Vaginal Drug Delivery Systems Research Articles

Novel Vaginal Drug Delivery Systems: A Review

The vagina, in addition to being a genital organ with functions related to conception, serves as a potential route for drug administration. Mainly used for local action in the cervico-vaginal region, it has the potential of delivering drugs for systemic effects and uterine targeting. Within recent years the level of interest in both local and systemic vaginal drug delivery systems has increased considerably. The vagina offers numerous advantages as a site for drug delivery, such as convenient access, prolonged retention of formulations, a great permeation area, high vascularization, relatively low enzymatic activity, and the avoidance of first-pass metabolism. Currently available vaginal dosage forms have several limitations, such as leakage and messiness necessitating the need to develop novel drug delivery systems. The purpose of writing this review was to compile the recent literature on novel vaginal drug delivery systems. Keywords: Novel vaginal delivery systems, polymers, drugs used in vaginal delivery

Nanoparticle-based vaginal drug delivery systems for HIV prevention

Importance of the Field: Several strategies are being investigated for the prevention of heterosexual transmission of HIV. Of these, topical vaginal drug delivery systems, microbicides, are being actively pursued. HIV prevention by means of a topical microbicide has several drug delivery challenges. These challenges include the vaginal mucosal barriers and potential degradation of the drugs in the vaginal lumen due to pH and enzymes present. Also, new drugs being evaluated as microbicides have specific mechanisms of action, which in some cases require drug targeting to a specific site of action. Nanoparticles provide a delivery strategy for targeted or controlled delivery to the vagina which can be applied in the field of HIV prevention.Areas covered in the review: This review summarizes nanoparticulate systems and their use in mucosal delivery to date. The sexual transmission of HIV along with the various targets to prevent transmission are discussed as well as the potential opportunities, challenges and advantages in using a nanoparticle-based approach for microbicidal drug delivery.What the reader will gain: This review provides a general understanding of vaginal drug delivery, its challenges, and nanoparticulate delivery systems. Additionally, insight will be gained as to the limited existing application of this technology to the field of HIV prevention.Take home message: To date, few studies have been published that exploit nanoparticle-based microbicidal delivery to the vagina. The use of nanoparticles for vaginal drug delivery provides an approach to overcome the existing barriers to success.

Mucoadhesive Vaginal Drug Delivery Systems

Vaginal delivery is an important route of drug administration for both local and systemic diseases. The vaginal route has some advantages due to its large surface area, rich blood supply, avoidance of the first-pass effect, relatively high permeability to many drugs and self-insertion. The traditional commercial preparations, such as creams, foams, gels, irrigations and tablets, are known to reside in the vaginal cavity for a relatively short period of time owing to the self-cleaning action of the vaginal tract, and often require multiple daily doses to ensure the desired therapeutic effect. The vaginal route appears to be highly appropriate for bioadhesive drug delivery systems in order to retain drugs for treating largely local conditions, or for use in contraception. In particular, protection against sexually-transmitted diseases is critical. To prolong the residence time in the vaginal cavity, bioadhesive therapeutic systems have been developed in the form of semi-solid and solid dosage forms. The most commonly used mucoadhesive polymers that are capable of forming hydrogels are synthetic polyacrylates, polycarbophil, chitosan, cellulose derivatives (hydroxyethycellulose, hydroxy-propylcellulose and hydroxypropylmethylcellulose), hyaluronic acid derivatives, pectin, tragacanth, carrageenan and sodium alginate. The present article is a comprehensive review of the patents related to mucoadhesive vaginal drug delivery systems.

