17-α Hydroxyprogesterone Nanoemulsifying Preconcentrate-Loaded Vaginal Tablet: A Novel Non-Invasive Approach for the Prevention of Preterm Birth

Abstract

Preterm birth (PTB) is a major cause of infant mortality in the United States and around the globe. Makena®—once-a-week intramuscular injection of 17-α Hydroxyprogesterone caproate (17P)—is the only FDA approved treatment for the prevention of PTB. Invasive delivery of 17P requires hospitalization and expert personnel for injection. Vaginal delivery of 17P would be preferable, because of high patient compliance, reduced systemic exposure, fewer side effects, and no need for hospitalization. The objective of the present study was to prepare and evaluate a self-nanoemulsifying vaginal tablet of 17P. A solid self-nanoemulsifying preconcentrate (S-SNEDDS) of 17P and dimethylacetamide (DMA) was developed using medium chain triglycerides, a non- immunogenic surfactant, and co-processed excipient (PVA-F100). The tablet prepared was characterized for emulsification time, particle size, solid state properties, and drug release. The formulation showed >50% inhibition of TNF-α release from LPS-stimulated RAW 264.7 cells. Importantly, there were significant differences in rates of PTB and average time to delivery between control and vaginal 17P-treated groups in LPS-stimulated timed pregnant E15.5 mice. Considering the lacuna of therapeutic approaches in this area, vaginal delivery of 17P for the prevention of preterm birth has significant clinical relevance.

Emulsion-Based Multicompartment Vaginal Drug Carriers: From Nanoemulsions to Nanoemulgels

“…For the preparation of vaginal microemulsions and SEDDS systems, fatty acid derivatives such as Captex ® 300 (ABITEC, Columbus, USA), Capryol ® 90 (Gattefossé, Saint-Priest, France), glycerol monolaurate and oleic acid have been used as the oil phase components [ 76 , 77 , 82 , 83 , 84 , 85 , 86 , 87 , 88 ]. These excipients exhibited high solubility of lipophilic compounds, e.g., clotrimazole or tetrahydrocurcumin and were also selected due to their additional properties, such as strong microemulsifying properties (Capryol ® 90, Gattefossé, Saint-Priest, France), anti-HIV activity (glycerol monolaurate) and low toxicity (Captex ® 300, ABITEC, Columbus, USA) [ 76 , 77 , 82 , 83 , 84 , 85 , 86 , 87 , 88 ]. Cetyl palmitate and other diesters and triesters of fatty acids, e.g., Labrasol ® (Gattefossé, Saint-Priest, France), triglycerides of medium-length fatty acids have also been proposed in the preparation of vaginal emulsions [ 76 , 79 , 82 , 83 , 84 , 85 , 86 , 89 , 90 , 91 , 92 ].…”

“…Optical microscopy is most frequently used for emulsions with droplet sizes in the micrometer range, i.e., macroemulsions, as it only allows the observation of particles larger than 200 nm [ 80 , 81 , 89 , 102 , 104 , 130 ]. The most commonly used method to determine the dispersed phase droplet size of micro- and nanoemulsion-based vaginal dosage forms is the dynamic light scattering (DLS) method, also known as photon correlation spectroscopy, that enables the measurement of droplet sizes in the range from 1 nm to 6 µm [ 74 , 75 , 76 , 77 , 78 , 79 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 98 , 99 , 103 , 105 ]. The accuracy of the obtained results depends on the measurement method and sample preparation, the sample dilution in particular [ 130 ].…”

“…II apparatus, however, the test formulation is placed in a dialysis bag or in a disc covered with a semipermeable membrane immersed below a paddle agitator in a vessel filled with acceptor medium. Citrate and phosphate buffer solutions or simulated vaginal discharge are used as the acceptor medium for pharmaceutical bioavailability studies, while sampling is performed in an automated manner at predefined time points [ 79 , 81 , 82 , 87 , 88 , 90 , 97 ]. As an alternative, the drug release/membrane penetration studies from EVDF can be performed using dialysis bags, tubes or chambers immersed in a vessel with mixed and thermostated acceptor medium, e.g., simulated vaginal discharge while samples are withdrawn at predefined time points [ 74 , 85 , 92 , 98 , 99 , 102 , 103 ].…”

Improved Pharmacodynamic Potential of Rosuvastatin by Self-Nanoemulsifying Drug Delivery System: An in vitro and in vivo Evaluation

“…A few reports based on these formulations have proven possible enhancement of BA of different drugs. [16][17][18][19][20] Nano-emulsions are emerging as very useful to improve performance of various biomedical systems based on drug delivery, food, cosmetics and pharmaceuticals because of their small size and useful properties such as high surface area per unit volume, robust dilution stability, optical transparency and tunable rheology. 21 Due to small droplet size, nano-emulsions possess stability against sedimentation or creaming with Ostwald ripening that is the main mechanism of nano-emulsion breakdown.…”

Design and optimization of candesartan loaded self-nanoemulsifying drug delivery system for improving its dissolution rate and pharmacodynamic potential

“…The excipients contained in the SNEDDS tend to facilitate bioavailability of the drugs not merely by improving drug solubility and permeability but by circumventing the metabolism by liver microsomes and inhibiting P-gp efflux, along with the ability to facilitate lymphatic drug absorption. Several literature studies on various self-emulsifying formulations have reported potential improvement in the bioavailability of various drugs (Kalantari et al, 2017;Alhasani et al, 2019;Patki et al, 2019;Alsk€ ar et al, 2018).…”