Layer-by-layer vaginal films for acyclovir controlled release to prevent genital herpes.

Genital herpes is one of the most common sexually transmitted infections worldwide. It mainly affects women, as the rate of sexual transmission from male-to-female is higher than from female-to-male. The application of vaginal antivirals drugs could reduce the prevalence of genital herpes and prevent future infections. Layer-by-layer vaginal films were prepared by the solvent evaporation method using iota-carrageenan, hydroxypropyl methylcellulose and the polymethacrylates Eudragit® RS PO and Eudragit® S100, for the controlled release of acyclovir. The films were characterized by texture analysis and Raman spectroscopy. Swelling, mucoadhesion, and drug release studies were conducted in simulated vaginal fluid. The results show that Layer-by-Layer films exhibited adequate mechanical properties. The structuring of the layer-by-layer films allowed the controlled release of acyclovir and produced a prolonged mucoadhesion residence time of up to 192 h. The films formed in layer 2 by the combination of Eudragit® RS PO and S100 showed a controlled release of acyclovir for eight days, and adequate mechanical properties. These promising formulations for the prevention of genital herpes deserve further evaluation.

Silicon Oxycarbide Porous Particles and Film Coating as Strategies for Tenofovir Controlled Release in Vaginal Tablets for HIV Prevention.

Sustained release of antiretroviral drugs is currently the most encouraging strategy for the prevention of the sexual transmission of HIV. Vaginal tablets based on hydrophilic gelling polymers are an interesting dosage form for this purpose, since they can be developed to modify the release of the drug depending on the tablet swelling. Tenofovir is a drug with proven activity in the prevention of HIV-1 infection, and it is possible to have it loaded in the surface of γ-aminopropyl trimethoxy silane-functionalized oxycarbide particles. These particles can be incorporated into the tablets, thus providing a sustained release of the drug. Moreover, the presence of the particles modifies the microstructure of the gel formed, as observed in scanning electron microscopy and Hg porosimetry studies, resulting into a gel with a narrow pore size distribution between 10 and 100 µm. This implies a lower volume of fluid incorporated into the gel during swelling studies, and therefore improved mucoadhesion times in ex vivo test. The coating of the formulations with Eudragit® RS modifies the swelling behavior of the tablets, which not only is decreased in magnitude but also extended in time, and as consequence the drug release is also prolonged for up to 7 days.

Applications of Chitosan in Surgical and Post-Surgical Materials.

The continuous advances in surgical procedures require continuous research regarding materials with surgical applications. Biopolymers are widely studied since they usually provide a biocompatible, biodegradable, and non-toxic material. Among them, chitosan is a promising material for the development of formulations and devices with surgical applications due to its intrinsic bacteriostatic, fungistatic, hemostatic, and analgesic properties. A wide range of products has been manufactured with this polymer, including scaffolds, sponges, hydrogels, meshes, membranes, sutures, fibers, and nanoparticles. The growing interest of researchers in the use of chitosan-based materials for tissue regeneration is obvious due to extensive research in the application of chitosan for the regeneration of bone, nervous tissue, cartilage, and soft tissues. Chitosan can serve as a substance for the administration of cell-growth promoters, as well as a support for cellular growth. Another interesting application of chitosan is hemostasis control, with remarkable results in studies comparing the use of chitosan-based dressings with traditional cotton gauzes. In addition, chitosan-based or chitosan-coated surgical materials provide the formulation with antimicrobial activity that has been highly appreciated not only in dressings but also for surgical sutures or meshes.

Bigels as drug delivery systems: From their components to their applications.

Bigels are systems that usually result from mixing a hydrogel and an organogel: the aqueous phase is commonly formed by a hydrophilic biopolymer, whereas the organic phase comprises a gelled vegetable oil because of the presence of an organogelator. The proportion of the corresponding gelling agent in each phase, the organogel/hydrogel ratio, and the mixing temperature and speed all need to be taken into consideration for bigel manufacturing. Bigels, which are particularly useful drug delivery systems, have already been formulated for transdermal, buccal, and vaginal routes. Mechanical assessments and microscopy are the most reported characterization techniques. As we review here, their composition and unique structure confer promising drug delivery attributes, such as mucoadhesion, the ability to control drug release, and the possibility of including both hydrophilic and lipophilic drugs in the same system.

