Intravaginal Drug Delivery Research Articles

Bacteria-responsive drug release platform for the local treatment of bacterial vaginosis

Bacterial vaginosis (BV) is a common vaginal infection affecting millions of women. Vaginal anaerobic dysbiosis occurs whenLactobacillusspp., the dominant flora in healthy vagina is replaced by certain overgrown anaerobes, resulting in unpleasant symptoms such as vaginal discharge and odor. With a high recurrence rate, BV also severely impacts the overall quality of life of childbearing women by inducing preterm delivery and increasing the risks of pelvic inflammatory disease and sexually transmitted infections. Among various BV-associated bacteria,Gardnerella vaginalis(G. vaginalis) has been identified as a primary pathogen since it has been isolated from almost all women carrying BV and exhibits higher virulence potential over other bacteria. When dealing with BV relapse, intravaginal drug delivery systems are superior to conventional oral antibiotic therapies in improving therapeutic efficacy owing to more effective drug dose, reduced drug resistance and minimized side effects such as stomach irritation. Traditional intravaginal drug administration generally involves solids, semi-solids and delivery devices inserted into the vaginal lumen to achieve sustained drug release. However, they are mostly designed for continuous drug release and are not preventative therapies, resulting in severe side effects caused by excess dosing. Stimuli-responsive systems that can release drug only when needed ('on-demand') can help diminish these negative side effects. Hence, we developed a bacteria-responsive liposomal platform for the prevention and treatment of BV. This platform demonstrated sustained drug release in the presence of vaginolysin, a toxin secreted specifically byG. vaginalis. We prepared four liposome formulations and evaluated their responsiveness toG. vaginalis. The results demonstrated that the liposome formulations could achieve cumulative drug release ranging from 46.7% to 51.8% over a 3-5 d period in response toG. vaginalisand hardly any drug release in the presence ofLactobacillus crispatus(L. crispatus), indicating the high specificity of the system. Overall, the bacteria-responsive drug release platform has great potential, since it will be the first time to realize sustained drug release stimulated by a specific pathogen for BV prevention and treatment. This on-demand therapy can potentially provide relief to the millions of women affected by BV.

Incorporation of efavirenz inclusion complex In Dissolvable Microneedle for enhanced effectiveness of intravaginal drug delivery: A proof of concept study

Efavirenz (EFV) is one of the first line treatments of HIV infection. EFV is one of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that can inhibit the responsible of reverse transcriptase enzyme for HIV replication. In oral administration, EFV exhibits low bioavailability (30–56 %) problem owing to its poor solubility (0.9 μg/mL). In this research, the poor solubility was overcome by formulating EFV as a complex inclusion (IC)with β-cyclodextrin (β-CD). Furthermore, considering the benefits of vaginal delivery, IC was further incorporated into dissolving microneedle systems (DMN) using polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP) as biocompatible and biodegradable polymes. The results showed that EFV successfully formed IC by the change of the molecular shape with β-CD polymer, confirmed by FTIR and XRD. Importantly, the results showed that the formulation did not cause lysis and irritation on erythrocytes and blood vessels, showing the safety of this approach. Following its incorporation into DMN, IC-DMN could permeate the skin ex vivo as 78.70 ± 14.22 μg/cm3, which was about 3-times higher compared to DMN containing pure EFV and patch control. The in vivo pharmacokinetic study showed that the maximum plasma concentration of IC-DMN was 13.74 ± 2.48 μg/cm3, EFV-oral 6.27 ± 1,13 μg/cm3, vaginal gel 14.83 ± 3.65 μg/cm3. AUC values for each treatment was 147.33 ± 26.62 h μg/mL, 22.33 ± 4.03 h μg/mL, 63.33 ± 11.44 h μg/mL, respectively, indicating that the purpose of this study which was to increase the bioavailability of EFV was succefully achieved. Therefore, this combibation approach could be new alternative to HIV treatment using EFV in woman.

In silico and in vitro assessment of an optimized QbD-guided myoinositol and metformin-loaded mucus-penetrating particle-based gel for the amelioration of PCOS.

