Vaginal Drug Delivery Research Articles

Acceptability and performance of a nonwoven device for vaginal drug delivery among women and their male partners in KwaZulu-Natal, South Africa

Background: Multipurpose prevention technologies are needed to provide protection against HIV and sexually transmitted infections. Gel-based vaginal microbicides inserted via an applicator are prone to leakage. A novel device for vaginal drug delivery was developed to contain gel-based formulations, aiming to improve gel retention and reduce leakage. The objectives of this study were to assess acceptability and performance of a nonwoven vaginal delivery device.Methods: A nonwoven vaginal delivery device was prepared, pre-saturated with a commercially available water-based lubricant, with a finger pocket for insertion and string for removal. Quantitative and qualitative methods were used to collect data from interviews with 40 women and 10 male partners recruited from a sexual and reproductive health clinic in Durban, KwaZulu-Natal, South Africa. Women wore one device in the clinic and one device overnight or with their partner during intercourse. The primary endpoint was acceptability including comfort, ease of insertion and removal, and opinions on device attributes.Results: Most women said the device was ‘easy’ to insert and remove. Six women reported leakage after insertion and 34 reported having sexual intercourse while wearing the device. One woman was lost-to-follow-up and five women only wore the device overnight because their partners did not agree to intercourse with the inserted device. The best-liked attribute was the device’s lubrication (22 women, 7 men); the least-liked was the removal string (9 women, 8 men).Conclusions: Data are promising for further development of this nonwoven device for vaginal drug delivery.Plain English summaryMultipurpose prevention technologies (MPTs) that protect against HIV and sexually transmitted infections (STIs) are urgently needed. A variety of vaginal gel-based products are actively being researched; however, these products can often have challenges with vaginal leakage and retention. This research investigates the acceptability and performance of a nonwoven device to deliver vaginal gel formulations. The gel used in this study was a currently available marketed personal lubricant. In South Africa, 40 women (and 10 male partners) were recruited and given the opportunity to comment on various device attributes after insertion, overnight wear and sexual intercourse with their male partners. Generally, participants found the device easy to use and acceptable, where many factors possibly contributed to the device’s acceptability (i.e., similarity to tampons, saturation with lubricant, minimal leakage, ease of insertion, comfort during intercourse and the male partners’ willingness to have vaginal intercourse with the device in place). Further studies of the vaginal delivery device for acceptability, safety and efficacy using a gel-based formulation with an active ingredient are warranted.

Nanocarriers For Vaginal Drug Delivery.

Vaginal drug delivery approach represents one of the imperative strategies for local and systemic delivery of drugs. The peculiar dense vascular networks, mucus permeability, and range of physiological characteristics of the vaginal cavity have been exploited for therapeutic benefit. Furthermore, the vaginal drug delivery has been curtailed due to the influence of different physiological factors like acidic pH, constant cervical secretion, microflora, cyclic changes during periods along with turnover of mucus of varying thickness. This review highlights advancement of nanomedicine and its prospective progress towards the clinic. Relevant literature reports and patents related to topics are retrieved and used. The extensive literature search and patent revealed that nanocarriers are efficacious over conventional treatment approaches. Recently, nanotechnology based drug delivery approach has promised better therapeutic outcomes by providing enhanced permeation and sustained drug release activity. Different nanoplatforms based on drugs, peptides, proteins, antigens, hormones, nucleic material, and microbicides are gaining momentum for vaginal therapeutics.

Mucoadhesive In Situ Gelling Liquid Crystalline Precursor System to Improve the Vaginal Administration of Drugs.

The vaginal mucosa is a very promising route for drug administration due to its high permeability and the possibility to bypass first pass metabolism; however, current vaginal dosage forms present low retention times due to their dilution in vaginal fluids, which hampers the efficacy of many pharmacological treatments. In order to overcome these problems, this study proposes to develop a mucoadhesive in situ gelling liquid crystalline precursor system composed of 30% of oleic acid and cholesterol (7:1), 40% of ethoxylated and propoxylated cetyl alcohol, and 30% of a dispersion of 16% Poloxamer 407. The effect of the dilution with simulated vaginal fluid (SVF) on this system was evaluated by polarized light microscopy (PLM), small-angle X-ray scattering (SAXS), rheological studies, texture profile analysis (TPA), mucoadhesion study, in vitro drug release test using hypericin (HYP) as drug model, and cytotoxicity assay. PLM and SAXS confirmed the formation of an isotropic system. After the addition of three different concentrations of SVF (30, 50, and 100%), the resultant formulations presented anisotropy and characteristics of viscous lamellar phases. Rheology shows that formulations with SVF behaved as a non-Newtonian fluid with suitable shear thinning for vaginal application. TPA and mucoadhesion assays indicated the formation of long-range ordered systems as the amount of SVF increases which may assist in the fixation of the formulation on the vaginal mucosa. The formulations were able to control about 75% of the released HYP demonstrating a sustained release profile. Finally, all formulations acted as safe vaginal drug delivery systems.