Recent advances in electrospun nanofiber vaginal formulations for women's sexual and reproductive health.

Electrospinning is an innovative technique that allows production of nanofibers and microfibers by applying a high voltage to polymer solutions of melts. The properties of these fibers - which include high surface area, high drug loading capacity, and ability to be manufactured from mucoadhesive polymers - may be particularly useful in a myriad of drug delivery and tissue engineering applications. The last decade has witnessed a surge of interest in the application of electrospinning technology for the fabrication of vaginal drug delivery systems for the treatment and prevention of diseases associated with women's sexual and reproductive health, including sexually transmitted infections (e.g. infection with human immunodeficiency virus and herpes simplex virus) vaginitis, preterm birth, contraception, multipurpose prevention technology strategies, cervicovaginal cancer, and general maintenance of vaginal health. Due to their excellent mechanical properties, electrospun scaffolds are also being investigated as next-generation materials in the surgical treatment of pelvic organ prolapse. In this article, we review the latest advances in the field.

Naturally Occurring Polyelectrolytes and Their Use for the Development of Complex-Based Mucoadhesive Drug Delivery Systems: An Overview.

Biopolymers have several advantages for the development of drug delivery systems, since they are biocompatible, biodegradable and easy to obtain from renewable resources. However, their most notable advantage may be their ability to adhere to biological tissues. Many of these biopolymers have ionized forms, known as polyelectrolytes. When combined, polyelectrolytes with opposite charges spontaneously form polyelectrolyte complexes or multilayers, which have great functional versatility. Although only one natural polycation-chitosan has been widely explored until now, it has been combined with many natural polyanions such as pectin, alginate and xanthan gum, among others. These polyelectrolyte complexes have been used to develop multiple mucoadhesive dosage forms such as hydrogels, tablets, microparticles, and films, which have demonstrated extraordinary potential to administer drugs by the ocular, nasal, buccal, oral, and vaginal routes, improving both local and systemic treatments. The advantages observed for these formulations include the increased bioavailability or residence time of the formulation in the administration zone, and the avoidance of invasive administration routes, leading to greater therapeutic compliance.

Smart vaginal bilayer films of Tenofovir based on Eudragit® L100/natural polymer for the prevention of the sexual transmission of HIV.

In the absence of an effective vaccine, vaginal microbicides are essential for preventing the sexual transmission of HIV to women. Antiretroviral vaginal films have emerged as promising choices, especially those offering mucoadhesivity and controlled drug release. Tenofovir-loaded bilayer films based on Eudragit® L100 (EL100) and a biopolymer - gum arabic, karaya gum, pectin or tragacanth gum - were developed in a single-stage process. Cytotoxicity studies in three human cell lines indicated no toxicity of the excipients at the concentrations tested. Raman spectroscopy and SEM confirmed the formation of the two layers and their anchoring. Texture analysis showed no major differences between the batches. The swelling of the film is conditioned by its biopolymer nature and by the amount of EL100, which acts as structuring agent thus enhancing swelling. Tragacanth gum-based batches showed high mucoadhesion regardless the amount of EL100. The controlled release of Tenofovir in simulated vaginal fluid was faster in the presence of simulated seminal fluid due to the dissolution of EL100. Films containing 400 mg of EL100 and tragacanth gum are promising candidates for future studies, as they could sexually safeguard women from HIV for at least one week and ensure greater protection during intercourse.

Influence of Plasticizers on the pH-Dependent Drug Release and Cellular Interactions of Hydroxypropyl Methylcellulose/Zein Vaginal Anti-HIV Films Containing Tenofovir.

