Emerging Trends and Potential Prospects in Vaginal Drug Delivery

Shikha      Mahant; Abhishek   Kumar   Sharma; Himanshu      Gandhi; Ridhima      Wadhwa; Kamal      Dua; Deepak   N.   Kapoor
Abstract

The vagina is an essential part of the female reproductive system and offers many potential benefits over conventional drug delivery, including a large surface area for drug absorption, relatively low enzymatic activity, avoiding first-pass effects, and ease of administration. The vaginal mucosal cavity is an effective route for administering therapeutic agents that are intended both for local and systemic administration. The present review provides a comprehensive overview of recent trends and developments in vaginal drug delivery. Marketed formulations and products under clinical study are also reviewed. Various novel vaginal delivery systems have been studied in recent years as effective tools for delivering a range of therapeutic agents to the vagina. These systems offer numerous benefits, including sustained delivery, improved bioavailability, effective permeation, and higher efficacy. The recent focus of the scientific community is on the development of safe and efficient drug delivery systems, such as nanoparticles, microparticles, vesicular systems, vaginal rings, microneedles, etc., for vaginal application. Various factors, such as the physicochemical properties of the drugs, the volume and composition of the vaginal fluid, the pH of the vaginal fluid, the thickness of the vaginal epithelium, and the influence of sexual intercourse may influence the release of drugs from the delivery system and subsequent absorption from the vaginal route. To date, only a limited number of in vivo studies on novel vaginal DDS have been reported. Additionally, drug release kinetics under varying vaginal environments is also not well understood. More research is needed to ensure the suitability, biocompatibility, and therapeutic effectiveness of novel DDS for vaginal delivery. Although numerous strategies and interventions have been developed, clinical translation of these systems remains a challenge. The toxicity of the carrier system is also an important consideration for future clinical applications.
Keywords: Vagina, vaginal drug delivery system, nanocarriers, mucoadhesive vaginal formulation, vaginal gel, vaginal rings.
Graphical Abstract

[1]
Shaikh, R.; Raj Singh, T.R.; Garland, M.J.; Woolfson, A.D.; Donnelly, R.F. Mucoadhesive drug delivery systems. J. Pharm. Bioallied Sci.,  2011, 3(1), 89-100.
 [http://dx.doi.org/10.4103/0975-7406.76478] [PMID: 21430958]

[2]
de Araújo Pereira, R.R.; Bruschi, M.L. Vaginal mucoadhesive drug delivery systems. Drug Dev. Ind. Pharm.,  2012, 38(6), 643-652.
 [http://dx.doi.org/10.3109/03639045.2011.623355] [PMID: 21999572]

[3]
Dobaria, N.; Mashru, R.; Vadia, N.H. Vaginal drug delivery systems: A review of current status. East Cent. Afr. J. Pharm. Sci.,  2007, 10(1), 3-13.

[4]
Jalalvandi, E.; Jafari, H.; Amorim, C.A.; Petri, D.F.S.; Nie, L.; Shavandi, A. Vaginal administration of contraceptives. Sci. Pharm.,  2021, 89(1), 3.
 [http://dx.doi.org/10.3390/scipharm89010003]

[5]
Han, Y.; Liu, Z.; Chen, T. Role of vaginal microbiota dysbiosis in gynecological diseases and the potential interventions. Front. Microbiol.,  2021, 12643422
 [http://dx.doi.org/10.3389/fmicb.2021.643422] [PMID: 34220737]

[6]
Osmałek, T.; Froelich, A.; Jadach, B.; Tatarek, A.; Gadziński, P.; Falana, A.; Gralińska, K.; Ekert, M.; Puri, V.; Wrotyńska-Barczyńska, J.; Michniak-Kohn, B. Recent advances in polymer-based vaginal drug delivery systems. Pharmaceutics,  2021, 13(6), 884.
 [http://dx.doi.org/10.3390/pharmaceutics13060884] [PMID: 34203714]

[7]
Chindamo, G.; Sapino, S.; Peira, E.; Chirio, D.; Gallarate, M. Recent advances in nanosystems and strategies for vaginal delivery of antimicrobials. Nanomaterials,  2021, 11(2), 311.
 [http://dx.doi.org/10.3390/nano11020311] [PMID: 33530510]

[8]
Iqbal, Z.; Dilnawaz, F. Nanocarriers for vaginal drug delivery. Recent Pat. Drug Deliv. Formul.,  2019, 13(1), 3-15.
 [http://dx.doi.org/10.2174/1872211313666190215141507] [PMID: 30767755]

[9]
Acartürk, F. Mucoadhesive vaginal drug delivery systems. Recent Pat. Drug Deliv. Formul.,  2009, 3(3), 193-205.
 [http://dx.doi.org/10.2174/187221109789105658] [PMID: 19925443]

[10]
Ghosal, K.; Ranjan, A.; Bhowmik, B.B. A novel vaginal drug delivery system: Anti-HIV bioadhesive film containing abacavir. J. Mater. Sci. Mater. Med.,  2014, 25(7), 1679-1689.
 [http://dx.doi.org/10.1007/s10856-014-5204-6] [PMID: 24699799]

[11]
Major, I.; McConville, C. Vaginal drug delivery for the localised treatment of cervical cancer. Drug Deliv. Transl. Res.,  2017, 7(6), 817-828.
 [http://dx.doi.org/10.1007/s13346-017-0395-2] [PMID: 28597123]

[12]
Wu, Q.; Li, L. Thermal sensitive Poloxamer/Chitosan hydrogel for drug delivery in vagina. Mater. Res. Express,  2020, 7(10)105401
 [http://dx.doi.org/10.1088/2053-1591/abbafd]

[13]
Srikrishna, S.; Cardozo, L. The vagina as a route for drug delivery: A review. Int. Urogynecol. J. Pelvic Floor Dysfunct.,  2013, 24(4), 537-543.
 [http://dx.doi.org/10.1007/s00192-012-2009-3] [PMID: 23229421]

[14]
Whaley, K.J.; Hanes, J.; Shattock, R.; Cone, R.A.; Friend, D.R. Novel approaches to vaginal delivery and safety of microbicides: Biopharmaceuticals, nanoparticles, and vaccines. Antiviral Res.,  2010, 88(Suppl. 1), S55-S66.
 [http://dx.doi.org/10.1016/j.antiviral.2010.09.006] [PMID: 21109069]

[15]
Yu, T.; Malcolm, K.; Woolfson, D.; Jones, D.S.; Andrews, G.P. Vaginal gel drug delivery systems: Understanding rheological characteristics and performance. Expert Opin. Drug Deliv.,  2011, 8(10), 1309-1322.
 [http://dx.doi.org/10.1517/17425247.2011.600119] [PMID: 21728886]

[16]
Woolfson, A.D.; Malcolm, R.K.; Gallagher, R. Drug delivery by the intravaginal route. Crit. Rev. Ther. Drug Carrier Syst.,  2000, 17(5), 509-555.
 [http://dx.doi.org/10.1615/CritRevTherDrugCarrierSyst.v17.i5.30] [PMID: 11108158]

[17]
Lalan, M.S.; Patel, V.N.; Misra, A. Polymers in vaginal drug delivery: Recent advancements. Applications of polymers in drug delivery; Elsevier, 2021, pp. 281-303.
 [http://dx.doi.org/10.1016/B978-0-12-819659-5.00010-0]

[18]
Soloyan, H.; De Filippo, R.E.; Sedrakyan, S. Tissue engineering of the reproductive system., 2019.
 [http://dx.doi.org/10.1016/B978-0-12-801238-3.65850-6]

[19]
Łaniewski, P.; Herbst-Kralovetz, M. Vagina. In: Encyclopedia of reproduction; Elsevier, 2018, pp. 353-359.
 [http://dx.doi.org/10.1016/B978-0-12-801238-3.64406-9]

[20]
Anderson, D.J.; Marathe, J.; Pudney, J. The structure of the human vaginal stratum corneum and its role in immune defense. Am. J. Reprod. Immunol.,  2014, 71(6), 618-623.
 [http://dx.doi.org/10.1111/aji.12230] [PMID: 24661416]

[21]
Jones, R.E.; Lopez, K.H. Human reproductive biology; Academic Press, 2013. 

