Vaginal Drug Delivery Research Articles

Research progress of hydrogels in the prevention of pelvic inflammatory disease

AbstractPelvic inflammatory disease (PID) is a critical global health concern with the potential to lead to adverse outcomes, including infertility and chronic pelvic pain. Since PID is often caused by ascending vaginal infections or urinary tract infections, understanding the treatment of both is critical to preventing PID. Meanwhile, the emergence of drug‐resistant and persistently infected strains poses a growing challenge. This review discusses current clinical treatments for the prevention of PID from the physiologic basis of PID, as well as summarizes the advantages and research progress of hydrogels in the prevention of PID. In contrast to conventional treatments, hydrogels serve as excellent vehicles for vaginal drug delivery, maintaining the presence of the drug at the target site and controlling its release. In the context of urinary tract infections (UTIs), hydrogels are employed primarily as coatings on catheters to prevent and treat catheter‐associated UTIs. Finally, this review summarizes the limitations of hydrogels in PID prevention and future directions for development with the aim of elucidating avenues for clinical treatment of PID and informing further research.

Formulation Development of Mucoadhesive Vaginal Gel of Secnidazole and Voriconazole.

Purpose: Over the preceding decades, developing conventional drug delivery in to modified form has acquired importance in the pharmaceutical industry. Vaginal drug delivery system offers localized drug administration of drug and also avoids unwanted side effects of oral drug delivery. Vaginal drug delivery system has significant role in medical practice. Even though VDDS has a lot of advantages over the other routes of administration. The goal of developing the Mucoadhesive Vaginal Gel was to achieve the synergistic effect of voriconazole and secnidazole in the treatment of bacterial and fungal vaginal infections. Method: Mucoadhesive antimicrobial vaginal gel was optimised using Design expert software using Carbopol 934, HPMC K4M polymers. Result: Formulation was evaluated for various rheological parameters ,antimicrobial activity, invitro drug release and stability study. The spreadability and pH was found to be 5.5 to 7.4 cm and 4.12. Its compatible with vaginal pH. The selected optimized F8 formulation is the best formulation and the drug ratio is 2:1. and optimum gel viscosity is 1874 cps. antimicrobial study revealed that faster drug release of test formulation was compared to marketed product. It indicates as inhibition zone. Conclusion: The combination of drugs can serves as better option for treating vaginitis, compared to single drug formulation. Mucoadesion increases contact time of drug with affected area which rendered formulation more effective.

Enhanced viability of Lactobacillus spp. via encapsulation in hyaluronan/PVA hybrid electrospun composites for vaginal drug delivery

BackgroundVaginal dysbiosis, a change in the beneficial vaginal microbiome, leads to a significant depletion in the essential lactobacilli thus increasing the possibility of vaginal infections such as bacterial vaginosis. Probiotics have gained more attention as a means of delivering exogenous lactobacilli but one of the challenges in delivery strategies is maintaining and improving their viability. The objective of this study is to enhance the viability of Lactobacillus spp., via encapsulation in hyaluronic acid/polyvinyl alcohol hybrid electrospun nanofibers. Polyvinyl alcohol (PVA) and hyaluronic acid (HA) composite nanofibers integrated with Lactobacillus spp. were fabricated by electrospinning. The survival of Lactobacillus spp. after its immobilization in electrospun nanofibers with polyvinyl alcohol and hyaluronic acid was evaluated.ResultsScanning electron microscopy indicated larger average diameters in PVA/HA nanofibers with Lactobacillus spp. encapsulation (0.189 ± 0.041 µm to 0.231 ± 0.061 µm between D3 and D4, and 0.177 ± 0.043 µm to 0.212 ± 0.041 µm between D5 and D6) which showed that the nanofibers had the bacterial cells successfully enclosed in them. The viability of the lactic acid bacteria enclosed in the PVA/HA nanofibers was observed to decrease by more than 2-log units.ConclusionThe electrospun nanofiber-based delivery system is promising for the encapsulation and delivery of lactic acid bacteria to the vagina to combat recurrent vaginal infections such as bacterial vaginosis.

Next-Generation Contraceptive Intravaginal Ring: Comparison of Etonogestrel and Ethinyl Estradiol In Vitro and In Vivo Release from 3D-Printed Intravaginal Ring and NuvaRing.

