Vaginal Delivery System Research Articles

Vaginal residence and pharmacokinetic preclinical study of topical vaginal mucoadhesive W/S emulsions containing ciprofloxacin

The aim of this work is to test the in vivo behavior of a mucoadhesive vaginal emulsion resistant to the clearance of vaginal fluids using ciprofloxacin (CPX) as an anti-infective model of drug. CPX is a broad-spectrum antibiotic used in the treatment of sexual tissues infections, as intravenous injection in a dose of 20 mg every 12 h. In this study, CPX was incorporated in water in silicone (W/S) mucoadhesive emulsions and the in vivo residence time and the CPX in vivo absorption and distribution to the sexual organs was studied using the rat as animal model. W/S emulsion shows excellent in vitro bioadhesion having high resistance to the vaginal fluids clearance. The drug release profiles show a constant release of CPX during at least 6 h according to a zero-order kinetics. In vivo computerized PET/CT Image Analysis after intravaginal administration to rats indicates that W/S emulsions remain in the vaginal area for a long time and shows a good absorption of the radiotracers used as markers through the vaginal mucosa. Ciprofloxacin pharmacokinetic studies developed after the single intravaginal administration of W/S emulsion shows a good absorption and distribution of CPX on the uterus and ovarian tissue. A significant concentration of CPX in the sexual tissues was observed after 24 h of administration of W/S emulsion. Therefore, W/S emulsions have a good in vivo residence and drug release in the vaginal mucosae showing a great potential for the treatment of sexual tissues infections, as vaginal bioadhesive delivery systems of antinfectious drugs.

Research Progress of Progesterone Preparations: A Mini Review.

Progesterone is a sex steroid hormone. Since it has been discovered, it is widely used in the prevention of spontaneous preterm birth, hormone replacement therapy and other gynecological conditions. We will review the progesterone preparations based on a comprehensive study of papers and patents from the traditional preparations up through the very recent literatures. This review mainly concentrates on oral, vaginal and micro delivery systems, involving different ways to prepare progesterone preparations. Although progesterone has first-pass effects, with these methods, the bioavailability and compliance can be greatly increased.

Review of use of Mysodelle as a method of induction of labour

Background: Mysodelle is a 200 mcg misoprostol, vaginal delivery system. It is a PGE1 analogue and accepted as a method of IOL by Scottish medicine consortium in 2014 (Medicines Health and Regulatory Authority; Wing et al., 2013).Aims: The main objective of this project was to determine efficacy of Mysodelle with regards to time interval between insertions to delivery. We also studied the safety profile of Mysodelle with regards to operative delivery rates, foetal concerns and incidence of hyperstimulation.Methodology: A protocol which outlined the criteria for suitability for the use of Mysodelle was developed. This method was used for IOL for primiparous women more than 38 weeks of gestations with unfavourable cervix and intact membranes with no foetal concerns on scan, i.e. suboptimal growth or reduced liquor. Mysodelle was left in situ for maximum duration of 24 hours and CTG was monitored every 4 hours. The data was collected prospectively over 1 year from January 2016.Results: We reviewed 50 women for the study period of one year. All women were primiparous with singleton term gestations between 38 + 5 weeks to term +11 days. The indications for IOL included postdates, reduced foetal movement, big baby and advanced maternal age. Following the use of Mysodelle, 55% of the women progressed to active labour and did not require oxytocin on labour ward. In 20% of the women, Mysodelle was removed for suspicious CTG or tachysystole. Four women failed IOL with Mysodelle. 14% women had hyperstimulation response to Mysodelle and needed terbutaline. 46% women had spontaneous vaginal delivery and 24% needed instrumental delivery. Remaining 30% patients delivered by caesarean section. The median time from Mysodelle administration to vaginal delivery was 21 hours (95% confidence interval 18.8–26.8 hours). There were no neonatal adverse outcomes.Conclusions: Results at AMH overall are in keeping with those from EXPEDITE study (Wing et al. 2013). It was found to be more efficacious in terms of insertion to delivery time, however, was associated with more tachysystole and hyperstimulation requiring terbutaline as previously highlighted in Cochrane review (Alfirevic and Weeks 2006; Hofmeyr et al. 2010). There was no increased risk of operative delivery or adverse neonatal outcome with the use of Mysodelle. A reduction in time to vaginal delivery and time to active labour associated with misoprostol vaginal delivery system may be an advantage for patients and the service (ISD Scotland 2013), but it needs to be seen if this benefit is offset due to increased requirements for foetal monitoring due to uterine tachysystole and hyperstimulation. MHRA have advised that Mysodelle can cause uterine tachysystole, that might not respond to tocolytic treatment. (MHRA medicine update 2018).

