Purpose: Endoxifen is a selective estrogen receptor modulator (SERM), structurally related to tamoxifen and considered to be its most active metabolite. While tamoxifen has been used successfully for the treatment of estrogen-dependent breast cancer, acceptance of tamoxifen for breast cancer prevention by women at high risk has been low. This is possibly due to the known increased risk of developing endometrial cancer and vascular events (especially deep vein thromboses, pulmonary emboli) as side effects of tamoxifen treatment. However, breast cancer prevention requires only that the breast be exposed to the drug; systemic exposure is both unnecessary and potentially harmful. As such, the purpose of this study was to develop a pharmaceutically stable, transdermal delivery strategy for endoxifen. To further support Phase I clinical trials, a cGMP manufacturing campaign was conducted along with analytical method development, validation and full product characterization.
The formulation methodology involved taking a 1:1 ratio of E/Z-endoxifen drug substance dissolved in ethanol, adding oleic acid as a permeation enhancer, and then adding phosphate-buffered water. Hydroxypropyl methyl cellulose was then added as a thickening agent to produce the final bulk gel. cGMP manufacturing was conducted in the same manner as the developmental batches, albeit using approved batch production records, in accordance with Good Manufacturing Practices. The final product was packaged in amber TopiPump® dispensers set to deliver a metered 1 mL dose per pump. Analytical methods for both product characterization and ICH stability monitoring is performed via HPLC with system UV detection at 243 nm. The elution gradient was made by using 40:60, 10 mM HCOONH4 in water, pH 4.3: 10 mM HCOONH4 in MeOH as mobile phase A and methanol with 10 mM HCOONH4 as mobile phase B. The separation was performed using a phenyl-hexyl column (3 mM, 150 x 4.6 mm), with a column temperature of 30 °C. The flow rate is set to 1.0 ml/min with a 30 minute run time. The nominal sample concentration is 0.2 mg/mL with a 20 mL injection volume. The method was validated in accordance with ICH and FDA guidelines and was shown to be stability indicating.
A topical dosage form of endoxifen was developed and shown to be stable over time. 0.5% and 1.0% drug product formulations were prepared to support preclinical (GLP) and clinical (cGMP) studies and full analytical characterization was performed using developed and validated analytical methods. ICH shelf life stability studies are currently underway and all data show that a stable, pharmaceutical dosage form for transdermal delivery has been achieved.
Nathan Duncan– MRIGlobal
William Sherman– MRIGlobal
Quentin Lawrence– MRIGlobal
Bradey Gould– MRIGlobal
Alison Wissmann– MRIGlobal
Michelle Kennedy– MRIGlobal, Kansas city, Missouri
Seema Khan– Northwestern University
Oukseub Lee– Research Assistant Professor, Northwestern University, Chicago, Illinois
Elizabeth Glaze– Program Director, National Cancer Institute, Bethesda, Maryland
Barbara Dunn– National Cancer Institute, Bethesda, Maryland
Daniel Boring– Program Director, National Cancer Institute, Bethesda, Maryland