Polycystic ovarian syndrome (PCOS) is a multi-factorial endocrine disorder affecting women of reproductive age. However, its high prevalence and the unsuccessful translation of conventional modalities have made PCOS a pharmaco-therapeutic challenge. In the present study, we explored bi-formulations (comprising metformin-loaded mucus-penetrating nanoparticles, MTF-MPPs, and myoinositol-loaded mucus-penetrating particles, MI-MPPs) incorporated in a carbomer gel tailored for intravaginal administration. For the development and optimization of the MPPs-gel, a QbD (quality by design) approach was employed, including the initial and final risk assessment, central composite design of experts, and method validation. The optimized MTF-MPPs and MI-MPPs possessed an optimum nanometric particle size (195.0 nm and 178.8 nm, respectively) and a PDI of 0.150 and 0.123, respectively, together with a negligible negative zeta potential (-5.19 mV and -6.19 mV, respectively) through the vaginal mucus. It was observed that the MPPs are small and monodisperse with a neutral surface charge. It was observed that the MPPs-gel formulations released approximately 69.86 ± 4.65% of MTF and 67.14 ± 5.74% of MI within 120 h (5 days), which was observed to be sustained unlike MFT-MI-gel with approximately 94.89 ± 4.17% of MTF and 90.91 ± 15% of MI drugs released within 12 h. The confocal microscopy study of rhodamine-loaded MPPs indicated that they possessed a high fluorescence intensity at a depth of 15 μm, while as the penetration trajectory in the vaginal tissue increased to 35 μm, their intensity was reduced, appearing to be more prominent in the blood vessels. The analyzed data of MPPs-gel suggest that the optimized MPPs-gel formulation has potential to reach the targeted area via the uterovaginal mucosa, which has a wide network of blood vessels. Subsequently, in vivo studies were conducted and the results revealed that the proposed MPPs-gel formulation could regulate the estrous cycle of the reproductive system compared to the conventional formulation. Moreover, the formulation significantly reduced the weight of the ovaries compared to the control and conventional vaginal gel. Biochemical estimation showed improved insulin and sex hormone levels. Thus, the obtained data revealed that the deep penetration and deposition of MTF and MI on the targeted area through intravaginal delivery resulted in better therapeutic effects than the conventional vaginal gel. The obtained results confirmed the amelioration of PCOS upon treatment using the prepared MPPs-gel formulation. According to the relevant evaluation studies, it was concluded that MPPs-gel was retained in the vaginal cavity for systemic effects. Also, the sustained and non-irritating therapeutic effect meets the safety aspects. This work serves as a promising strategy for intravaginal drug delivery.

Low intensity ultrasound-mediated drug-loaded nanoparticles intravaginal drug delivery: an effective synergistic therapy scheme for treatment of vulvovaginal candidiasis

PurposeVulvovaginal candidiasis (VVC) is a mucosal infection of the female lower genital tract for which treatment using conventional antifungal drugs shows limited effectiveness. Herein, amphotericin B-loaded poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) nanoparticles (AmB-NPs) were fabricated and combined with low intensity ultrasound (US) to mediate AmB-NPs intravaginal drug delivery to achieve productive synergistic antifungal activity in a rabbit model of VVC.MethodsPolymeric AmB-NPs were fabricated by a double emulsion method and the physical characteristics and biosafety of nanoparticles were analyzed. The distribution and tissue permeability of nanoparticles after intravaginal ultrasound irradiation (1.0 MHz, 1.0 W/cm2, 5 min, 50% duty ratio) were observed in the vagina. The synergistic therapeutic activity of US-mediated AmB-NPs treatment was evaluated using an experimental rabbit model of VVC. Vaginal C. albicans colony counts, the pathological structure of the vagina epithelium, and Th1/Th2/Th17-type cytokine and oxidative stress levels were analyzed to investigate the therapeutic effect in vivo.ResultsThe prepared AmB-NPs showed an obvious shell and core structure with uniform size and good dispersion and displayed high biosafety and US-sensitive slow drug release. Ultrasound significantly enhanced nanoparticle transport through the mucus and promoted permeability in the vaginal tissue. US-mediated AmB-NPs treatment effectively increased drug sensitivity, even in the presence of the vaginal mucus barrier in vitro. On the seventh day after treatment in vivo, the combination treatment of AmB-NPs and US significantly reduced the fungal load in the vagina, achieving over 95% clearance rates, and also improved the pathological epithelium structural damage and glycogen secretion function. The expression of Th1 (IFN-γ, IL-2) and Th17 (IL-17) cytokines were significantly increased and Th2 (IL-6, IL-10) cytokines significantly decreased in the US + AmB-NP group. Furthermore, US-mediated AmB-NPs treatment effectively increased C. albicans intracellular reactive oxygen species (ROS) levels and promoted vaginal oxidation and antioxidants to normal levels.ConclusionUS-mediated drug-loaded nanoparticles with intravaginal drug delivery exhibited a productive synergistic antifungal effect, which may provide a new non-invasive, safe, and effective therapy for acute or recurrent fungal vaginitis.Graphical

