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Pharmaceutics
Special Issues
Vaginal Drug Delivery for Local and Systemic Applications
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Vaginal Drug Delivery for Local and Systemic Applications

A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (10 June 2019) | Viewed by 46227

Special Issue Editors

Prof. Dr. Lisa Cencia Rohan

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Magee-Women’s Research Institute, Pittsburgh, PA 15213, USA
Interests: drug delivery; translational research; infectious diseases; contraception
Dr. Sravan Kumar Patel

E-Mail Website
Guest Editor
School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
Interests: drug delivery; nanomedicine; manufacturing; infectious diseases

Special Issue Information

Dear Colleagues,

There has been growing interest in delivering drugs via the vaginal route for local and systemic delivery. The large surface area, high vasculature, access to the lymphatic system and potential for drug delivery throughout the female reproductive tract makes the vagina a desirable route of administration. As a result, this route has been exploited for delivering a wide variety of drugs including antimicrobials, antifungals, contraceptives, anticancer drugs, and labor-inducing drugs. In addition to small molecule drugs, labile drugs such as antibodies, proteins, genes, and probiotics have also been delivered via the vaginal route. A range of dosage forms designed for this route of administration allows for both immediate and sustained drug delivery.

Despite these advantages, due to the dynamic nature of this compartment, a number of challenges and knowledge gaps exist, driving a need to advance scientific knowledge in this area. There are several questions that need to be addressed in order to realize the full potential of vaginal drug delivery. New reports show a considerable presence of efflux and uptake transporters and metabolizing enzymes. At this point, their role in drug exposure to tissues or systemic circulation is unknown. Questions still remain regarding whether the excipients used in pharmaceutical products have any effect on innate protective factors such as the glycome and the microbiome. The role of the microbiome on drug stability, drug distribution and pharmacokinetics is an additional fascinating new area of research in the field. The first PBPK models are being developed. Such models would facilitate the translation of newly developed vaginal products more efficiently to the clinic. However, there exists a lack of critical data describing the physical and functional attributes of the female lower reproductive tract to facilitate optimal model development. Further, extensive characterization of the attributes that could predict in vivo performance such as drug dissolution, spreadability, and mucoadhesiveness are limited due to the unavailability of compendial methods for the evaluation of these critical factors.

Unlike oral and other traditional routes of delivery, the vaginal route is not a common route for drug delivery and hence women’s preferences for product attributes are not clearly known. The topic of product acceptability by women is critical to the development of effective vaginal products. New data is being developed in this area, which can contribute to a better definition of target product specifications. Behavioral and social research combined with product development efforts will shape the future of vaginal product design.

This Special Issue welcomes any topics regarding aspects that impact vaginal drug delivery research including research toward a better understanding of the biological components that impact drug disposition within the female lower reproductive tract, novel vaginal drug delivery systems, the design of new vaginal products, new animal or imaging methods to evaluate vaginal products, novel in vitro experimental methods to facilitate vaginal product development, compartment-specific modeling, in vitro–in vivo relationships, behavioral research, and preclinical assessments.

Prof. Lisa Cencia Rohan
Dr. Sravan Kumar Patel
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Vaginal Drug Delivery
  • Microbicides
  • Sexually Transmitted Infections
  • Nanomedicine
  • Contraception
  • Gynecological Oncology
  • Female Genital Tract

Published Papers (7 papers)

