Vaginal Drug Delivery Research Articles

Development of in situ poloxamer-chitosan hydrogels for vaginal drug delivery of benzydamine hydrochloride: Textural, mucoadhesive and in vitro release properties

The use of in situ hydrogel systems for vaginal drug delivery is an important strategy in the treatment of vaginitis. The aim of this study was to develop in situ vaginal hyrogels for benzydamine hydrochloride (BNZ) which were composed of poloxamer and chitosan. The reason for development of these hydrogels was to obtain a vaginal delivery system with improved mechanical and mucoadhesive properties that could provide prolonged retention time for the treatment of vaginits. The hydrogels were also designed for once a day dosage of the drug and to obtain a controlled release of the BNZ. For this purpose BNZ containing hydrogel formulations using thermosensitive polymer (Poloxamer 407) and mucoadhesive polymer (Chitosan H, Chitosan M and Chitosan L) were developed. The hydrogels are composed of polymers which have promising potential for vaginal delivery systems. These formulations were evaluated by rheology, texture, mucoadhesive profiles and drug diffusion with a Franz diffusion cell. It was observed that the diffusion of BNZ from the in situ poloxamer-chitosan hydrogel was more sustained and controlled than with the poloxamer gel. The hydrogel formulations diffused about 65.3±5.1, 80.6±3.8, 88.1±7.3 and 100.4±4.8% of BNZ at 6h. The formulation containing Poloxamer 407 and Chitosan H has the best controlled release profile and mucoadhesive properties, results which indicate that it could suitable for use once a day on the vaginal route. Moreover, the hydrogels higher mucoadhesion exhibited by this formulation prolongs the drug residence time compared with the poloxamer gel and may increase the BNZ efficacy. These BNZ mucoadhesive vaginal hydrogel formulations may be a promising alternative to conventional dosage forms for vaginal topical therapy.

Layer-by-Layer Engineered Microbicide Drug Delivery System Targeting HIV-1 gp120: Physicochemical and Biological Properties.

The purpose of this study was to engineer a model anti-HIV microbicide (tenofovir) drug delivery system targeting HIV-1 envelope glycoprotein gp120 (HIV-1 g120) for the prevention of HIV sexual transmission. HIV-1 g120 and mannose responsive particles (MRP) were prepared through the layer-by-layer coating of calcium carbonate (CaCO3) with concanavalin A (Con A) and glycogen. MRP average particle size ranged from 881.7 ± 15.45 nm to 1130 ± 15.72 nm, depending on the number of Con A layers. Tenofovir encapsulation efficiency in CaCO3 was 74.4% with drug loading of 16.3% (w/w). MRP was non-cytotoxic to Lactobacillus crispatus, human vaginal keratinocytes (VK2), and murine macrophage RAW 264.7 cells and did not induce any significant proinflammatory nitric oxide release. Overall, compared to control, no statistically significant increase in proinflammatory cytokine IL-1α, IL-1β, IL-6, MKC, IL-7, and interferon-γ-inducible protein 10 (IP10) levels was observed. Drug release profiles in the presence of methyl α-d-mannopyranoside and recombinant HIV-1 envelope glycoprotein gp120 followed Hixson-Crowell and Hopfenberg kinetic models, indicative of a surface-eroding system. The one Con A layer containing system was found to be the most sensitive (∼2-fold increase in drug release vs control SFS:VFS) at the lowest HIV gp120 concentration tested (25 μg/mL). Percent mucoadhesion, tested ex vivo on porcine vaginal tissue, ranged from 10% to 21%, depending on the number of Con A layers in the formulation. Collectively, these data suggested that the proposed HIV-1 g120 targeting, using MRP, potentially represent a safe and effective template for vaginal microbicide drug delivery, if future preclinical studies are conclusive.

Designing and developing suppository formulations for anti-HIV drug delivery.

Despite a long history of use for rectal and vaginal drug delivery, the current worldwide market for suppositories is limited primarily due to a lack of user acceptability. Therefore, virtually no rational pharmaceutical development of antiviral suppositories has been performed. However, suppositories offer several advantages over other antiviral dosage forms. Current suppository designs have integrated active pharmaceutical ingredients into existing formulation designs without optimization. As such, emerging suppository development has been focused on improving upon the existing classical design to enhance drug delivery and is poised to open suppository drug delivery to a broader range of drugs, including antiretroviral products. Thus, with continuing research into rational suppository design and development, there is significant potential for antiretroviral suppository drug delivery.

