Modified silicone elastomer vaginal gels for sustained release of antiretroviral HIV microbicides

Abstract

We previously reported nonaqueous silicone elastomer gels (SEGs) for sustained vaginal administration of the CCR5-targeted entry inhibitor maraviroc (MVC). Here, we describe chemically modified SEGs (h-SEGs) in which the hydrophobic cyclomethicone component was partially replaced with relatively hydrophilic silanol-terminated polydimethylsiloxanes (st-PDMS). MVC and emtricitabine (a nucleoside reverse transcriptase inhibitor), both currently under evaluation as topical microbicides to counter sexual transmission of human immunodeficiency virus type 1 (HIV-1), were used as model antiretroviral (ARV) drugs. Gel viscosity and in vitro ARV release were significantly influenced by st-PDMS molecular weight and concentration in the h-SEGs. Unexpectedly, gels prepared with lower molecular weight grades of st-PDMS showed higher viscosities. h-SEGs provided enhanced release over 24 h compared with aqueous hydroxyethylcellulose (HEC) gels, did not modify the pH of simulated vaginal fluid (SVF), and were shown to less cytotoxic than standard HEC vaginal gel. ARV solubility increased as st-PDMS molecular weight decreased (i.e., as percentage hydroxyl content increased), helping to explain the in vitro release trends. Dye ingression and SVF dilution studies confirmed the increased hydrophilicity of the h-SEGs. h-SEGs have potential for use in vaginal drug delivery, particularly for ARV-based HIV-1 microbicides.

Keywords: HIV/AIDS; HIVmicrobicides; antiinfectives; drug delivery systems; formulation; gels; rheology; silicone elastomer; sustained release; viscosity.

Figure 1

Chemical structures of silanol-terminated polydimethylsiloxane (st-PDMS), cyclomethicone, ST Elastomer 10, the nucleoside reverse transcriptase inhibitor emtricitabine and the HIV-1 entry inhibitor maraviroc.

Figure 2

Representative flow rheograms for h-SEGs prepared from (A) DMS S12 and (B) DMS S51. Data for SEG 80/20 and HEC 250 HX control gels are also presented in A.

Figure 3

Viscosities (Pa.S) of (A) placebo SEGs and h-SEGs having different ST-Elastomer 10 / cyclomethicone and ST-Elastomer 10 / st-PDMS ratios, and (B) placebo HEC gels having different HEC concentrations. The viscosities of five commercially available vaginal gels are presented in C.

Figure 4

In vitro mean cumulative release versus time plots for maraviroc and emtricitabine from 80/20 SEG, DMS S12, DMS S21, DMS S27, DMS S35 and DMS S51 h-SEGs and the 2.2% w/w HEC gel into SVF (A) and IPA/ water (1:1) (B) over 24 h (n=4)

Figure 5

Solubility of maraviroc and emtricitabine in st-DMS S12 (6% hydroxyl groups), DMS S14 (3.5% hydroxyl groups), DMS S15 (1.05% hydroxyl groups) and DMS S21 (0.85% hydroxyl groups). Solubility was also assessed in cyclomethicone (0% hydroxyl groups), although values were below the limit of HPLC quantification.

Figure 6

Ingression of aqueous methylene blue solution (blue top layer) into silicone elastomer gels (bottom layer). Bottom layer in photographs A–D comprise either SEG (80/20) (left vial in each photo) or DMS S51 h-SEG (97.5/2.5) (right vial in each photo) after 0 h (A), 6 h (B), 24 h (C) and 48 h (D). Photographs E–H show ingression into SEG (80/20) (left vial) and DMS S12 h-SEG (89/11) (right vial) at the same time points. The main point to note here is that the aqueous methylene blue solution only ingresses into the relatively hydrophilic DMS S12 gel.

Figure 7

Viscosity of placebo SEG, DMS S12 h-SEG and DMS S51 h-SEG expressed as a percentage of initial viscosity following dilution with SVF at 0, 6, 24 and 48 h. A 2.2% w/w HEC gel was also tested, but the viscosity had declined to non-measurable values by 6 h.

Figure 8

Influence of silicone gel formulation on pH of simulated vaginal fluid.