Development and anti-Candida evaluation of the vaginal delivery system of amphotericin B nanosuspension-loaded thermogel

Vulvovaginal candidiasis (VVC) is a typical kind of vaginal mucosal infection. Herein, we developed a novel vaginal delivery system of amphotericin B (AmB) nanosuspension-loaded thermogel (AmB NPs/thermogel) utilising pharmaceutical technique of high-pressure homogenisation and Poloxamer P407/P188 hydrogel. The stabiliser and hydrogel materials of the formulation were tested to maintain proper sol–gel transition as well as the relative stability of the particle size of AmB nanosuspension in the thermogel. The particle size of AmB nanosuspensions in the hydrogel was ∼247 nm. Transmission electron microscopy images confirmed the round-shape morphology of AmB nanoparticles in AmB NPs/thermogel, while that of irregular morphology of merely AmB nanosuspensions without stabiliser and hydrogel materials. AmB could be sustained release for ∼12 h in vitro. In vivo drug content in the vaginal tissue was also evaluated with 87, 47, 33 and 6.7% drug remaining after 1, 3, 6 and 12 h, respectively. The in vivo anti-Candida test was conducted on candidiasis-infected mice model. In the same drug dose of 2.5 mg/kg, AmB NPs/thermogel showed better anti-Candida efficiency compared with commercial AmB effervescent tablet. This delivery system might show some insights for the vaginal formulation development of other hydrophobic antifungal drugs.

The development of progesterone-loaded nanofibers using pressurized gyration: A novel approach to vaginal delivery for the prevention of pre-term birth

Recent evidence has continued to support the applicability of progesterone in preventing preterm birth, hence the development of an appropriate vaginal delivery system for this drug would be of considerable interest. Here, we describe the development of progesterone-loaded bioadhesive nanofibers using pressurized gyration for potential incorporation into a vaginal insert, with a particular view to addressing the challenges of incorporating a poorly water-soluble drug into a hydrophilic nanofiber carrier. Polyethylene oxide and carboxymethyl cellulose were chosen as polymers to develop the carrier systems, based on previous evidence of their yielding mucoadhesive nanofibers using the pressurized gyration technique. The fabrication parameters such as solvent system, initial drug loading and polymer composition were varied to facilitate optimisation of fiber structure and efficiency of drug incorporation. Such studies resulted in the formation of nanofibers with satisfactory surface appearance, diameters in the region of 400 nm and loading of up to 25% progesterone. Thermal and spectroscopic analyses indicated that the drug was incorporated in a nanocrystalline state. Release from the drug-loaded fibers indicated comparable rates of progesterone dissolution to that of Cyclogest, a commercially available progesterone pessary, allowing release over a period of hours. Overall, the study has shown that pressurized gyration may produce bioadhesive progesterone-loaded nanofibers which have satisfactory loading of a poorly water-soluble drug as well as having suitable structural and release properties. The technique is also capable of producing fibers at a yield commensurate with practical applicability, hence we believe that the approach shows considerable promise for the development of progesterone dosage forms for vaginal application.