[22]
Palacios Jaraquemada, J.M.; García Mónaco, R.; Barbosa, N.E.; Ferle, L.; Iriarte, H.; Conesa, H.A. Lower uterine blood supply: Extrauterine anastomotic system and its application in surgical devascularization techniques. Acta Obstet. Gynecol. Scand.,  2007, 86(2), 228-234.
 [http://dx.doi.org/10.1080/00016340601089875] [PMID: 17364288]

[23]
Richardson, J.L.; Illum, L. VIII: The vaginal route of peptide and protein drug delivery. Adv. Drug Deliv. Rev.,  1992, 8(2-3), 341-366.
 [http://dx.doi.org/10.1016/0169-409X(92)90008-E]

[24]
Woodrow, K.A.; Bennett, K.M.; Lo, D.D. Mucosal vaccine design and delivery. Annu. Rev. Biomed. Eng.,  2012, 14(1), 17-46.
 [http://dx.doi.org/10.1146/annurev-bioeng-071811-150054] [PMID: 22524387]

[25]
Ensign, L.M.; Cone, R.; Hanes, J. Nanoparticle-based drug delivery to the vagina: A review. J. Control. Release,  2014, 190, 500-514.
 [http://dx.doi.org/10.1016/j.jconrel.2014.04.033] [PMID: 24830303]

[26]
Wira, C.R.; Patel, M.V.; Ghosh, M.; Mukura, L.; Fahey, J.V. Innate immunity in the human female reproductive tract: Endocrine regulation of endogenous antimicrobial protection against HIV and other sexually transmitted infections. Am. J. Reprod. Immunol.,  2011, 65(3), 196-211.
 [http://dx.doi.org/10.1111/j.1600-0897.2011.00970.x] [PMID: 21294805]

[27]
Wira, C.R.; Fahey, J.V.; Sentman, C.L.; Pioli, P.A.; Shen, L. Innate and adaptive immunity in female genital tract: Cellular responses and interactions. Immunol. Rev.,  2005, 206(1), 306-335.
 [http://dx.doi.org/10.1111/j.0105-2896.2005.00287.x] [PMID: 16048557]

[28]
Anjuère, F.; Bekri, S.; Bihl, F.; Braud, V.M.; Cuburu, N.; Czerkinsky, C.; Hervouet, C.; Luci, C. B cell and T cell immunity in the female genital tract: Potential of distinct mucosal routes of vaccination and role of tissue-associated dendritic cells and natural killer cells. Clin. Microbiol. Infect.,  2012, 18(Suppl. 5), 117-122.
 [http://dx.doi.org/10.1111/j.1469-0691.2012.03995.x] [PMID: 22882377]

[29]
Shen, Z.; Rodriguez-Garcia, M.; Patel, M.V.; Bodwell, J.; Wira, C.R. Epithelial cells and fibroblasts from the human female reproductive tract accumulate and release TFV and TAF to sustain inhibition of HIV infection of CD4+ T cells. Sci. Rep.,  2019, 9(1), 1864.
 [http://dx.doi.org/10.1038/s41598-018-38205-y] [PMID: 30755713]

[30]
Wira, C.R.; Rodriguez-Garcia, M.; Patel, M.V. The role of sex hormones in immune protection of the female reproductive tract. Nat. Rev. Immunol.,  2015, 15(4), 217-230.
 [http://dx.doi.org/10.1038/nri3819] [PMID: 25743222]

[31]
Hel, Z.; Stringer, E.; Mestecky, J. Sex steroid hormones, hormonal contraception, and the immunobiology of human immunodeficiency virus-1 infection. Endocr. Rev.,  2010, 31(1), 79-97.
 [http://dx.doi.org/10.1210/er.2009-0018] [PMID: 19903932]

[32]
Bouman, A.; Heineman, M.J.; Faas, M.M. Sex hormones and the immune response in humans. Hum. Reprod. Update,  2005, 11(4), 411-423.
 [http://dx.doi.org/10.1093/humupd/dmi008] [PMID: 15817524]

[33]
Duluc, D.; Gannevat, J.; Anguiano, E.; Zurawski, S.; Carley, M.; Boreham, M.; Stecher, J.; Dullaers, M.; Banchereau, J.; Oh, S. Functional diversity of human vaginal APC subsets in directing T-cell responses. Mucosal Immunol.,  2013, 6(3), 626-638.
 [http://dx.doi.org/10.1038/mi.2012.104] [PMID: 23131784]

[34]
Barr, F.D.; Ochsenbauer, C.; Wira, C.R.; Rodriguez-Garcia, M. Neutrophil extracellular traps prevent HIV infection in the female genital tract. Mucosal Immunol.,  2018, 11(5), 1420-1428.
 [http://dx.doi.org/10.1038/s41385-018-0045-0] [PMID: 29875403]

[35]
Shen, R.; Richter, H.E.; Smith, P.D. Early HIV-1 target cells in human vaginal and ectocervical mucosa. Am. J. Reprod. Immunol.,  2011, 65(3), 261-267.
 [http://dx.doi.org/10.1111/j.1600-0897.2010.00939.x] [PMID: 21118402]

[36]
Gibbs, A.; Leeansyah, E.; Introini, A.; Paquin-Proulx, D.; Hasselrot, K.; Andersson, E.; Broliden, K.; Sandberg, J.K.; Tjernlund, A. MAIT cells reside in the female genital mucosa and are biased towards IL-17 and IL-22 production in response to bacterial stimulation. Mucosal Immunol.,  2017, 10(1), 35-45.
 [http://dx.doi.org/10.1038/mi.2016.30] [PMID: 27049062]

[37]
Spinner, M.A.; Sanchez, L.A.; Hsu, A.P.; Shaw, P.A.; Zerbe, C.S.; Calvo, K.R.; Arthur, D.C.; Gu, W.; Gould, C.M.; Brewer, C.C.; Cowen, E.W.; Freeman, A.F.; Olivier, K.N.; Uzel, G.; Zelazny, A.M.; Daub, J.R.; Spalding, C.D.; Claypool, R.J.; Giri, N.K.; Alter, B.P.; Mace, E.M.; Orange, J.S.; Cuellar-Rodriguez, J.; Hickstein, D.D.; Holland, S.M. GATA2 deficiency: A protean disorder of hematopoiesis, lymphatics, and immunity. Blood,  2014, 123(6), 809-821.
 [http://dx.doi.org/10.1182/blood-2013-07-515528] [PMID: 24227816]

[38]
Wang, Y.Y.; Kannan, A.; Nunn, K.L.; Murphy, M.A.; Subramani, D.B.; Moench, T.; Cone, R.; Lai, S.K. IgG in cervicovaginal mucus traps HSV and prevents vaginal herpes infections. Mucosal Immunol.,  2014, 7(5), 1036-1044.
 [http://dx.doi.org/10.1038/mi.2013.120] [PMID: 24496316]

[39]
Biagi, E.; Vitali, B.; Pugliese, C.; Candela, M.; Donders, G.G.G.; Brigidi, P. Quantitative variations in the vaginal bacterial population associated with asymptomatic infections: A real-time polymerase chain reaction study. Eur. J. Clin. Microbiol. Infect. Dis.,  2009, 28(3), 281-285.
 [http://dx.doi.org/10.1007/s10096-008-0617-0] [PMID: 18762999]

