Rilpivirine Ionic Liquid Nanoemulsion Augments the Oral Bioavailability of Rilpivirine and Its Delivery to the HIV Sanctuary Sites.

Rilpivirine (RPV) is a potent antiretroviral drug used for the long-term management of HIV infection. The high crystallinity and very low aqueous solubility of RPV are responsible for the highly variable pharmacokinetics of RPV seen in HIV-infected patients. While fatty meals can increase the absorption of RPV, the low lipid solubility of RPV precludes the development of oral lipid-based formulations such as self-nanoemulsifying systems (SNES).

Sweetening the Deal: Sweetener-Based Ionic Liquid of Albendazole Significantly Enhances Its Solubility and Oral Bioavailability.

Albendazole (ABZ) is a hydrophobic and weakly basic anthelmintic benzimidazole with a very low (5%) oral bioavailability. Conversion of hydrophobic ionizable drugs such as ABZ into ionic liquids (ILs) or liquid salts is an emerging strategy for improving their solubility and oral bioavailability. To date, FDA-approved non-nutritive anionic sweeteners have not been evaluated for the development of ILs of weakly basic and hydrophobic drugs.

Development of phenyllactic acid ionic liquids and evaluation of cytotoxicity to human cervical epithelial cells.

Phenyllactic acid (PLA), is a naturally produced, broad-spectrum antimicrobial compound with activity against bacteria and fungi. PLA can be produced by a variety of lactic acid bacteria, including vaginal species, which are healthy constituents of the vaginal microbiome with a protective role against invading pathogenic bacteria and/or fungi. Additionally, PLA has been shown to exhibit anti-inflammatory and immunomodulatory properties, overall indicating its therapeutic potential as an intravaginally delivered compound for modulation of the vaginal microbiome.

Oral Self-Nanoemulsifying System Containing Ionic Liquid of BX795 Is Effective against Genital HSV-2 Infection in Mice.

BX795 is an emerging drug candidate that has shown a lot of promise as a next-generation non-nucleoside antiviral agent for the topical treatment of herpes simplex virus type-1 (HSV-1) and herpes simplex virus type-2 (HSV-2) infections. Our studies indicated that BX795 has limited oral bioavailability, which could be attributed to its low and pH-dependent solubility. Lipid-based formulations such as self-nanoemulsifying systems (SNESs) can improve the solubility and oral bioavailability of BX795, but the poor lipid solubility of BX795 further limits the development of SNES.

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.

Hypo-osmolar rectal douche tenofovir formulation prevents simian/human immunodeficiency virus acquisition in macaques.

In spite of the rollout of oral pre-exposure prophylaxis (PrEP), the rate of new HIV infections remains a major health crisis. In the United States, new infections occur predominantly in men having sex with men (MSM) in rural settings where access to PrEP can be limited. As an alternative congruent with MSM sexual behavior, we have optimized and tested tenofovir (TFV) and analog-based iso-osmolar and hypo-osmolar (HOsm) rectal douches for efficacy against rectal simian/human immunodeficiency virus (SHIV) infection of macaques.

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.

DJ4 Targets the Rho-Associated Protein Kinase Pathway and Attenuates Disease Progression in Preclinical Murine Models of Acute Myeloid Leukemia.

The poor prognosis of acute myeloid leukemia (AML) and the highly heterogenous nature of the disease motivates targeted gene therapeutic investigations. Rho-associated protein kinases (ROCKs) are crucial for various actin cytoskeletal changes, which have established malignant consequences in various cancers, yet are still not being successfully utilized clinically towards cancer treatment. This work establishes the therapeutic activity of ROCK inhibitor (5)-2-5-(1H-pyrrolo[2,3-]pyridine-3-ylmethylene)-1,3-thiazol-4(5H)-one (DJ4) in both in vitro and in vivo preclinical models of AML to highlight the potential of this class of inhibitors.

An ion-paired moxifloxacin nanosuspension eye drop provides improved prevention and treatment of ocular infection.

There are numerous barriers to achieving effective intraocular drug administration, including the mucus layer protecting the ocular surface. For this reason, antibiotic eye drops must be used multiple times per day to prevent and treat ocular infections. Frequent eye drop use is inconvenient for patients, and lack of adherence to prescribed dosing regimens limits treatment efficacy and contributes to antibiotic resistance.

Docusate-Based Ionic Liquids of Anthelmintic Benzimidazoles Show Improved Pharmaceutical Processability, Lipid Solubility, and Activity against .

As the existing therapeutic modalities for the treatment of cryptococcal meningitis (CM) have suboptimal efficacy, repurposing existing drugs for the treatment of CM is of great interest. The FDA-approved anthelmintic benzimidazoles, albendazole, mebendazole, and flubendazole, have demonstrated potent but variable activity against , the predominant fungal species responsible for CM. We performed molecular docking studies to ascertain the interaction of albendazole, mebendazole, and flubendazole with a β-tubulin structure, which revealed differential binding interactions and explained the different efficacies reported previously and observed in this investigation.

Ion-Complex Microcrystal Formulation Provides Sustained Delivery of a Multimodal Kinase Inhibitor from the Subconjunctival Space for Protection of Retinal Ganglion Cells.

Glaucoma is the leading cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) is one of the major risk factors for glaucoma onset and progression, and available pharmaceutical interventions are exclusively targeted at IOP lowering. However, degeneration of retinal ganglion cells (RGCs) may continue to progress despite extensive lowering of IOP.

Microemulsion-based gel for the transdermal delivery of rasagiline mesylate: In vitro and in vivo assessment for Parkinson's therapy.