Controlled-release biodegradable nanoparticles: From preparation to vaginal applications

This study aimed to prepare poly (d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) with chitosan (CTS) surface modification to be used as a vaginal delivery system for antimycotic drugs. Clotrimazole was encapsulated with entrapment efficiencies of 86.1 and 68.9% into Clotrimazole-PLGA-NPs (CLT-PLGA-NPs) and PLGA-NPs with CTS-modified surface (CLT-PLGA-CTS-NPs), respectively. The later NPs exhibited a larger size and higher positive zeta potential (Z potential) in comparison to unmodified NPs. In vitro release kinetic studies indicated that Clotrimazole was released in percentages of >98% from both nanoparticulate systems after 18days. Antifungal activity and mucoadhesive properties of NPs were enhanced when CTS was added onto the surface. In summary, these results suggested that Clotrimazole loaded into PLGA-CTS-NPs has great potential for vaginal applications in treating vaginal infections generated by Candida albicans.

Novel mixed vesicles containing lactobacilli biosurfactant for vaginal delivery of an anti-Candida agent

The purpose of this work was to prepare and characterize an innovative formulation for vaginal delivery of econazole nitrate, commonly used for the treatment of Candida infections. A novel biosurfactant isolated from a vaginal Lactobacillus strain was used to prepare phosphatidylcholine based mixed vesicles. Biosurfactant was produced by Lactobacillus gasseri BC9, isolated from the vagina of a healthy premenopausal woman, and was chemically characterized by FT-IR and ESI-MS. Mixed vesicles, obtained through film rehydration and extrusion method, were characterized in terms of size, zeta potential, encapsulation efficiency, mucoadhesion properties and econazole release. Moreover, the antimicrobial activity of the mixed vesicles was tested towards both planktonic cultures and biofilms of Candida albicans. Biosurfactant produced by L. gasseri BC9 was composed by peptide-like molecules containing hydrocarbon chains and possessed a high surface activity together with a low critical micelle concentration. All the mixed vesicles presented optimal diameter range (226–337nm) for topical vaginal administration. Econazole-loaded mixed vesicles containing biosurfactant showed higher encapsulation efficiency and mucoadhesion ability with respect to vesicles containing Tween 80. Further, they allowed a sustained release of econazole nitrate, maintaining the antifungal activity against C. albicans planktonic culture. Notably, biosurfactant-based vesicles were significantly more active than free econazole in the eradication of Candida biofilm. In conclusion, mixed vesicles are promising new vaginal delivery systems for the potential employment in the treatment of chronic infections.

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.

Intravaginal Delivery Approaches for Contraception: An Overview with Emphasis on Gels.

The rising population with grave ramifications for the future is a fundamental issue, demanding for newer and better contraceptive modalities. Also, in order to achieve the contraceptive purpose, the choice of the most suitable delivery system is of unquestionable importance. Out of all dosage forms, vaginal gel formulations present indubitable benefits for contraceptive administration. Therefore, this review summarizes the history of research in the field of vaginal delivery systems with special emphasis on the development of vaginal gels containing safer and more effective contraceptive agents.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

A multi-microcarrier of metronidazole-biopolymers complexes as a potential vaginal delivery system

ABSTRACTThe advantages of multiparticulate carriers over monolithic one are well known. In this study, mucoadhesive micropellets (MPs) composed of metronidazole (MTZ)–polysaccharide(s) polyelectrolytes complexes were prepared to be used as a localized vaginal healthcare product. The prepared all-natural MPs were characterized using FTIR spectroscopy as well as scanning electron microscopy studies. The MPs were evaluated by determination of drug encapsulation efficiency (EE), particle size (PS), drug release parameters, and ex vivo bioadhesivity using vaginal mucosa. MP-D composed of (MTZ:alginate:polycarbophil = 1:0.5:0.5) attained the highest EE (97.67%) as well as the most extended drug release properties. Microbiological study comparing MP-D to the market product (Amrizole vaginal suppository) showed the superiority of MP-D by its capability to constantly inhibit fungal growth all-over 24 h, while Amrizole suppository was effective for only 8 h.