Intravaginal rings (IVRs) represent a well-established, woman-controlled and sustained vaginal drug delivery system suitable for a wide range of applications. Here, we sought to investigate the differences in etonogestrel (ENG) and ethinyl estradiol (EE) release from a 3D-printed IVR utilizing continuous liquid interface production (CLIP™) (referred to as CLIPLOW for low drug loading and CLIPHIGH IVRs for high drug loading) and NuvaRing, a commercially available injection molded IVR. We conducted in vitro release studies in simulated vaginal fluid to compare the release of ENG and EE from CLIPLOW IVRs and NuvaRing. CLIPLOW IVRs had a similar hormone dose to NuvaRing and exhibited slightly slower ENG release and greater EE release in vitro compared to NuvaRing. When administered to female sheep, NuvaRing demonstrated greater ENG/EE levels in plasma, vaginal tissue and vaginal fluids compared to CLIPLOW IVR despite similar drug loadings. Leveraging observed hormones levels in sheep from NuvaRing as an effective contraceptive benchmark, we developed a long-acting CLIPHIGH IVR with increased ENG and EE doses that demonstrated systemic and local hormone levels greater than the NuvaRing for 90 days in sheep. No signs of toxicity were noted regarding general health, colposcopy, or histological analysis in sheep after CLIPHIGH IVR administration. Our results provided (1) a comparison of ENG and EE release between a 3D-printed IVR and NuvaRing in vitro and in vivo, (2) a preclinical pharmacokinetic benchmark for vaginally delivered ENG and EE and (3) the generation of a 90-day CLIP IVR that will be utilized in future work to support the development of a long-acting ENG/EE IVR combined with an antiretroviral for the prevention of HIV and unplanned pregnancy.

Imiquimod-Loaded Nanosystem for Treatment Human Papillomavirus-Induced Lesions.

Human papillomavirus (HPV)-associated cervical cancer is the most common cancer among women worldwide. The treatment options are strongly related to increased infertility in women. Imiquimod (IQ) is an imidazoquinoline, which has proven antiviral effects against persistent HPV infection by activating immune cells via Toll-like receptors 7/8 when formulated in carriers, like nanogels, for topical use. An effective alternative to conventional therapies is the nanoparticle drug delivery system. We studied lipidic nanoparticles with IQ (Lipo IQ) and functionalized them with a DNA aptamer, AT11 (Lipo IQ AT11), to improve the selectivity for cervical cancer cells combined with the efficacy of essential oils. The formulations showed that the physicochemical properties are adequate for vaginal drug delivery and have antimicrobial activity at higher concentrations (with MIC50 starting from 0.625%). The final formulations exhibited cytotoxicity in cancer cells, enhanced by essential oils without affecting healthy cells, resulting in less than 10% cell viability in HeLa cells and over 60% in NHDF cells. Essential oils potentiate Lipo IQ's effectiveness, while AT11 increases the selectivity for cervical cancer cells. As suggested by the results of the permeation assay, the formulations were internalized by the cancer cells. Overall, the obtained results suggested that the synergistic effect of the essential oils and the nanosystem potentiate the cytotoxic effect of Lipo IQ and that Lipo IQ AT11 promotes selectivity towards cancer cells.

3D-printed short nanofibers/hydrogel-based vaginal films as a novel system for the delivery of anti-HIV microbicide drugs

Acquired immunodeficiency syndrome (AIDS) is a global epidemic that affects the lives of millions of young women, particularly those who live in poverty-stricken regions and engage in unsafe sexual behaviors, forcing the development of unique pre-exposure anti-HIV prophylaxis tools. Using a combination of antiretroviral medications with various antiviral mechanisms significantly improves the prognosis for HIV patients. The integration of 3D printing technology, short nanofiber technology, and hydrogel into a single system known as “3D-printed nanocomposites” is an emerging approach that is gaining traction in tissue engineering, regenerative medicine, and biomedical applications. Based on these foundations, the current study aims to develop, for the first time, a 3D-printed short nanofiber/film for the vaginal delivery of ritonavir and efavirenz in a fixed-dose combination. To identify an optimal 3D-printable short nanofibers/hydrogel formulation, multiple formulations, and fragmentation methods were investigated. Following that, the generated vaginal films were evaluated using several physicochemical characterizations, mechanical properties measurements, and in vitro release studies. The findings revealed that only cryocutting is effective for polycaprolactone nanofiber fragmentation. The 3D-printed short nanofibers-loaded films had an ultimate tensile strength of 6.75 ± 1.27 MPa and elongation at break of 262.67 ± 44.32 MPa, suggesting their reliability for handling and vaginal application. Furthermore, the in vitro release study demonstrated that rapid EFZ release occurred during the first 45 min, whereas RIT release lasted more than 72 h, indicating that the complex drug release profile was met. In summary, the study emphasizes that 3D printing of short nanofiber-based films is likely to be an effective platform for localized vaginal drug delivery, particularly anti-HIV therapies.