Nanoparticle-releasing nanofiber composites for enhanced invivo vaginal retention.

Current approaches for topical vaginal administration of nanoparticles result in poor retention and extensive leakage. To overcome these challenges, we developed a nanoparticle-releasing nanofiber delivery platform and evaluated its ability to improve nanoparticle retention in a murine model. We individually tailored two components of this drug delivery system for optimal interaction with mucus, designing (1) mucoadhesive fibers for better retention in the vaginal tract, and (2) PEGylated nanoparticles that diffuse quickly through mucus. We hypothesized that this novel dual-functioning (mucoadhesive/mucus-penetrating) composite material would provide enhanced retention of nanoparticles in the vaginal mucosa. Equivalent doses of fluorescent nanoparticles were vaginally administered to mice in either water (aqueous suspension) or fiber composites, and fluorescent content was quantified in cervicovaginal mucus and vaginal tissue at time points from 24h to 7d. We also fabricated composite fibers containing etravirine-loaded nanoparticles and evaluated the pharmacokinetics over 7d. We found that our composite materials provided approximately 30-fold greater retention of nanoparticles in the reproductive tract at 24h compared to aqueous suspensions. Compared to nanoparticles in aqueous suspension, the nanoparticles in fiber composites exhibited sustained and higher etravirine concentrations after 24h and up to 7d, demonstrating the capabilities of this new delivery platform to sustain nanoparticle release out to 3d and drug retention out to one week after a single administration. This is the first report of nanoparticle-releasing fibers for vaginal drug delivery, as well as the first study of a single delivery system that combines two components uniquely engineered for complementary interactions with mucus.

Amino-functionalized poloxamer 407 with both mucoadhesive and thermosensitive properties: preparation, characterization and application in a vaginal drug delivery system

Lack of mucoadhesive properties is the major drawback to poloxamer 407 (F127)-based in situ hydrogels for mucosal administration. The objective of the present study was to construct a novel mucoadhesive and thermosensitive in situ hydrogel drug delivery system based on an amino-functionalized poloxamer for vaginal administration. First, amino-functionalized poloxamer 407 (F127-NH2) was synthesized and characterized with respect to its micellization behavior and interaction with mucin. Then using acetate gossypol (AG) as model drug, AG-loaded F127-NH2-based in situ hydrogels (NFGs) were evaluated with respect to rheology, drug release, ex vivo vaginal mucosal adhesion, in vivo intravaginal retention and local irritation after vaginal administration to healthy female mice. The results show that F127-NH2 is capable of forming a thermosensitive in situ hydrogel with sustained drug release properties. An interaction between positively charged F127-NH2 and negatively charged mucin was revealed by changes in the particle size and zeta potential of mucin particles as well as an increase in the complex modulus of NFG caused by mucin. Ex vivo and in vivo fluorescence imaging and quantitative analysis of the amount of AG remaining in mouse vaginal lavage all demonstrated greater intravaginal retention of NFG than that of an unmodified F127-based in situ hydrogel. In conclusion, amino group functionalization confers valuable mucoadhesive properties on poloxamer 407.

Freeze-dried cylinders carrying chitosan nanoparticles for vaginal peptide delivery

Recently nanoparticle-based vaginal drug delivery formulations have been acquiring great attention for the administration of peptide based-vaccines or microbicides to prevent or treat sexually transmitted diseases.In this work, a straightforward and efficient strategy for the vaginal application and release of peptide-loaded mucoadhesive nanoparticles was developed. This essentially consists of chitosan nanoparticles encapsulated in suitable hydrophilic freeze-dried cylinders. Chitosan nanoparticles are responsible for carrying the peptide drug and allowing adhesion to the vaginal mucosal epithelium. Hydrophilic freeze-dried cylinders facilitate the application and quick release of the nanoparticles to the vaginal zone. Upon contact with the aqueous vaginal medium, the excipients constituting these sponge-like systems are quickly dissolved enabling the release of their content.In vitro release studies showed the ability of the sponge-like systems and chitosan nanoparticles to deliver the mucoadhesive nanoparticles and peptide respectively. CLSM micrographs proved the nanoparticles ability promoting the peptide penetration inside the vaginal mucosa.

Expansible thermal gelling foam aerosol for vaginal drug delivery

Vaginal delivery of antimicrobial drugs is the most effective method for the local treatment of the vaginal infections. However, current vaginal drug delivery systems (VDDS), including gel, lotion, aerosol and cream, are suffering from low penetration in the deep vaginal rugae and easy elimination by self-cleaning of vaginal canal. To address these issues, a foam aerosol based on the thermal transformation was designed to improve penetration efficiency and achieve the extended retention. The expansible thermal gelling foam aerosol (ETGFA) consisting of thermal sensitive matrix, silver nanoparticle, adhesive agent and propellant, was optimized by evaluations of precursor viscosity, foam expansion, thermal gelation, gel adhesiveness, antimicrobial effects and tissue irritation. The ETGFA would penetrate to the deep vaginal rugae to cover the infectious sites by foam expansion. Drug leakage was intended to be avoided by the thermal gelation at physiological temperature before foam collapse. The gel could be retained in the vaginal canal for extended time due to its superior adhesiveness when compared to the commercial gel Asimi®. The ETGFA provided extended drug release for over 4 h and maintained effective drug concentrations at the infectious sites. The ETGFA containing silver nanoparticles showed dose-dependent antimicrobial effects on the vaginal floras and irritation reduction to the vaginal tissues. The results demonstrated that the ETGFA could overcome the limitations of conventional dosage forms, including poor drug penetration, carrier retention and patient compliance and satisfied the requirements for vaginal drug delivery.

Vaginal Delivery of Benzydamine Hydrochloride through Liposomes Dispersed in Mucoadhesive Gels.

Liposomal vaginal drug delivery systems are important strategy in the treatment of both topical and systemic diseases. The aim of this study was to develop a vaginal delivery system for benzydamine hydrochloride (BNZ) loaded liposomes dispersed into mucoadhesive gels. The delivery system was also designed for a once a day dosage and to obtain controlled release of the BNZ. For this purpose BNZ containing gel formulations using hydroxypropyl methylcellulose (HPMC) K100M and Carbopol® 974P, which are composed of polymers that show promising potential as mucoadhesive vaginal delivery systems, were developed. In addition, a BNZ containing liposome formulation was developed for vaginal administration. To improve the vaginal retention time, liposome was incorporated in HPMC K100M and Carbopol® 974P gel formulations. This system is called lipogel. The developed BNZ liposomes have a slightly negative zeta potential (-1.50±0.16 mV), a 2.25±0.009 µm particle size and a 34% entrapment efficiency. These gels and lipogels have appropriate pH, viscosity, textural properties and mucoadhesive value for vaginal administration. Lipogels were found to be the best formulations for in vitro diffusion and ex vivo mucoadhesion. The work of mucoadhesion obtained from liposomes was in the range of 0.027±0.045 and 0.030±0.017 mJ/cm2, while the value obtained from lipogels was between 0.176±0.037 and 0.243±0.53 mJ/cm2. N1 and N2 lipogel formulations diffused 57 and 67% of BNZ respectively at the end of 24 h. Moreover, a higher mucoadhesion, which increases drug residence time in comparison to liposomes, could improve BNZ efficacy. In conclusion, BNZ mucoadhesive vaginal lipogel formulations can be promising alternatives to traditional dosage forms for vaginal topical therapy.

Thermosensitive Chitosan Hydrogels Containing Polymeric Microspheres for Vaginal Drug Delivery.

Thermosensitive hydrogels have increasingly received considerable attention for local drug delivery based on many advantages. However, burst release of drugs is becoming a critical challenge when the hydrogels are employed. Microspheres- (MS-) loaded thermosensitive hydrogels were thus fabricated to address this limitation. Employing an orthogonal design, the spray-dried operations of tenofovir (TFV)/Bletilla striata polysaccharide (BSP)/chitosan (CTS) MS were optimized according to the drug loading (DL). The physicochemical properties of the optimal MS (MS F) were characterized. Depending on the gelation temperature and gelating time, the optimal CTS-sodium alginate- (SA-) α,β-glycerophosphate (GP) (CTS-SA-GP) hydrogel was obtained. Observed by scanning electron microscope (SEM), TFV/BSP/CTS MS were successfully encapsulated in CTS-SA-GP. In vitro releasing demonstrated that MS F-CTS-SA-GP retained desirable in vitro sustained-release characteristics as a vaginal delivery system. Bioadhesion measurement showed that MS-CTS-SA-GP exhibited the highest mucoadhesive strength. Collectively, MS-CTS-SA-GP holds great promise for topical applications as a sustained-release vaginal drug delivery system.