[40]
Beigi, R.H.; Wiesenfeld, H.C.; Hillier, S.L.; Straw, T.; Krohn, M.A. Factors associated with absence of H2O2-producing Lactobacillus among women with bacterial vaginosis. J. Infect. Dis.,  2005, 191(6), 924-929.
 [http://dx.doi.org/10.1086/428288] [PMID: 15717268]

[41]
Fredricks, D.N.; Fiedler, T.L.; Marrazzo, J.M. Molecular identification of bacteria associated with bacterial vaginosis. N. Engl. J. Med.,  2005, 353(18), 1899-1911.
 [http://dx.doi.org/10.1056/NEJMoa043802] [PMID: 16267321]

[42]
Pandey, M.; Choudhury, H.; Abdul-Aziz, A.; Bhattamisra, S.K.; Gorain, B.; Carine, T.; Wee Toong, T.; Yi, N.J.; Win Yi, L. Promising drug delivery approaches to treat microbial infections in the vagina: A recent update. Polymers (Basel),  2020, 13(1), 26.
 [http://dx.doi.org/10.3390/polym13010026] [PMID: 33374756]

[43]
Pramanick, R.; Mayadeo, N.; Warke, H.; Begum, S.; Aich, P.; Aranha, C. Vaginal microbiota of asymptomatic bacterial vaginosis and vulvovaginal candidiasis: Are they different from normal microbiota? Microb. Pathog.,  2019, 134103599
 [http://dx.doi.org/10.1016/j.micpath.2019.103599] [PMID: 31212037]

[44]
Mirmonsef, P.; Krass, L.; Landay, A.; Spear, G.T. The role of bacterial vaginosis and trichomonas in HIV transmission across the female genital tract. Curr. HIV Res.,  2012, 10(3), 202-210.
 [http://dx.doi.org/10.2174/157016212800618165] [PMID: 22384839]

[45]
Smayevsky, J.; Canigia, L.F.; Lanza, A.; Bianchini, H. Vaginal microflora associated with bacterial vaginosis in nonpregnant women: Reliability of sialidase detection. Infect. Dis. Obstet. Gynecol.,  2001, 9(1), 17-22.
 [http://dx.doi.org/10.1155/S1064744901000047] [PMID: 11368254]

[46]
Sobel, J.D. Epidemiology and pathogenesis of recurrent vulvovaginal candidiasis. Am. J. Obstet. Gynecol.,  1985, 152(7 Pt 2), 924-935.
 [http://dx.doi.org/10.1016/S0002-9378(85)80003-X] [PMID: 3895958]

[47]
Eckert, L.O.; Hawes, S.E.; Stevens, C.E.; Koutsky, L.A.; Eschenbach, D.A.; Holmes, K.K. Vulvovaginal candidiasis: Clinical manifestations, risk factors, management algorithm. Obstet. Gynecol.,  1998, 92(5), 757-765.
 [http://dx.doi.org/10.1097/00006250-199811000-00004] [PMID: 9794664]

[48]
Sobel, J.D. Vulvovaginal candidosis. Lancet,  2007, 369(9577), 1961-1971.
 [http://dx.doi.org/10.1016/S0140-6736(07)60917-9] [PMID: 17560449]

[49]
Fenton, K.A.; Lowndes, C.M. Recent trends in the epidemiology of sexually transmitted infections in the European Union. Sex. Transm. Infect.,  2004, 80(4), 255-263.
 [http://dx.doi.org/10.1136/sti.2004.009415]

[50]
Workowski, K.A.; Berman, S.M. Centers for disease control and prevention sexually transmitted diseases treatment guidelines. MMWR Recomm. Rep.,  2006, 55(RR-11), 1-94.
 [PMID: 16888612]

[51]
Manavi, K. A review on infection with Chlamydia trachomatis. Best Pract. Res. Clin. Obstet. Gynaecol.,  2006, 20(6), 941-951.
 [http://dx.doi.org/10.1016/j.bpobgyn.2006.06.003]

[52]
Torpy, J.M.; Lynm, C.; Golub, R.M. Gonorrhea. JAMA -. JAMA,  2013, 309(2), 196.
 [http://dx.doi.org/10.1001/2012.jama.10802] [PMID: 23299613]

[53]
Birkmann, A.; Zimmermann, H. HSV Antivirals - Current and Future treatment options. Curr. Opin. Virol. Elsevier B.V.,  2016, vol. 18, pp. 9-13.

[54]
Nayak, B.S.; Ellaiah, P.; Sudhahar, D. Novel approaches in vaginal drug delivery systems for local and systemic treatments. J. Pharm. Res.,  2010, 3(4), 675-680.

[55]
Caramella, C.M.; Rossi, S.; Ferrari, F.; Bonferoni, M.C.; Sandri, G. Mucoadhesive and thermogelling systems for vaginal drug delivery. Adv. Drug Deliv. Rev.,  2015, 92, 39-52.
 [http://dx.doi.org/10.1016/j.addr.2015.02.001] [PMID: 25683694]

[56]
Valenta, C. The use of mucoadhesive polymers in vaginal delivery. Adv. Drug Deliv. Rev.,  2005, 57(11), 1692-1712.
 [http://dx.doi.org/10.1016/j.addr.2005.07.004] [PMID: 16182407]

[57]
Kohane, D.S. Microparticles and nanoparticles for drug delivery. Biotechnol. Bioeng.,  2007, 96(2), 203-209.
 [http://dx.doi.org/10.1002/bit.21301] [PMID: 17191251]

[58]
Palmeira-de-Oliveira, R.; Palmeira-de-Oliveira, A.; Martinez-de-Oliveira, J. New strategies for local treatment of vaginal infections. Adv. Drug Deliv. Rev.,  2015, 92, 105-122.
 [http://dx.doi.org/10.1016/j.addr.2015.06.008] [PMID: 26144995]

[59]
das Neves. J.; Araújo, F.; Andrade, F.; Michiels, J.; Ariën, K.K.; Vanham, G.; Amiji, M.; Bahia, M.F.; Sarmento, B. In vitro and ex vivo evaluation of polymeric nanoparticles for vaginal and rectal delivery of the anti-HIV drug dapivirine. Mol. Pharm.,  2013, 10(7), 2793-2807.
 [http://dx.doi.org/10.1021/mp4002365] [PMID: 23738946]

[60]
Albertini, B.; Passerini, N.; Di Sabatino, M.; Vitali, B.; Brigidi, P.; Rodriguez, L. Polymer-lipid based mucoadhesive microspheres prepared by spray-congealing for the vaginal delivery of econazole nitrate. Eur. J. Pharm. Sci.,  2009, 36(4-5), 591-601.
 [http://dx.doi.org/10.1016/j.ejps.2008.12.009] [PMID: 19150403]

[61]
Martín-Villena, M.J.; Fernández-Campos, F.; Calpena-Campmany, A.C.; Bozal-de Febrer, N.; Ruiz-Martínez, M.A.; Clares-Naveros, B. Novel microparticulate systems for the vaginal delivery of nystatin: Development and characterization. Carbohydr. Polym.,  2013, 94(1), 1-11.
 [http://dx.doi.org/10.1016/j.carbpol.2013.01.005] [PMID: 23544502]

[62]
Maestrelli, F.; Jug, M.; Cirri, M.; Kosalec, I.; Mura, P. Characterization and microbiological evaluation of chitosan-alginate microspheres for cefixime vaginal administration. Carbohydr. Polym.,  2018, 192, 176-183. https://linkinghub.elsevier.com/retrieve/pii/S0144861718303187
 [http://dx.doi.org/10.1016/j.carbpol.2018.03.054] [PMID: 29691010]

[63]
Zhang, T.; Zhang, C.; Agrahari, V.; Murowchick, J.B.; Oyler, N.A.; Youan, B.B.C. Spray drying tenofovir loaded mucoadhesive and pH-sensitive microspheres intended for HIV prevention. Antiviral Res.,  2013, 97(3), 334-346.
 [http://dx.doi.org/10.1016/j.antiviral.2012.12.019] [PMID: 23274788]