Application of Sol-Gels for Treatment of Gynaecological Conditions-Physiological Perspectives and Emerging Concepts in Intravaginal Drug Delivery.

Approaches for effective and sustained drug delivery to the female reproductive tract (FRT) for treating a range of gynaecological conditions remain limited. The development of versatile delivery platforms, such as soluble gels (sol–gels) coupled with applicators/devices, holds considerable therapeutic potential for gynaecological conditions. Sol–gel systems, which undergo solution-to-gel transition, triggered by physiological conditions such as changes in temperature, pH, or ion composition, offer advantages of both solution- and gel-based drug formulations. Furthermore, they have potential to be used as a suitable drug delivery vehicle for other novel drug formulations, including micro- and nano-particulate systems, enabling the delivery of drug molecules of diverse physicochemical character. We provide an anatomical and physiological perspective of the significant challenges and opportunities in attaining optimal drug delivery to the upper and lower FRT. Discussion then focuses on attributes of sol–gels that can vastly improve the treatment of gynaecological conditions. The review concludes by showcasing recent advances in vaginal formulation design, and proposes novel formulation strategies enabling the infusion of a wide range of therapeutics into sol–gels, paving the way for patient-friendly treatment regimens for acute and chronic FRT-related conditions such as bacterial/viral infection control (e.g., STDs), contraception, hormone replacement therapy (HRT), infertility, and cancer.

Long lasting mucoadhesive membrane based on alginate and chitosan for intravaginal drug delivery.

The intravaginal route of administration can be exploited to treat local diseases and for systemic delivery. In this work, we developed an alginate/chitosan membrane sufficiently stable in a simulated vaginal fluid and able to dissolve over time at a very slow and linear rate. The membrane demonstrated good mechanical properties both in its swollen and dry form. As a study case, we evaluated the viability of this potential drug delivery system for the treatment of bacterial vaginosis, a common disease affecting women in their reproductive age. Metronidazole was effectively included in the alginate/chitosan membrane and its bactericide effect was demonstrated against Staphylococcus aureus and Gardnerella vaginalis, simultaneously showing good biocompatibility with a cervix epithelial cell line. Since this alginate/chitosan membrane is stable in a simulated vaginal environment, is easy to fabricate and can be used for the controlled release of a model drug, it represents a promising drug delivery system for local intravaginal applications.

Research and development of a silicone letrozole-releasing device to control reproduction in cattle

Two experiments were conducted to test the effectiveness of a silicone matrix as an intravaginal drug delivery device for letrozole, an aromatase inhibitor used for synchronization protocols in cattle. A wax dip-coat formulation of the intravaginal device used in previous studies was effective in releasing letrozole but was cumbersome to manufacture and deploy, resulting in unwanted variation in drug delivery and circulating concentrations of letrozole. In Experiment 1, a 3 × 3 design was used to test the release kinetics of letrozole from silicone in vitro. Silicone was mixed with 3 different letrozole drug loads (5%, 10%, 15%) and 3 different mineral oil loads (5%, 10%, 15%), and letrozole release into 62.5% ethanol was compared with the wax dip-coat formulation (positive control) by UV spectrophotometry. Letrozole was released from silicone in a dose-dependent manner, with no effect of mineral oil. Release kinetics were then examined in vivo (Experiment 2) in nulliparous beef heifers assigned randomly to six groups (n = 6/group) and given either a large surface area (LSA) with 5% or 15% drug load, a standard surface area (SSA) intravaginal silicone device impregnated with 10% or 15% drug load, a wax dip-coat device (positive control), or a blank device (negative control). Devices were inserted on Day 3 (Day 0 = ovulation) until Day 11. Blood samples were collected at 0, 30 min, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h, and twice daily until Day 11 to determine letrozole plasma concentrations by LC-MS/MS and estradiol plasma concentrations by radioimmunoassay The ovaries were examined once daily from Day 3–13 by ultrasonography to determine follicular and luteal responses to treatment. Letrozole plasma concentrations were higher in heifers given a device with an LSA vs SSA (P < 0.05). Plasma concentrations of estradiol decreased the most in heifers given the 15% LSA device (P = 0.06). The interval between emergence of successive follicular waves was longest (P < 0.05) in the positive control and the 15% LSA groups. As well, the diameter profiles of the dominant follicle and the corpus luteum were largest (P < 0.01) in the positive control and 15% LSA groups. In conclusion, letrozole was released from a silicone matrix in vitro in a dose-dependent manner, and the 15% LSA devices achieved target effects on ovarian function. Results may be used to manufacture a silicone intravaginal device for delivering aromatase inhibitors in a novel synchronization protocol for cattle.

THE PREVALENCE OF VULVOVAGINAL CANDIDIASIS IN PREGNANT WOMEN ATTENDING SEVERAL HOSPITALS IN SANA’A, YEMEN

Candida species are opportunistic yeasts affecting the genitourinary tract which causes the vulvovaginal candidiasis in the most female especially in developing countries. This study aims to determine the prevalence of vulvovaginal candidiasis caused by Candida species causing among pregnant women in Sana'a City, Yemen. This study was carried out at the department of microbiology of AL-Kuwait University Hospital. 250 vaginal swabs were collected and cultured on Sabouraud dextrose agar. Candida species identification and antifungal susceptibility testing were determined according to standard microbiological methods. The results showed that out of 250 samples, 63(25.2%) were positive for Candida species. It was found that the C. albicans (68.3%) was the most common species isolated followed by non-albicans species that are C. tropicalis (20.6%), C. glabrata (6.3%), and C. kefyr (4.8%). Also, it was recorded that the highest prevalence of Candida species was within group aged of 36-46 year. Susceptibility tests revealed that the most isolated species of C. andida were sensitive to nystatin (95%). miconazole was the next effective drug with 64% sensitive followed by amphotericin B (29%) and clotrimazole (24%). But only 6% of the isolates were sensitive to fluconazole. It can be concluded that the vulvovaginal candidiasis are quite common in Yemen country with a high prevalence. Also, the nystatin remains the effective agent against all isolated of Candida species. In contrast, the increase resistance of Candida species to fluconazole that commonly used antifungal is an alarming increase of vaginal candidiasis caused by antifungal-resistant Candida species.&#x0D; Peer Review History: &#x0D; UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency.&#x0D; Received file &#x0D; &#x0D; Average Peer review marks at initial stage: 5.0/10&#x0D; Average Peer review marks at publication stage: 8.0/10&#x0D; Reviewer(s) detail:&#x0D; Name: Dr. Hassan A.H. Al-Shamahy&#x0D; Affiliation: Sana'a University, Yemen&#x0D; E-mail: shmahe@yemen.net.ye&#x0D; &#x0D; Name: Dr. Tamer Mohamed Ali El Habibi&#x0D; Affiliation: Suez Canal University, Egypt.&#x0D; E-mail: tamer_hassan@pharm.suez.edu.eg&#x0D; &#x0D; Name: Rola Jadallah&#x0D; Affiliation: Arab American University, Palestine&#x0D; E-mail: rola@aauj.edu&#x0D; Comments of reviewer(s): &#x0D; &#x0D; Similar Articles:&#x0D; AN EXHAUSTIVE STATISTIC ON CURRENT MUCOADHESIVE INTRAVAGINAL DRUG DELIVERY METHODOLOGIES&#x0D; TETANUS IMMUNIZATION AMONG PREGNANT WOMEN: COVERAGE RATE AND RATE OF PROTECTION AT TIME OF DELIVERY

Intravaginal Drug Delivery System: Compherensive Approach to Vaginal Formulations.

