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Polymer Gels pp 197-246 | Cite as

Polymer Gels in Vaginal Drug Delivery Systems

  • María-Dolores Veiga
  • Roberto Ruiz-Caro
  • Araceli Martín-Illana
  • Fernando Notario-Pérez
  • Raúl Cazorla-Luna
Chapter
Part of the Gels Horizons: From Science to Smart Materials book series (GHFSSM)

Abstract

Vaginal drug delivery is a promising route for the treatment and prevention of local and systemic diseases such as genital herpes or AIDS. Suitable excipients must be selected to optimize the residence time of formulations in vaginal mucosa and could be included in the formulation. Many polymers are excellent choices for the development of vaginal drug delivery systems due to their properties of mucoadhesion, biocompatibility and biodegradability. These polymers swell in the aqueous medium of the vaginal environment and generate a gel layer which allows controlled release of the drug. The thickness and viscosity of the gel layer determine the drug release process. The aim of this chapter is to review the different polymers available for the development of vaginal delivery systems and to describe their physicochemical (swelling, viscosity, mucoadhesion), biopharmaceutical (drug release, biodegradability) and cytotoxic properties.

Keywords

Bigels Biocompatibility Biodegradability Drug delivery systems Gels Microbicide Mucoadhesion Polymers Vagina Vaginal environment 

References

  1. Acartürk F (2009) Mucoadhesive vaginal drug delivery systems. Recent Pat Drug Deliv Formul 3:193–205PubMedCrossRefGoogle Scholar
  2. Ahmad FJ, Alam MA, Khan ZI, Khar RK, Ali M (2008) Development and in vitro evaluation of an acid buffering bioadhesive vaginal gel for mixed vaginal infections. Acta Pharm 58:407–419PubMedCrossRefGoogle Scholar
  3. Akil A, Agashe H, Dezzutti CS, Moncla BJ, Hillier SL, Devlin B, Shi Y, Uranker K, Rohan LC (2015) Formulation and characterization of polymeric films containing combinations of antiretrovirals (ARVs) for HIV prevention. Pharm Res 32:458–468PubMedCrossRefGoogle Scholar
  4. Alexander NJ, Baker E, Kaptein M, Karck U, Miller L, Zampaglione E (2004) Why consider vaginal drug administration. Fertil Steril 82:1–12PubMedCrossRefGoogle Scholar
  5. Al-Saqi SH, Jonasson AF, Naessén T, Uvnäs-Moberg K (2016) Oxytocin improves cytological and histological profiles of vaginal atrophy in postmenopausal women. Post Reprod Health 22:25–33PubMedCrossRefGoogle Scholar
  6. Anseth KS, Metters AT, Bryant SJ, Martens PJ, Elisseeff JH, Bowman CN (2002) In situ forming degradable networks and their application in tissue engineering and drug delivery. J Control Release 78:199–209PubMedCrossRefGoogle Scholar
  7. Anton PA, Cranston RD, Kashuba A, Hendrix CW, Bumpus NN, Richardson-Harman N, Elliott J, Janocko L, Khanukhova E, Dennis R, Cumberland WG, Ju C, Carballo-Diéguez A, Mauck C, McGowan I (2012) RMP-02/MTN-006: A phase 1 rectal safety, acceptability, pharmacokinetic, and pharmacodynamic study of tenofovir 1% gel compared with oral tenofovir disoproxil fumarate. AIDS Res Hum Retroviruses 28:1412–1421PubMedPubMedCentralCrossRefGoogle Scholar
  8. Arredondo A, Patiño JF, Londoño ME, Echeverri CE (2011) Matriz a partir de un hidrogel de alcohol polivinílico (PVA) combinada con sulfadiazina de plata con potencial aplicación en el manejo y control de la sepsis en heridas dérmicas. Revista Iberoamericana de Polímeros 12:178–187Google Scholar
  9. Auslander BA, Perfect MM, Breitkopf DM, Succop PA, Rosenthal SL (2007) Microbicides: information, beliefs, and preferences for insertion. J Womens Health 16:1458–1467CrossRefGoogle Scholar
  10. Avendaño-Romero GC, López-Malo A, Palou E (2013) Propiedades del alginato y aplicaciones en alimentos. Temas Selectos de Ingeniería de Alimentos 7:87–97Google Scholar
  11. Baena Y, Dallos LJ, Manzo RH, Ponce D’León LF (2011) Estandarización de celdas de Franz para la realización de ensayos de liberación de fármacos a partir de complejos con polielectrolitos. RevDOI Colomb Cienc Quím Farm 40(2):174–188Google Scholar
  12. Baloğlu E, Ozyazici M, Yaprak Hizarcioğlu S, Senyiğit T, Ozyurt D, Pekçetin C (2006) Bioadhesive controlled release systems of ornidazole for vaginal delivery. Pharm Dev Technol 11:477–484PubMedCrossRefGoogle Scholar
  13. Baloglu E, Senyigit ZA, Karavana SY, Bernkop-Schnurch A (2009) Strategies to prolong the intravaginal residence time of drug delivery systems. J Pharm Pharm Sci 12:312–336PubMedCrossRefGoogle Scholar
  14. Barnable P, Calenda G, Bonnaire T, Menon R, Levendosky K, Gettie A, Blanchard J, Cooney ML, Fernández-Romero JA, Zydowsky TM, Teleshova N (2015) MIV-150/zinc acetate gel inhibits cell-associated simian-human immunodeficiency virus reverse transcriptase infection in a macaque vaginal explant model. Antimicrob Agents Chemother 59:3829–3837PubMedPubMedCentralCrossRefGoogle Scholar
  15. Beckmann M, Kumar S, Flenady V, Harker E (2015) Prostaglandin vaginal gel induction of labor comparing amniotomy with repeat prostaglandin gel. Am J Obstet Gynecol 213:1–9CrossRefGoogle Scholar
  16. Beckmann M, Merollini K, Kumar S, Flenady V (2016) Induction of labor using prostaglandin vaginal gel: cost analysis comparing early amniotomy with repeat prostaglandin gel. Eur J Obstet Gynecol Reprod Biol 199:96–101PubMedCrossRefGoogle Scholar
  17. Berknop-Snürch A, Hornof M, Guggi D (2004) Thiolated chitosans. Eur J Pharm Biopharm 57:9–17CrossRefGoogle Scholar
  18. Berretta AA, de Castro PA, Cavalheiro AH, Fortes VS, Bom VP, Nascimento AP, Marquele-Oliveira F, Pedrazzi V, Ramalho LN, Goldman GH (2013) Evaluation of mucoadhesive gels with propolis (EPP-AF) in preclinical treatment of candidiasis vulvovaginal infection. Evid Based Complement Alternat Med 2013:641480PubMedPubMedCentralCrossRefGoogle Scholar
  19. Bhardwaj TR, Kanwar M, Lal R, Gupta A (2009) Natural gums and modified natural gums as sustained-release carriers. Drug Devel Ind Pharm 26:1025–1038CrossRefGoogle Scholar
  20. Bonferoni MC, