Vaginal Sheets with Thymbra capitata Essential Oil for the Treatment of Bacterial Vaginosis: Design, Characterization and In Vitro Evaluation of Efficacy and Safety.

We aimed to incorporate Thymbra capitata essential oil (TCEO), a potent antimicrobial natural product against bacterial vaginosis (BV)-related bacteria, in a suitable drug delivery system. We used vaginal sheets as dosage form to promote immediate relief of the typical abundant vaginal discharge with unpleasant odour. Excipients were selected to promote the healthy vaginal environment reestablishment and bioadhesion of formulations, while the TCEO acts directly on BV pathogens. We characterized vaginal sheets with TCEO in regard to technological characterization, predictable in vivo performance, in vitro efficacy and safety. Vaginal sheet D.O (acid lactic buffer, gelatine, glycerine, chitosan coated with TCEO 1% w/w) presented a higher buffer capacity and ability to absorb vaginal fluid simulant (VFS) among all vaginal sheets with EO, showing one of the most promising bioadhesive profiles, an excellent flexibility and structure that allow it to be easily rolled for application. Vaginal sheet D.O with 0.32 µL/mL TCEO was able to significantly reduce the bacterial load of all in vitro tested Gardnerella species. Although vaginal sheet D.O presented toxicity at some concentrations, this product was developed for a short time period of treatment, so this toxicity can probably be limited or even reversed when the treatment ends.

Synergistic effects of carvacrol, α-terpinene, γ-terpinene, ρ-cymene and linalool against Gardnerella species.

Bacterial vaginosis (BV) is the most common vaginal infection affecting women worldwide. This infection is characterized by the loss of the dominant Lactobacillus community in the vaginal microbiota and an increase of anaerobic bacteria, that leads to the formation of a polymicrobial biofilm, mostly composed of Gardnerella spp. Treatment of BV is normally performed using broad-spectrum antibiotics, such as metronidazole and clindamycin. However, the high levels of recurrence of infection after treatment cessation have led to a demand for new therapeutic alternatives. Thymbra capitata essential oils (EOs) are known to have a wide spectrum of biological properties, including antibacterial activity. Thus, herein, we characterized two EOs of T. capitata and tested their antimicrobial activity as well as some of their main components, aiming to assess possible synergistic effects. Our findings showed that carvacrol and ρ-cymene established a strong synergistic antimicrobial effect against planktonic cultures of Gardnerella spp. On biofilm, carvacrol and linalool at sub-MIC concentrations proved more efficient in eliminating biofilm cells, while showing no cytotoxicity observed in a reconstituted human vaginal epithelium. The antibiofilm potential of the EOs and compounds was highlighted by the fact cells were not able to recover culturability after exposure to fresh medium.

Women's preferences and acceptance for different drug delivery routes and products.

To use or not to use, that is the first decision to take regarding a drug product. This mandatory step for adherence dictates product efficacy. The determinants for such decision do not only rely on the priority of the therapeutic or preventive strategy, but are related to a complex network of perceptions, preferences, personal and cultural backgrounds, and results from previous experiences. Women's preferences for dosage forms and even for drug delivery routes have been mainly studied in the fields of contraception and HIV prevention (and their related multipurpose approaches). Much less attention has been devoted to other therapeutic or preventive strategies. In a time when patient-centred approaches and shared decisions are increasingly valued, considering women's preferences and their main determinants is essential for product development and selection. Such products will be more likely to be chosen and used as intended, increasing efficacy, and reducing the overall costs related with these treatments. This knowledge shall be integrated in early stages of product development. This article reviews the state of the art related with women's preferences and acceptance for different dosage forms and drug delivery routes involved in women's health. The methodologies used for collecting these data and their major drawbacks are discussed. Results obtained from acceptability studies and the main determinants for selection of preventive and treatment drug products are discussed as tools for new developments in the field.

Drug Formulations for Localized Treatment of Human Papillomavirus-Induced Lesions.

BACKGROUND: The human papillomavirus (HPV) is responsible for over 90% of all cervical cancer cases. The use of vaginal gels is often indicated for local vaginal drug delivery. Previous studies have shown that Thymus vulgaris essential oil (TEO) exhibits anticancer properties besides antifungal and antibacterial properties. Its activity derives from a specific increase in free radicals and oxidative stress caused in cancer cells. Furthermore, mitoxantrone (MTX), an anthracenedione, and C8, an acridine orange derivative, were shown to inhibit the growth of the cervical cancer cell line HeLa. RESULTS: The results showed that TEO + C8 is the most promising formulation in terms of viscosity and osmolality properties in vaginal fluid simulant (VFS). The combined action of TEO with the compounds MTX and C8 resulted in HeLa cell viability reduction compared with the effect obtained with the individual formulations containing each one of the compounds. CONCLUSIONS: The formulation TEO + C8 holds promise in terms of cost-benefit and topical application of the active compound for the HeLa cells.