Current Advances in Chitosan Nanoparticles Based Drug Delivery and Targeting.

Nanoparticles (NPs) have been found to be potential targeted and controlled release drug delivery systems. Various drugs can be loaded in the NPs to achieve targeted delivery. Chitosan NPs being biodegradable, biocompatible, less toxic and easy to prepare, are an effective and potential tool for drug delivery. Chitosan is natural biopolymer which can be easily functionalized to obtain the desired targeted results and is also approved by GRAS (Generally Recognized as Safe by the United States Food and Drug Administration [US FDA]). Various methods for preparation of chitosan NPs include, ionic cross-linking, covalent cross-linking, reverse micellar method, precipitation and emulsion-droplet coalescence method. Chitosan NPs are found to have plethora of applications in drug delivery diagnosis and other biological applications. The key applications include ocular drug delivery, per-oral delivery, pulmonary drug delivery, nasal drug delivery, mucosal drug delivery, gene delivery, buccal drug delivery, vaccine delivery, vaginal drug delivery and cancer therapy. The present review describes the formation of chitosan, synthesis of chitosan NPs and their various applications in drug delivery.

Modifications in Vaginal Microbiota and Their Influence on Drug Release: Challenges and Opportunities.

Vaginal drug delivery represents an attractive alternative to achieve local and systemic effects due to the high contact surface exposed, the mucoadhesion of the epithelium, and the high innervation that facilitates the absorption of drugs into the bloodstream. However, despite the confinement of the vaginal cavity, it is an organ with a highly variable microenvironment. Mechanical alterations such as coitus, or chemical changes such as pH and viscosity, modify the release of drugs. In addition, changes in vaginal microbiota can influence the entire vaginal microenvironment, thus determining the disposition of drugs in the vaginal cavity and decreasing their therapeutic efficacy. Therefore, the influence of microorganisms on vaginal homeostasis can change the pre-established scenario for the application of drugs. This review aims to provide an explanation of normal vaginal microbiota, the factors that modify it, its involvement in the administration of drugs, and new proposals for the design of novel pharmaceutical dosage forms. Finally, challenges and opportunities directed toward the conception of new effective formulations are discussed.

An Overview of Nanogel –Novel Drug Delivery System

Nanogels are innovative drug delivery system that can play an integral part in pointing out many issues related to old and modern courses of treatment such as nonspecific effects and poor stability. Biomedical and pharmaceutical applications of Nanogels have been explored for tissue regeneration, wound healing, surgical device, implantation, and peroral, rectal, vaginal, ocular, and transdermal drug delivery. Nanogels are proficiently internalized by the target cells, avoid accumulating in nontarget tissues thereby lower the therapeutic dosage and minimize harmful side effects. Nanogels may be defined as highly cross linked nano-sized hydrogels ranges from 20-200 nm. They can be administered through various routes, including oral, pulmonary, nasal, parenteral, intra-ocular etc. They have a high degree of drug loading capacity and it shows better permeation capabilities due to smaller size. Nanogels are the novel drug delivery systems for both hydrophilic and hydrophobic drugs.

Evaluation of Topical Dispenser Systems for Vaginal Delivery of Feminine Medications

The vaginal route of administration has a large surface area with a rich blood supply demonstrating capacity for local absorption and systemic bioavailability of drugs. However, there are problems associated with current vaginal delivery method in terms of dosing precision and accuracy. In this report, the potential utility of the metered-dose Topi-CLICK^® Perl^™ system for vaginal delivery of feminine medication is presented. The aim was to evaluate the efficiency of Topi-CLICK^® Perl^™ for dosing accuracy, precision, and residual waste of medicaments relative to currently available dispensing systems. The results showed Topi-CLICK^® Perl^™ system to have the highest accuracy for a dose being correctly delivered more than 88% of the time. Whereas other commonly used dispenser systems, such as plastic or metal (aluminum) ointment tubes with smooth or ribbed applicators, exhibited not more than 10% of doses being within acceptable limits for accuracy. Medication waste was significantly minimized using Topi-CLICK^® Perl^™, which has an estimated overfill volume less than 6%. This required overfill volume ranged from 39% to 88% respectively, for the plastic and metal ointment tubes. Qualitatively, operators of Topi-CLICK^® Perl^™ found the metered-dose system the easiest to use with little mess. Based on these results, Topi-CLICK^® Perl^™ outperformed other traditional dispensing systems for vaginal drug delivery in accuracy and precision, with the least amount of residual medication waste.