Rasagiline mesylate (RSM) is a selective and irreversible monoamine oxidase B inhibitor used for the treatment of Parkinson's disease (PD). However, its unfavorable biopharmaceutical properties, such as extensive degradation in the gastrointestinal tract and first-pass metabolism are responsible for its low oral bioavailability and suboptimal therapeutic efficacy. Here, we report the feasibility of delivering RSM via the transdermal route using RSM containing microemulsion-based gel (RSM-MEG) to achieve effective management of PD.

Synthesis and Characterization of Lipophilic Salts of Metformin to Improve Its Repurposing for Cancer Therapy.

Epidemiological evidence has accentuated the repurposing of metformin hydrochloride for cancer treatment. However, the extreme hydrophilicity and poor permeability of metformin hydrochloride are responsible for its poor anticancer activity and . Here, we report the synthesis and characterization of several lipophilic metformin salts containing bulky anionic permeation enhancers such as caprate, laurate, oleate, cholate, and docusate as counterions.

Preclinical evaluation of a hypotonic docetaxel nanosuspension formulation for intravesical treatment of non-muscle-invasive bladder cancer.

Intravesical chemotherapy is a key approach for treating refractory non-muscle-invasive bladder cancer (NMIBC). However, the effectiveness of intravesical chemotherapy is limited by bladder tissue penetration and retention. Here, we describe the development of a docetaxel nanosuspension that, when paired with a low osmolality (hypotonic) vehicle, demonstrates increased uptake by the bladder urothelium with minimal systemic exposure.

Pharmaceutically Acceptable Carboxylic Acid-Terminated Polymers Show Activity and Selectivity against HSV-1 and HSV-2 and Synergy with Antiviral Drugs.

Polyanionic macromolecules including carboxylate-terminated polymers (polycarboxylates) are capable of inhibiting sexually transmitted viruses such as human immunodeficiency virus (HIV) and herpes simplex virus (HSV). Cellulose acetate phthalate (CAP), a pharmaceutically acceptable pH-sensitive polycarboxylate polymer, showed promising prophylactic activity against HIV and HSV, but the instability of CAP in an aqueous environment prevented its clinical development. Interestingly, several pharmaceutically acceptable polycarboxylates have features similar to CAP with an aqueous stability significantly higher than that of CAP.

Release Testing of Acyclovir Topical Formulations Using Immersion Cells.

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Fenugreek Leaf Extract and Its Gel Formulation Show Activity Against .

spp. are commensal yeasts that can cause cutaneous ailments such as dandruff and seborrheic dermatitis. We sought to develop a cost-effective, herbal formulation for the treatment of cutaneous ailments related to spp.

Development of Nanoemulsion Preconcentrate of Capsanthin with Improved Chemical Stability.

Capsanthin, like other carotenoids, exhibits poor aqueous solubility, poor stability, and low/variable oral bioavailability that limit its utility as a nutraceutical. In this study, we describe the development of anhydrous nanoemulsion preconcentrate of capsanthin, which upon dilution with water, spontaneously forms nanoemulsion resulting in improved solubility of capsanthin without compromising its chemical stability and antioxidant activity. We chose Food and Drug Administration-approved ingredients to develop capsanthin nanoemulsion preconcentrates.

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

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.

Mucus-penetrating budesonide nanosuspension enema for local treatment of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory gastrointestinal disorder that affects more than 1 million individuals in the USA. Local therapy with enema formulations, such as micronized budesonide (Entocort), is a common strategy for treating patients with distally active IBD. However, we hypothesize that micronized particulates are too large to effectively penetrate colorectal mucus, limiting the extent of drug delivery to affected tissues prior to clearance.

Local enema treatment to inhibit FOLH1/GCPII as a novel therapy for inflammatory bowel disease.

Here we evaluate the potential for local administration of a small molecule FOLH1/GCPII inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA) as a novel treatment for inflammatory bowel disease (IBD). We found that FOLH1/GCPII enzyme activity was increased in the colorectal tissues of mice with TNBS-induced colitis, and confirmed that 2-PMPA inhibited FOLH1/GCPII enzyme activity ex vivo. In order to maximize local enema delivery of 2-PMPA, we studied the effect of vehicle tonicity on the absorption of 2-PMPA in the colon.

Nanoparticles for oral delivery: Design, evaluation and state-of-the-art.

The oral route is a preferred method of drug administration, though achieving effective drug delivery and minimizing off-target side effects is often challenging. Formulation into nanoparticles can improve drug stability in the harsh gastrointestinal (GI) tract environment, providing opportunities for targeting specific sites in the GI tract, increasing drug solubility and bioavailability, and providing sustained release in the GI tract. However, the unique and diverse physiology throughout the GI tract, including wide variation in pH, mucus that varies in thickness and structure, numerous cell types, and various physiological functions are both a barrier to effective delivery and an opportunity for nanoparticle design.

Topical Tenofovir Disoproxil Fumarate Nanoparticles Prevent HIV-1 Vaginal Transmission in a Humanized Mouse Model.

Preexposure prophylaxis (PrEP) with 1% tenofovir (TFV) vaginal gel has failed in clinical trials. To improve TFV efficacy in vaginal gel, we formulated tenofovir disoproxil fumarate nanoparticles in a thermosensitive (TMS) gel (TDF-NP-TMS gel). TDF-NPs were fabricated using poly(lactic-co-glycolic acid) (PLGA) polymer and an ion-pairing agent by oil-in-water emulsification.