Self-emulsifying drug delivery systems: Design of a novel vaginal delivery system for curcumin

AimThe aim of this study was to develop a vaginal self-emulsifying delivery system for curcumin being capable of spreading, of permeating the mucus gel layer and of protecting the drug being incorporated in oily nanodroplets towards mucus interactions and immobilization. MethodsThe emulsifying properties of curcumin loaded SEDDS containing 30% Cremophor RH40, 20% Capmul PG-8, 30% Captex 300, 10% DMSO and 10% tetraglycol (SEDD formulation A) as well as 25% PEG 200, 35% Cremophor RH40, 20% Captex 355, 10% Caprylic acid and 10% Tween 80 (SEDD formulation B) after diluting 1+2 with artificial vaginal fluid were characterized regarding droplet size and zeta potential. Collagen swelling test was used to examine the irritation potential of SEDDS. Additionally to mucus binding studies, permeation studies in the mucus were performed. Furthermore, spreading potential of the novel developed formulations was compared with a commercial available o/w cream (non-ionic hydrophilic cream) on vaginal mucosa. ResultsSEDDS displayed a mean droplet size between 38 and 141nm and a zeta potential of −0.3 to −1.6mV. The collagen swelling test indicated no significant irritation potential of both formulations over 24h. An immediate interaction of unformulated curcumin with the mucus was determined, whereas both SEDDS facilitated drug permeation through the mucus layer. Formulation B showed a 2.2-fold improved transport ratio of curcumin compared to SEDD formulation A. In comparison to the vaginal cream, SEDD formulation A and B were able to spread over the vaginal mucosa and cover the tissue to a 17.8- and 14.8-fold higher extent, respectively. ConclusionAccording to these results, SEDDS seems to be a promising tool for vaginal application.

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.

Karakteristike terapijskih sistema za vaginalnu primenu

The lumen of vagina is the usual route for application of vaginal preparations with antimicrobial drug substances, however, good vascularisation and high permeability of the large surface of vaginal mucosa, as well as the circumvention of metabolic degradation in the gastrointestinal tract (GIT), favor the absorption of numerous active substances for systemic administration or targeted drug delivery in the uterus. The development of drug delivery systems for vaginal administration is a significant current strategy for improving therapy in this way, compared to conventional vaginal preparations, with the primary interest to ensure good spreading and prolonged retention at the site of administration and the desired profile of delivery of the active substance to the site of action or absorption. The article provides an overview of available data on vaginal rings, vaginal delivery systems for cervical maturation before childbirth and SILCS diaphragm. It was also pointed out the exceptional importance of intense development of vaginal rings with microbicides for effective prevention of human immunodeficiency virus (HIV) infection, as well as those designed for multipurpose prevention of pregnancy and sexually transmitted diseases.

Combining different types of multifunctional liposomes loaded with ammonium bicarbonate to fabricate microneedle arrays as a vaginal mucosal vaccine adjuvant-dual delivery system (VADDS)