Optimized Chitosan/Anion Polyelectrolyte Complex Based Inserts for Vaginal Delivery of Fluconazole: In Vitro/In Vivo Evaluation.

(1) Background: Fluconazole, used orally for vaginal candidiasis, has reported gastrointestinal side effects. Therefore, researchers directed towards the drug vaginal delivery. However, vaginal delivery is limited by poor retention and leakage. Thus, this work aimed at exploring chitosan/anion polyelectrolyte complex (PEC) for the formulation of fluconazole vaginal inserts with controlled release and appreciable mucoadhesion. (2) Methods: PECs were prepared and assessed for interactions. Fluconazole PEC based vaginal inserts were prepared by lyophilization using mannitol. 3151 factorial design was applied to investigate the effect of the anion type and Chitosan/anion ratio on the inserts mucoadhesion and release properties. The optimized insert [based on 5:5 chitosan: anionic polymer (sodium alginate)] release was modulated by the release retardant; Compritol® 888. The selected formulation was subjected to microbiological and histological evaluation. (3) Results: Fluconazole inserts showed satisfactory drug content, acceptable friability percentages and highest swelling indices at six hours. Statistical analysis showed significant effect of the studied factors on detachment force and release properties. Microbiological assays revealed significantly higher antifungal activity of inserts compared to fluconazole solution. Reduced inflammatory cells were confirmed by histological evaluation. (4) Conclusion: CH/Alg based vaginal insert could be a promising platform for vaginal delivery of antifungal drugs used for vaginal candidiasis treatment.

Qualitative exploration of intrinsic and extrinsic factors that influence acceptability of semisoft vaginal suppositories

BackgroundVaginal microbicides are a promising means to prevent the transmission of HIV and other sexually transmitted infections, by empowering women to initiate use prophylactically when they perceive themselves to be at risk. However, in clinical trials, microbicides have shown mixed results, with the consistent finding that effectiveness varies substantially as a function of user adherence.MethodsBased on the assumption that adherence is driven, at least in part, by product properties that influence acceptability, we used softgel technology to develop vaginal drug delivery systems in the intermediate texture space between solids and liquids to overcome potential shortcomings of current dosage forms. Here, we used focus groups and surveys to determine women’s initial reactions (i.e., acceptance and willingness-to-try) for semisoft vaginal suppositories intended for HIV and STI prevention, with a specific focus on how perception of and preferences for vaginal suppositories may be influenced by product characteristics such as size, shape, and firmness.ResultsVia focus groups, we identified intrinsic and extrinsic factors relevant to acceptability of semisoft suppository prototypes. Willingness-to-try depended on factors like intended functionality, anticipated leakage, type of sex, recommended frequency of use, type of sexual partner, and perceived risk. When handled ex vivo, shape, size, and firmness of suppositories communicated information about ease of imagined insertion and handling, perceived effectiveness, anticipated awareness and comfort of the product in the body. These impressions were partly based on prior experience with vaginal products.ConclusionsSensory attributes appear to play a substantial role in women’s preferences and willingness to try the semisoft suppositories. Using these methods during preclinical development should help efficiently optimize a final product that is both biologically efficacious and preferred by women, toward a goal of enhancing adherence and effectiveness.