[64]
Szekalska, M.; Citkowska, A.; Wróblewska, M.; Winnicka, K. The impact of gelatin on the pharmaceutical characteristics of fucoidan microspheres with posaconazole. Materials,  2021, 14(15), 4087.
 [http://dx.doi.org/10.3390/ma14154087] [PMID: 34361285]

[65]
Salah, S.; Awad, G.E.A.; Makhlouf, A.I.A. Improved vaginal retention and enhanced antifungal activity of miconazole microsponges gel: Formulation development and in vivo therapeutic efficacy in rats. Eur. J. Pharm. Sci.,  2018, 114, 255-266.
 [http://dx.doi.org/10.1016/j.ejps.2017.12.023] [PMID: 29288706]

[66]
Amaral, A.C.; Saavedra, P.H.V.; Oliveira Souza, A.C.; de Melo, M.T.; Tedesco, A.C.; Morais, P.C.; Soares Felipe, M.S.; Bocca, A.L. Miconazole loaded chitosan-based nanoparticles for local treatment of vulvovaginal candidiasis fungal infections. Colloids Surf. B Biointerfaces,  2019, 174, 409-415.
 [http://dx.doi.org/10.1016/j.colsurfb.2018.11.048] [PMID: 30481701]

[67]
Martínez-Pérez, B.; Quintanar-Guerrero, D.; Tapia-Tapia, M.; Cisneros-Tamayo, R.; Zambrano-Zaragoza, M.L.; Alcalá-Alcalá, S.; Mendoza-Muñoz, N.; Piñón-Segundo, E. Controlled-release biodegradable nanoparticles: From preparation to vaginal applications. Eur. J. Pharm. Sci.,  2018, 115, 185-195.
 [http://dx.doi.org/10.1016/j.ejps.2017.11.029] [PMID: 29208486]

[68]
Jain, S.; Jain, V.; Mahajan, S.C. Lipid based vesicular drug delivery systems. Adv. Pharm.,  2014, 2014, 12.
 [http://dx.doi.org/10.1155/2014/574673]

[69]
More, S.B.; Nandgude, T.D.; Poddar, S.S. Vesicles as a tool for enhanced topical drug delivery. Asian J. Pharm.,  2016, 10(3), S196-S209.

[70]
Karimunnisa, S.; Atmaram, P. Mucoadhesive nanoliposomal formulation for vaginal delivery of an antifungal. Drug Dev. Ind. Pharm.,  2013, 39(9), 1328-1337.
 [http://dx.doi.org/10.3109/03639045.2012.707204] [PMID: 22866766]

[71]
Vanić Ž.; Hurler, J.; Ferderber, K.; Golja Gašparović P.; Škalko-Basnet, N.; Filipović-Grčić J. Novel vaginal drug delivery system: Deformable propylene glycol liposomes-in-hydrogel. J. Liposome Res.,  2014, 24(1), 27-36.
 [http://dx.doi.org/10.3109/08982104.2013.826242] [PMID: 23931627]

[72]
Berginc, K. Suljaković S.; Škalko-Basnet, N.; Kristl, A. Mucoadhesive liposomes as new formulation for vaginal delivery of curcumin. Eur. J. Pharm. Biopharm.,  2014, 87(1), 40-46.
 [http://dx.doi.org/10.1016/j.ejpb.2014.02.006] [PMID: 24534774]

[73]
Jøraholmen, M.W. Vanić Z.; Tho, I.; Škalko-Basnet, N. Chitosan-coated liposomes for topical vaginal therapy: Assuring localized drug effect. Int. J. Pharm.,  2014, 472(1-2), 94-101.
 [http://dx.doi.org/10.1016/j.ijpharm.2014.06.016] [PMID: 24928137]

[74]
Ning, M.; Guo, Y.; Pan, H.; Yu, H.; Gu, Z. Niosomes with sorbitan monoester as a carrier for vaginal delivery of insulin: Studies in rats. Drug Deliv.,  2005, 12(6), 399-407.
 [http://dx.doi.org/10.1080/10717540590968891] [PMID: 16253956]

[75]
Ning, M.; Guo, Y.; Pan, H.; Chen, X.; Gu, Z. Preparation, in vitro and in vivo evaluation of liposomal/niosomal gel delivery systems for clotrimazole. Drug Dev. Ind. Pharm.,  2005, 31(4-5), 375-383.
 [http://dx.doi.org/10.1081/DDC-54315] [PMID: 16093203]

[76]
Salem, H.F.; Kharshoum, R.M.; Abou-Taleb, H.A.; AbouTaleb, H.A.; AbouElhassan, K.M. Progesterone-loaded nanosized transethosomes for vaginal permeation enhancement: Formulation, statistical optimization, and clinical evaluation in anovulatory polycystic ovary syndrome. J. Liposome Res.,  2019, 29(2), 183-194.
 [http://dx.doi.org/10.1080/08982104.2018.1524483] [PMID: 30221566]

[77]
Mbah, C.; Builders, P.; Nzekwe, I.; Kunle, O.; Adikwu, M.; Attama, A. Formulation and in vitro evaluation of pH-responsive ethosomes for vaginal delivery of metronidazole. J. Drug Deliv. Sci. Technol.,  2014, 24(6), 565-571.
 [http://dx.doi.org/10.1016/S1773-2247(14)50120-7]

[78]
Justin-Temu, M.; Damian, F.; Kinget, R.; Van Den Mooter, G. Intravaginal gels as drug delivery systems. J. Womens Health (Larchmt.),  2004, 13(7), 834-844.
 [http://dx.doi.org/10.1089/jwh.2004.13.834] [PMID: 15385078]

[79]
das Neves. J.; Bahia, M.F. Gels as vaginal drug delivery systems. Int. J. Pharm.,  2006, 318(1-2), 1-14.
 [http://dx.doi.org/10.1016/j.ijpharm.2006.03.012] [PMID: 16621366]

[80]
Notario-Pérez, F.; Cazorla-Luna, R.; Martín-Illana, A.; Galante, J.; Ruiz-Caro, R. das Neves, J.; Veiga, M.D. Design, fabrication and characterisation of drug-loaded vaginal films: State-of-the-art. J. Control. Release,  2020, 327, 477-499.
 [http://dx.doi.org/10.1016/j.jconrel.2020.08.032] [PMID: 32853730]

[81]
De Seta, F.; Caruso, S.; Di Lorenzo, G.; Romano, F.; Mirandola, M.; Nappi, R.E. Efficacy and safety of a new vaginal gel for the treatment of symptoms associated with vulvovaginal atrophy in postmenopausal women: A double-blind randomized placebo-controlled study. Maturitas,  2021, 147, 34-40.
 [http://dx.doi.org/10.1016/j.maturitas.2021.03.002] [PMID: 33832645]

[82]
Karthick, R.A.; Devi, D.R.; Hari, B.N.V. Investigation of sustained release mucoadhesive in-situ gel system of {Secnidazole} for the persistent treatment of vaginal infections. J. Drug Deliv. Sci. Technol.,  2018, 43, 362-368.
 [http://dx.doi.org/10.1016/j.jddst.2017.11.001]

[83]
Deshkar, S.S.; Palve, V.K. Formulation and development of thermosensitive cyclodextrin-based in situ gel of voriconazole for vaginal delivery. J. Drug Deliv. Sci. Technol.,  2019, 49, 277-285.
 [http://dx.doi.org/10.1016/j.jddst.2018.11.023]

[84]
Martín-Illana, A.; Cazorla-Luna, R.; Notario-Pérez, F.; Bedoya, L.M.; Ruiz-Caro, R.; Veiga, M.D. Freeze-dried bioadhesive vaginal bigels for controlled release of Tenofovir. Eur. J. Pharm. Sci.,  2019, 127, 38-51.
 [http://dx.doi.org/10.1016/j.ejps.2018.10.013] [PMID: 30343152]