Nanoparticles-in-film for the combined vaginal delivery of anti-HIV microbicide drugs

Combining two or more antiretroviral drugs in one medical product is an interesting but challenging strategy for developing topical anti-HIV microbicides. We developed a new vaginal delivery system comprising the incorporation of nanoparticles (NPs) into a polymeric film base – NPs-in-film – and tested its ability to deliver tenofovir (TFV) and efavirenz (EFV). EFV-loaded poly(lactic-co-glycolic acid) NPs were incorporated alongside free TFV into fast dissolving films during film manufacturing. The delivery system was characterized for physicochemical properties, as well as genital distribution, local and systemic 24h pharmacokinetics (PK), and safety upon intravaginal administration to mice. NPs-in-film presented suitable technological, mechanical and cytotoxicity features for vaginal use. Retention of NPs in vivo was enhanced both in vaginal lavages and tissue when associated to film. PK data evidenced that vaginal drug levels rapidly decreased after administration but NPs-in-film were still able to enhance drug concentrations of EFV. Obtained values for area-under-the-curve for EFV were around one log10 higher than those for the free drugs in aqueous vehicle (phosphate buffered saline). Film alone also contributed to higher and more prolonged local drug levels as compared to the administration of TFV and EFV in aqueous vehicle. Systemic exposure to both drugs was low. NPs-in-film was found to be safe upon once daily vaginal administration to mice, with no significant genital histological changes or major alterations in cytokine/chemokine profiles being observed. Overall, the proposed NPs-in-film system seems to be an interesting delivery platform for developing combination vaginal anti-HIV microbicides.

Vaginal delivery of carboplatin-loaded thermosensitive hydrogel to prevent local cervical cancer recurrence in mice

Local tumor recurrence after cervical cancer surgery remains a clinical problem. Vaginal delivery of thermosensitive hydrogel may be suited to reduce tumor relapse rate with more efficacy and safety. A pilot study was carried out to evaluate the efficacy of carboplatin-loaded poloxamer hydrogel to prevent local recurrence of cervical cancer after surgery. In vivo vaginal retention evaluation of 27% poloxamer hydrogel in mice was proven to be a suitable vaginal drug delivery formulation due to its low gelation temperature. A mimic orthotopic cervical/vaginal cancer recurrence model after surgery was established by injecting murine cervical cancer cell line U14 into the vaginal submucosa to simulate the residual tumor cells infiltrated in the surgical site, followed by drug administration 24 h later to interfere with the formation/recurrence of the tumor. By infusing fluorescein sodium-loaded hydrogel into the vagina of mice, a maximized accumulation of fluorescein sodium (Flu) in the vagina was achieved and few signals were observed in other organs. When used in the prevention of the cervical cancer formation/recurrence in mice, the carboplatin-loaded poloxamer hydrogel exhibited great efficacy and systemic safety. In conclusion, thermosensitive hydrogel presents a simple, practical approach for the local drug delivery via vagina against cervical cancer recurrence.

Coupled gel spreading and diffusive transport models describing microbicidal drug delivery