Effect of Intravaginal Application of Palasha Udumbaradi Ointment on Pelvic Organ Prolapse

Prolapse is a downward descent of the female pelvic organs as a result of weakness of the structures that normally retain them in position. The main symptoms of pelvic organ prolapse include micturition disturbances like stress incontinence, imperfect control of micturition, a feeling of lump coming down, postural low back ache, constipation and leucorrhoea. The management of pelvic organ prolapse includes preventive conservative and surgical measures. Surgery is indicated when conservative management fails. The three different conditions like Phalini, Prasramsini and Mahayoni vyapath mentioned by different Acharyas explain the prolapsed condition according to the stage and part prolapsed out. Palasha udumbaradi yoga mentioned in Bhaishajya Ratnavali containing ingredients such as Palasha beeja, Udumbara phala, Thilathaila and Madhu was taken for this study. The Lepa was applied in the modified form of an ointment. The study is an attempt to assess the effect of Palasha udumbaradi ointment on uterine prolapse. The ointment was applied intra vaginally. The presence of dense blood vasculature makes the vagina a potential site for local and systemic drug administration. The key advantages of vaginal drug delivery over oral administration is that this is able to circumvent the harsh gastric environment and also bypass hepatic first-pass metabolism. A 38 year woman with complaints of increased frequency of micturition, stress incontinence, burning micturition, low back ache and dyspareunia consulted the OPD of Govt. Ayurveda Medical College, Tripunithura. Palasha udumbaradi ointment was self-applied intra-vaginally. Administration of ointment was advised for 60 consecutive days excluding the days of menstruation with follow up on 90th day. Assessment was done on 0th, 30th and 60th day and follow up was done on 90th day using POP-Q Scale, urinary incontinence scale, and visual analogue scale.

Molecular stratification of the human fetal vaginal epithelium by spatial transcriptome analysis.

The human vaginal epithelium is a crucial component of numerous reproductive processes and serves as a vital protective barrier against pathogenic invasion. Despite its significance, a comprehensive exploration of its molecular profiles, including molecular expression and distribution across its multiple layers, has not been performed. In this study, we perform a spatial transcriptomic analysis within the vaginal wall of human fetuses to fill this knowledge gap. We successfully categorize the vaginal epithelium into four distinct zones based on transcriptomic profiles and anatomical features. This approach reveals unique transcriptomic signatures within these regions, allowing us to identify differentially expressed genes and uncover novel markers for distinct regions of the vaginal epithelium. Additionally, our findings highlight the varied expressions of keratin ( KRT) genes across different zones of the vaginal epithelium, with a gradual shift in expression patterns observed from the basal layer to the surface/superficial layer. This suggests a potential differentiation trajectory of the human vaginal epithelium, shedding light on the dynamic nature of this tissue. Furthermore, abundant biological processes are found to be enriched in the basal zone by KEGG pathway analysis, indicating an active state of the basal zone cells. Subsequently, the expressions of latent stem cell markers in the basal zone are identified. In summary, our research provides a crucial understanding of human vaginal epithelial cells and the complex mechanisms of the vaginal mucosa, with potential applications in vaginal reconstruction and drug delivery, making this atlas a valuable tool for future research in women's health and reproductive medicine.

A Review on Suppositories and Application of Vaginal Drug Delivery System

Historically, medications that caused unconsciousness, haemorrhoidal, germicidal, and purgative effects were administered the rectal route as suppository injections. The majority of medicinal drugs on the market today are designed to be administered rectal in order to increase their bioavailability and achieve the necessary therapeutic blood concentration. Historically, only locally acting medications, such as steroids, prostaglandins, spermicidal, antifungal, antibacterial, and antiviral, were allowed during vaginal birth. The capacity to avoid first-pass hepatic processing, accessibility, a healthy blood supply, and permeability to big molecular weight medications, such as peptides and proteins, are the main benefits of this route. Vaginal medicine delivery devices that are frequently utilised include suppositories, creams, gels, pills, and vaginal rings. This message is intended to give the reader an overview of the developments in the area of vaginal medication delivery.