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Research

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19 pages, 3757 KiB  
Article
Rational Design of a Multipurpose Bioadhesive Vaginal Film for Co-Delivery of Dapivirine and Levonorgestrel
by Jing Li, Galit Regev, Sravan Kumar Patel, Dorothy Patton, Yvonne Sweeney, Philip Graebing, Sheila Grab, Lin Wang, Vinayak Sant and Lisa C. Rohan
Pharmaceutics 2020, 12(1), 1; https://doi.org/10.3390/pharmaceutics12010001 - 18 Dec 2019
Cited by 23 | Viewed by 6570
Abstract
Human immunodeficiency virus (HIV) infection and unintended pregnancy, which can lead to life-threatening complications, are two major burdens for female reproductive health. To address these pressing health issues, multipurpose prevention technologies (MPTs) are proposed to deliver two or more drugs simultaneously. MPTs could [...] Read more.
Human immunodeficiency virus (HIV) infection and unintended pregnancy, which can lead to life-threatening complications, are two major burdens for female reproductive health. To address these pressing health issues, multipurpose prevention technologies (MPTs) are proposed to deliver two or more drugs simultaneously. MPTs could offer several benefits for users such as improved convenience, increased effectiveness, reduced cost, and decreased environmental burden. Here, we report the development, and in vitro and in vivo assessment of a bioadhesive vaginal film as a coitally-independent MPT dosage form for delivering dapivirine (DPV) and levonorgestrel (LNG) to prevent HIV infection and unintended pregnancy, respectively. After confirming the feasibility of bioadhesive film use for weekly drug delivery in vivo through colpophotography and MRI evaluation, the pharmacokinetics (PK) of DPV/LNG single entity and combination bioadhesive films was investigated in pigtailed macaques (n = 5). Both drugs from single entity or combination films were able to provide sustained drug release in vivo. The combination film showed lower local tissue clearance for DPV and exhibited significantly increased plasma concentration for LNG as compared to the single entity film. This proof-of-concept study demonstrates the ability of this novel bioadhesive film platform to deliver LNG and DPV simultaneously as an MPT product for the prevention of HIV infection and unintended pregnancy. Full article
(This article belongs to the Special Issue Vaginal Drug Delivery for Local and Systemic Applications)
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27 pages, 1289 KiB  
Article
Rational Development of Liposomal Hydrogels: A Strategy for Topical Vaginal Antiretroviral Drug Delivery in the Context of HIV Prevention
by Maria J. Faria, Raul Machado, Artur Ribeiro, Hugo Gonçalves, Maria Elisabete C. D. Real Oliveira, Teresa Viseu, José das Neves and Marlene Lúcio
Pharmaceutics 2019, 11(9), 485; https://doi.org/10.3390/pharmaceutics11090485 - 18 Sep 2019
Cited by 34 | Viewed by 6554
Abstract
HIV/AIDS stands as a global burden, and vaginal microbicides constitute a promising strategy for topical pre-exposure prophylaxis. Preceding the development of a microbicide containing tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), in silico and in vitro studies were performed to evaluate the physicochemical [...] Read more.
HIV/AIDS stands as a global burden, and vaginal microbicides constitute a promising strategy for topical pre-exposure prophylaxis. Preceding the development of a microbicide containing tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), in silico and in vitro studies were performed to evaluate the physicochemical characteristics of both drugs, and to study their biophysical impact in lipid model systems. Results from these pre-formulation studies defined hydrogels as adequate vehicles to incorporate TDF-loaded liposomes and FTC. After studying interactions with mucin, zwitterionic liposomes with a mean diameter of 134 ± 13 nm, an encapsulation TDF efficiency of approximately 84%, and a transition temperature of 41 °C were selected. The chosen liposomal formulation was non-cytotoxic to HEC-1-A and CaSki cells, and was able to favor TDF permeation across polysulfone membranes (Jss = 9.9 μg·cm−2·h−1). After the incorporation of TDF-loaded liposomes and FTC in carbomer hydrogels, the drug release profile was sustained over time, reaching around 60% for both drugs within 3–6 h, and best fitting the Weibull model. Moreover, liposomal hydrogels featured pseudoplastic profiles that were deemed suitable for topical application. Overall, the proposed liposomal hydrogels may constitute a promising formulation for the vaginal co-delivery of TDF/FTC. Full article
(This article belongs to the Special Issue Vaginal Drug Delivery for Local and Systemic Applications)
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14 pages, 2326 KiB  
Article
17-α Hydroxyprogesterone Nanoemulsifying Preconcentrate-Loaded Vaginal Tablet: A Novel Non-Invasive Approach for the Prevention of Preterm Birth
by Manali Patki, Kiersten Giusto, Samir Gorasiya, Sandra E. Reznik and Ketan Patel
Pharmaceutics 2019, 11(7), 335; https://doi.org/10.3390/pharmaceutics11070335 - 14 Jul 2019
Cited by 26 | Viewed by 5940
Abstract
Preterm birth (PTB) is a major cause of infant mortality in the United States and around the globe. Makena®—once-a-week intramuscular injection of 17-α Hydroxyprogesterone caproate (17P)—is the only FDA approved treatment for the prevention of PTB. Invasive delivery of 17P requires [...] Read more.
Preterm birth (PTB) is a major cause of infant mortality in the United States and around the globe. Makena®—once-a-week intramuscular injection of 17-α Hydroxyprogesterone caproate (17P)—is the only FDA approved treatment for the prevention of PTB. Invasive delivery of 17P requires hospitalization and expert personnel for injection. Vaginal delivery of 17P would be preferable, because of high patient compliance, reduced systemic exposure, fewer side effects, and no need for hospitalization. The objective of the present study was to prepare and evaluate a self-nanoemulsifying vaginal tablet of 17P. A solid self-nanoemulsifying preconcentrate (S-SNEDDS) of 17P and dimethylacetamide (DMA) was developed using medium chain triglycerides, a non- immunogenic surfactant, and co-processed excipient (PVA-F100). The tablet prepared was characterized for emulsification time, particle size, solid state properties, and drug release. The formulation showed >50% inhibition of TNF-α release from LPS-stimulated RAW 264.7 cells. Importantly, there were significant differences in rates of PTB and average time to delivery between control and vaginal 17P-treated groups in LPS-stimulated timed pregnant E15.5 mice. Considering the lacuna of therapeutic approaches in this area, vaginal delivery of 17P for the prevention of preterm birth has significant clinical relevance. Full article
(This article belongs to the Special Issue Vaginal Drug Delivery for Local and Systemic Applications)
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19 pages, 2231 KiB  
Article
Smart Freeze-Dried Bigels for the Prevention of the Sexual Transmission of HIV by Accelerating the Vaginal Release of Tenofovir during Intercourse
by Araceli Martín-Illana, Fernando Notario-Pérez, Raúl Cazorla-Luna, Roberto Ruiz-Caro and María Dolores Veiga
Pharmaceutics 2019, 11(5), 232; https://doi.org/10.3390/pharmaceutics11050232 - 13 May 2019
Cited by 34 | Viewed by 5318
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Vaginal Drug Delivery for Local and Systemic Applications)
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Review