[85]
Chang, J.Y.; Oh, Y-K.; Kong, H.S.; Kim, E.J.; Jang, D.D.; Nam, K.T.; Kim, C.K. Prolonged antifungal effects of clotrimazole-containing mucoadhesive thermosensitive gels on vaginitis. J. Control. Release,  2002, 82(1), 39-50.
 [http://dx.doi.org/10.1016/S0168-3659(02)00086-X] [PMID: 12106975]

[86]
Baloglu, E.; Karavana, S.Y.; Senyigit, Z.A.; Hilmioglu-Polat, S.; Metin, D.Y.; Zekioglu, O.; Guneri, T.; Jones, D.S. In-situ gel formulations of econazole nitrate: Preparation and in-vitro and in-vivo evaluation. J. Pharm. Pharmacol.,  2011, 63(10), 1274-1282.
 [http://dx.doi.org/10.1111/j.2042-7158.2011.01315.x] [PMID: 21899542]

[87]
Soliman, G.M.; Fetih, G.; Abbas, A.M. Thermosensitive bioadhesive gels for the vaginal delivery of sildenafil citrate: In vitro characterization and clinical evaluation in women using clomiphene citrate for induction of ovulation. Drug Dev. Ind. Pharm.,  2017, 43(3), 399-408.
 [http://dx.doi.org/10.1080/03639045.2016.1254239] [PMID: 27783532]

[88]
Jalalvandi, E.; Shavandi, A. In situ-forming and pH-responsive hydrogel based on chitosan for vaginal delivery of therapeutic agents. J. Mater. Sci. Mater. Med.,  2018, 29(11), 158.
 [http://dx.doi.org/10.1007/s10856-018-6166-x] [PMID: 30349982]

[89]
Adnan, M.; Kumar, K.S.; Sreejith, L. Micellar nanocomposites hydrogels films for pH sensitive controlled drug delivery. Mater. Lett.,  2020, 277128286
 [http://dx.doi.org/10.1016/j.matlet.2020.128286]

[90]
Mirani, A.; Kundaikar, H.; Velhal, S.; Patel, V.; Bandivdekar, A.; Degani, M.; Patravale, V. Tetrahydrocurcumin-loaded vaginal nanomicrobicide for prophylaxis of HIV/AIDS: In silico study, formulation development, and in vitro evaluation. Drug Deliv. Transl. Res.,  2019, 9(4), 828-847.
 [http://dx.doi.org/10.1007/s13346-019-00633-2] [PMID: 30900133]

[91]
Kenechukwu, F.C.; Attama, A.A.; Ibezim, E.C.; Nnamani, P.O.; Umeyor, C.E.; Uronnachi, E.M.; Gugu, T.H.; Momoh, M.A.; Ofokansi, K.C.; Akpa, P.A. Surface-modified mucoadhesive microgels as a controlled release system for miconazole nitrate to improve localized treatment of vulvovaginal candidiasis. Eur. J. Pharm. Sci.,  2018, 111, 358-375.
 [http://dx.doi.org/10.1016/j.ejps.2017.10.002] [PMID: 28986195]

[92]
de Lima, J.A.; Paines, T.C.; Motta, M.H.; Weber, W.B.; Dos Santos, S.S.; Cruz, L.; da Silva, C.B. Novel Pemulen/Pullulan blended hydrogel containing clotrimazole-loaded cationic nanocapsules: Evaluation of mucoadhesion and vaginal permeation. Mater. Sci. Eng. C,  2017, 79, 886-893.
 [http://dx.doi.org/10.1016/j.msec.2017.05.030] [PMID: 28629093]

[93]
Ravani, L.; Esposito, E.; Bories, C.; Moal, V.L.; Loiseau, P.M.; Djabourov, M.; Cortesi, R.; Bouchemal, K. Clotrimazole-loaded nanostructured lipid carrier hydrogels: Thermal analysis and in vitro studies. Int. J. Pharm.,  2013, 454(2), 695-702.
 [http://dx.doi.org/10.1016/j.ijpharm.2013.06.015] [PMID: 23792467]

[94]
Ham, A.S.; Rohan, L.C.; Boczar, A.; Yang, L.; W., Buckheit K.; Buckheit, R.W., Jr Vaginal film drug delivery of the pyrimidinedione IQP-0528 for the prevention of HIV infection. Pharm. Res.,  2012, 29(7), 1897-1907.
 [http://dx.doi.org/10.1007/s11095-012-0715-7] [PMID: 22392331]

[95]
Machado, R.M.; Palmeira-de-Oliveira, A.; Martinez-De-Oliveira, J.; Palmeira-de-Oliveira, R. Vaginal films for drug delivery. J. Pharm. Sci.,  2013, 102(7), 2069-2081.
 [http://dx.doi.org/10.1002/jps.23577] [PMID: 23649325]

[96]
Akil, A.; Parniak, M.A.; Dezzuitti, C.S.; Moncla, B.J.; Cost, M.R.; Li, M.; Rohan, L.C. Development and characterization of a vaginal film containing dapivirine, a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), for prevention of HIV-1 sexual transmission. Drug Deliv. Transl. Res.,  2011, 1(3), 209-222.
 [http://dx.doi.org/10.1007/s13346-011-0022-6] [PMID: 22708075]

[97]
Jalil, A.; Asim, M.H.; Le, N.N.; Laffleur, F.; Matuszczak, B.; Tribus, M.; Bernkop-Schnürch, A. S-protected gellan gum: Decisive approach towards mucoadhesive antimicrobial vaginal films. Int. J. Biol. Macromol.,  2019, 130, 148-157.
 [http://dx.doi.org/10.1016/j.ijbiomac.2019.02.092] [PMID: 30779984]

[98]
Dolci, L.S.; Albertini, B.; Di Filippo, M.F.; Bonvicini, F.; Passerini, N.; Panzavolta, S. Development and in vitro evaluation of mucoadhesive gelatin films for the vaginal delivery of econazole. Int. J. Pharm.,  2020, 591119979
 [http://dx.doi.org/10.1016/j.ijpharm.2020.119979] [PMID: 33068694]

[99]
Calvo, N.L.; Svetaz, L.A.; Alvarez, V.A.; Quiroga, A.D.; Lamas, M.C.; Leonardi, D. Chitosan-hydroxypropyl methylcellulose tioconazole films: A promising alternative dosage form for the treatment of vaginal candidiasis. Int. J. Pharm.,  2019, 556, 181-191.
 [http://dx.doi.org/10.1016/j.ijpharm.2018.12.011] [PMID: 30553009]

[100]
Dobaria, N.; Mashru, R. Design and in vitro evaluation of a novel bioadhesive vaginal drug delivery system for clindamycin phosphate. Pharm. Dev. Technol.,  2010, 15(4), 405-414.
 [http://dx.doi.org/10.3109/10837450903262058] [PMID: 19842917]

[101]
Bassi, P.; Kaur, G. Bioadhesive vaginal drug delivery of nystatin using a derivatized polymer: Development and characterization. Eur. J. Pharm. Biopharm.,  2015, 96, 173-184.
 [http://dx.doi.org/10.1016/j.ejpb.2015.07.018] [PMID: 26235393]

[102]
Cautela, M.P.; Moshe, H.; Sosnik, A.; Sarmento, B. das Neves, J. Composite films for vaginal delivery of tenofovir disoproxil fumarate and emtricitabine. Eur. J. Pharm. Biopharm.,  2019, 138, 3-10.
 [http://dx.doi.org/10.1016/j.ejpb.2018.02.001] [PMID: 29408341]

