Cellulose Acetate Phthalate (CAP): An ‘Inactive” Pharmaceutical Excipient with Antiviral Activity in the Mouse Model of Genital Herpesvirus Infection

Abstract

The spread of sexually transmitted infections caused by herpes simplex virus type 2 (HSV-2) has continued unabated. At least 20% of the United States population has been infected with HSV-2 and there is a high probability of further virus transmission by asymptomatic carriers. Given the absence of effective vaccines, this indicates the need to develop prophylactic measures such as topical microbicides that have antiviral activity. Recent studies indicate that cellulose acetate phthalate (CAP), an inactive pharmaceutical excipient commonly used in the production of enteric tablets and capsules, is a broad specificity microbicide against diverse sexually transmitted pathogens. When appropriately formulated in micronized form, it inactivates various viruses, including HSV-2, in vitro. Here we show that CAP inhibits HSV-2 infection in the mouse model of genital HSV-2 infection. Pretreatment with micronized CAP formulated in a glycerol-based cream with colloidal silicone dioxide significantly reduced the proportion of HSV-2-infected mice (10% virus shedding, 0-5% lesion development and 0% fatality for CAP as compared to 84% shedding, 63% lesion development and 63% fatality in saline-treated mice). These differences were significant (P < or = 0.0002 by the test of equality of two proportions). Virus titres in the minority of mice that developed infection were similar to those in untreated mice. HSV-2 infection was not inhibited by treatment with CAP formulated with other inactive ingredients (for example povidone plus crosprovidone) instead of silicone dioxide, presumably reflecting CAP complexation/inactivation. These data suggest that properly formulated, CAP may be an efficacious agent for preventing vaginal transmission of genital herpesvirus infections.

Effect of a Cellulose Acetate Phthalate Topical Cream on Vaginal Transmission of Simian Immunodeficiency Virus in Rhesus Monkeys

“…When formulated in a vehicle, a micronized form of CAP has been shown to inactivate HIV-1, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), cytomegalovirus, Neisseria gonorrhoeae, Trichomonas vaginalis, Haemophilus ducreyi, and Chlamydia trachomatis in vitro (23). Formulated CAP has also recently been shown to be effective against HSV-2 in vivo (4). Another advantage of CAP is that it does not appear to affect lactobacilli, part of the natural vaginal flora which contributes to the resistance to STDs (23).…”

“…In this study, we used the SIV female rhesus monkey model of heterosexual HIV transmission to evaluate the efficacy of CAP in a glycerol-based cream containing povidone plus crospovidone (CAP:I) or colloidal silicon dioxide (CAP:II) (4,23) to prevent vaginal infection with cell-free SIV. Colloidal silicon dioxide meets all the requirements listed in the U.S. Pharmacopeia National Formulary and the European Pharmacopoeia.…”

In-vitro Antiviral Activity of a Novel Phthalic Acid Ester Derivative Isolated from the Bangladeshi Mangrove Fern Acrostichum aureum

“…The synthetic pharmaceutical excipient CAP was also investigated due to its previously reported antiviral activities [16,17,27]. The cytotoxicity of both compoundswas established against monkey kidney cells (Vero and LLC-MK2).…”

“…Moreover, some phthalates, such as bis(2-methylheptyl) phthalate isolated from the medicinal plant Pongamiapinnata and a fraction from the root bark extract of the guava tree Psidiumguajava, which contains diethyl phthalate and phthalic acid, displayed antiviral activity against White Spot Syndrome Virus [14,15]. Another phthalate, cellulose acetate phthalate (CAP), which is commonly used as a pharmaceutical excipient for the enteric coating of tablets and capsules, has been shown to inactivate herpes simplex virus types 1 and 2 (HSV-1 and 2) and cytomegalovirus in vitro [16], as well as HSV-2 in vivo [16,17].…”

Vaginal Drug Delivery Systems for HIV Prevention

“…Another study investigated the effects of cellulose acetate 1,2-benzenedicarboxylate (CAP), a film-coating excipient, to inhibit infection by cell-free and cell-associated HIV-1 isolates (119)(120)(121). CAP was formulated with hydroxyl propyl cellulose into a polymeric film by organic solvent evaporation method (122), and safety and efficacy studies are planned.…”