formation after drying only when using EtOH or DMSO as solvent. Microscopic pictures from freshly prepared TDDS (A, B) and after drying process (C) before considering crystallization inhibitors. Abbreviations: DMSO, dimethyl sulfoxide; EA, ethyl acetate; EtOH, ethanol; TDDS, transdermal drug delivery systems; THF, tetrahydrofuran.

Figure 3

Cumulative permeation of anastrozole through the hairless excised mouse skin to HEPES acceptor medium (pH 7.3) in Franz diffusion cells within 48 h. Notes: (A) Mean value curve (bold) and single experiments (n=4) from freshly manufactured silicone-based, ethanol-solubilized anastrozole TDDS. (B) Microscopic picture of anastrozole crystal clusters formed in these TDDS after drying and storage at room temperature for 24 h up to 1 month. Scale bar, 1.11 µm. Abbreviation: TDDS, transdermal drug delivery systems.

Figure 4

Effect of PEG 400 (A) and glycerol (B) in ethyl acetate-based TDDS on permeation of 1% (closed circles) or 2.5% anastrozole (open circles) through the excised hairless mouse skin into Franz diffusion cells. Notes: Data are summarized from two separate experiments. Mean and SD values are summarized from triplicates. Abbreviations: PEG, poly-ethylene glycol; TDDS, transdermal drug delivery systems.

Figure 5

Relationship between cumulative average anastrozole release from final transdermal films through the hairless excised mouse skin vs SQRT (filled line) and regression fit (dotted line) using the Higuchi kinetic model in 1 and 2.5% of anastrozole/glycerol containing ethyl acetate-based TDDS. Note: Cumulative average percentage of drug release (filled line) and Higuchi kinetic model fit (dotted line). Abbreviations: SQRT, square root of time; TDDS, transdermal drug delivery systems.

Figure 6

Typical LC–MS chromatograms of anastrozole and d12-deuterated anastrozole (A) in blank (upper panel) and spiked plasma sample (lower panel) as well as (B) fragmentation pattern of anastrozole in relation to the CID voltage. Notes: Arrows indicate signal noise at RT of anastrozole in blank plasma sample. m/z, mass-to-charge ratio. Abbreviations: AH, absolute peak height; CID, collision-induced dissociation; LC–MS, liquid chromatography–mass spectrometry; MS ICIS, mass spectrometry interactive information system; RT, retention time; TIC, total ion current.

Figure 7

(A) Pharmacokinetic profile of anastrozole after application of the optimized (ethyl acetate and glycerol) TDDS formulation containing 2.8% of anastrozole (dotted line: mean of both animals) in dog plasma and (B) mean concentration time course in previously published data from healthy human study following oral administration of 1 mg of anastrozole film tablet. Reprinted from Journal of Chromatography B, vol 850, Mendes GD, Hamamoto D, Ilha J, Pereira AS, de Nucci G Anastrozole, Anastrozole quantification in human plasma by high-performance liquid chroma tography coupled to photospray tandem mass spectrometry applied to pharmacokinetic studies, pages 553–559, copyright (2007), with permission from Elsevier. Note: Plasma concentration course from the in vivo study (A) compared with published data obtained from human following oral drug application (B) of anastrozole standard dose. Abbreviation: TDDS, transdermal drug delivery systems.