Design and in vitro evaluation of a novel bioadhesive vaginal drug delivery system for clindamycin phosphate

To develop more effective treatment for bacterial vaginosis, bioadhesive film formulations of clindamycin phosphate (CL) for vaginal delivery were studied. The bioadhesive films were prepared by solvent evaporation method. A 32 full factorial design was utilized for optimization of the effect of independent variables such as amount of hydroxypropyl cellulose (X1), amount of xanthan gum (X2) on mechanical properties, and % drug retained on vaginal mucosa. The films were evaluated for various aesthetic and physicodynamic properties. Batch F86 showed highest overall desirability of 0.99. Batch F86 was considered optimal composition for a novel bioadheive vaginal formulation, as they have good peelability, high % elongation at break, moderate tensile strength, and retained on vaginal mucosa up to 8 h. Also, films were non-cytotoxic as indicated by negligible decrease in cell viability. Our study may provide a potential vaginal delivery system of CL against bacterial vaginosis.

A Novel Itraconazole Bioadhesive Film for Vaginal Delivery: Design, Optimization, and Physicodynamic Characterization

The purpose of this work was to design and optimize a novel vaginal drug delivery system for more effective treatment against vaginal candidiasis. Itraconazole was formulated in bioadhesive film formulations that could be retained in the vagina for prolonged intervals. The polymeric films were prepared by solvent evaporation and optimized for various physicodynamic and aesthetic properties. In addition, percentage drug retained on vaginal mucosa was evaluated using a simulated dynamic vaginal system as function of time. A polymeric film containing 100 mg itraconazole per unit (2.5 cm x 2.5 cm) have been developed using generally regarded as safe listed excipients. The pH of vaginal film was found to be slightly acidic (4.90 +/- 0.04) in simulated vaginal fluid and alkaline (7.04 +/- 0.07) in water. The little moisture content (7.66 +/- 0.51% w/w) was present in the film, which helps them to remain stable and kept them from being completely dry and brittle. The mechanical properties, tensile strength, and percentage elongation at break (9.64 N/mm(2) and 67.56% for ITRF(65)) reveal that the formulations were found to be soft and tough. The films (ITRF(65)) contained solid dispersion of itraconazole (2.5)/hydroxypropyl cellulose (1)/polyethylene glycol 400 (0.5), which was found to be the optimal composition for a novel bioadhesive vaginal formulation, as they showed good peelability, relatively good swelling index, and moderate tensile strength and retained vaginal mucosa up to 8 h. Also, the film did not markedly affect normal vaginal flora (lactobacillus) and was noncytotoxic as indicated by the negligible decrease in cell viability.

Design and In Vitro Evaluation of a Novel Vaginal Drug Delivery System Based on Gelucire

Carbamazepine indicated for the control of epilepsy, undergoes extensive hepatic first-pass metabolism after oral administration. A vaginal dosage form of carbamazepine is not commercially available. Conventional suppository having poor retention in the vaginal tract, as they are removed in a short time by the tract's self-cleansing action, having poor patient compliance. To overcome such problems, delivery system with mucoadhesive polymers polyox WSR N-60K and Ucarflock 302 that prolong drug permanence on the vaginal mucosa were developed. In the present study the suitability of gelucires to formulate vaginal pesseries was investigated. The possible modification of carbamazepine release kinetics by using gelucires blends and hydrophilic additives in the pesseries was evaluated. It was observed that among gelucire grades melting point higher than 37 degrees C, the release rate proved to be highly dependant on HLB value and matrix composition. In most of the formulations carbamazepine release occurred by disintegration and erosion of the matrices which is depending upon the vehicle employed. The aging study revealed that the formulations containing G50/13 and G50/13-G44/14 blends undergo some changes during one year of shelf aging. From the results obtained it can be concluded that different gelucire grades and their blends along with hydrophilic polymer could be successesively used to formulate prolong release carbamazepine pesseries.