Intra-vaginal route of administration is a route of administration where the dosage form is applied vaginally for the convenient release of the dosage form and for better therapeutic action of the medicament, it is usually used in HIV patients. Vaginal route is been used as a traditional delivery system used for the conventional delivery of several locally acting drugs like antimicrobial agents. The various types of formulations as well as the dosage forms are available for intra-vaginal drug delivery system such as tablets gels vaginal rings etc. the disease’s such as HIV or other diseases caused into the vaginal area due to causative agents like bacteria fungi etc. For efficient vaginal delivery of drugs, the delivery system should reside at the site of infection for a prolonged period of time.

Producing hybrid nanofiber-based on /PAN/Fe3 O4 /zeolite/nettle plant extract/urease and a deformed coaxial natural polymer to reduce toxicity materials in the blood of dialysis patients.

On incidence of kidney failure, the concentration of urea increases and there is need for patients to visit the hospital all through the week for blood purification. However, current hemodialysis has been found to reduce only 66-75% urea in the blood of patients. The main goal of this article is to observe the effect of biocompatible and high mechanical hemodiafiltration in reducing urea and creatinine within the shortest time frame, using two methods of Nano electrospinning fiber (hybrid and coaxial). Hybrid electrospinning was made by zeolite 940-HOA(beta), Fe3 O4 , polyacrylonitrile as well as the addition of nettle plant's leaf extract. Dispersing solution and enzymes were added to two different syringes and was used in making hybrid nanofibers by the electrospinning process. Nessler's Reagent adsorption method was used for measuring the concentration of ammonia after urease enzyme activation. Second coaxial filter was made by the core-shell electrospinning system and cellulose acetate phthalate (CAP) as well as polyurethane (PU) were utilized. The data show hybrid hemodiafiltration with enzyme coating, decomposed urea and enzymes were activated for two days after electrospinning. The core-shell filtration can also reduce creatinine. Core-shell CAP-PU nanofiber was previously used for intravaginal drug delivery and PU was used as an artificial renal microfluidic chip. Thus, our study focused on using CAP-PU to reduce creatinine in dialysis patients. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1736-1743, 2019.

Sodium alginate in oil-poloxamer organogels for intravaginal drug delivery: Influence on structural parameters, drug release mechanisms, cytotoxicity and in vitro antifungal activity

Local administration of antimicrobial agents is the first therapeutic approach for the treatment of Candida albicans infections. The duration of contact of formulations with the vaginal mucosa is critical for therapeutic efficacy. This study describes the development of organogels employing an oil phase composed of oleic acid (OA) and an aqueous phase consisting of the poloxamer PL407, alone or in association with PL188, together with 0.25–1% sodium alginate (SA), in order to obtain an intravaginal drug delivery system capable of modulating the release of voriconazole (VRC). VRC was solubilized in oleic acid homogenized with the PL-SA aqueous phase, at a final concentration of 5 mg/mL. Physicochemical characterization was performed for evaluation of the influence of SA on organogel structural organization, biopharmaceutical properties, pharmacological efficacy, and cytotoxicity, envisaging use of the formulation for the treatment of vaginal candidiasis. The enthalpy variation values showed greater changes in the presence of PL188 and after the incorporation of SA or VRC in the organogels. Rheological analysis showed Tsol-gel values in the ranges 11–39 °C and 27–30 °C for the OA-PL407 and OA-PL407-188 formulations, respectively. Oscillatory analysis of OA-PL407–188 showed that G' was ~20-fold higher than G″, even after submitting the formulation to temperature variation. VRC-OA-PL407 showed fast drug release from 0.5 to 4 h, maintaining total release (~100%) up to 24 h. The incorporation of SA in the organogels enabled modulation of VRC release, with different release percentages for 0.25% SA (~75%), 0.5% SA (~55%), and 1% SA (~35%). The formulation was non-cytotoxic towards HeLa and Vero cell lines. In diffusion tests, it was able to prevent the growth of Candida albicans and Candida krusei. In conclusion, the results suggested that OA-PL407-188-SA organogels could be possible new systems for VRC delivery, with potential for use in future vaginal applications.

