D-peptide hydrogels as a long-acting multipurpose drug delivery platform for combined contraception and HIV prevention.

New multipurpose prevention technology products for use by women, focused on reducing HIV infection and preventing unwanted pregnancies, are a global health priority. Discreet long-acting formulations will empower women with greater choice around their sexual health. This paper outlines the development of a long-acting technology that enables multiple drugs to be incorporated within one injectable platform. This fixed-dose combination product is formed from a phosphorylated D-peptide (naphthalene-2-ly)-acetyl-diphenylalanine-lysine-tyrosine-glycine-OH (Napffky(p)G-OH) that enables the highly hydrophobic drugs MIV-150 (HIV antiretroviral) and etonogestrel (contraceptive) to be solubilized together within aqueous solvents. Upon subcutaneous injection, this D-peptide-drug combination self-assembles in response to phosphatase enzymes present within the skin space to form an in situ forming drug-releasing hydrogel depot. Oscillatory rheology confirmed the formation of hydrogels, which began within ~10 s exposure to 3.98 U/mL phosphatase enzymes and continued for ~198 mins for a Napffk(MIV-150)y(p)G-OH + Napffk(ENG)y(p)G-OH combination (8:2 ratio). Biostability against proteases, an important consideration for long-acting injectables, was demonstrated for at least 28 days in vitro. Covalent attachment of each drug to the D-peptide via an ester linkage enabled sustained release of the drug in an unmodified form via hydrolysis of the D-peptide-drug linker. This significantly reduced the initial drug burst. Low toxicity was also demonstrated in vitro via cell culture (MTS, LHS, Live/Dead®) and within in vivo studies (H&E staining). The fixed dose combination was able to deliver clinically relevant concentrations of each drug to Sprague-Dawley rats for 49 days, providing proof-of-concept for the use of hydrogel-forming D-peptides (Napffky(p)G-OH) as a long-acting injectable platform for the delivery of multiple hydrophobic drugs.