Vaginal Drug Delivery Systems for HIV Prevention

Microbicides have become a principal focus for HIV prevention strategies. The successful design of drug delivery systems for vaginal microbicide drug candidates brings with it a multitude of challenges. It is imperative that the chemical and physical characteristics of the drug candidate and its mechanism of action be clearly understood and considered to successfully deliver and target drug candidates efficiently. In addition, an understanding of the dynamic nature of the vaginal environment, the tissue and innate barriers present, as well as patient preferences are critical considerations in the design of effective microbicide products. Although the majority of drug candidates clinically evaluated to date have been delivered using conventional semisolid aqueous-based gel dosage forms, drug delivery system design has recently been extended to include advanced delivery systems such as vaginal rings, quick-dissolve films, and tablets. Ultimately, it may be necessary to develop multiple dosage platforms for a single active agent to provide users with options that can be used within the constraints of their social environment, personal choice, and environmental conditions.

Compressed matrix dual-component vaginal drug delivery system containing metoclopramide hydrochloride

The purpose of the present investigation was to produce a quick/slow biphasic delivery system for metoclopramide hydrochloride using the superdisintegrant Ac-di-sol for the fast release layer and hydroxypropyl methylcellulose K100M and Ucarflock 302 to modulate the release of the drug. A dual component tablet made up of a sustained release and an immediate release layer was prepared by direct compression. A 3(2) full factorial design was applied to systematically optimize the drug release profile of the sustained release layer. The results of the full factorial design indicate that a small amount of HPMC K100M and a large amount of Ucarflock 302 favor sustained release of the metoclopramide hydrochloride vaginal dual component system. The ex vivo residence time reveals that the formulation was retained for more than 10 h. The formulation gave an initial burst effect to provide the loading dose of the drug followed by sustained release for 12 h, thus solving the problem of repeated administration, especially in pregnancy.

Vaginal drug delivery systems: A Review of Current Status

Among the various routes of drug delivery, the vaginal route offers many advantages due to its large permeation area, rich vascularization, avoidance of first pass metabolism and relatively low enzymatic activity. Several studies have shown that the vaginal cavity is an effective route for drug administration intended mainly for local action. In addition, it has the potential of delivering drugs for systemic effects and uterine targeting. Use of the vaginal mucosa for drug absorption was first attempted by Sobrero and since then much research has been done on the administration of drugs through this route. In recent years, the level of interest in the design and application of different dosage forms for vaginal use has increased considerably. Vaginal drug delivery specifically refers to the delivery of drugs within or through the vaginal mucosa for local or systemic pharmacological action. The rate and extent of drug absorption after intravaginal administration may vary depending on vaginal physiology, age of the patient, stage in the menstrual cycle, pathological conditions and formulation factors. This review highlights the benefits and limitations of vaginal drug delivery, methodology in evaluation of vaginal drug delivery systems, pharmaceutical aspects and gives a summary of recent advances made in the field of vaginal drug delivery. The various dosage forms in different stages of development and in the market are also reviewed. Keywords: Vaginal delivery, microbicide delivery, solubility modifier, bioadhesion; formulation design.East and Central African Journal of Pharmaceutical Studies Vol. 10 (1) 2007: pp. 3-13

Polymers for Mucoadhesive Drug Delivery System: A Current Status

To overcome the relatively short gastrointestinal (GI) time and improve localization for oral controlled or sustained release drug delivery systems, bioadhesive polymers that adhere to the mucin/epithelial surface are effective and lead to significant improvement in oral drug delivery. Improvements are also expected for other mucus-covered sites of drug administration. Bioadhesive polymers find application in the eye, nose, and vaginal cavity as well as in the GI tract, including the buccal cavity and rectum. This article lays emphasis mainly on mucoadhesive polymers, their properties, and their applications in buccal, ocular, nasal, and vaginal drug delivery systems with its evaluation methods.

Intravaginal gels as drug delivery systems.

Recently, there has been a great deal of interest in the design and application of different dosage forms via the vaginal route. Several studies have proven that the vagina is an effective route for drug administration intended mainly for local action, but systemic effects of some drugs also can be attained. The major advantages of this route include accessibility, good blood supply, the ability to bypass first-pass liver metabolism, and permeability to large molecular weight drugs, such as peptides and proteins. Among the delivery systems proposed for this route is the use of intravaginal gels, which have been found to be potential vaginal drug delivery systems. The bioadhesives used in the formulation of gels play a key role in the release of the drug through the attachment to the vaginal mucosa, where the drug diffuses from the gel to the mucus.

