Effect of formulation parameters on 2-methoxyestradiol release from injectable cylindrical poly(dl-lactide-co-glycolide) implants

Abstract

The objective of this study was to investigate the potential of various formulation strategies to achieve 1-month continuous (improved) release of the novel anti-cancer drug, 2-methoxyestradiol (2-ME), from injectable cylindrical poly(DL-lactide-co-glycolide) (PLGA) implants. PLGA implants were prepared by a solvent extrusion method. PLGA 50:50 (M w = 51 kDa, end group = lauryl ester) (PLGA-lauryl ester) implants loaded with 3-30 wt% 2-ME exhibited a pronounced lag phase (i.e., corresponding to induction time to polymer mass loss) and triphasic release profile. Incorporation of 5 wt% hydroxypropyl-β-cyclodextrin (HP-β-CD) (~57% release after 28 days) or Pluronic ® F127 (~42% release after 28 days) in PLGA-lauryl ester implants reduced the lag-phase and improved the drug release moderately over a period of 28 days. The formation and the incorporation of a 2-ME/ polyethylene glycol (PEG) 8000 solid dispersion in PLGA-lauryl ester implants further increased drug release (~21% and 73% release after 1 and 28 days, respectively), attributable to improved drug solubility/dissolution, higher matrix porosity, and accelerated polymer degradation. Blending of PLGA 50:50 (M w = 24 kDa, end group = COOH) (PLGA-COOH) with the PLGA-lauryl ester also provided moderate enhancement of 2-ME release over a period of 28 days. PLGA-COOH (M w = 24 kDa) implants with 3-5% w/w pore-forming MgCO 3 exhibited the most desirable drug release among all the formulations tested, and, demonstrated 1-month slow and continuous in vitro release of ~80% 2-ME after a minimal initial burst. Hence, these formulation approaches provide several possible avenues to improve release rates of the hydrophobic drug, 2-ME, from PLGA for future application in regional anti-cancer therapy.

Development and In Vitro-In Vivo Evaluation of Polymeric Implants for Continuous Systemic Delivery of Curcumin

“…They may increase or decrease the drug release rates by changing the matrix lipophilicity, matrix porosity, microclimate pH and or polymer drug interactions (37,38). Excipients, especially hydrophilic polymers compatible with the polymeric matrix, are helpful in providing aqueous channels to facilitate the diffusion-mediated drug release.…”

Encapsulation of 2-methoxyestradiol within multifunctional poly(amidoamine) dendrimers for targeted cancer therapy

“…2-ME is highly lipophilic with very low water solubility (solubility of 2-ME in water at 37 C was determined to be about 1.8 mg/mL) [39] and can be quickly metabolized, thus losing the therapeutic efficacy on cancer cells. Using dendrimer/2-ME complexes as a formulation could overcome the water-insolubility and improve the bioavailability of the drug.…”

Novel in silico-designed estradiol analogues are cytotoxic to a multidrug-resistant cell line at nanomolar concentrations

“…2 a The effect of six sulphamoylated 2ME derivatives on tubulin polymerization. DMSO was used as a negative control, while CMO2 was used as a positive control [14]. [7].…”

“…Those with no cytotoxic effects below 10,000 nM are denoted by '>10 k.' Values depict nanomolar (nM) concentrations. All experiments are conducted in triplicate (2MEbisMATE) and an azaindole derivative CMO2 [14] were used as positive controls. Following a 10-min incubation, tubulin assembly was initiated by injection of 1 mmol/L guanine triphosphate (GTP) and 5 mmol/L MgCl 2 .…”

“…In vitro tubulin polymerization assays were performed as previously described [14]. Pure bovine tubulin was prepared as described [15].…”