Advances in Vaginal Drug Delivery

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 14996

Special Issue Editors

Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain
Interests: drug controlled release; HIV; microbicides; mucoadhesiveness; natural polymers; vaginal route
Special Issues, Collections and Topics in MDPI journals
Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain
Interests: film technology; HIV/ADS prevention; mucoadhesion; topical pre-exposure prophylaxis; vaginal drug delivery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Vaginal drug delivery has been largely used for both local and systemic purposes. Contraception, treatment, and prevention of genital diseases, or hormone replacement therapy are some examples of therapeutic approaches by this route. Technological resources must be applied to overcome those physiological characteristics of the vagina that could hinder the administration of drugs; namely, the presence of a mucus barrier, low available fluid, and vaginal clearance. The focus of this Special Issue are advances in drug delivery systems for vaginal administration. Strategies to improve crucial factors such as mucoadhesion, drug absorption, controlled drug delivery, and drug targeting are welcomed. The use of nanotechnology to improve bioavailability, as well as the development of multipurpose prevention technologies (MPTs), are of interest. We will also consider research and review articles concerning vaginal systems that provide substantial advances to the field. Additionally, papers concerning user preferences and personalized therapy (e.g., vaginal administration in pregnancy, post-menopausal women, or with concomitant vaginal infections) will be welcomed.

Dr. Roberto Ruiz-Caro
Dr. Fernando Notario-Pérez
Guest Editors

Manuscript Submission Information

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Keywords

  • contraceptives
  • drug-controlled release
  • gynecological oncology
  • microbicides
  • mucoadhesion
  • mucosal administration
  • multipurpose prevention technologies (MPTs)
  • nanotechnology
  • pharmaceutical technology
  • post-exposure prophylaxis (PEP)
  • pre-exposure prophylaxis (PrEP)
  • sexually transmitted infections (STIs)
  • vaginal administration

Published Papers (8 papers)

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Research

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16 pages, 2338 KiB  
Article
Development of Thermoresponsive Hydrogels with Mucoadhesion Properties Loaded with Metronidazole Gel-Flakes for Improved Bacterial Vaginosis Treatment
by Andi Dian Permana, Rangga Meidianto Asri, Muhammad Nur Amir, Achmad Himawan, Andi Arjuna, Nana Juniarti, Rifka Nurul Utami and Sandra Aulia Mardikasari
Pharmaceutics 2023, 15(5), 1529; https://doi.org/10.3390/pharmaceutics15051529 - 18 May 2023
Cited by 1 | Viewed by 1419
Abstract
Bacterial vaginosis is an infectious disease that has significantly affected women’s health. Metronidazole has been widely used as a drug for treating bacterial vaginosis. Nevertheless, the currently available therapies have been found to be inefficient and inconvenient. Here, we developed the combination approach [...] Read more.
Bacterial vaginosis is an infectious disease that has significantly affected women’s health. Metronidazole has been widely used as a drug for treating bacterial vaginosis. Nevertheless, the currently available therapies have been found to be inefficient and inconvenient. Here, we developed the combination approach of gel flake and thermoresponsive hydrogel systems. The gel flakes were prepared using gellan gum and chitosan, showing that the incorporation of metronidazole was able to provide a sustained release pattern for 24 h with an entrapment efficiency of >90%. Moreover, the gel flakes were incorporated into Pluronics-based thermoresponsive hydrogel using the combination of Pluronic F127 and F68. The hydrogels were found to exhibit the desired thermoresponsive properties, showing sol-gel transition at vaginal temperature. Following the addition of sodium alginate as a mucoadhesive agent, the hydrogel was retained in the vaginal tissue for more than 8 h, with more than 5 mg of metronidazole retained in the ex vivo evaluation. Finally, using the bacterial vaginosis infection model in rats, this approach could decrease the viability of Escherichia coli and Staphylococcus aureus with reduction percentages of more than 95% after 3 days of treatment, with the healing ability similar to normal vaginal tissue. In conclusion, this study offers an effective approach for the treatment of bacterial vaginosis. Full article
(This article belongs to the Special Issue Advances in Vaginal Drug Delivery)
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17 pages, 3020 KiB  
Article
A Novel Approach for the Treatment of Aerobic Vaginitis: Azithromycin Liposomes-in-Chitosan Hydrogel
by Ana Čačić, Daniela Amidžić Klarić, Sabina Keser, Maja Radiković, Zora Rukavina, May Wenche Jøraholmen, Lidija Uzelac, Marijeta Kralj, Nataša Škalko-Basnet, Maja Šegvić Klarić and Željka Vanić
Pharmaceutics 2023, 15(5), 1356; https://doi.org/10.3390/pharmaceutics15051356 - 28 Apr 2023
Cited by 3 | Viewed by 1882
Abstract
Biocompatible mucoadhesive formulations that enable a sustained drug delivery at the site of action, while exhibiting inherent antimicrobial activity, are of great importance for improved local therapy of vaginal infections. The aim of this research was to prepare and evaluate the potential of [...] Read more.
Biocompatible mucoadhesive formulations that enable a sustained drug delivery at the site of action, while exhibiting inherent antimicrobial activity, are of great importance for improved local therapy of vaginal infections. The aim of this research was to prepare and evaluate the potential of the several types of azithromycin (AZM)-liposomes (180–250 nm) incorporated into chitosan hydrogel (AZM-liposomal hydrogels) for the treatment of aerobic vaginitis. AZM-liposomal hydrogels were characterized for in vitro release, and rheological, texture, and mucoadhesive properties under conditions simulating the vaginal site of application. The role of chitosan as a hydrogel-forming polymer with intrinsic antimicrobial properties was explored against several bacterial strains typical for aerobic vaginitis as well as its potential effect on the anti-staphylococcal activity of AZM-liposomes. Chitosan hydrogel prolonged the release of the liposomal drug and exhibited inherent antimicrobial activity. Additionally, it boosted the antibacterial effect of all tested AZM-liposomes. All AZM-liposomal hydrogels were biocompatible with the HeLa cells and demonstrated mechanical properties suitable for vaginal application, thus confirming their potential for enhanced local therapy of aerobic vaginitis. Full article
(This article belongs to the Special Issue Advances in Vaginal Drug Delivery)
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16 pages, 2660 KiB  
Article
Locust Bean Gum Nano-Based Hydrogel for Vaginal Delivery of Diphenyl Diselenide in the Treatment of Trichomoniasis: Formulation Characterization and In Vitro Biological Evaluation
by Fernanda Padoin dos Reis, Graziela Vargas Rigo, Cristina Wayne Nogueira, Tiana Tasca, Marcel Henrique Marcondes Sari and Letícia Cruz
Pharmaceutics 2022, 14(10), 2112; https://doi.org/10.3390/pharmaceutics14102112 - 03 Oct 2022
Cited by 4 | Viewed by 1462
Abstract
Trichomoniasis is the most common nonviral sexually transmitted infection in the world, but its available therapies present low efficacy and high toxicity. Diphenyl diselenide (PhSe2) is a pharmacologically active organic selenium compound; however, its clinical use is hindered by its lipophilicity [...] Read more.
Trichomoniasis is the most common nonviral sexually transmitted infection in the world, but its available therapies present low efficacy and high toxicity. Diphenyl diselenide (PhSe2) is a pharmacologically active organic selenium compound; however, its clinical use is hindered by its lipophilicity and toxicity. Nanocarriers are an interesting approach to overcome the limitations associated with this compound. This study designed and evaluated a vaginal hydrogel containing PhSe2-loaded Eudragit® RS100 and coconut oil nanocapsules for the treatment of trichomoniasis. Nanocapsules presented particle sizes in the nanometric range, positive zeta potential, a compound content close to the theoretical value, and high encapsulation efficiency. The nanoencapsulation maintained the anti-Trichomonas vaginalis action of the compound while improving the scavenger action in a DPPH assay. The hydrogels were prepared by thickening nanocapsule suspensions with locust bean gum (3%). The semisolids maintained the nanometric size of the particles and the PhSe2 content at around the initial concentration (1.0 mg/g). They also displayed non-Newtonian pseudo-plastic behavior and a highly mucoadhesive property. The chorioallantoic membrane method indicated the absence of hemorrhage, coagulation, or lysis. The compound, from both non-encapsulated and nano-based hydrogel delivery systems, remained on the surface of the bovine vaginal mucosa. Therefore, the formulations displayed the intended properties and could be a promising alternative for the treatment of trichomoniasis. Full article
(This article belongs to the Special Issue Advances in Vaginal Drug Delivery)
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20 pages, 3416 KiB  
Article