Formulation and evaluation of in situ herbal gel containing aqueous and methanolic extract of fruits of Quercus infectoria Oliv. for vaginal application

Conventional vaginal dosage forms frequently produce leakages and drip. There is a need for the development of innovative vaginal formulation technology that fulfills certain criteria such as desirable product dispersion throughout the vagina, retention for intended intervals, and adequate release of drug. These features can be achieved by the use of bioadhesive based novel delivery systems. In-situ gelation is a process of gel formation at the site of application after the composition or formulation has been applied the site. Formulation and evaluation of one such bioadhesive based novel drug delivery system for an effective and patient friendly use of an antifungal drug to formulated In-situ gel. Quercus infectoria is medicinally important plant grown wildly in India and is useful in the treatment of fungal and microbial infection by tribal’s of India. The plant is used by tribal women to treat vaginal infection as mentioned in folk-lore. Therefore, the present plant as selected to formulate in-situ herbal gel using Quercus infectoria as active ingredients for the treatment of vaginal infection.
 Keywords: Herbal Gels, Quercus infectoria, bioadhesive, vaginal drug delivery

Solid state 13C NMR spectroscopy provides direct evidence for reaction between ethinyl estradiol and a silicone elastomer vaginal ring drug delivery system

Steroid molecules have a long history of incorporation into silicone elastomer materials for controlled release drug delivery applications. Previously, based on in vitro release testing and drug content analysis, we demonstrated indirectly that the contraceptive progestin levonorgestrel (LNG) chemically and irreversibly binds to addition cure silicone elastomers, presumably via a hydrosilylation reaction between the levonorgestrel ethynyl group and the hydrosilane groups in the poly(dimethylsiloxane-co-methylhydrosiloxane) crosslinker of the silicone elastomer. Here, for the first time, we report that solid state 13C nuclear magnetic resonance (NMR) spectroscopy provides direct evidence for the irreversible binding of ethinyl estradiol (EE) – an estrogenic steroid molecule also containing an ethynyl functional group – to an addition cure silicone elastomer. By preparing silicone elastomer samples containing 13C-labelled EE, signals in the NMR spectra could readily be assigned to both the free and bound EE. Additional depolymerisation studies, performed on an addition cure silicone elastomer system from which the unbound EE fraction was completely extracted, further confirmed the presence of bound EE through the formation of coloured reaction mixtures resulting from the reaction of bound EE and trifluoroacetic acid (TFA). These methods will be particularly useful in the ongoing development of new steroid-releasing silicone drug delivery devices, including various vaginal ring devices for contraception, HIV prevention and multipurpose prevention technology 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.

Approaches in Polymeric Nanoparticles for Vaginal Drug Delivery: A Review of the State of the Art.

The vagina is a region of administration with a high contact surface to obtain local or systemic effects. This anatomical area represents special interest for government health systems for different sexually transmitted infections. However, the chemical changes of the vagina, as well as its abundant mucus in continuous exchange, act as a barrier and a challenge for the development of new drugs. For these purposes, the development of new pharmaceutical forms based on nanoparticles has been shown to offer various advantages, such as bioadhesion, easy penetration of the mucosa, and controlled release, in addition to decreasing the adverse effects of conventional pharmaceutical forms. In order to obtain nanoparticles for vaginal administration, the use of polymers of natural and synthetic origin including biodegradable and non-biodegradable systems have gained great interest both in nanospheres and in nanocapsules. The main aim of this review is to provide an overview of the development of nanotechnology for vaginal drug release, analyzing the different compositions of polymeric nanoparticles, and emphasizing new trends in each of the sections presented. At the end of this review, a section analyzes the properties of the vehicles employed for the administration of nanoparticles and discusses how to take advantage of the properties that they offer. This review aims to be a reference guide for new formulators interested in the vaginal route.

Nanogels for Pharmaceutical and Biomedical Applications and Their Fabrication Using 3D Printing Technologies.

Nanogels are hydrogels formed by connecting nanoscopic micelles dispersed in an aqueous medium, which give an opportunity for incorporating hydrophilic payloads to the exterior of the micellar networks and hydrophobic payloads in the core of the micelles. Biomedical and pharmaceutical applications of nanogels have been explored for tissue regeneration, wound healing, surgical device, implantation, and peroral, rectal, vaginal, ocular, and transdermal drug delivery. Although it is still in the early stages of development, due to the increasing demands of precise nanogel production to be utilized for personalized medicine, biomedical applications, and specialized drug delivery, 3D printing has been explored in the past few years and is believed to be one of the most precise, efficient, inexpensive, customizable, and convenient manufacturing techniques for nanogel production.