To develop effective mucosal vaccines, two types of multifunctional liposomes, the mannosylated lipid A-liposomes (MLLs) with a size of 200nm and the stealth lipid A-liposomes (SLLs) of 50nm, both loaded with a model antigen and NH4HCO3, were fabricated together into microneedles, forming the proSLL/MLL-constituted microneedle array (proSMMA), which upon rehydration dissolved rapidly recovering the initial MLLs and SLLs. Mice vaccinated with proSMMAs by vaginal mucosa patching other than conventional intradermal administration established robust antigen-specific humoral and cellular immunity at both systemic and mucosal levels, especially, in the reproductive and intestinal ducts. Further exploration demonstrated that the MLLs reconstituted from the administered proSMMAs were mostly taken up by vaginal mucosal dendritic cells, whereas the recovered SLLs trafficked directly to draining lymph nodes wherein to be picked up by macrophages. Moreover, the antigens delivered by either liposomes were also cross-presented for MHC-I displaying by APCs thanks to lysosome escape and ROS (reactive oxygen species) stimulation, both of which occurred when lysosomal acidifying the liposome-released NH4HCO3 into CO2 and NH4+/NH3 to rupture lysosomes by gas expansion and to cause ROS production by excessive ammonia induction, resulting in a mixed Th1/Th2 type response which was also promoted by liposomal lipid A via activation of TLR4. In addition, vaginal vaccination of the engineered HSV2 antigen gD-loaded proSMMAs successfully protected mice from the virus challenge. Thus, the proSMMAs are in fact a vaccine adjuvant-dual delivery system capable of eliciting robust humoral and cellular immunity against the invading pathogens, especially, the sexually transmitted ones.

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.

Development and in vivo safety assessment of tenofovir-loaded nanoparticles-in-film as a novel vaginal microbicide delivery system.

Topical pre-exposure prophylaxis (PrEP) with antiretroviral drugs holds promise in preventing vaginal transmission of HIV. However, significant biomedical and social issues found in multiple past clinical trials still need to be addressed in order to optimize protection and users' adherence. One approach may be the development of improved microbicide products. A novel delivery platform comprising drug-loaded nanoparticles (NPs) incorporated into a thin polymeric film base (NPs-in-film) was developed in order to allow the vaginal administration of the microbicide drug candidate tenofovir. The system was optimized for relevant physicochemical features and characterized for biological properties, namely cytotoxicity and safety in a mouse model. Tenofovir-loaded poly(lactic-co-glycolic acid) (PLGA)/stearylamine (SA) composite NPs with mean diameter of 127nm were obtained with drug association efficiency above 50%, and further incorporated into an approximately 115μm thick, hydroxypropyl methylcellulose/poly(vinyl alcohol)-based film. The system was shown to possess suitable mechanical properties for vaginal administration and to quickly disintegrate in approximately 9min upon contact with a simulated vaginal fluid (SVF). The original osmolarity and pH of SVF was not affected by the film. Tenofovir was also released in a biphasic fashion (around 30% of the drug in 15min, followed by sustained release up to 24h). The incorporation of NPs further improved the adhesive potential of the film to ex vivo pig vaginal mucosa. Cytotoxicity of NPs and film was significantly increased by the incorporation of SA, but remained at levels considered tolerable for vaginal delivery of tenofovir. Moreover, histological analysis of genital tissues and cytokine/chemokine levels in vaginal lavages upon 14days of daily vaginal administration to mice confirmed that tenofovir-loaded NPs-in-film was safe and did not induce any apparent histological changes or pro-inflammatory response. Overall, obtained data support that the proposed delivery system combining the use of polymeric NPs and a film base may constitute an exciting alternative for the vaginal administration of microbicide drugs in the context of topical PrEP. The development of nanotechnology-based microbicides is a recent but promising research field seeking for new strategies to circumvent HIV sexual transmission. Different reports detail on the multiple potential advantages of using drug nanocarriers for such purpose. However, one important issue being frequently neglected regards the development of vehicles for the administration of microbicide nanosystems. In this study, we propose and detail on the development of a nanoparticle-in-film system for the vaginal delivery of the microbicide drug candidate tenofovir. This is an innovative approach that, to our best knowledge, had never been tested for tenofovir. Results, including those from in vivo testing, sustain that the proposed system is safe and holds potential for further development as a vaginal microbicide product.

Development of cyclodextrin hydrogels for vaginal delivery of dehydroepiandrosterone.