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23 pages, 995 KiB  
Review
In Vitro Methods for Evaluating Drug Release of Vaginal Ring Formulations—A Critical Review
by Katharina Tietz and Sandra Klein
Pharmaceutics 2019, 11(10), 538; https://doi.org/10.3390/pharmaceutics11100538 - 16 Oct 2019
Cited by 21 | Viewed by 5653
Abstract
The vagina is a promising site for both local and systemic drug delivery and represents an interesting administration route for compounds with poor oral bioavailability. Whereas most of the currently marketed dosage forms were designed as immediate release formulations, intravaginal rings (IVRs) offer [...] Read more.
The vagina is a promising site for both local and systemic drug delivery and represents an interesting administration route for compounds with poor oral bioavailability. Whereas most of the currently marketed dosage forms were designed as immediate release formulations, intravaginal rings (IVRs) offer the possibility of a controlled vaginal drug delivery over several weeks or months. For a long time, the development of IVRs was limited to steroid-releasing formulations. Recently, IVRs have witnessed a surge of new interest as promising delivery systems for microbicides. Therefore, various novel IVR designs have been introduced. To ensure that only safe and effective IVRs will be administered to patients, it is important to properly distinguish between IVRs with desired and undesired release performance. In vitro methods for evaluating drug release of IVRs that present with sufficient predictive capacity for in vivo drug release, and discriminatory power with regard to IVRs quality, are an essential tool for this purpose. The objective of the present review article is to present the current status of in vitro drug release testing of IVRs and to critically discuss current compendial and non-official in vitro drug release methods with regard to their discriminatory power and in vivo predictivity. Full article
(This article belongs to the Special Issue Vaginal Drug Delivery for Local and Systemic Applications)
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17 pages, 1647 KiB  
Review
Topical Inserts: A Versatile Delivery Form for HIV Prevention
by M. Melissa Peet, Vivek Agrahari, Sharon M. Anderson, Homaira Hanif, Onkar N. Singh, Andrea R. Thurman, Gustavo F. Doncel and Meredith R. Clark
Pharmaceutics 2019, 11(8), 374; https://doi.org/10.3390/pharmaceutics11080374 - 01 Aug 2019
Cited by 22 | Viewed by 8708
Abstract
The development of topical inserts for the prevention of sexually transmitted infections (STIs), particularly human immunodeficiency virus (HIV), represents a promising alternative to oral and parenteral pre-exposure prophylaxis (PrEP) dosage forms. They may be used for vaginal and/or rectal administration of a variety [...] Read more.
The development of topical inserts for the prevention of sexually transmitted infections (STIs), particularly human immunodeficiency virus (HIV), represents a promising alternative to oral and parenteral pre-exposure prophylaxis (PrEP) dosage forms. They may be used for vaginal and/or rectal administration of a variety of agents with antiviral activity. Topical inserts deliver drugs to the portal of viral entry, i.e., the genital or rectal mucosa, with low systemic exposure, and therefore are safer and have fewer side effects than systemic PrEP agents. They may dissolve fast, releasing the active drugs within minutes of insertion, or slowly for long-acting drug delivery. Furthermore, they are user-friendly being easy to administer, discreet and highly portable. They are also economical and easy to manufacture at scale and to distribute, with excellent stability and shelf-life. Altogether, topical inserts represent a particularly promising form of drug delivery for HIV and STI prevention. Highlighted within this review are end-user acceptability research dedicated to understanding preferred attributes for this form of drug delivery, advantages and disadvantages of the formulation platform options, considerations for their development, clinical assessment of select placebo prototypes, future directions, and the potential impact of this dosage form on the HIV prevention landscape. Full article
(This article belongs to the Special Issue Vaginal Drug Delivery for Local and Systemic Applications)
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18 pages, 1397 KiB  
Review
Modifications in Vaginal Microbiota and Their Influence on Drug Release: Challenges and Opportunities
by Gerardo Leyva-Gómez, María L. Del Prado-Audelo, Silvestre Ortega-Peña, Néstor Mendoza-Muñoz, Zaida Urbán-Morlán, Maykel González-Torres, Manuel González-Del Carmen, Gabriela Figueroa-González, Octavio D. Reyes-Hernández and Hernán Cortés
Pharmaceutics 2019, 11(5), 217; https://doi.org/10.3390/pharmaceutics11050217 - 06 May 2019
Cited by 45 | Viewed by 5148
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Vaginal Drug Delivery for Local and Systemic Applications)
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