Investigation of sustained release mucoadhesive in-situ gel system of Secnidazole for the persistent treatment of vaginal infections

Vaginitis is a common infection caused by bacteria and fungi leading to inflammation, itching and redness in the vaginal mucosal region, which can be treated by antibacterial and antifungal drug therapy. The current work is focused on development of aerosol foam formulation of an in situ gel for treatment of vaginitis. For this purpose, in situ gel formulations were prepared using carbopol 940, carrageenan and cellulose polymers at different composition and converted to foam spray using sodium lauryl sulphate as foaming agent. The prepared formulations were evaluated for standard quality parameters and the results confirmed the significance of the optimized formulation to deliver the drug in vaginal region and provide sustained release for 8 h. Based on the results obtained, it was evident that the in situ gel formulations comprising of 0.45% of carbopol 940 with 0.35% HPMC K4M and the 0.35% of carbopol 940 with 0.35% HPC were optimum for gelation process. These formulations also released less than 50% of drug in simulated vaginal fluid at the end of 8 h. In conclusion, optimization of polymer concentration for the in vivo gelation process would be the efficient way to develop stable vaginal drug delivery systems.

Dynamic mechanical behaviour of nanoparticle loaded biodegradable PVA films for vaginal drug delivery.

In this study, we investigated the viscoelastic and mechanical behaviour of polyvinyl alcohol films formulated along with carrageenan, plasticizing agents (polyethylene glycol and glycerol), and when loaded with nanoparticles as a model for potential applications as microbicides. The storage modulus, loss modulus and glass transition temperature were determined using a dynamic mechanical analyzer. Films fabricated from 2% to 5% polyvinyl alcohol containing 3 mg or 5 mg of fluorescently labeled nanoparticles were evaluated. The storage modulus and loss modulus values of blank films were shown to be higher than the nanoparticle-loaded films. Glass transition temperature determined using the storage modulus, and loss modulus was between 40-50℃ and 35-40℃, respectively. The tensile properties evaluated showed that 2% polyvinyl alcohol films were more elastic but less resistant to breaking compared to 5% polyvinyl alcohol films (2% films break around 1 N load and 5% films break around 7 N load). To our knowledge, this is the first study to evaluate the influence of nanoparticle and film composition on the physico-mechanical properties of polymeric films for vaginal drug delivery.

Development of Thiolated Chitosan Nanoparticles Based Mucoadhesive Vaginal Drug Delivery Systems

The aim of the present study was to evaluate the influence of the chitosan chain length on the drug loading and releasing in VFS (vaginal fluid simulant). Thiolated chitosan nanoparticles (TCS-NPs) were prepared using thioglycolic acid and 1-ethyl-3-3-(3-dimethylaminopropyl)carbodimide hydrochloride (EDC) and characterized with FTIR. The degree of thiol substitution was found out by Ellman’s method. TCS-NPs were developed using ionic cross-linking reaction with pentasodiumtripolyphosphate (TPP). Curcumin (CUR) loaded nanoparticles were obtained by encapsulation. DLS and SEM characterized these NPs with diameter between 200 ± 50 nm. Zeta potential of NPs was 11–38 mv. The maximal encapsulation efficiency was 86.26%. The in vitro drug release studies in VFA at pH 4.2 showed a sustained release profile over a period of 3 days.

Chitosan Ascorbate Nanoparticles for the Vaginal Delivery of Antibiotic Drugs in Atrophic Vaginitis.

The aim of the present work was the development of chitosan ascorbate nanoparticles (CSA NPs) loaded into a fast-dissolving matrix for the delivery of antibiotic drugs in the treatment of atrophic vaginitis. CSA NPs loaded with amoxicillin trihydrate (AX) were obtained by ionotropic gelation in the presence of pentasodium tripolyphosphate (TPP). Different CSA:TPP and CSA:AX weight ratios were considered and their influence on the particle size, polydispersion index and production yield were investigated. CSA NPs were characterized for mucoadhesive, wound healing and antimicrobial properties. Subsequently, CSA NPs were loaded in polymeric matrices, whose composition was optimized using a DoE (Design of Experiments) approach (simplex centroid design). Matrices were obtained by freeze-drying aqueous solutions of three hydrophilic excipients, polyvinylpirrolidone, mannitol and glycin. They should possess a mechanical resistance suitable for the administration into the vaginal cavity and should readily dissolve in the vaginal fluid. In addition to antioxidant properties, due to the presence of ascorbic acid, CSA NPs showed in vitro mucoadhesive, wound healing and antimicrobial properties. In particular, nanoparticles were characterized by an improved antimicrobial activity with respect to a chitosan solution, prepared at the same concentration. The optimized matrix was characterized by mechanical resistance and by the fast release in simulated vaginal fluid of nanoparticles characterized by unchanged size.