An Overview on Stimuli Sensitive Drug Delivery System

Stimuli-sensitive systems are a state of reactivity to sensory stimulation or excitability. These systems respond to changes in the body’s physiology due to environmental factors such as temperature, enzymes, glucose, magnetic fields, redox reactions, ions, and more. They are particularly useful for the controlled and sustained delivery of drugs in the body. Controlled drug delivery has become a standard criterion in modern pharmaceutical product design, with ongoing intensive research aimed at achieving a superior drug product characterized by effectiveness, reliability, and safety. These stimuli-sensitive systems are employed in various forms for different purposes, including parenteral, ocular, peroral, rectal, vaginal, nasal, dermal, and transdermal drug delivery. This study focuses on the latest advancements in stimuli-sensitive drug delivery systems, aiming to address the limitations of traditional therapeutic methods. The goal is to achieve targeted drug release in specific areas using various endogenous and exogenous stimuli. This allows for personalized and patient-centric treatment strategies. The development of stimuli-sensitive drug delivery systems remains a significant human endeavor for successful drug delivery, given the various shortcomings of existing conventional systems. To overcome these limitations, various stimuli-sensitive drug delivery systems (DDSs) have been developed in recent years

Hydrogel- and Nanocomposite-Based Drug-Delivery Strategies in the Treatment of Vaginal Infections.

The reproductive health of women is governed by an optimal balance in the host-microbiota interaction. Depletion of the beneficial vaginal microflora caused by depletion of Lactobacillus species and increased proliferation of pathogens results in gynaecological infections. Among women of reproductive age, vaginal infections are increasingly prevalent. Attaining therapeutic efficacy using conventional formulations remains a challenge as vaginal fluids quickly remove or dilute the therapeutic formulations. Hydrogels have been widely exploited for targeted delivery of therapeutics directly into the vaginal mucus. With a careful choice of polymers (natural, synthetic, or semisynthetic), hydrogels with specific properties, such as stimuli responsiveness, antimicrobial, and muco-adhesiveness, can be tailored for higher therapeutic efficacy. In this review, the advances in hydrogel strategies for the treatment of vaginal infections are presented with emphasis on the types and properties that play a significant role in vaginal drug delivery systems.

Protein Coronas Derived from Mucus Act as Both Spear and Shield to Regulate Transferrin Functionalized Nanoparticle Transcellular Transport in Enterocytes.

The epithelial mucosa is a key biological barrier faced by gastrointestinal, intraoral, intranasal, ocular, and vaginal drug delivery. Ligand-modified nanoparticles demonstrate excellent ability on this process, but their efficacy is diminished by the formation of protein coronas (PCs) when they interact with biological matrices. PCs are broadly implicated in affecting the fate of NPs in vivo and in vitro, yet few studies have investigated PCs formed during interactions of NPs with the epithelial mucosa, especially mucus. In this study, we constructed transferrin modified NPs (Tf-NPs) as a model and explored the mechanisms and effects that epithelial mucosa had on PCs formation and the subsequent impact on the transcellular transport of Tf-NPs. In mucus-secreting cells, Tf-NPs adsorbed more proteins from the mucus layers, which masked, displaced, and dampened the active targeting effects of Tf-NPs, thereby weakening endocytosis and transcellular transport efficiencies. In mucus-free cells, Tf-NPs adsorbed more proteins during intracellular trafficking, which enhanced transcytosis related functions. Inspired by soft coronas and artificial biomimetic membranes, we used mucin as an "active PC" to precoat Tf-NPs (M@Tf-NPs), which limited the negative impacts of "passive PCs" formed during interface with the epithelial mucosa and improved favorable routes of endocytosis. M@Tf-NPs adsorbed more proteins associated with endoplasmic reticulum-Golgi functions, prompting enhanced intracellular transport and exocytosis. In summary, mucus shielded against the absorption of Tf-NPs, but also could be employed as a spear to break through the epithelial mucosa barrier. These findings offer a theoretical foundation and design platform to enhance the efficiency of oral-administered nanomedicines.

The Know-how of Polymeric Nanocarrier Based Vaginal Drug Delivery System: Pitfalls, Challenges and Trends.