Novel Intravaginal Drug Delivery System Based on Molecularly PEGylated Lipid Matrices for Improved Antifungal Activity of Miconazole Nitrate.

The aim of this study was to investigate the potential of microparticles based on biocompatible phytolipids [Softisan® 154 (SF) (hydrogenated palm oil) and super-refined sunseed oil (SO)] and polyethylene glycol- (PEG-) 4000 to improve intravaginal delivery of miconazole nitrate (MN) for effective treatment of vulvovaginal candidiasis (VVC). Lipid matrices (LMs) consisting of rational blends of SF and SO with or without PEG-4000 were prepared by fusion and characterized and employed to formulate MN-loaded solid lipid microparticles (SLMs) by melt-homogenization. The SLMs were characterized for physicochemical properties, anticandidal activity, and stability. Spherical discrete microparticles with good physicochemical properties and mean diameters suitable for vaginal drug delivery were obtained. Formulations based on SO:SF (1:9) and containing highest concentrations of PEG-4000 (4 %w/w) and MN (3.0 %w/w) were stable and gave highest encapsulation efficiency (83.05–87.75%) and inhibition zone diameter (25.87±0.94–26.33±0.94 mm) and significantly (p<0.05) faster and more powerful fungicidal activity regarding killing rate constant values (7.10 x 10−3–1.09 x 10−2 min−1) than commercial topical solution of MN (Fungusol®) (8.00 x 10−3 min−1) and pure MN sample (5.160 x 10−3 min−1). This study has shown that MN-loaded SLMs based on molecularly PEGylated lipid matrices could provide a better option to deal with VVC.

Self-assembled nanoparticles made from a new PEGylated poly(aspartic acid) graft copolymer for intravaginal delivery of poorly water-soluble drugs

New amphiphilic PEGylated poly(aspartic acid) graft copolymer (PASP-PEG-Ph) was synthesized as a nanocarrier for intravaginal drug delivery of poorly water-soluble drugs. PASP-PEG-Ph self-assembled into negatively charged spherically shaped nanoparticles in the presence of pH 4.5 and pH 7.0 vaginal fluid simulants with a diameter of approximately 200 nm as evidenced by Zeta-potentiometer, scanning electron microscope (SEM), dynamic light scattering (DLS) analysis. A significant number of stable NPs could be maintained at pH 4.5, 37 °C for 13 days. The PASP-PEG-Ph NP showed no significant cytotoxicity toward the T-cell line SupT1 and human vaginal epithelial cell line Vk2/E6E7 up to 1 mg/mL. The highest encapsulation efficiency of the model drug coumarin 6 (C6) by PASP-PEG-Ph was 92.0 ± 5.7%. The sustained release profile of the encapsulated C6 was demonstrated by an in vitro release study. An in vitro cellular uptake study revealed strong cellular uptake of the C6 loaded NP by SupT1 cells within 2 h.

Polyethylene glycol-functionalized poly (Lactic Acid-co-Glycolic Acid) and graphene oxide nanoparticles induce pro-inflammatory and apoptotic responses in Candida albicans-infected vaginal epithelial cells.