Vaginal films featuring the pH-dependent release of tenofovir (TFV) were developed for the prevention of sexual transmission of human immunodeficiency syndrome (HIV). Films based on hydroxypropyl methylcellulose and zein were prepared incorporating different plasticizers [oleic acid, lactic acid, glycerol, and polyethylene glycol 400 (PEG)] and evaluated for in vitro drug release in an acidic simulated vaginal fluid (pH 4.2) and a slightly alkaline mixture of simulated seminal and vaginal fluids (pH 7.5). Results revealed that optimal biphasic TFV release was possible with proper combination of plasticizers (PEG and oleic acid, 1:7 w/w) and by adjusting the plasticizer/matrix-forming material ratio. The films had similar or higher levels of TFV associated with genital epithelial cells (Ca Ski or HEC-1-A cells) but lower drug permeability compared to the free drug. These data confirm that films have the potential to achieve suitable mucosal levels of TFV with low systemic exposure. The films developed could protect women from HIV sexual transmission.

Development of pH-sensitive vaginal films based on methacrylate copolymers for topical HIV-1 pre-exposure prophylaxis.

Interest is growing in "smart" vaginal microbicides as a strategy to protect women from sexual transmission of human immunodeficiency virus (HIV). The concept is based on the development of products featuring low drug release in acidic media such as vaginal fluid but switch to a fast release profile when the medium becomes neutral or slightly alkaline. This mimics the surge in pH occurring in the vagina after sexual intercourse due to the seminal fluid. Semen is the main vehicle for HIV-1, and increasing antiretroviral drug levels in the vagina upon ejaculation may contribute to enhanced protection against viral sexual transmission. This work explores the use of different pharmaceutical-grade methacrylic acid-based polymers (EudragitⓇ RL, RS, L and S) for developing vaginal films allowing the pH-dependant release of the antiretroviral drug tenofovir (TFV). EudragitⓇ L 100 and EudragitⓇ S 100, containing triethyl citrate as plasticiser, proved to be suitable for manufacturing films with optimal dual in vitro drug-release behaviour. TFV-release can be sustained for several days after film administration and all the drug is released in a few hours in conditions simulating ejaculation. The films' mechanical properties were also deemed suitable for comfortable vaginal administration. Two optimized films were further assessed using HEC-1-A and Ca Ski cell monolayer models and were found to possess favourable drug permeability profiles and drug levels associated to cell monolayer as compared to free TFV. Overall, pH-dependant films containing tenofovir may constitute promising candidates for "smart" vaginal microbicides to protect women from sexual HIV transmission.

Carrageenan: Drug Delivery Systems and Other Biomedical Applications.

Marine resources are today a renewable source of various compounds, such as polysaccharides, that are used in the pharmaceutical, medical, cosmetic, and food fields. In recent years, considerable attention has been focused on carrageenan-based biomaterials due to their multifunctional qualities, including biodegradability, biocompatibility, and non-toxicity, in addition to bioactive attributes, such as their antiviral, antibacterial, antihyperlipidemic, anticoagulant, antioxidant, antitumor, and immunomodulating properties. They have been applied in pharmaceutical formulations as both their bioactive and physicochemical properties make them suitable biomaterials for drug delivery, and recently for the development of tissue engineering. This article provides a review of recent research on the various types of carrageenan-based biomedical and pharmaceutical applications.

Design, fabrication and characterisation of drug-loaded vaginal films: State-of-the-art.

Films have undoubtedly seen the most significant advances in their development in recent years of all the pharmaceutical forms for the vaginal administration of drugs. Films combine the advantages of gels and solid pharmaceutical forms, and their great versatility is largely determined by the numerous polymers that can be used for their fabrication. They may be based on many natural polymers, and cellulose derivatives, polyvinyl alcohol or acrylic derivatives - among others - are also frequently used. The combination of different polymers and the inclusion of plasticizing agents makes them extremely versatility for responding to a range of therapeutic needs. The techniques used to produce films have also undergone substantial development. Although the solvent casting technique is by far the most widely used in fabrication, alternative options have also emerged such as electrospinning, moulding extrusion and 3D printing. Various research groups have proposed a proliferation of assays to characterise vaginal films in recent years, which highlight the importance of the preliminary evaluation and determination of the films' uniformity, in addition to tests to determine their permeability and hydrophilic/hydrophobic coefficient and their mechanical properties, the application of imaging techniques and thermal analysis, and especially the evaluation of the mucoadhesive properties and control over the drug release. This article offers a critical overview of the advances in the development and fabrication of films intended for vaginal drug delivery, and summarises current clinical applications for vaginal films.