[103]
Cunha-Reis, C.; Machado, A.; Barreiros, L.; Araújo, F.; Nunes, R.; Seabra, V.; Ferreira, D.; Segundo, M.A.; Sarmento, B. das Neves, J. Nanoparticles-in-film for the combined vaginal delivery of anti-HIV microbicide drugs. J. Control. Release,  2016, 243, 43-53.
 [http://dx.doi.org/10.1016/j.jconrel.2016.09.020] [PMID: 27664327]

[104]
Bunge, K.E.; Dezzutti, C.S.; Rohan, L.C.; Hendrix, C.W.; Marzinke, M.A.; Richardson-Harman, N.; Moncla, B.J.; Devlin, B.; Meyn, L.A.; Spiegel, H.M.; Hillier, S.L.A. {Phase} 1 trial to assess the safety, acceptability, pharmacokinetics and pharmacodynamics of a novel dapivirine vaginal film. J. Acquir. Immune Defic. Syndr.,  2016, 71(5), 498-505.
 [http://dx.doi.org/10.1097/QAI.0000000000000897] [PMID: 26565716]

[105]
Akil, A.; Devlin, B.; Cost, M.; Rohan, L.C. Increased Dapivirine tissue accumulation through vaginal film codelivery of dapivirine and Tenofovir. Mol. Pharm.,  2014, 11(5), 1533-1541.
 [http://dx.doi.org/10.1021/mp4007024] [PMID: 24693866]

[106]
Grammen, C.; Van den Mooter, G.; Appeltans, B.; Michiels, J.; Crucitti, T.; Ariën, K.K.; Augustyns, K.; Augustijns, P.; Brouwers, J. Development and characterization of a solid dispersion film for the vaginal application of the anti-HIV microbicide UAMC01398. Int. J. Pharm.,  2014, 475(1-2), 238-244.
 [http://dx.doi.org/10.1016/j.ijpharm.2014.08.054] [PMID: 25175729]

[107]
Li, J.; Regev, G.; Patel, S.K.; Patton, D.; Sweeney, Y.; Graebing, P.; Grab, S.; Wang, L.; Sant, V.; Rohan, L.C. Rational design of a multipurpose bioadhesive vaginal film for co-delivery of dapivirine and levonorgestrel. Pharmaceutics,  2019, 12(1), 1.
 [http://dx.doi.org/10.3390/pharmaceutics12010001] [PMID: 31861267]

[108]
Vhora, I.; Khatri, N.; Misra, A. Applications of Polymers in Parenteral Drug Delivery.In: Applications of Polymers in Drug Delivery; Elsevier, 2021, pp. 221-261.
 [http://dx.doi.org/10.1016/B978-0-12-819659-5.00008-2]

[109]
Dykxhoorn, D.M.; Lieberman, J. Silencing viral infection. PLoS Med.,  2006, 3(7)e242
 [http://dx.doi.org/10.1371/journal.pmed.0030242] [PMID: 16848617]

[110]
Steinbach, J.M.; Weller, C.E.; Booth, C.J.; Saltzman, W.M. Polymer nanoparticles encapsulating siRNA for treatment of HSV-2 genital infection. J. Control. Release,  2012, 162(1), 102-110.
 [http://dx.doi.org/10.1016/j.jconrel.2012.06.008] [PMID: 22705461]

[111]
Palliser, D.; Chowdhury, D.; Wang, Q.Y.; Lee, S.J.; Bronson, R.T.; Knipe, D.M.; Lieberman, J. An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection. Nature,  2006, 439(7072), 89-94.
 [http://dx.doi.org/10.1038/nature04263] [PMID: 16306938]

[112]
Woodrow, K.A.; Cu, Y.; Booth, C.J.; Saucier-Sawyer, J.K.; Wood, M.J.; Saltzman, W.M. Intravaginal gene silencing using biodegradable polymer nanoparticles densely loaded with small-interfering RNA. Nat. Mater.,  2009, 8(6), 526-533.
 [http://dx.doi.org/10.1038/nmat2444] [PMID: 19404239]

[113]
Gu, J.; Yang, S.; Ho, E.A. Biodegradable film for the targeted delivery of siRNA-loaded nanoparticles to vaginal immune cells. Mol. Pharm.,  2015, 12(8), 2889-2903.
 [http://dx.doi.org/10.1021/acs.molpharmaceut.5b00073] [PMID: 26099315]

[114]
Kale, V. Vaginal mucosa – A promising site for drug therapy. Br. J. Pharm. Res.,  2013, 3(4), 983-1000.
 [http://dx.doi.org/10.9734/BJPR/2013/3895]

[115]
Husain, S.; Allotey, J.; Drymoussi, Z.; Wilks, M.; Fernandez-Felix, B.M.; Whiley, A.; Dodds, J.; Thangaratinam, S.; McCourt, C.; Prosdocimi, E.M.; Wade, W.G.; de Tejada, B.M.; Zamora, J.; Khan, K.; Millar, M. Effects of oral probiotic supplements on vaginal microbiota during pregnancy: A randomised, double-blind, placebo-controlled trial with microbiome analysis. BJOG: Int. J. Obstet. Gynaecol.,  2020, 127(2), 275-284.
 [http://dx.doi.org/10.1111/1471-0528.15675] [PMID: 30932317]

[116]
Verdenelli, M.C.; Cecchini, C.; Coman, M.M.; Silvi, S.; Orpianesi, C.; Coata, G.; Cresci, A.; Di Renzo, G.C. Impact of probiotic {SYNBIO}® administered by vaginal suppositories in promoting vaginal health of apparently healthy women. Curr. Microbiol.,  2016, 73(4), 483-490.
 [http://dx.doi.org/10.1007/s00284-016-1085-x] [PMID: 27324341]

[117]
Rodrigues, F.; Maia, M.J. das Neves, J.; Sarmento, B.; Amaral, M.H.; Oliveira, M.B.P.P. Vaginal suppositories containing Lactobacillus acidophilus: Development and characterization. Drug Dev. Ind. Pharm.,  2015, 41(9), 1518-1525.
 [http://dx.doi.org/10.3109/03639045.2014.963864] [PMID: 25265366]

[118]
Di Vito, M.; Mattarelli, P.; Modesto, M.; Girolamo, A.; Ballardini, M.; Tamburro, A.; Meledandri, M.; Mondello, F. In vitro activity of tea tree oil vaginal suppositories against {Candida} spp. and probiotic vaginal microbiota. Phytother. Res.,  2015, 29(10), 1628-1633.
 [http://dx.doi.org/10.1002/ptr.5422] [PMID: 26235937]

[119]
Zaveri, T.; Hayes, J.E.; Ziegler, G.R. Release of tenofovir from carrageenan-based vaginal suppositories. Pharmaceutics,  2014, 6(3), 366-377.
 [http://dx.doi.org/10.3390/pharmaceutics6030366] [PMID: 24999606]

[120]
Gomaa, E.; Abu Lila, A.S.; Hasan, A.A.; Ghazy, F.S. Preparation and characterization of intravaginal vardenafil suppositories targeting a complementary treatment to boost in vitro fertilization process. Eur. J. Pharm. Sci.,  2018, 111, 113-120.
 [http://dx.doi.org/10.1016/j.ejps.2017.09.044] [PMID: 28964952]

[121]
Mahjabeen, S.; Hatipoglu, M.K.; Chandra, V.; Benbrook, D.M.; Garcia-Contreras, L. Optimization of a vaginal suppository formulation to deliver {SHetA}2 as a novel treatment for cervical dysplasia. J. Pharm. Sci.,  2018, 107(2), 638-646.
 [http://dx.doi.org/10.1016/j.xphs.2017.09.018] [PMID: 28989018]

[122]
Ren, C.; Li, X.; Mao, L.; Xiong, J.; Gao, C.; Shen, H.; Wang, L.; Zhu, D.; Ding, W.; Wang, H. An effective and biocompatible polyethylenimine based vaginal suppository for gene delivery. Nanomedicine,  2019, 20101994
 [http://dx.doi.org/10.1016/j.nano.2019.03.016] [PMID: 31028885]