Mucous-penetrating nanoparticles consisting of poly lactic acid-co-glycolic acid (PLGA)-polyethylene glycol (PEG) could improve targeting of microbicidal drugs for sexually transmitted diseases by intravaginal inoculation. Nanoparticles can induce inflammatory responses, which may exacerbate the inflammation that occurs in the vaginal tracts of women with yeast infections. This study evaluated the effects of these drug-delivery nanoparticles on VK2(E6/E7) vaginal epithelial cell proinflammatory responses to Candida albicans yeast infections. Vaginal epithelial cell monolayers were infected with C. albicans and exposed to 100 μg/ml 49.5 nm PLGA-PEG nanospheres or 20 μg/ml 1.1 x 500 nm PEG-functionalized graphene oxide (GO-PEG) sheets. The cells were assessed for changes in mRNA and protein expression of inflammation-related genes by RT-qPCR and physiological markers of cell stress using high content analysis and flow cytometry. C. albicans exposure suppressed apoptotic gene expression, but induced oxidative stress in the cells. The nanomaterials induced cytotoxicity and programmed cell death responses alone and with C. albicans. PLGA-PEG nanoparticles induced mRNA expression of apoptosis-related genes and induced poly (ADP-ribose) polymerase (PARP) cleavage, increased BAX/BCL2 ratios, and chromatin condensation indicative of apoptosis. They also induced autophagy, endoplasmic reticulum stress, and DNA damage. They caused the cells to excrete inflammatory recruitment molecules chemokine (C-X-C motif) ligand 1 (CXCL1), interleukin-1α (IL1A), interleukin-1β (IL1B), calprotectin (S100A8), and tumor necrosis factor α (TNF). GO-PEG nanoparticles induced expression of necrosis-related genes and cytotoxicity. They reduced autophagy and endoplasmic reticulum stress, and apoptotic gene expression responses. The results show that stealth nanoparticle drug-delivery vehicles may cause intracellular damage to vaginal epithelial cells by several mechanisms and that their use for intravaginal drug delivery may exacerbate inflammation in active yeast infections by increased inflammatory recruitment.

Reversibly pH-responsive polyurethane membranes for on-demand intravaginal drug delivery.

A reversible and sharp switch between "off" and "on" drug release is achieved for the first time through new pH-sensitive polyurethane membranes, which can serve as window membranes in reservoir-type intravaginal rings for on-demand drug delivery to prevent sexually transmitted infections (STIs). Close to zero drug release occurs at the normal vaginal pH (4.5) for minimal side effects. Drug release is only triggered by elevation of pH to 7 during heterosexual intercourse. The reversibly sharp and fast "on-and-off" switch arises from the creative incorporation of a pH-sensitive monomer in the soft segment of polyurethane. This polyurethane biomaterial holds great potential to better protect women who are generally at higher risk and are more vulnerable to STIs.

PH responsive polyurethane (core) and cellulose acetate phthalate (shell) electrospun fibers for intravaginal drug delivery

In this study we present the use of co-axial electrospinning to produce core-shell composite micro-/nano- fibers of polyurethane (PU) and cellulose acetate phthalate (CAP). The designed fibers possess enhanced mechanical properties with a tensile strength of 13.27±2.32MPa, which is a clear improvement over the existing CAP fibers that suffer from a poor mechanical strength (0.2±0.03MPa). The CAP imparts pH responsiveness to the core-shell structure giving the fibers potential for “semen sensitive” (intravaginal) drug delivery.

Poly(ethylene glycol) enclatherated pectin-mucin submicron matrices for intravaginal anti-HIV-1 drug delivery

This paper explores the potential of polyethylene glycol enclatherated pectin-mucin (PEG-encl-PEC:MUC) submicron matrices (SMMs) as an intravaginal drug delivery system capable of delivering an anti-HIV-1 agent (zidovudine; AZT) over a prolonged duration. A three factor and three level (33) Box-Behnken statistical design was employed to optimize the SMMs. Optimized PEG-encl-PEC:MUC SMMs prepared as a stable W/O emulsion (determined by the degree of reversible colloidal phenomena) were spherical with a mean particle size of 270.6±5.533nm and mean zeta potential of −34.4±0.539mV. The microencapsulation of AZT and the hydrogen bonding mediated shielding of AZT by SMMs was confirmed by Fourier Transform Infrared (FTIR) analysis. The thermochemical (differential scanning calorimetry and thermogravimetric analysis) data proposed that Ca2+-based macromolecular ionic crosslinking as well as the intermolecular interactions may be responsible for the thermal stability of the delivery system. The partially amorphous nature of drug-loaded SMMs, as confirmed by X-ray diffraction patterns, further strengthened the matricization of AZT into the pectin-mucin matrix. In vitro drug release studies from the SMMs showed approximately 91% zidovudine release in simulated vaginal fluid (SVF) and 94% in phosphate buffered saline (PBS) in 24h. The mean dissolution time (MDT) of zidovudine from the SMMs was 5.974h. The attainment of required dimensional structure and drug release profiles from SMMs highlights the potential of their inclusion into a secondary carrier system for extended and controlled intravaginal stay.