Intravaginal Drug Delivery Systems

Within recent years the level of interest in both local and systemic vaginal drug delivery systems has increased considerably. The vagina offers numerous advantages as a site for drug delivery, such as convenient access, prolonged retention of formulations, a great permeation area, high vascularization, relatively low enzymatic activity, and the avoidance of first-pass metabolism.

Characterization of a female controlled drug delivery system for microbicides

In this study, the feasibility of a carbopol 934P-HPMC-based gel formulation as a vaginal drug delivery system was evaluated. A vaginal fluid simulant (VFS) was utilized to simulate human vaginal mucus. The viscosity of the carbopol-HPMC gel system and VFS was examined using a cone and plate viscometer. The surface tension of VFS was measured using a capillary rising method. Differential scanning calorimetry (DSC) was employed to investigate the effect of carbopol gel on the conformational changes of rat vaginal membrane. The viscosity of carbopol gel increased as the pH of the system increased from 4.0 to 6.0. The viscosity of HPMC gel remained the same irrespective of pH of the system. The viscosity of the carbopol gel significantly increased, when HPMC (0.5–1.5%) was added to the system. The optimal viscosity value (1.5∼2.0 poises) was achieved at 1.0∼1.5% carbopol (pH 4.0) with the presence of 1.0∼1.5% HPMC. There were mucin concentration dependent changes in viscosity and surface tension of VFS. The results of DSC analysis of rat vaginal membrane showed that the profiles of thermal stability for both carbopol-treated and the untreated control at the temperature ranging from 40 to 90°C were almost identical. The thermal denaturation temperatures (Td) of the carbopol-treated membrane and the untreated control were not significantly different from each other. The combination of carbopol and HPMC seems to be an ideal formulation as a vaginal delivery system. Mucin played an important role in the regulation of viscosity and surface tension of VFS. DSC study demonstrated that carbopol gel showed good biocompatibility and did not cause any conformational changes in rat vaginal membrane.

Design and in vitro evaluation of a novel bioadhesive vaginal drug delivery system for clotrimazole

It was the purpose of this study to design and evaluate a new bioadhesive vaginal drug delivery system for clotrimazole. Chitosan, a cationic biopolymer derived by deacetylation of chitin, was modified by the introduction of thioglycolic acid (TGA). The modification was achieved by utilising a carbodiimide to link the carboxylic acid moieties of TGA covalently to the primary amino groups of chitosan. The amount of added carbodiimide was thereby varied, resulting in chitosan–TGA conjugates A and B with 160 μM (=μmol) and 280 μM thiol groups per gram polymer, respectively. In order to characterise the new polymers the water uptake, the disintegration behaviour, the bioadhesive properties utilising the rotating cylinder method, as well as the release of clotrimazole from tablets based on these derivatives were studied. The water uptake and cohesive properties of vaginal tablets consisting of these new conjugates could be significantly ( p<0.05) improved. By adding clotrimazole the disintegration time of the conjugates was prolonged 1.6-fold for conjugate A and even 100-fold for conjugate B. Furthermore, the adhesion on vaginal mucosal tissue could be significantly improved. The addition of clotrimazole had also an impact on the adhesion time of chitosan–TGA conjugate B, which remained 26-times longer on vaginal mucosa than the corresponding unmodified polymer. The immobilisation of thiol groups guarantees a controlled drug release. Results of this study demonstrate that these new chitosan–TGA conjugates are very promising vehicles for the vaginal application of clotrimazole in treatment of mycotic infections.