Comprehensive Study of Antiretroviral Drug Permeability at the Cervicovaginal Mucosa via an In Vitro Model
by Constandinos Carserides, Kieron Smith, Marta Zinicola, Abhinav Kumar, Magda Swedrowska, Carlo Scala, Gary Cameron, Zoe Riches, Francesco Iannelli, Gianni Pozzi, Georgina L. Hold, Ben Forbes, Charles Kelly and Karolin Hijazi
Pharmaceutics 2022, 14(9), 1938; https://doi.org/10.3390/pharmaceutics14091938 - 13 Sep 2022
Viewed by 1356
Abstract
Modulation of drug transporter activity at mucosal sites of HIV-1 transmission may be exploited to optimize retention of therapeutic antiretroviral drug concentrations at target submucosal CD4+ T cells. Previously, we showed that darunavir was a substrate for the P-glycoprotein efflux drug transporter in [...] Read more.
Modulation of drug transporter activity at mucosal sites of HIV-1 transmission may be exploited to optimize retention of therapeutic antiretroviral drug concentrations at target submucosal CD4+ T cells. Previously, we showed that darunavir was a substrate for the P-glycoprotein efflux drug transporter in colorectal mucosa. Equivalent studies in the cervicovaginal epithelium have not been reported. Here, we describe the development of a physiologically relevant model to investigate the permeability of antiretroviral drugs across the vaginal epithelium. Barrier properties of the HEC-1A human endometrial epithelial cell line were determined, in a dual chamber model, by measurement of transepithelial electrical resistance, immunofluorescent staining of tight junctions and bi-directional paracellular permeability of mannitol. We then applied this model to investigate the permeability of tenofovir, darunavir and dapivirine. Efflux ratios indicated that the permeability of each drug was transporter-independent in this model. Reduction of pH to physiological levels in the apical compartment increased absorptive transfer of darunavir, an effect that was reversed by inhibition of MRP efflux transport via MK571. Thus, low pH may increase the transfer of darunavir across the epithelial barrier via increased MRP transporter activity. In a previous in vivo study in the macaque model, we demonstrated increased MRP2 expression following intravaginal stimulation with darunavir which may further increase drug uptake. Stimulation with inflammatory modulators had no effect on drug permeability across HEC-1A barrier epithelium but, in the VK2/E6E7 vaginal cell line, increased expression of both efflux and uptake drug transporters which may influence darunavir disposition. Full article
(This article belongs to the Special Issue Advances in Vaginal Drug Delivery)
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18 pages, 3441 KiB  
Article
Silicon Oxycarbide Porous Particles and Film Coating as Strategies for Tenofovir Controlled Release in Vaginal Tablets for HIV Prevention
by Araceli Martín-Illana, Raúl Cazorla-Luna, Fernando Notario-Pérez, Roberto Ruiz-Caro, Juan Rubio, Aitana Tamayo and María Dolores Veiga
Pharmaceutics 2022, 14(8), 1567; https://doi.org/10.3390/pharmaceutics14081567 - 28 Jul 2022
Cited by 2 | Viewed by 1692
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Advances in Vaginal Drug Delivery)
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16 pages, 1767 KiB  
Article
Ovarian Follicular Growth through Intermittent Vaginal Gonadotropin Administration in Diminished Ovarian Reserve Women
by Chao-Chin Hsu, Isabel Hsu, Li-Hsuan Lee, Rosie Hsu, Yuan-Shuo Hsueh, Chih-Ying Lin and Hui Hua Chang
Pharmaceutics 2022, 14(4), 869; https://doi.org/10.3390/pharmaceutics14040869 - 15 Apr 2022
Cited by 2 | Viewed by 1818
Abstract
It is a challenge to obtain enough oocytes during in vitro fertilization (IVF) in women who have a poor ovarian response (POR) in achieving conception. We have adopted the characteristics of the first uterine pass effect, which we pioneered in employing the vaginal [...] Read more.
It is a challenge to obtain enough oocytes during in vitro fertilization (IVF) in women who have a poor ovarian response (POR) in achieving conception. We have adopted the characteristics of the first uterine pass effect, which we pioneered in employing the vaginal administration of gonadotropins in women receiving IVF treatments. In our previous study employing vaginal administration, faster absorption and slower elimination of gonadotropins were demonstrated, and, female subjects presented proper ovarian follicle growth and pregnancy rates. In this study, during 2016–2020, 300 to 675 IU of gonadotropins were administered vaginally every three days in 266 POR women for their controlled ovarian hyperstimulation (COH). The injections were performed with needles angled at 15–30° towards the middle-upper portions of the bilateral vaginal wall, with an injection depth of 1–2 mm. For the COH results, these women, on average, received 3.0 ± 0.9 vaginal injections and a total dose of 1318.4 ± 634.4 IU gonadotropins, resulting in 2.2 ± 1.9 mature oocytes and 1.0 ± 1.2 good embryos. Among these embryos, 0.9 ± 1.0 were transferred to reach a clinical pregnancy rate of 18.1% and a live birth rate of 16.7%. In conclusion, the intermittent vaginal administration of gonadotropins proved to be effective in POR women for their IVF treatments. Full article
(This article belongs to the Special Issue Advances in Vaginal Drug Delivery)
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23 pages, 2527 KiB  
Article
The Chitosan-Based System with Scutellariae baicalensis radix Extract for the Local Treatment of Vaginal Infections
by Justyna Chanaj-Kaczmarek, Natalia Rosiak, Daria Szymanowska, Marcin Rajewski, Ewa Wender-Ozegowska and Judyta Cielecka-Piontek
Pharmaceutics 2022, 14(4), 740; https://doi.org/10.3390/pharmaceutics14040740 - 29 Mar 2022
Cited by 7 | Viewed by 1945
Abstract
Scutellarie baicalensis radix, as a flavone-rich source, exhibits antibacterial, antifungal, antioxidant, and anti-inflammatory activity. It may be used as a therapeutic agent to treat various diseases, including vaginal infections. In this study, six binary mixtures of chitosan with stable S. baicalensis radix [...] Read more.
Scutellarie baicalensis radix, as a flavone-rich source, exhibits antibacterial, antifungal, antioxidant, and anti-inflammatory activity. It may be used as a therapeutic agent to treat various diseases, including vaginal infections. In this study, six binary mixtures of chitosan with stable S. baicalensis radix lyophilized extract were obtained and identified by spectral (ATR-FTIR, XRPD) and thermal (TG and DSC) methods. The changes in dissolution rates of active compounds and the significant increase in the biological properties towards metal chelating activity were observed, as well as the inhibition of hyaluronic acid degradation after mixing plant extract with chitosan. Moreover, the combination of S. baicalensis radix lyophilized extract with a carrier allowed us to obtain the binary systems with a higher antifungal activity than the pure extract, which may be effective in developing new strategies in the vaginal infections treatment, particularly vulvovaginal candidiasis. Full article
(This article belongs to the Special Issue Advances in Vaginal Drug Delivery)
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Review