Gynecological health is a global concern, and thus, the formulator researcher strives to improve the quality of life through innovative feminine pharmaceutical formulations. Vaginal delivery appears to be one of the vital strategies for local and systemic action of the therapeutically active agent. The rich vascular network, mucosal permeability, bypass of hepatic first-pass effect, and low enzymatic activity are the exclusive advantages of the vaginal route. But certain hindrances truncate the vaginal route, such as physiological factors including lower pH, self-cleansing mucus with constant secretion, and varying thickness of mucus layer due to menstrual cycle and microbiota. Significance of Review: This present review envisages the advances in the polymeric nanocarriers in the delivery to the vaginal route. Polymeric (mucoadhesive and PEGylated, etc.) nanocarriers have been recently utilized for drug delivery purposes. The modernized analysis of the updated advancements in the polymeric nanocarrier-based vaginal drug delivery system with the budding development is compiled in the present review. The literature search reveals that the novel polymeric nanocarrier design strategies currently being proposed to perk up the delivery of customary drugs through the vaginal route prove effective. Polymeric nanocarrier for vaginal delivery has provided better therapeutic efficacy due to higher drug residence, improved permeation, and sustained release of the active therapeutic agent. The polymeric nanocarriers can deliver different proteins, peptides, nuclear materials, hormones, etc., vaginally that are difficult for administration.

Ex Vivo and In Vivo Retention Time Evaluation of Fucoidan Isolated from Macrocystis pyrifera Through a Thermosensitive Gel System in The Vaginal Route

This study evaluated Fucoidan from Macrocystis pyrifera as a potential treatment for cervical cancer. The research aimed to examine Fucoidan’s in vivo retention capacities in poloxamer-based in situ gels for vaginal drug delivery systems. Five different thermosensitive gel formulations were developed, each with varying concentrations of Pluronic F127 and F68 polymers. The incorporation of HPMC affected the gelation temperature, viscosity, and bioadhesive strength. The accepted formula, F3, had a bioadhesive value of 5415.93 ± 98.74 dyne/cm2 and could form a gel at physiological temperature. Ex vivo animal models showed that Fucoidan components retained well on vaginal tissue. Only F1, F2, and F3 achieved the media after 8 hours of examination. In vivo evaluation showed F3 had the highest drug concentration retained in the vaginal mucosa of female rats after 8 hours (24,115 ± 4,842 g), slowly removed after 24 hours (13,014 ± 5,596 g). In conclusion, increases in the hydrophilic content of formulations led to the retained hydrogel formula, which increased drug release and lowered intravaginal elimination.

Investigation of Luliconazole-Loaded Mucoadhesive Electrospun Nanofibers for Anticandidal Activity in the Management of Vaginal Candidiasis.

In this study, we fabricated and evaluated luliconazole-loaded electrospun nanofibers for anticandidal activity in the management of vaginal candidiasis. Polycaprolactone (PCL)/gelatin nanofibers were designed by the electrospinning technique, and the Box-Behnken design (BBD) was adopted for optimization to get tailored fibers. The luliconazole (LCZ) drug was mixed into different concentrations (2.5, 5, 7.5, and 10%) of tea tree oil (TT oil) and loaded into the PCL/gelatin nanofibrous mats. The effective anticandidal potential of nanofiber samples were analyzed by the disk-diffusion method. Scanning electron microscopy (SEM), Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), XRD analysis, and in silico study were performed. The entrapment efficiency, swelling degree, mechanical strength, contact angle, mucoadhesion, drug release, and permeation study were assessed. The average diameter of the PCL/gelatin-optimized nanofiber was 153 nm. SEM reflected that the fabricated nanofibers were uniform and bead-free. FTIR and DSC analyzed the interaction and physical entrapment of the drug in the polymeric fibers. The entrapment efficiency of the drug-loaded nanofiber was found to be 89.2 ± 0.8%. Maximum swelling percentages at 4 h were 40.8, 18.9, and 14.0% and contact angles were 46.5°, 62.95°, and 65.78° for the blank, TT oil-loaded, and drug-loaded nanofiber, respectively, which indicated the hydrophilic nature of the fibers. The drug-loaded nanofiber had a high tensile strength with satisfactory mucoadhesive property that led to its adhesion to the vaginal mucosa with no tear. The drug-loaded nanofiber had a cumulative drug release of 67.7 ± 3.4% in 48 h, and the 12.8 ± 0.53 mm of zone of inhibition (ZOI) in 48 h illustrated an effective anticandidal activity. The TT oil-loaded nanofiber also exhibited a small ZOI of 4.3 ± 0.30 mm, indicating a synergistic effect to the antifungal activity of the drug-loaded nanofiber. LCZ-loaded nanofibers can emerge as a novel approach for vaginal drug delivery in the treatment of candida infection. Thus, this pharmaceutical investigation can help in formulating preclinical and clinical models.