Assemblies for In Vitro Measurement of Bioadhesive Strength and Retention Characteristics in Simulated Vaginal Environment

ABSTRACTThe vaginal route of administration offers a promising option for local and systemic delivery of drugs. Conventional vaginal formulations are associated with limitations of poor retention, leakage, and messiness, thereby causing inconvenience to users. To overcome these limitations, formulations that adhere to the vaginal mucosa for a sufficient period of time need to be developed. Bioadhesion and retention are desirable characteristics of a vaginal formulation to achieve desired efficacy. These properties can be built in during formulation development by the use of bioadhesive polymers. In the present study, assemblies for in vitro measurement of bioadhesive strength and retention characteristics of vaginal formulations have been developed. A modified simulated vaginal fluid (SVFM) was used to simulate vaginal conditions for bioadhesion studies. Cellophane hydrated with SVFM and isolated sheep vaginal mucosa were used as model membranes. The bioadhesive potential of various polymers and their combinations was evaluated. Among the polymers evaluated, xanthan gum (XG), sodium alginate (SA), Polycarbophil (PC), and their combinations (XG + SA and XG + PC) were found to possess significant bioadhesive strength. In retention experiments, XG, SA, and combinations (XG + SA and XG + PC) were retained in isolated sheep vaginal tissue, while PC exhibited poor retention under experimental conditions. Based on the results of the study conducted, XG, SA, and combinations (XG + SA and XG + PC) have been proposed as potential candidates for developing bioadhesive vaginal drug delivery systems.

Novel vaginal danazol ring therapy for pelvic endometriosis, in particular deeply infiltrating endometriosis.

Danazol is routinely administered orally to inhibit ovulation and to treat pelvic endometriosis. However, recent evidence suggests that danazol can act directly on endometriotic tissue in vitro to inhibit DNA synthesis and induce apoptosis. Danazol was administered via the vagina in this study, using a vaginal ring drug delivery system containing 1500 mg of danazol. This therapy was effective for treatment of pelvic endometriosis, especially for deeply infiltrating endometriosis, resulting in a cure of dysmenorrhoea and tenderness in the cul-de-sac within 3 months, and of induration or nodularity in the cul-de-sac within 7 months. Moreover, conception was possible during insertion of the vaginal ring in 17 out of 31 infertile women with deeply infiltrating endometriosis, and in two out of eight infertile women with ovarian endometriotic cysts not adhering to the cul-de-sac and without deeply infiltrating endometriosis. Serum danazol concentrations, high during oral daily 400 mg danazol therapy, but undetectable during vaginal danazol ring therapy, explain why ovulation and conception could occur during insertion of the vaginal danazol ring, and why general side-effects, which are often observed during oral danazol therapy, were not observed during vaginal danazol ring therapy. Danazol seems to be absorbed through the vaginal mucosa and reaches the deeply infiltrating endometriosis via diffusion.

In vitro retinoid binding and release from a collagen sponge material in a simulated intravaginal environment.

Four in vitro preparations were constructed to simulate the intravaginal release of two retinoids, all-trans-retinoic acid (t-RA) and 13-cis-retinoic acid (c-RA), from a 0.7% collagen sponge diaphragm insert. Four t-RA concentrations, 0.019, 0.05, 0.1, and 0.15% in methanol were added to the sponge. The release into an artificial vaginal fluid was monitored serially over 72 h by serial analysis for t-RA and c-RA using high-pressure liquid chromatography. In each preparation, retinoid release was immediate and noncontinuous. At 37 degrees C, the retinoids were stable for at least 48 h. Trans-retinoic acid was the predominant retinoid recovered. Only trace amounts of the cis-isomer were released. Peak t-RA levels were 20 microM after 0.01%, 60-80 microM after 0.05%, 100-200 microM after 0.1%, and 320 microM after 0.15%. When the vaginal fluid bath was changed after 5 h, no further significant retinoid release occurred. There was significant loss of up to 70% of the applied t-RA into the collagen sponge. The retinoid binding was concentration dependent (higher binding with higher concentrations) and was maximal only after 24 h of co-incubation. The discontinuous release of t-RA and the high degree of binding to collagen would seem to preclude use of the diaphragm insert as a vaginal drug delivery system, at least for retinoids.