[123]
Koutsamanis, I.; Eder, S.; Beretta, M.; Witschnigg, A.; Paudel, A.; Nickisch, K.; Friedrich, M.; Eggenreich, K.; Roblegg, E. Formulation and processability screening for the rational design of ethylene-vinyl acetate based intra-vaginal rings. Int. J. Pharm.,  2019, 564, 90-97.
 [http://dx.doi.org/10.1016/j.ijpharm.2019.04.041] [PMID: 30999046]

[124]
Saxena, B.B.; Han, Y.A.; Fu, D.; Rathnam, P.; Singh, M.; Laurence, J.; Lerner, S. Sustained release of microbicides by newly engineered vaginal rings. AIDS,  2009, 23(8), 917-922.
 [http://dx.doi.org/10.1097/QAD.0b013e32832af57c] [PMID: 19381077]

[125]
Chen, B.A.; Panther, L.; Marzinke, M.A.; Hendrix, C.W.; Hoesley, C.J.; van der Straten, A.; Husnik, M.J.; Soto-Torres, L. Nel, A.; Johnson, S.; Richardson-Harman, N.; Rabe, L.K.; Dezzutti, C.S. Phase 1 safety, pharmacokinetics, and pharmacodynamics of dapivirine and maraviroc vaginal rings: A double-blind randomized trial. J. Acquir. Immune Defic. Syndr.,  2015, 70(3), 242-249.
 [http://dx.doi.org/10.1097/QAI.0000000000000702] [PMID: 26034880]

[126]
Smith, J.M.; Rastogi, R.; Teller, R.S.; Srinivasan, P.; Mesquita, P.M.M.; Nagaraja, U.; McNicholl, J.M.; Hendry, R.M.; Dinh, C.T.; Martin, A.; Herold, B.C.; Kiser, P.F. Intravaginal ring eluting tenofovir disoproxil fumarate completely protects macaques from multiple vaginal simian-HIV challenges. Proc. Natl. Acad. Sci.,  2013, 110(40), 16145-16150.
 [http://dx.doi.org/10.1073/pnas.1311355110] [PMID: 24043812]

[127]
Malcolm, R.K.; Veazey, R.S.; Geer, L.; Lowry, D.; Fetherston, S.M.; Murphy, D.J.; Boyd, P.; Major, I.; Shattock, R.J.; Klasse, P.J.; Doyle, L.A.; Rasmussen, K.K.; Goldman, L.; Ketas, T.J.; Moore, J.P. Sustained release of the CCR5 inhibitors CMPD167 and maraviroc from vaginal rings in rhesus macaques. Antimicrob. Agents Chemother.,  2012, 56(5), 2251-2258.
 [http://dx.doi.org/10.1128/AAC.05810-11] [PMID: 22330914]

[128]
McBride, J.W.; Boyd, P.; Dias, N.; Cameron, D.; Offord, R.E.; Hartley, O.; Kett, V.L.; Malcolm, R.K. Vaginal rings with exposed cores for sustained delivery of the HIV CCR5 inhibitor 5P12-RANTES. J. Control. Release,  2019, 298, 1-11.
 [http://dx.doi.org/10.1016/j.jconrel.2019.02.003] [PMID: 30731150]

[129]
Fu, J.; Yu, X.; Jin, Y. 3D printing of vaginal rings with personalized shapes for controlled release of progesterone. Int. J. Pharm.,  2018, 539(1-2), 75-82.
 [http://dx.doi.org/10.1016/j.ijpharm.2018.01.036] [PMID: 29366944]

[130]
Huang, Y.; Jensen, J.T.; Brache, V.; Cochon, L.; Williams, A.; Miranda, M.J.; Croxatto, H.; Kumar, N.; Sussman, H.; Hoskin, E.; Plagianos, M.; Roberts, K.; Merkatz, R.; Blithe, D.; Sitruk-Ware, R. A randomized study on pharmacodynamic effects of vaginal rings delivering the progesterone receptor modulator ulipristal acetate: Research for a novel estrogen-free, method of contraception. Contraception,  2014, 90(6), 565-574.
 [http://dx.doi.org/10.1016/j.contraception.2014.08.006] [PMID: 25193534]

[131]
Boyd, P.; Major, I.; Wang, W.; McConville, C. Development of disulfiram-loaded vaginal rings for the localised treatment of cervical cancer. Eur. J. Pharm. Biopharm.,  2014, 88(3), 945-953.
 [http://dx.doi.org/10.1016/j.ejpb.2014.08.002] [PMID: 25128854]

[132]
Brzezinski, A.; Stern, T.; Arbel, R.; Rahav, G.; Benita, S. Efficacy of a novel pH-buffering tampon in preserving the acidic vaginal pH during menstruation. Int. J. Gynaecol. Obstet.,  2004, 85(3), 298-300.
 [http://dx.doi.org/10.1016/j.ijgo.2004.03.003] [PMID: 15145277]

[133]
Alidjinou, E.K.; Ebatetou-Ataboho, E.; Sané, F.; Moukassa, D.; Dewilde, A.; Hober, D. Cervical samples dried on filter paper and dried vaginal tampons can be useful to investigate the circulation of high-risk HPV in Congo. J. Clin. Virol.,  2013, 57(2), 161-164.
 [http://dx.doi.org/10.1016/j.jcv.2013.02.010] [PMID: 23478164]

[134]
Ball, C.; Krogstad, E.; Chaowanachan, T.; Woodrow, K.A. Drug-eluting fibers for HIV-1 inhibition and contraception. PLoS One,  2012, 7(11)e49792
 [http://dx.doi.org/10.1371/journal.pone.0049792] [PMID: 23209601]

[135]
Eriksson, K.; Carlsson, B.; Forsum, U.; Larsson, P.G. A double-blind treatment study of bacterial vaginosis with normal vaginal lactobacilli after an open treatment with vaginal clindamycin ovules. Acta Derm. Venereol.,  2005, 85(1), 42-46.
 [http://dx.doi.org/10.1080/00015550410022249] [PMID: 15848990]

[136]
Ristić T.; Persin, Z.; Kralj Kuncic, M.; Kosalec, I.; Zemljic, L.F. The evaluation of the in vitro antimicrobial properties of fibers functionalized by chitosan nanoparticles. Text. Res. J.,  2019, 89(5), 748-761.
 [http://dx.doi.org/10.1177/0040517518755785]

[137]
Waghule, T.; Singhvi, G.; Dubey, S.K.; Pandey, M.M.; Gupta, G.; Singh, M.; Dua, K. Microneedles: A smart approach and increasing potential for transdermal drug delivery system. Biomed. Pharmacother.,  2019, 109, 1249-1258.
 [http://dx.doi.org/10.1016/j.biopha.2018.10.078] [PMID: 30551375]

[138]
Quinn, H.L.; Kearney, M.C.; Courtenay, A.J.; McCrudden, M.T.C.; Donnelly, R.F. The role of microneedles for drug and vaccine delivery. Expert Opin. Drug Deliv.,  2014, 11(11), 1769-1780.
 [http://dx.doi.org/10.1517/17425247.2014.938635] [PMID: 25020088]

[139]
Larraneta, E.; Lutton, R.E.M.; Woolfson, A.D.; Donnelly, R.F. Microneedle arrays as transdermal and intradermal drug delivery systems: Materials science, manufacture and commercial development. Mater. Sci. Eng. Rep.,  2016, 104, 1-32.
 [http://dx.doi.org/10.1016/j.mser.2016.03.001]

[140]
Dang, N.; Liu, T.Y.; Prow, T.W. Nano- and Microtechnology in Skin Delivery of Vaccines. Micro- and Nanotechnology in Vaccine Development; Elsevier, 2017, pp. 327-341.
 [http://dx.doi.org/10.1016/B978-0-323-39981-4.00017-8]

[141]
Wang, N.; Zhen, Y.; Jin, Y.; Wang, X.; Li, N.; Jiang, S.; Wang, T. Erratum to Combining different types of multifunctional liposomes loaded with ammonium bicarbonate to fabricate microneedle arrays as a vaginal mucosal vaccine adjuvant-dual delivery system (VADDS). J. Control. Release,  2017, 246, 12-29.
 [http://dx.doi.org/10.1016/j.jconrel.2017.03.001] [PMID: 28285849]

[142]
Wang, N.; Wang, X.; Zhen, Y.; Li, N.; Jiang, S.; Wang, T. Microneedle arrays fabricated with the aluminum-based cochleates as an effective vaginal Vaccine Adjuvant-Delivery System (VADS). Nanomed Nanotechnol. Biol. Med.,  2018, 14(5), 1745.