Imiquimod-Loaded Chitosan-Decorated Di-Block and Tri-Block Polymeric Nanoparticles Loaded In Situ Gel for the Management of Cervical Cancer.

Cervical intraepithelial neoplasia, the predisposing factor for cervical cancer (CC), is caused by human papillomavirus (HPV) infection and can be treated with imiquimod (IMQ). However, poor water solubility and side effects such as local inflammation can render IMQ ineffective. The aim of this study is to design a prolonged release nano system in combination with mucoadhesive-thermosensitive properties for an effective vaginal drug delivery. Polylactic-co-glycolic acid (PLGA), polycaprolactone (PCL), poly lactide-co-caprolactone (PLA-PCL), and poly L-lactide-co-caprolactone-co-glycolide (PLGA-PCL) were used to create IMQ nanoparticles. Chitosan (CS) was then added to the surfaces of the IMQ NPs for its mucoadhesive properties. The NPs were then incorporated into poloxamer hydrogels. The NPs' size and morphology, encapsulation efficiency (EE), in vitro drug release, gel characterization, ex vivo drug permeation, and in vitro safety and efficacy were characterized. Two batches of NPs were prepared, IMQ NPs and CS-coated NPs (CS-IMQ NPs). In general, both types of NPs were uniformly spherical in shape with average particle sizes of 237.3 ± 4.7 and 278.2 ± 5.4 nm and EE% of 61.48 ± 5.19% and 37.73 ± 2.88 for IMQ NPs and CS-IMQ NPs, respectively. Both systems showed prolonged drug release of about 80 and 70% for IMQ NPs and CS-IMQ NPs, respectively, within 48 h. The gelation temperatures for the IMQ NPs and CS-IMQ NPs were 30 and 32 °C, respectively; thus, suitable for vaginal application. Although ex vivo permeability showed that CS-IMQ NPs showed superior penetration compared to IMQ NPs, both systems enhanced drug penetration (283 and 462 µg/cm2 for IMQ NPs and CS-IMQ NPs, respectively) relative to the control (60 µg/cm2). Both systems reduced the viability of cervical cancer cells, with a minimal effect of the normal vaginal epithelium. However, IMQ NPs exhibited a more pronounced cytotoxic effect. Both systems were able to reduce the production of inflammatory cytokines by at least 25% in comparison to free IMQ. IMQ and CS-IMQ NP in situ gels enhanced stability and drug release, and improved IMQ penetration through the vaginal tissues. Additionally, the new systems were able to increase the cytotoxic effect of IMQ against CC cells with a reduction in inflammatory responses. Thus, we believe that these systems could be a good alternative to commercial IMQ systems for the management of CC.

Mucoadhesive 3D printed vaginal ovules to treat endometriosis and fibrotic uterine diseases

Gynaecological health is a neglected field of research that includes conditions such as endometriosis, uterine fibroids, infertility, viral and bacterial infections, and cancers. There is a clinical need to develop dosage forms for gynecological diseases that increase efficacy and reduce side effects and explore new materials with properties tailored to the vaginal mucosa and milieu. Here, we developed a 3D printed semisolid vaginal ovule containing pirfenidone, a repurposed drug candidate for endometriosis. Vaginal drug delivery allows direct targeting of the reproductive organs via the first uterine pass effect, but vaginal dosage forms can be challenging to self-administer and retain in situ for periods of more than 1–3 h. We show that a semisoft alginate-based vaginal suppository manufactured using semisolid extrusion additive manufacturing is superior to vaginal ovules made using standard excipients. The 3D-printed ovule showed a controlled release profile of pirfenidone in vitro in standard and biorelevant release tests, as well as better mucoadhesive properties ex vivo. An exposure time of 24 h of pirfenidone to a monolayer culture of an endometriotic epithelial cell line, 12Z, is necessary to reduce the cells’ metabolic activity, which demonstrates the need for a sustained release formulation of pirfenidone. 3D printing allowed us to formulate mucoadhesive polymers into a semisolid ovule with controlled release of pirfenidone. This work enables further preclinical and clinical studies into vaginally administered pirfenidone to assess its efficacy as a repurposed endometriosis treatment.