Entirely S-protected chitosan: A promising mucoadhesive excipient for metronidazole vaginal tablets

Synthesis and evaluation of an entirely S-protected chitosan as mucoadhesive excipient for vaginal drug delivery. N-acetyl-cysteine was linked to 6-mercaptonicotinamide via disulphide exchange reaction. The obtained ligand, NAC-6-MNA, was subsequently attached to chitosan by carbodiimide mediated amide bond formation in two concentrations. The synthesized S-protected chitosan was chemically characterized and mucoadhesive properties and stability against oxidation were investigated. Moreover, metronidazole tablets comprising the S-protected chitosan were evaluated regarding water uptake capacity, disintegration behaviour, residence time on vaginal mucosa, release of the encapsulated drug and antimicrobial activity. S-protected chitosan displayed 160±19 (CS-MNA-160) and 320±38 (CS-MNA-320)µmol of ligand per gram of polymer. At pH 4.2, CS-MNA-160 and CS-MNA-320 showed 5.2-fold and 6.2-fold increase in mucus viscosity in comparison to unmodified chitosan (One-way ANOVA, p<.001), whereas, 9.9-fold (CS-MNA-160) and 15.6-fold (CS-MNA-320) (One-way ANOVA, p<.001) increase in viscosity was measured at pH 6. The S-protected chitosan remained stable against oxidation in presence of 0.5%v/v hydrogen peroxide. Metronidazole tablets consisting in S-protected chitosan showed prolonged residence time on vaginal mucosa and improved water uptake capacity and disintegration time in comparison to tablets consisting of unmodified chitosan. Moreover, CS-MNA-320 metronidazole tablets displayed prolonged drug release and antimicrobial activity. On the basis of the achieved results, entirely S-protected chitosan represents a promising excipient for the development of metronidazole vaginal tablets. S-protected thiomers are polymers modified with thiol groups protected by aromatic ligands and characterized by strong mucoadhesive properties and high stability against oxidation. Up to date, the entirely S-protection of thiol groups was achieved via the synthesis of the ligand 2-((2-amino-2-carboxyethyl)disulfanyl)nicotinic acid) which can be directly bound to the backbone of polymers bearing carboxylic moieties as pectin. However, this ligand is not suitable for positively charged polymers due to the negative charge. In this paper, the synthesis of a suitable ligand for the entirely S-protection of positively charged polymers is presented. The first entirely S-protected chitosan was synthesized, characterized and its mucoadhesive properties were assessed. Moreover, metronidazole tablets comprising the entirely S-protected chitosan were developed and evaluated as vaginal drug delivery system.

Surface-modified mucoadhesive microgels as a controlled release system for miconazole nitrate to improve localized treatment of vulvovaginal candidiasis

The use of conventional vaginal formulations of miconazole nitrate (MN) in the treatment of deep-seated VVC (vulvovaginal candidiasis) is limited by poor penetration capacity and low solubility of MN, short residence time and irritation at the application site. Surface-modified mucoadhesive microgels were developed to minimize local irritation, enhance penetration capacity and solubility and prolong localized vaginal delivery of MN for effective treatment of deep-seated VVC. Solid lipid microparticles (SLMs) were prepared from matrices consisting of hydrogenated palm oil (Softisan® 154, SF) and super-refined sunseed oil (SO) with or without polyethylene glycol (PEG)-4000, characterized for physicochemical performance and used to prepare mucoadhesive microgels (MMs) encapsulating MN, employing Polycarbophil as bioadhesive polymer. The MMs were evaluated for physicochemical performance and in vitro drug release in simulated vaginal fluid (pH=4.2), whereas mucoadhesive, rheological and stability tests, anticandidal efficacy in immunosuppressed estrogen-dependent female rats and vaginal tolerance test in rabbits were performed with optimized formulation. The amorphicity of 1:9 phytolipid blend (SO:SF) was increased in the presence of PEG-4000. The physicochemical properties of the SLMs and MMs indicated their suitability for vaginal drug delivery. Overall, MN-loaded PEGylated MMs exhibited significantly (p<0.05) more prolonged drug release than non-PEGylated MMs. Additionally, optimized PEGylated MMs was stable at 40±2°C over a period of 6months, viscoelastic, mucoadhesive, non-sensitizing, histopathologically safe and gave remarkably (p<0.05) higher reduction in Candida albicans load (86.06%) than Daktarin® (75.0%) and MN-loaded polymeric-hydrogel (47.74%) in treated rats in 12days. Thus, PEGylated MMs is promising for effective and convenient treatment of VVC.