Sodium bicarbonate gels: a new promising strategy for the treatment of vulvovaginal candidosis.

Vulvovaginal candidosis (VVC), caused mainly by the yeast Candida albicans, is the second most prevalent vaginal infection. It has been found to have a large impact on women's quality of life, self-esteem and routines. The prevalence of recurrent vulvovaginal candidosis (RVVC) remains high so the development of alternative treatments is needed. The main objective of this study was to develop and characterize sodium bicarbonate gels to treat VVC. We described key formulation characteristics and analyzed their influence on in vitro performance evaluations. The potential to inhibit Candida albicans's growth, the pH, osmolality, viscosity and rheological performance in contact with vaginal fluid simulant and the bioadhesion's profile (using a vaginal ex vivo porcine model) were studied for all formulations. Among the formulations, formulation C (5% sodium bicarbonate, 1% carbomer and 94% water) was the most effective in inhibiting the C. albicans' growth. This gel presented the same potential (the same MIC 2.5%) to inhibit other etiological agents of VVC (C. glabrata, C. krusei, C. tropicalis and C. parapsilosis) for all species tested. Additionally, sensorial characteristics of gel C were in accord with users' preferences. This gel exhibited physicochemical characteristics acceptable for short term treatments, suggesting good overall performance for the treatment of VVC. Furthermore, Gel C was biocompatible with the HeLa cell line (MTT assay) and was classified as a non-severe irritant in the HET-CAM assay (irritation score 4 ± 1). Overall, gel C was deemed the best performing of the set tested, and suitable for further development.

Bacterial vaginosis: Standard treatments and alternative strategies.

Bacterial vaginosis (BV) affects many women and has a high influence on their self-esteem, being associated with huge discomfort and changes in the routines, especially the sexual life. International guidelines recommend the administration of metronidazole, clindamycin or tinidazole orally or intravaginally as the standard treatment. However, the treatment with these antibiotics is associated with high levels of failure and recurrence rates. These may be associated with antibiotic resistance, the inability to eradicate the polymicrobial biofilms, and failure to reestablish acidic pH and the lactobacillus-dominated commensal flora. Therefore, it is emergent to study alternative strategies to replace or to be combined with standard therapies in order to prevent and treat BV more efficiently. Alternative strategies may include antimicrobial substances (other antimicrobials, antiseptics and natural compounds) or substances that aim to reestablish the physiologic vaginal environment (probiotics, prebiotics and acidifying agents) while improving the local immunity response. Besides, the development of formulation strategies and new dosage forms and drug delivery systems can improve treatment efficacy and overcome some limitations associated with conventional products.

The vaginal sheet: an innovative form of vaginal film for the treatment of vaginal infections.

Objective: To develop and characterize a new form of vaginal film.Significance: This formulation is intended to overcome some known limitations of traditional dosage forms. It has an absorptive intention to control symptoms and to improve the treatment of vaginal infections characterized by excessive fluid. The vaginal sheet is a thick drug delivery system easy to manipulate, nontoxic and composed by biocompatible macromolecules and polymers, such as gelatin and chitosan.Methods: The sheets were prepared by formulating gelatin or chitosan based gels isolated or in combination, in association with a plasticizer. Gels were subsequently lyophilized. Different proportions of polymer:plasticizer were tested. Lactose was used as a surrogate to study powder incorporation in the formulation. All formulations were analyzed regarding their organoleptic characteristics, texture (hardness and resilience), in vitro absorption efficiency of vaginal fluid simulant - VFS (pH 4 and 5), pH and acid-buffering capacity.Results: Different properties were obtained by varying polymer and plasticizer proportions. Combinations including gelatin with propylene glycol showed the best organoleptic characteristics. The best proportions were 4:3 and 4:5. Up to 10% of powder was successfully incorporated in the formulation. Hardness and resilience of formulations were largely dependent on the concentration of plasticizer. Absorption of vaginal fluid was found to be highly efficient, especially at pH 5. Buffering capacity, upon dilution in normal saline and VFS, was generally higher for VFS pH 4.Conclusions: The vaginal sheet is a promising solid drug delivery system able to further incorporate drugs to treat vaginal clinical conditions characterized by excessive fluid.