Gels are a drug delivery platform that is being evaluated for application of active pharmaceutical ingredients, termed microbicides, that act topically against vaginal and rectal mucosal infection by sexually transmitted HIV. Despite success in one Phase IIb trial of a vaginal gel delivering tenofovir, problems of user adherence to designed gel application scheduling have compromised results in two other trials. The microbicides field is responding to this dilemma by expanding behavioral analysis of the determinants of adherence while simultaneously improving the pharmacological, biochemical, and biophysical analyses of the determinants of microbicide drug delivery. The intent is to combine results of these two complementary perspectives on microbicide performance and epidemiological success to create an improved product design paradigm. Central to both user sensory perceptions and preferences, key factors that underlie adherence, and to vaginal gel mucosal drug delivery, that underlies anti-HIV efficacy, are gel properties (e.g. rheology) and volume. The specific engineering problem to be solved here is to develop a model for how gel rheology and volume, interacting with loaded drug concentration, govern the transport of the microbicide drug tenofovir into the vaginal mucosa to its stromal layer. These are factors that can be controlled in microbicide gel design. The analysis here builds upon our current understanding of vaginal gel deployment and drug delivery, incorporating key features of the gel's environment, the vaginal canal, fluid production and subsequent gel dilution, and vaginal wall elasticity. These have not previously been included in the modeling of drug delivery. We consider the microbicide drug tenofovir, which is the drug most completely studied for gels: in vitro, in animal studies in vivo, and in human clinical trials with both vaginal or rectal gel application. Our goal is to contribute to improved biophysical and pharmacological understanding of gel functionality, providing a computational tool that can be used in future vaginal microbicide gel design.

Drivers of Vaginal Drug Delivery System Acceptability from Internet-Based Conjoint Analysis.

Vaginal microbicides potentially empower women to protect themselves from HIV and other sexually transmitted infections (STIs), especially when culture, religion, or social status may prevent them from negotiating condom use. The open literature contains minimal information on factors that drive user acceptability of women’s health products or vaginal drug delivery systems. By understanding what women find to be most important with regard to sensory properties and product functionality, developers can iteratively formulate a more desirable product. Conjoint analysis is a technique widely used in market research to determine what combination of elements influence a consumer’s willingness to try or use a product. We applied conjoint analysis here to better understand what sexually-active woman want in a microbicide, toward our goal of formulating a product that is highly acceptable to women. Both sensory and non-sensory attributes were tested, including shape, color, wait time, partner awareness, messiness/leakage, duration of protection, and functionality. Heterosexually active women between 18 and 35 years of age in the United States (n = 302) completed an anonymous online conjoint survey using IdeaMap software. Attributes (product elements) were systematically presented in various combinations; women rated these combinations of a 9-point willingness-to-try scale. By coupling systematic combinations and regression modeling, we can estimate the unique appeal of each element. In this population, a multifunctional product (i.e., broad spectrum STI protection, coupled with conception) is far more desirable than a microbicide targeted solely for HIV protection; we also found partner awareness and leakage are potentially strong barriers to use.

A vaginal drug delivery model

Efficient drug delivery at vaginal cavity is often a challenge owing to its peculiar physiological variations including vast differences in pH. Keeping in view this attribute of the target site, the current work was aimed at developing formulation strategies which could overcome this and successfully deliver molecules like itraconazole through SLNs. Optimized SLNs with the given composition was selected for further development into mucoadhesive and thermosensitive gel. Stearic acid and Compritol 888 (1:1, w/w ratio) as lipid, a mixture of 3% Poloxomer 188 and 0.5% sodium taurocholate as surfactant and organic to aqueous ratio of 10:50 was taken. Carbopol 934 and Pluronic F 127 were taken for the development of gel. Optimized gel exhibited a desired gelling temperature (35 °C); viscosity (0.920 PaS) and appreciable in vitro drug release (62.2% in 20 h). MTT assay did not show any cytotoxic effect of the gel. When evaluated in vivo, it did not exhibit any irritation potential despite appreciable bioadhesion. A remarkable decrease in CFUs was also observed in comparison with control and marketed formulation when evaluated in rat infection model. Thus, the proposed study defines the challenges for developing a suitable formulation system overcoming the delivery barriers of the vaginal site.

Effect of Vaginal Sponge and Drug Delivery System to Estrous Synchronization in Local Goats

Effect of Vaginal Sponge and Drug Delivery System to Estrous Synchronization in Local Goats

Propylene glycol-embodying deformable liposomes as a novel drug delivery carrier for vaginal fibrauretine delivery applications

