Development of multipurpose technologies products for pregnancy and STI prevention: update on polyphenylene carboxymethylene MPT gel development†

Abstract

<jats:title>Abstract</jats:title> <jats:p>Current modern contraceptives rely heavily on the use of hormones. These birth control drug products, including pills, patches, injections, and IUDS, have been extremely beneficial to millions of women and their families over the past 50 years. But a surprisingly high number of women abandon such modern methods, many because they cannot tolerate the side effects and others because they have medical issues for which hormonal methods are contraindicated. In addition, modern hormonal methods are simply not available to many women. The extent of this problem is steadily becoming more apparent.</jats:p> <jats:p>We present the case for developing simple nonhormonal vaginal products that women can use when needed, ideal products that are multipurpose and offer both contraception and sexually transmitted disease protection. Gel-based vaginal products are particularly well suited for this purpose. Gels are easy to use, highly acceptable to many women, and can be safely formulated to enhance natural vaginal defenses against infection. However, the development of a new chemical entity for this application faces significant technical and regulatory hurdles. These challenges and our solutions are described for polyphenylene carboxymethylene (PPCM), a novel topical drug in a vaginal gel nearing human clinical trials. We have advanced PPCM from benchtop to IND-enabling studies and provide a brief description of the complex development process. We also describe a simple lab assay which can be used as a biomarker for contraceptive activity to enable pharmacodynamic studies in vaginal contraceptive development, both preclinically and in early human clinical trials.</jats:p>

Polyphenylene carboxymethylene (PPCM) microbicide repurposed as antiviral against SARS-CoV-2. Proof of concept in primary human undifferentiated epithelial cells

“…The goal of this study was to evaluate the antiviral efficacy of PPCM against SARS-CoV-2, which would support future studies on repurposing PPCM as a prophylaxis or therapeutic antiviral treatment method via aerosol delivery against respiratory viruses. PPCM has previously demonstrated in vitro broad-spectrum activity against several sexually transmitted infections including some of viral origin such as HIV-1, HSV-1 and 2, BPV, and Ebola virus ( Chang et al, 2007 ; Escaffre et al, 2019 ; Herold et al, 2002 ; Mesquita et al, 2008 ; Weitzel et al, 2020 ; Zaneveld et al, 2002 ). In addition, PPCM toxicity studies have shown that a 4% gel formulation was safe in a vaginal irritation assay in New Zealand White rabbits ( Zaneveld et al, 2002 ), and did not cause any apparent disease in BALB/c mice ( Mesquita et al, 2008 ).…”

“…Polyphenylene Carboxymethylene (PPCM) is a mandelic acid condensation polymer under development as a multipurpose prevention technology, and has a low cost of manufacturing under different formulations ( Weitzel et al, 2020 ). PPCM has previously demonstrated microbicidal broad-spectrum activity against sexually transmitted infections in vitro and in animal models.…”

“…PPCM has previously demonstrated microbicidal broad-spectrum activity against sexually transmitted infections in vitro and in animal models. Focusing on viruses, PPCM specifically prevented HIV, HSV, BPV and ebolavirus infection by binding to both the virus envelope glycoproteins and target cells ( Chang et al, 2007 ; Escaffre et al, 2019 ; Herold et al, 2002 ; Mesquita et al, 2008 ; Weitzel et al, 2020 ; Zaneveld et al, 2002 ) while having low cell cytotoxicity in the vaginal flora ( Zaneveld et al, 2002 ). These characteristics suggest that PPCM is a small molecule candidate to be tested as an antiviral against a broad range of human infectious diseases.…”

Multipurpose Prevention Technologies: Oral, Parenteral, and Vaginal Dosage Forms for Prevention of HIV/STIs and Unplanned Pregnancy

“…Due to this, there have been attempts to develop nonhormonal vaginal MPTs. For example, Weitzel et al developed a nonhormonal MPT vaginal gel utilizing polyphenylene carboxymethylene (PPCM) [ 97 ]. PPCM is an anionic mandelic acid condensation polymer that has been demonstrated to be active against HIV-1, HSV-1, and HSV-2 [ 98 , 99 , 100 ].…”

“…PPCM has also been shown to act as a noncytotoxic contraceptive that causes a premature loss of the sperm acrosome and does not cause epithelial surface damage unlike nonoxynol-9 [ 101 ]. The MPT formulation consisted of 4% PPCM sodium salt and excipients such as HPMC K100, xanthan gum, glycerin, methyl paraben, and propyl paraben and would be administered precoitally [ 97 ]. Only preliminary in vitro studies have been conducted to determine the contraceptive efficacy of this formulation and showed up to 80% sperm inactivation.…”