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16 pages, 1221 KiB  
Review
Vaginal Nanoformulations for the Management of Preterm Birth
by Asad Mir, Richa V. Vartak, Ketan Patel, Steven M. Yellon and Sandra E. Reznik
Pharmaceutics 2022, 14(10), 2019; https://doi.org/10.3390/pharmaceutics14102019 - 23 Sep 2022
Cited by 3 | Viewed by 1938
Abstract
Preterm birth (PTB) is a leading cause of infant morbidity and mortality in the world. In 2020, 1 in 10 infants were born prematurely in the United States. The World Health Organization estimates that a total of 15 million infants are born prematurely [...] Read more.
Preterm birth (PTB) is a leading cause of infant morbidity and mortality in the world. In 2020, 1 in 10 infants were born prematurely in the United States. The World Health Organization estimates that a total of 15 million infants are born prematurely every year. Current therapeutic interventions for PTB have had limited replicable success. Recent advancements in the field of nanomedicine have made it possible to utilize the vaginal administration route to effectively and locally deliver drugs to the female reproductive tract. Additionally, studies using murine models have provided important insights about the cervix as a gatekeeper for pregnancy and parturition. With these recent developments, the field of reproductive biology is on the cusp of a paradigm shift in the context of treating PTB. The present review focuses on the complexities associated with treating the condition and novel therapeutics that have produced promising results in preclinical studies. Full article
(This article belongs to the Special Issue Advances in Vaginal Drug Delivery)
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