To develop a new vaginal delivery system for a sustained release of dehydroepiandrosterone (DHEA) in the treatment of postmenopausal symptoms, aimed to overcome the problems of poor bioavailability of the drug related to its very low water solubility. Cyclodextrin (CD)-containing hydrogels were developed, combining in a single device the hydrogel controlled release and mucoadhesion properties, and the CD solubilizing power towards DHEA. The effect of different CDs, alone or in mixtures, on the hydrogel technological and mucoadhesion characteristics was investigated. The best formulations were loaded with DHEA and characterized for loading efficiency and release properties. Hydrogels based on HPβCD/γCD (15/10%w/w) or HPβCD/HP γCD (30/20%w/w) combinations proved to be the most effective, giving ovules with the desired mechanical and mucoadhesive properties. Both formulations showed high drug loading efficiency, due to the solubilizing effect of CDs, and provided a sustained in-situ release, with a rate suitably tunable by varying the drug loaded amount and/or the CD combination. The proposed formulative strategy allowed to develop an intravaginal device with right consistency and elasticity, easy to apply, able to be retained in situ over 8 h, and to provide an effective DHEA loading and a tunable release rate.

Thiolated Cyclodextrin: Development of a Mucoadhesive Vaginal Delivery System for Acyclovir

The objective of this study was the development of a mucoadhesive vaginal delivery system for acyclovir (Acv). Sodium-per-iodate (NaIO4) was used to introduce aldehyde substructures into beta-cyclodextrin (β-CD) by oxidative cleavage of vicinal diol bonds. Cysteamine was covalently attached to β-CD-CHO via reductive amination. Ellman’s reagent was utilized for quantification of free thiol groups attached and resazurin assay was used for cytotoxicity studies. Mucoadhesive properties were evaluated on porcine vaginal mucosa in comparison to intestinal mucosa. Quantification of thiol groups revealed 851.84 ± 107, 1040.44 ± 132, and 1563.72 ± 171 μmol/g of free thiol groups attached to the β-CD-SH851, β-CD-SH1040, and β-CD-SH1563, respectively. β-CD-SH derivatives at concentrations of 0.5% (m/v) did not show significant reduction of viability of Caco-2 cells within 24 h. Furthermore, water solubility of β-CD-SH1563 was improved 7.6-fold in comparison to unmodified β-CD. β-CD-SH851, β-CD-SH1040, and β-CD-SH1563 showed 5.84-, 15.95-, and 17.14-fold improved mucoadhesive properties on porcine vaginal mucosa and 3-, 12.47-, and 32.13-fold on porcine intestinal mucosa, respectively. Inclusion complex of Acv with β-CD-SH1563 resulted in significantly improved drug dissolution. According to the results, β-CD-SH derivatives might be promising new tools for local vaginal delivery of Acv.

A critical appraisal of the misoprostol removable, controlled-release vaginal delivery system of labor induction.

BackgroundInduction of labor is a major issue in pregnancy management. Finding strategies to increase rate and decrease time to vaginal delivery is an important goal, but maternal or neonatal safety must remain the primary objective. Misoprostol is a synthetic analogue of prostaglandin used off label to ripen the cervix and induce labor. The misoprostol vaginal insert (MVI) was designed to allow a controlled-release delivery of misoprostol (from 50 to 200 μg) with a removal tape. The objective of this review was to make a critical appraisal of this device referring to the literature.MethodsA literature search was performed in the PubMed and Cochrane databases using the keywords “vaginal misoprostol insert”.ResultsSeveral studies compared different doses of MVI (50, 100, 150, and 200 μg) with the 10 mg dinoprostone insert. The 100 μg MVI compared with the dinoprostone vaginal insert (DVI) showed similar efficacy and no significant differences in cesarean delivery rate. MVI 200 μg compared with DVI showed a reduced time to vaginal delivery and oxytocin need but had an increased risk of uterine hyperstimulation. The rate of hyperstimulation syndrome was two to three times more frequent with the 200 μg MVI than the 100 μg.ConclusionCurrent data suggest that the 100 μg MVI would provide the best balance between efficacy and safety. Further studies should be performed to evaluate this dose, especially in high-risk situations needing induction of labor.