Development of probiotic loaded multilayer microcapsules incorporated into dissolving microneedles for potential improvement treatment of vulvovaginal candidiasis: A proof of concept study

Vulvovaginal candidiasis (VVC) is a vaginal infection caused by abnormal growth of Candida sp., especially Candida albicans, in the vaginal mucosa. A shift in vaginal microbiota is prominent in VVC. The presence of Lactobacillus plays a vital role in maintaining vaginal health. However, several studies have reported resistance of Candida sp. against azoles drugs, which is recommended as VVC treatment. The use of L. plantarum as a probiotic would be an alternative to treat VVC. In order to exert their therapeutic activity, the probiotics needed to remain viable. Multilayer double emulsion was formulated to obtain L. plantarum loaded microcapsules (MCs), thus improving its viability. Furthermore, a vaginal drug delivery system using dissolving microneedles (DMNs) for VVC treatment was developed for the first time. These DMNs showed sufficient mechanical and insertion properties, dissolved rapidly upon insertion, facilitating probiotic release. All formulations proved non-irritating, non-toxic, and safe to apply on the vaginal mucosa. Essentially, the DMNs could inhibit the growth of Candida albicans up to 3-fold than hydrogel and patch dosage forms in ex vivo infection model. Therefore, this study successfully developed the formulation of L. plantarum-loaded MCs with multilayer double emulsion and its combination in DMNs for vaginal delivery to treat VVC.

Nanoemulsion Loaded with Clotrimazole Based on Rapeseed Oil for Potential Vaginal Application-Development, Initial Assessment, and Pilot Release Studies.

Vaginal candidiasis (VC) is an emerging global hardly treated health issue affecting millions of women worldwide. In this study, the nanoemulsion consisting of clotrimazole (CLT), rapeseed oil, Pluronic F-68, Span 80, PEG 200, and lactic acid was prepared using high-speed and high-pressure homogenization. Yielded formulations were characterized by an average droplet size of 52-56 nm, homogenous size distribution by volume, and a polydispersity index (PDI) < 0.2. The osmolality of nanoemulsions (NEs) fulfilled the recommendations of the WHO advisory note. NEs were stable throughout 28 weeks of storage. The stationary and dynamic (USP apparatus IV) pilot study of the changes of free CLT over time for NEs, as well as market cream and CLT suspension as references, were conducted. Test results of the changes in the amount of free CLT released from the encapsulated form were not coherent; in the stationary method, NEs yielded up to 27% of the released CLT dose within 5 h, while in the USP apparatus IV method, NEs released up to 10% of the CLT dose. NEs are promising carriers for vaginal drug delivery in the treatment of VC; however, further development of the final dosage form and harmonized release or dissolution testing protocols are needed.

Cervicovaginal mucus barrier properties during pregnancy are impacted by the vaginal microbiome.

Mucus in the female reproductive tract acts as a barrier that traps and eliminates pathogens and foreign particles via steric and adhesive interactions. During pregnancy, mucus protects the uterine environment from ascension of pathogens and bacteria from the vagina into the uterus, a potential contributor to intrauterine inflammation and preterm birth. As recent work has demonstrated the benefit of vaginal drug delivery in treating women's health indications, we sought to define the barrier properties of human cervicovaginal mucus (CVM) during pregnancy to inform the design of vaginally delivered therapeutics during pregnancy. CVM samples were self-collected by pregnant participants over the course of pregnancy, and barrier properties were quantified using multiple particle tracking. 16S rRNA gene sequencing was performed to analyze the composition of the vaginal microbiome. Participant demographics differed between term delivery and preterm delivery cohorts, with Black or African American participants being significantly more likely to delivery prematurely. We observed that vaginal microbiota is most predictive of CVM barrier properties and of timing of parturition. Lactobacillus crispatus dominated CVM samples showed increased barrier properties compared to polymicrobial CVM samples. This work informs our understanding of how infections occur during pregnancy, and directs the engineering of targeted drug treatments for indications during pregnancy.