Amino Functionalized Micro-Mesoporous Hybrid Particles for the Sustained Release of the Antiretroviral Drug Tenofovir.

The sustained release of an antiretroviral agent to women mucosa has been proved as an excellent strategy to reduce the sexual transmission of HIV. Hybrid micro-mesoporous particles have been synthesized and functionalized with a silane coupling agent followed by loading the antiretroviral tenofovir. It has been observed that the disposition of the silane molecule on the surface of the particles determines the interaction mechanism with the antiretroviral molecule loaded independently on the surface area of the particles. In this sense, available and free amino groups are required to achieve a smart pH-responsive material, a condition that is only achieved in those materials containing a silane chemisorbed monolayer. Moreover, the modulation of the release kinetics attributed to the presence of the silane monolayer covering the mesopores has been confirmed by fitting the releasing curves to the first order and Weibull models. The developed micro-mesoporous particles have been demonstrated to be excellent smart-release vehicles for antiviral agents and can be safely used in polymer mucoadhesive vaginal gels.

Carrageenan-Based Acyclovir Mucoadhesive Vaginal Tablets for Prevention of Genital Herpes.

Women are the most affected by genital herpes, which is one of the most common sexually transmitted infections, affecting more than 400 million people worldwide. The application of vaginal microbicides could provide a safe method of protection. Acyclovir is a safe and effective medication for vaginal administration, and numerous benefits have been observed in the treatment of primary or recurrent lesions due to genital herpes. Vaginal tablets based on a combination of the polymers iota-carrageenan and hydroxypropyl methylcellulose were developed for the controlled release of acyclovir. Swelling, mucoadhesion and drug release studies were carried out in simulated vaginal fluid. The tablets, containing a combination of iota-carrageenan and hydroxypropyl methylcellulose, have an adequate uptake of the medium that allows them to develop the precise consistency and volume of gel for the controlled release of acyclovir. Its high mucoadhesive capacity also allows the formulation to remain in the vaginal area long enough to ensure the complete release of acyclovir. These promising formulations for the prevention of genital herpes deserve further evaluation.

Development and In Vitro/Ex Vivo Characterization of Vaginal Mucoadhesive Bilayer Films Based on Ethylcellulose and Biopolymers for Vaginal Sustained Release of Tenofovir.

Young women in sub-Saharan Africa have the highest risk of human immunodeficiency virus (HIV) acquisition through sexual contact of all groups. Vaginal controlled release of antiretrovirals is a priority option for the prevention of sexual transmission of the virus in women. In this manuscript, bilayer films were prepared based on ethylcellulose and a natural polymer (xanthan or tragacanth gum) plasticized with glycerol and tributylcitrate for tenofovir-controlled release. The mechanical properties and microstructure of the blank films were characterized by texture analysis, Fourier transform infrared spectroscopy, and scanning electron microscopy. The loaded films were evaluated in simulated vaginal fluid through release and swelling studies and ex vivo mucoadhesion assessments. The results show that the preparation method produced bilayer films with adequate mechanical properties. The contribution of both layers allowed the sustained release of tenofovir and a mucoadhesion time of up to 360 h. The toxicity of the materials was evaluated in three cell lines of vaginal origin. The films constituted by ethylcellulose and xanthan gum in a 2:1 proportion (EX2-D) showed the longest mucoadhesion time, with 15 days of tenofovir-controlled release, zero toxicity, and optimal mechanical properties. These films are therefore a promising option for offering women a means of self-protection against the sexual transmission of HIV.

Mucoadhesive Vaginal Discs based on Cyclodextrin and Surfactants for the Controlled Release of Antiretroviral Drugs to Prevent the Sexual Transmission of HIV.