The purpose of this work was to develop and characterize the fibrauretine (FN) loaded propylene glycol-embodying deformable liposomes (FDL), and evaluate the pharmacokinetic behavior and safety of FDL for vaginal drug delivery applications. FDL was characterized for structure, particle size, zeta potential, deformability and encapsulation efficiency; the ability of FDL to deliver FN across vagina tissue in vitro and the distribution behavior of FN in rat by vaginal drug delivery were investigated, the safety of FDL to the vagina of rabbits and rats as well as human vaginal epithelial cells (VK2/E6E7) were also evaluated. Results revealed that: (i) the FDL have a closed spherical shape and lamellar structure with a homogeneous size of 185±19nm, and exhibited a negative charge of −53±2.7mV, FDL also have a good flexibility with a deformability of 92±5.6 (%phospholipids/min); (ii) the dissolving capacity of inner water phase and hydrophilicity of phospholipid bilayers of deformable liposomes were increased by the presence of propylene glycol, this may be elucidated by the fluorescent probes both lipophilic Nile red and hydrophilic calcein that were filled up the entire volume of the FDL uniformly, so the FDL with a high entrapment capacity (were calculated as percentages of total drug) for FN was 78±2.14%; (iii) the permeability of FN through vaginal mucosa was obviously improved by propylene glycol-embodying deformable liposomes, no matter whether the FN loaded in liposomes or not, although FN loaded in liposomes caused the highest permeability and drug reservoir in vagina; (iv) the FN mainly aggregated in the vagina and uterus, then the blood, spleen, liver, kidney, heart and lungs for vaginal drug delivery, this indicating vaginal delivery of FDL have a better ‘vaginal local targeting effect’; and (v) the results of safety evaluation illustrate that the FDL is non-irritant and well tolerated in vivo, thereby establishing its vaginal drug delivery potential. These results indicate that the propylene glycol-embodying deformable liposomes may be a promising drug delivery carrier for vaginal delivery of fibrauretine.

Quantitative analyses of variability in normal vaginal shape and dimension on MR images.

We present a technique for quantifying inter-individual variability in normal vaginal shape, axis, and dimension, and report findings in healthy women. Eighty women (age: 28∼70years) with normal pelvic organ support underwent supine, multi-planar proton-density MRI. Vaginal width was assessed at five evenly-spaced locations, and vaginal axis, length, and surface area were quantified via ImageJ and MATLAB. The mid-sagittal plane angles, relative to the horizontal, of three vaginal axes were 90 ± 11, 72 ± 21, and 41 ± 22° (caudal to cranial, p < 0.001). The mean (± SD) vaginal widths were 17 ± 5, 24 ± 4, 30 ± 7, 41 ± 9, and 45 ± 12mm at the five locations (caudal to cranial, p < 0.001). Mid-sagittal lengths for anterior and posterior vaginal walls were 63 ± 9 and 98 ± 18mm respectively. The vaginal surface area was 72 ± 21cm(2) (range: 34 ∼ 164cm(2)). The coefficient of determination between any demographic variable and any vaginal dimension did not exceed 0.16. Large variations in normal vaginal shape, axis, and dimensions were not explained by body size or other demographic variables. This variation has implications for reconstructive surgery, intravaginal and surgical product design, and vaginal drug delivery.

Making mucoadhesive nanofibres for vaginal drug delivery applications

Making mucoadhesive nanofibres for vaginal drug delivery applications

Controlling the hydration rate of a hydrophilic matrix in the core of an intravaginal ring determines antiretroviral release

Intravaginal ring technology is generally limited to releasing low molecular weight species that can diffuse through the ring elastomer. To increase the diversity of drugs that can be delivered from intravaginal rings, we designed an IVR that contains a drug matrix encapsulated in the core of the IVR whereby the mechanism of drug release is uncoupled from the interaction of the drug with the ring elastomer. We call the device a flux controlled pump, and it is comprised of compressed pellets of a mixture of drug and hydroxypropyl cellulose within the hollow core of the ring. The pump orifice size and chemistry of the polymer pellets control the rate of hydration and diffusion of the drug-containing hydroxypropyl cellulose gel from the device. A mechanistic model describing the hydration and diffusion of the hydroxypropyl cellulose matrix is presented. Good agreement between the quantitative model predictions and the experimental studies of drug release was obtained. We achieved controlled release rates of multiple antiretrovirals ranging from μg/d to mg/d by altering the orifice design, drug loading, and mass of pellets loaded in the device. This device could provide an adaptable platform for the vaginal drug delivery of many molecules.

Special issue on vaginal drug delivery

Special issue on vaginal drug delivery