Thermosensitive Gel Containing Cellulose Acetate Phthalate-Efavirenz Combination Nanoparticles for Prevention of HIV-1 Infection

The objective of this investigation was to develop and evaluate a nano-microbicide containing a combination of cellulose acetate phthalate (HIV-1 entry inhibitor) and efavirenz (anti-HIV agent) for HIV prophylaxis. Cellulose acetate phthalate-efavirenz combination nanoparticles (CAP-EFV-NPs) were fabricated by the nanoprecipitation method and were characterized for particle size, zeta potential and encapsulation efficiency of efavirenz. CAP-EFV-NPs were incorporated into a thermosensitive gel (CAP-EFV-NP-Gel). CAP-EFV-NPs, CAP-EFV-NP-Gel and efavirenz solution were evaluated for cytotoxicity to HeLa cells and for in vitro short-term (1-day) and long-term (3-day) prophylaxis against HIV-1 infection in TZM-bl cells. CAP-EFV-NPs had size \u3c 100 nm, negative surface charge and encapsulation efficiency of efavirenz was \u3e 98%. CAP-EFV-NPs and CAP-EFV-NP-Gel were significantly less toxic (P \u3c 0 01) to HeLa cells as compared to efavirenz solution. CAP-EFV-NPs showed significantly higher prophylactic activity (P \u3c 0 01) against HIV-1 infection to TZM-bl cells as compared to efavirenz solution and blank CAP nanoparticles. CAP-EFV-NP-Gel can be a promising nano-microbicide for long-term HIV prophylaxis

Correction: Nanoformulations of Rilpivirine for Topical Pericoital and Systemic Coitus-Independent Administration Efficiently Prevent HIV Transmission

Vaginal HIV transmission accounts for the majority of new infections worldwide. Currently, multiple efforts to prevent HIV transmission are based on pre-exposure prophylaxis with various antiretroviral drugs. Here, we describe two novel nanoformulations of the reverse transcriptase inhibitor rilpivirine for pericoital and coitus-independent HIV prevention. Topically applied rilpivirine, encapsulated in PLGA nanoparticles, was delivered in a thermosensitive gel, which becomes solid at body temperature. PLGA nanoparticles with encapsulated rilpivirine coated the reproductive tract and offered significant protection to BLT humanized mice from a vaginal high-dose HIV-1 challenge. A different nanosuspension of crystalline rilpivirine (RPV LA), administered intramuscularly, protected BLT mice from a single vaginal high-dose HIV-1 challenge one week after drug administration. Using transmitted/founder viruses, which were previously shown to establish de novo infection in humans, we demonstrated that RPV LA offers significant protection from two consecutive high-dose HIV-1 challenges one and four weeks after drug administration. In this experiment, we also showed that, in certain cases, even in the presence of drug, HIV infection could occur without overt or detectable systemic replication until levels of drug were reduced. We also showed that infection in the presence of drug can result in acquisition of multiple viruses after subsequent exposures. These observations have important implications for the implementation of long-acting antiretroviral formulations for HIV prevention. They provide first evidence that occult infections can occur, despite the presence of sustained levels of antiretroviral drugs. Together, our results demonstrate that topically- or systemically administered rilpivirine offers significant coitus-dependent or coitus-independent protection from HIV infection

Tolerability, pharmacokinetics, and anti-herpetic activity of orally administered BX795

Herpes simplex viruses type-1 (HSV-1) and type-2 (HSV-2) are ubiquitous human pathogens causing serious pathologies in the ocular, orofacial and anogenital regions. While current treatments such as nucleoside analogs are effective in most cases, the emergence of drug resistance necessitates the development of newer antivirals with different mechanisms of action. In this regard, BX795, a small molecule inhibitor has shown significant benefit in the treatment of herpesvirus infections previously when dosed topically. However, the efficacy of BX795′s systemic dosage remains to be tested. In this study, we evaluated acute and short-term toxicity of orally administered BX795 at a concentration of 400 and 100 mg/kg respectively in mice. This was followed by an evaluation of pharmacokinetics and tissue distribution of BX795 on intravenous and oral administration. Based on these studies, we performed an in vivo antiviral study using murine models of ocular HSV-1 and genital HSV-2 infection. Our results indicate that orally administered BX795 is very well tolerated, had oral bioavailability of 56%, and reached ocular and genital tissues within the first 15 min of dosing. Our studies indicate that BX795 administered orally can significantly reduce herpesvirus replication in the ocular and genital tissue

Development and evaluation of taste masked dry syrup formulation of potassium chloride

Abstract Potassium chloride (KCl) syrup is widely used for the oral treatment of the hypokalemia. However, it is associated with unacceptable taste. In the present study, we sought to develop a palatable and easy to reconstitute KCl dry syrup as a commercially viable alternative to currently available KCl syrup. We explored the potential of Eudragit E100 as a taste-masking polymer to coat and improve the palatability of the KCl. With the help of fluid bed processor, KCl was coated with the solution containing varying amounts of Eudragit E100 (4, 6, 10 and 15%). Coating with 10% polymer solution enabled optimal fluid bed processing, higher entrapment of the KCl (81%) and better in vitro release profile in 0.1 N HCl and pH 6.8 phosphate buffer. A dry syrup formulation containing Eudragit E100 coated KCl with good physical and chemical stability in dry and reconstituted state was developed. The palatability of the optimized formulation and commercially available KCl syrup was evaluated using the Electronic Taste Sensing Machine. The developed formulation showed~ 2-fold better taste-masking compared to the commercial KCl syrup. Thus, present investigation describes the development of an effective alternative to the current KCl syrup that can offer better palatability, stability and patient compliance