The strategies for developing vaginal microbicides to protect women against human immunodeficiency virus (HIV) sexual transmission are constantly changing. Although the initial dosage forms required daily administration to offer effective protection, the trend then moved towards sustained-release dosage forms that require less frequency of administration in order to improve women's compliance with the treatment. Nevertheless, another possible strategy is to design on-demand products that can be used in a coitally-dependent manner and only need to be administered immediately before intercourse to offer protection. Vaginal discs based on freeze-dried hydroxypropylmethyl cellulose gels have been developed for this purpose, containing two surfactants, i.e., sodium dodecyl sulphate and polysorbate 60, alone or in combination with 2-hydroxypropyl-ß-cyclodextrin, to achieve a formulation capable of incorporating both hydrophilic and lipophilic drugs. Several studies have been carried out to evaluate how the inclusion of these substances modifies the structure of gels (viscosity and consistency studies) and the porosimetry of the freeze-dried discs (scanning electron microscopy micrographs, mechanical properties, swelling behaviour). The drug release and mucoadhesive properties of the discs have also been evaluated with a view to their clinical application. The systems combining sodium dodecyl sulphate and 2-hydroxypropyl-ß-cyclodextrin were found to be adequate for the vaginal administration of both Tenofovir and Dapivirine and also offer excellent mucoadhesion to vaginal tissue; these discs could therefore be an interesting option for a coitally-dependent administration to protect women against HIV transmission.

Vaginal Polyelectrolyte Layer-by-Layer Films Based on Chitosan Derivatives and Eudragit® S100 for pH Responsive Release of Tenofovir.

Women are still at high risk of contracting the human immunodeficiency virus (HIV) virus due to the lack of protection methods under their control, especially in sub-Saharan countries. Polyelectrolyte multilayer smart vaginal films based on chitosan derivatives (chitosan lactate, chitosan tartate, and chitosan citrate) and Eudragit® S100 were developed for the pH-sensitive release of Tenofovir. Films were characterized through texture analysis and scanning electron microscopy (SEM). Swelling and drug release studies were carried out in simulated vaginal fluid and a mixture of simulated vaginal and seminal fluids. Ex vivo mucoadhesion was evaluated in bovine vaginal mucosa. SEM micrographs revealed the formation of multilayer films. According to texture analysis, chitosan citrate was the most flexible compared to chitosan tartrate and lactate. The swelling studies showed a moderate water uptake (<300% in all cases), leading to the sustained release of Tenofovir in simulated vaginal fluid (up to 120 h), which was accelerated in the simulated fluid mixture (4-6 h). The films had high mucoadhesion in bovine vaginal mucosa. The multilayer films formed by a mixture of chitosan citrate and Eudragit® S100 proved to be the most promising, with zero toxicity, excellent mechanical properties, moderate swelling (<100%), high mucoadhesion capacity, and Tenofovir release of 120 h and 4 h in vaginal fluid and the simulated fluid mixture respectively.

Development of mucoadhesive vaginal films based on HPMC and zein as novel formulations to prevent sexual transmission of HIV.

Although vaginal films were initially developed for a fast release of the drug, with the adequate formulation they can also be useful for sustained release. The latest strategies for the prevention of the sexual transmission of HIV have moved towards sustained-release dosage forms, so films may be an effective strategy that could also improve the patient's comfort. A hydrophilic polymer (hydroxypropylmethyl cellulose) and an amphiphilic polymer (zein) have been evaluated for the development of Tenofovir sustained-release vaginal films. The modification of the film's properties by the inclusion of polar (glycerol and polyethylene glycol 400 (PEG)) and amphiphilic (tributyl citrate and oleic acid) plasticisers was also evaluated. The films' physicochemical and mechanical properties were determined. The in vitro release of Tenofovir from the films and their bioadhesive capacity and behaviour in simulated vaginal fluid were also assessed. The combination of hydroxypropylmethyl cellulose and zein in films (ratio 1:5), with the inclusion of PEG (40% w/w) proved not only to have excellent mechanical properties, but was also able to release TFV in a sustained manner for 120 h and remain attached to biological tissues throughout this time. This film could be an interesting option for the prevention of sexual transmission of HIV.

