Sriramakamal Jonnalagadda

Despite advances in oral and injectable HIV prevention options and oral prophylaxis for sexually transmitted infections (STIs) of bacterial origin, there remains a critical need for effective on-demand topical (vaginal and rectal) products for pre- and post-exposure prophylaxis (PrEP and PEP). To fill this gap, we have developed single and first-in-kind multi-active topical inserts for bacterial STIs and HIV/STIs prevention. We have formulated two different inserts, one containing doxycycline (DOX) at 10, 50, and 100 mg doses for bacterial STI prevention, and a multipurpose prevention product (TED insert) that combines DOX (10 mg) with the antiretrovirals tenofovir alafenamide (TAF; 20 mg) and elvitegravir (EVG; 16 mg) to target both bacterial STIs and HIV. Inserts were manufactured using a simple and cost-effective process. Drug loading was within 95-105% of the labeled amount, confirming a robust manufacturing process. In vitro, the inserts disintegrated within 10 min with > 95% drug release within 60 min. The dissolution behavior of DOX inserts showed surface erosion but was affected by medium volume and drug amount. The inserts met key physicochemical targets: hardness (5-8 kg), friability (< 1%), moisture content (< 2%), and osmolality (< 550 mOsm/kg). Based on 6-month storage stability, DOX inserts maintained their physicochemical properties, indicating a shelf life of > 2 years. Preliminary 1-month stability of TED inserts under accelerated conditions showed preservation of their physicochemical properties. These data describe the formulation development and in vitro characterization of topical inserts containing DOX alone or in combination with antiretrovirals (TAF and EVG). Both inserts offer a novel, on-demand topical STI prevention option that supports flexible PrEP/PEP use by both women and men.

Hydrogel formulation is often optimized through empirical adjustment of compositional variables, limiting quantitative resolution of structure-property relationships in composite polymer networks. In amphiphilic block copolymer systems, micellar organization contributes to network connectivity and transport behavior; however, its role as a distinct structural variable within interpenetrating polymer networks (IPNs) has not been systematically isolated. Here, we investigate the independent and coupled effects of alginate crosslink density and poloxamer architecture on mechanical stiffness and drug uptake in poloxamer/alginate composite hydrogels. A full 2⁴ factorial design was implemented varying poloxamer polyethylene oxide (PEO) fraction (70% vs 80%), alginate concentration (0.25-1.5% w/v), neomycin loading solution concentration (2-8% w/v), and exposure time (15-60 min). Elastic modulus and total released drug after loading were quantified, spanning nearly two orders of magnitude in stiffness (10.7-1926 Pa) and over one order of magnitude in drug release (0.27-4.09 mg). Statistical modeling revealed alginate concentration as the dominant determinant of stiffness, while loading solution concentration governed the magnitude of drug uptake/subsequent release. Modulation of PEO fraction produced mirrored secondary shifts in both responses, indicating that micellar architecture influences both mechanical resistance and network accessibility within the IPN. Response surface regression yielded predictive models for stiffness (R²(predicted) = 0.89) and drug uptake (R² (predicted) = 0.97), and CART® analysis confirmed the hierarchical separation of crosslink density-driven and micellar architecture-driven effects. These results resolve partially decoupled structural control domains within composite poloxamer/alginate networks and demonstrate that statistically rigorous experimental design enables quantitative mapping of mechanical and transport behavior in amphiphilic IPNs.

Purpose: Despite advances in oral and injectable HIV prevention options and oral prophylaxis for sexually transmitted infections (STIs) of bacterial origin, there remains a critical need for effective on-demand topical (vaginal/rectal) products for pre- and post-exposure prophylaxis (PrEP and PEP). To fill this gap, we have developed single and first-in-kind multi-active topical inserts for bacterial STIs and HIV/STIs prevention. Methods: We have formulated two different inserts, one containing doxycycline (DOX) at 10, 50, and 100mg doses for bacterial STI prevention, and a multipurpose prevention product (TED insert) that combines DOX (10mg) with the antiretrovirals tenofovir alafenamide (TAF; 20mg) and elvitegravir (EVG; 16mg) to target both bacterial STIs and HIV. Results: Inserts were manufactured through a simple, cost-effective process. Drug loading was within 95-105% of the labeled amount, confirming a robust manufacturing process. In vitro, they disintegrated within 10min with >95% drug release within 60min. The dissolution behavior of DOX inserts showed surface erosion but was affected by medium volume and drug amount. The inserts met key physicochemical targets: hardness (5-8kg), friability (<1%), moisture content (<2%), and osmolality (2years. Preliminary 1-month stability of TED inserts under accelerated conditions showed preservation of their physicochemical properties. Conclusion: This study represents the first formulation development report on topical inserts containing DOX alone or in combination with antiretrovirals. Both inserts offer a novel, on-demand topical STI prevention option that supports flexible PrEP/PEP use by both women and men.

Objective The development of protein formulations is grappled by the complexity of maintaining protein integrity during the arduous formulation process. While several excipients have been employed for the stabilization of proteins, including the recombinant human growth hormone (rhGH), a precise process control is still paramount. This study aims to investigate the effect of mannitol polymorphism on the structural stability of rhGH in its spray-dried formulations. Methods rhGH was co-spray dried with mannitol at protein:mannitol ratios (1:0.5 to 1:6, w/w). Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) characterized mannitol crystallinity. Furthermore, circular dichroism (CD) spectroscopy measured secondary structure pre- and post-accelerated storage (40°C/75% RH, 4 weeks), and SDS-PAGE was leveraged to evaluate protein aggregation. Results Spray-dried powders exhibited spherical particles (1–5 µm) with surface indentations. PXRD reported high levels of mannitol crystallization with ratios of 1:0.5, 1:1.5, and 1:6, which was corroborated by the change in crystallization index using DSC. Parallelly, it corresponded to reductions in α-helix content ranging from 21.8 to 25%, after storage. In contrast, the 1:4 ratio predominantly demonstrated an 8.4% increase in α-helix content, indicating enhanced stability. SDS-PAGE confirmed greater aggregation in samples with higher mannitol crystallization, whereas the 1:4 formulation minimized aggregation. Conclusion Mannitol crystallization strongly influences rhGH stability in spray-dried powders. An optimal protein:mannitol ratio of 1:4 helped maintain mannitol in the amorphous state, preserved secondary structure, and reduced aggregation during storage. These findings underscore excipient crystallization as a key determinant of protein stability and identify a stabilizing composition for spray-dried rhGH.