Thermosensitive Gel Containing Cellulose Acetate Phthalate-Efavirenz Combination Nanoparticles for Prevention of HIV-1 Infection

The objective of this investigation was to develop and evaluate a nano-microbicide containing a combination of cellulose acetate phthalate (HIV-1 entry inhibitor) and efavirenz (anti-HIV agent) for HIV prophylaxis. Cellulose acetate phthalate-efavirenz combination nanoparticles (CAP-EFV-NPs) were fabricated by the nanoprecipitation method and were characterized for particle size, zeta potential and encapsulation efficiency of efavirenz. CAP-EFV-NPs were incorporated into a thermosensitive gel (CAP-EFV-NP-Gel). CAP-EFV-NPs, CAP-EFV-NP-Gel and efavirenz solution were evaluated for cytotoxicity to HeLa cells and for in vitro short-term (1-day) and long-term (3-day) prophylaxis against HIV-1 infection in TZM-bl cells. CAP-EFV-NPs had size \u3c 100 nm, negative surface charge and encapsulation efficiency of efavirenz was \u3e 98%. CAP-EFV-NPs and CAP-EFV-NP-Gel were significantly less toxic (P \u3c 0 01) to HeLa cells as compared to efavirenz solution. CAP-EFV-NPs showed significantly higher prophylactic activity (P \u3c 0 01) against HIV-1 infection to TZM-bl cells as compared to efavirenz solution and blank CAP nanoparticles. CAP-EFV-NP-Gel can be a promising nano-microbicide for long-term HIV prophylaxis

BX795-Organic Acid Coevaporates: Evaluation of Solid-State Characteristics, In Vitro Cytocompatibility and In Vitro Activity against HSV-1 and HSV-2

BX795 is a TANK binding kinase-1 inhibitor that has shown excellent therapeutic activity in murine models of genital and ocular herpes infections on topical delivery. Currently, only the BX795 free base and its hydrochloride salt are available commercially. Here, we evaluate the ability of various organic acids suitable for vaginal and/or ocular delivery to form BX795 salts/cocrystals/co-amorphous systems with the aim of facilitating pharmaceutical development of BX795. We characterized BX795-organic acid coevaporates using powder X-ray diffractometry, Fourier-transform infrared spectroscopy (FT-IR), Raman spectroscopy, 1H-nuclear magnetic resonance spectroscopy, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) to elucidate the interaction between BX795 and various organic acids such as taurine, maleic acid, fumaric acid, tartaric acid, and citric acid. Furthermore, using human corneal epithelial cells and HeLa cells, we evaluated BX795-organic acid coevaporates for in vitro cytocompatibility and in vitro antiviral activity against herpes simplex virus-type 1 (HSV-1) and type-2 (HSV-2). Our studies indicate that BX795 forms co-amorphous systems with tartaric acid and citric acid. Interestingly, the association of organic acids with BX795 improved its thermal stability. Our in vitro cytocompatibility and in vitro antiviral studies to screen suitable BX795-organic acid coevaporates for further development show that all BX795-organic acid systems, at a concentration equivalent to 10 µM BX795, retained antiviral activity against HSV-1 and HSV-2 but showed differential cytocompatibility. Further, dose-dependent in vitro cytocompatibility and antiviral activity studies on the BX795-fumaric acid system, BX795-tartaric acid co-amorphous system, and BX795-citric acid co-amorphous system show similar antiviral activity against HSV-1 and HSV-2 compared to BX795, whereas only the BX795-citric acid co-amorphous system showed higher in vitro cytocompatibility compared to BX795

BX795-Organic Acid Coevaporates: Evaluation of Solid-State Characteristics, In Vitro Cytocompatibility and In Vitro Activity against HSV-1 and HSV-2

BX795 is a TANK binding kinase-1 inhibitor that has shown excellent therapeutic activity in murine models of genital and ocular herpes infections on topical delivery. Currently, only the BX795 free base and its hydrochloride salt are available commercially. Here, we evaluate the ability of various organic acids suitable for vaginal and/or ocular delivery to form BX795 salts/cocrystals/co-amorphous systems with the aim of facilitating pharmaceutical development of BX795. We characterized BX795-organic acid coevaporates using powder X-ray diffractometry, Fourier-transform infrared spectroscopy (FT-IR), Raman spectroscopy, 1H-nuclear magnetic resonance spectroscopy, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) to elucidate the interaction between BX795 and various organic acids such as taurine, maleic acid, fumaric acid, tartaric acid, and citric acid. Furthermore, using human corneal epithelial cells and HeLa cells, we evaluated BX795-organic acid coevaporates for in vitro cytocompatibility and in vitro antiviral activity against herpes simplex virus-type 1 (HSV-1) and type-2 (HSV-2). Our studies indicate that BX795 forms co-amorphous systems with tartaric acid and citric acid. Interestingly, the association of organic acids with BX795 improved its thermal stability. Our in vitro cytocompatibility and in vitro antiviral studies to screen suitable BX795-organic acid coevaporates for further development show that all BX795-organic acid systems, at a concentration equivalent to 10 µM BX795, retained antiviral activity against HSV-1 and HSV-2 but showed differential cytocompatibility. Further, dose-dependent in vitro cytocompatibility and antiviral activity studies on the BX795-fumaric acid system, BX795-tartaric acid co-amorphous system, and BX795-citric acid co-amorphous system show similar antiviral activity against HSV-1 and HSV-2 compared to BX795, whereas only the BX795-citric acid co-amorphous system showed higher in vitro cytocompatibility compared to BX795