Smart Freeze-Dried Bigels for the Prevention of the Sexual Transmission of HIV by Accelerating the Vaginal Release of Tenofovir during Intercourse.

Sub-Saharan African women are still at risk from the human immunodeficiency virus (HIV), and sex with men is the main route of transmission. Vaginal formulations containing antiretroviral drugs are promising tools to give women the power to protect themselves. The aim of this work was to obtain freeze-dried bigels containing pectin, chitosan, or hypromellose for the vaginal controlled release of Tenofovir, which is accelerated in the presence of semen. Nine batches of bigels were formulated using different proportions of these polymers in the hydrogel (1, 2, and 3% w/w). The bigels obtained were freeze-dried and then underwent hardness and deformability, mucoadhesion, swelling, and drug release tests, the last two in simulated vaginal fluid (SVF) and SVF/simulated seminal fluid (SSF) mixture. The formulation containing 3% pectin (fd3P) has the highest values for hardness, resistance to deformation, and good mucoadhesivity. Its swelling is conditioned by the pH of the medium, which is responsive to the controlled release of Tenofovir in SVF, with the fastest release in the SVF/SSF mixture. fd3P would be an interesting smart microbicidal system to allow faster release of Tenofovir in the presence of semen, and thus increase women's ability to protect themselves from the sexual transmission of HIV.

Dapivirine Bioadhesive Vaginal Tablets Based on Natural Polymers for the Prevention of Sexual Transmission of HIV.

Young sub-Saharan women are a group that is vulnerable to the sexual transmission of HIV. Pre-exposure prophylaxis through vaginal microbicides could provide them an option for self-protection. Dapivirine has been demonstrated to have topical inhibitory effects in HIV, and to provide protection against the sexual transmission of this virus. This paper reports on the studies into swelling behaviour, bioadhesion and release carried out on dapivirine tablets based on chitosan, locust bean gum and pectin, to select the most suitable formulation. The modified simulated vaginal fluid led to a high solubility of dapivirine and allowed the dapivirine release profiles to be characterized in sink conditions; this aqueous medium is an alternative to organic solvents, which are not a realistic option when evaluating systems whose behaviour varies in aqueous and organic media. Of the formulations evaluated, dapivirine/pectin tablets containing 290 mg of polymer and 30 mg of dapivirine present the most moderate swelling, making them the most comfortable dosage forms. Their high bioadhesive capacity would also allow the formulation to remain in the action zone and release the drug in a sustained manner, pointing to this formulation as the most promising candidate for future evaluations of vaginal microbicides for the prevention of HIV.

Tenofovir Hot-Melt Granulation using Gelucire® to Develop Sustained-Release Vaginal Systems for Weekly Protection against Sexual Transmission of HIV.

Hot-melt granulation is a technique used to obtain granules by dispersing a drug in polymers at a high temperature. Tenofovir, an antiretroviral drug with proven activity as a vaginal microbicide, was dispersed in melted Gelucire® (or a mixture of different Gelucire®) to obtain drug-loaded granules. Studies performed on the granules proved that the drug is not altered in the hot-melt granulation process. The granules obtained were included in a matrix formed by the hydrophilic polymers hydroxypropylmethylcellulose and chitosan to obtain vaginal tablets that combine different mechanisms of controlled release: The Gelucire® needs to soften to allow the release of the Tenofovir, and the hydrophilic polymers must form a gel so the drug can diffuse through it. The studies performed with the tablets were swelling behavior, Tenofovir release, and ex vivo mucoadhesion. The tablets containing granules obtained with Tenofovir and Gelucire® 43/01 in a ratio of 1:2 in a matrix formed by hydroxypropylmethylcellulose and chitosan in a ratio of 1.9:1 were selected as the optimal formulation, since they release Tenofovir in a sustained manner over 216h and remain attached to the vaginal mucosa throughout. A weekly administration of these tablets would therefore offer women protection against the sexual transmission of HIV.