[143]
Mc Crudden, M.T.C.; Larrañeta, E.; Clark, A.; Jarrahian, C.; Rein-Weston, A.; Creelman, B.; Moyo, Y.; Lachau-Durand, S.; Niemeijer, N.; Williams, P.; McCarthy, H.O.; Zehrung, D.; Donnelly, R.F. Design, formulation, and evaluation of novel dissolving microarray patches containing rilpivirine for intravaginal delivery. Adv. Healthc. Mater.,  2019, 8(9)e1801510
 [http://dx.doi.org/10.1002/adhm.201801510] [PMID: 30838804]

[144]
Kozlowski, P.A.; Cu-Uvin, S.; Neutra, M.R.; Flanigan, T.P. Comparison of the oral, rectal, and vaginal immunization routes for induction of antibodies in rectal and genital tract secretions of women. Infect. Immun.,  1997, 65(4), 1387-1394.
 [http://dx.doi.org/10.1128/iai.65.4.1387-1394.1997] [PMID: 9119478]

[145]
Wassén, L.; Schön, K.; Holmgren, J.; Jertborn, M.; Lycke, N. Local intravaginal vaccination of the female genital tract. Scand. J. Immunol.,  1996, 44(4), 408-414.
 [http://dx.doi.org/10.1046/j.1365-3083.1996.d01-320.x] [PMID: 8845036]

[146]
Johansson, E.L.; Wassén, L.; Holmgren, J.; Jertborn, M.; Rudin, A. Nasal and vaginal vaccinations have differential effects on antibody responses in vaginal and cervical secretions in humans. Infect. Immun.,  2001, 69(12), 7481-7486.
 [http://dx.doi.org/10.1128/IAI.69.12.7481-7486.2001] [PMID: 11705923]

[147]
Kozlowski, P.A.; Williams, S.B.; Lynch, R.M.; Flanigan, T.P.; Patterson, R.R.; Cu-Uvin, S.; Neutra, M.R. Differential induction of mucosal and systemic antibody responses in women after nasal, rectal, or vaginal immunization: Influence of the menstrual cycle. J. Immunol.,  2002, 169(1), 566-574.
 [http://dx.doi.org/10.4049/jimmunol.169.1.566] [PMID: 12077289]

[148]
Pettini, E.; Prota, G.; Ciabattini, A.; Boianelli, A.; Fiorino, F.; Pozzi, G.; Vicino, A.; Medaglini, D. Vaginal immunization to elicit primary T-cell activation and dissemination. PLoS One,  2013, 8(12)e80545
 [http://dx.doi.org/10.1371/journal.pone.0080545] [PMID: 24349003]

[149]
Marrazzo, J.M.; Dombrowski, J.C.; Wierzbicki, M.R.; Perlowski, C.; Pontius, A.; Dithmer, D.; Schwebke, J. Safety and efficacy of a novel vaginal anti-infective, TOL-463, in the treatment of bacterial vaginosis and vulvovaginal candidiasis: A randomized, single-blind, phase 2, controlled trial. Clin. Infect. Dis.,  2019, 68(5), 803-809.
 [http://dx.doi.org/10.1093/cid/ciy554] [PMID: 30184181]

[150]
Zarin, D.A.; Tse, T.; Williams, R.J.; Califf, R.M.; Ide, N.C. The ClinicalTrials. gov results database—update and key issues. New England J. Med.,  2011, 364(9), 852-860.

[151]
McGowan, I.; Gomez, K.; Bruder, K.; Febo, I.; Chen, B.A.; Richardson, B.A.; Husnik, M.; Livant, E.; Price, C.; Jacobson, C. MTN-004 Protocol Team. Phase 1 randomized trial of the vaginal safety and acceptability of SPL7013 gel (VivaGel) in sexually active young women (MTN-004). AIDS,  2011, 25(8), 1057-1064.
 [http://dx.doi.org/10.1097/QAD.0b013e328346bd3e] [PMID: 21505316]

[152]
Matthews, L.T.; Sibeko, S.; Mansoor, L.E.; Yende-Zuma, N.; Bangsberg, D.R.; Karim, Q.A. Women with pregnancies had lower adherence to 1% tenofovir vaginal gel as HIV preexposure prophylaxis in CAPRISA 004, a phase IIB randomized-controlled trial. PLoS One,  2013, 8(3)e56400
 [http://dx.doi.org/10.1371/journal.pone.0056400] [PMID: 23472071]

[153]
Nel, A.; van Niekerk, N.; Kapiga, S.; Bekker, L.G.; Gama, C.; Gill, K.; Kamali, A.; Kotze, P.; Louw, C.; Mabude, Z.; Miti, N.; Kusemererwa, S.; Tempelman, H.; Carstens, H.; Devlin, B.; Isaacs, M.; Malherbe, M.; Mans, W.; Nuttall, J.; Russell, M.; Ntshele, S.; Smit, M.; Solai, L.; Spence, P.; Steytler, J.; Windle, K.; Borremans, M.; Resseler, S.; Van Roey, J.; Parys, W.; Vangeneugden, T.; Van Baelen, B.; Rosenberg, Z. Ring study team. Safety and efficacy of a dapivirine vaginal ring for HIV prevention in women. N. Engl. J. Med.,  2016, 375(22), 2133-2143.
 [http://dx.doi.org/10.1056/NEJMoa1602046] [PMID: 27959766]

[154]
Nel, A.; van Niekerk, N.; Van Baelen, B.; Malherbe, M.; Mans, W.; Carter, A.; Steytler, J.; van der Ryst, E.; Craig, C.; Louw, C.; Gwetu, T.; Mabude, Z.; Kotze, P.; Moraba, R.; Tempelman, H.; Gill, K.; Kusemererwa, S.; Bekker, L.G.; Devlin, B.; Rosenberg, Z. DREAM study team. Safety, adherence, and HIV-1 seroconversion among women using the dapivirine vaginal ring (DREAM): An open-label, extension study. Lancet HIV,  2021, 8(2), e77-e86.
 [http://dx.doi.org/10.1016/S2352-3018(20)30300-3] [PMID: 33539761]

[155]
Bunge, K.E.; Levy, L.; Szydlo, D.W.; Zhang, J.; Gaur, A.H.; Reirden, D.; Mayer, K.H.; Futterman, D.; Hoesley, C.; Hillier, S.L.; Marzinke, M.A.; Hendrix, C.W.; Gorbach, P.M.; Wilson, C.M.; Soto-Torres, L.; Kapogiannis, B. Nel, A.; Squires, K.E. MTN-023/IPM 030 study team. Brief report: Phase IIa safety study of a vaginal ring containing dapivirine in adolescent young women. J. Acquir. Immune Defic. Syndr.,  2020, 83(2), 135-139.
 [http://dx.doi.org/10.1097/QAI.0000000000002244] [PMID: 31929401]
Cite As
Current Drug Delivery

Emerging Trends and Potential Prospects in Vaginal Drug Delivery

Abstract

Graphical Abstract