Mathematical model of microbicidal flow dynamics and optimization of rheological properties for intra-vaginal drug delivery: Role of tissue mechanics and fluid rheology

Topically applied microbicide gels can provide a self-administered and effective strategy to prevent sexually transmitted infections (STIs). We have investigated the interplay between vaginal tissue elasticity and the yield-stress of non-Newtonian fluids during microbicide deployment. We have developed a mathematical model of tissue deformation driven spreading of microbicidal gels based on thin film lubrication approximation and demonstrated the effect of tissue elasticity and fluid yield-stress on the spreading dynamics. Our results show that both elasticity of tissue and yield-stress rheology of gel are strong determinants of the coating behavior. An optimization framework has been demonstrated which leverages the flow dynamics of yield-stress fluid during deployment to maximize retention while reaching target coating length for a given tissue elasticity.

A Review on Vaginal Drug Delivery System

Purpose: This review article has been written with a purpose to collate both conventional and novel vaginal drug delivery systems, highlighting the need and advantages of the novel vaginal drug delivery systems. This article will benefit the researchers working in the field of vaginal drug delivery with information about the current research being done in this area. Approach: The unique anatomy and physiology of the vagina is briefly described and then the various conventional and novel drug delivery systems such as vaginal films, vaginal rings, vaginal microspheres, vaginal liposomes, vaginal mucoadhesive caplets, vaginal mini tablets, and vaginal nanofibres are discussed. Research studies focusing on the novel vaginal drug delivery and their findings have also been reported. Findings: The novel vaginal drug delivery systems offer various advantages such as improved mucoadhesion, targeted drug delivery, prolonged drug delivery, improved stability and less frequency of dosing. Conclusion: Traditionally, intravaginal drug delivery has been restricted to delivery of anti infectives to the local vaginal cavity. With the rediscovery of the vaginal route as a potential route for the delivery of therapeutically important molecules, such as microbicides, novel vaginal drug delivery systems are being investigated. These novel systems would enhance the delivery of many drugs offering better therapeutic outcomes.

Novel Intravaginal Drug Delivery Systems of the Antiviral for Prophylaxis of HIV/AIDS and Prevention of Sexually Transmitted Diseases

AIDS Research and Human RetrovirusesVol. 30, No. S1 Preclinical Evaluation of Vaginal Films and GelsNovel Intravaginal Drug Delivery Systems of the Antiviral for Prophylaxis of HIV/AIDS and Prevention of Sexually Transmitted DiseasesMahesh R. Sherkar, Ashok V. Bhosale, and Mala D. MenonMahesh R. SherkarShri Vivekanand Nursing Home Trust's College of B Pharmacy, Pharmaceutics, Rahuri, IndiaSearch for more papers by this author, Ashok V. BhosalePune District Education Association's Seth Govind Raghunath Sable College of Pharmacy, Pharmaceutics, Saswad, Pune, IndiaSearch for more papers by this author, and Mala D. MenonBombay College of Pharmacy, Kalina, Santacruze(E), Pharmaceutics, Mumbai, IndiaSearch for more papers by this authorPublished Online:30 Oct 2014https://doi.org/10.1089/aid.2014.5326.abstractAboutSectionsView articleView Full TextPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Novel Intravaginal Drug Delivery Systems of the Antiviral for Prophylaxis of HIV/AIDS and Prevention of Sexually Transmitted Diseases ." AIDS Research and Human Retroviruses, 30(S1), p. A158FiguresReferencesRelatedDetails Volume 30Issue S1Oct 2014 InformationCopyright 2014, Mary Ann Liebert, Inc.To cite this article:Mahesh R. Sherkar, Ashok V. Bhosale, and Mala D. Menon.Novel Intravaginal Drug Delivery Systems of the Antiviral for Prophylaxis of HIV/AIDS and Prevention of Sexually Transmitted Diseases.AIDS Research and Human Retroviruses.Oct 2014.A158-A158.http://doi.org/10.1089/aid.2014.5326.abstractPublished in Volume: 30 Issue S1: October 30, 2014PDF download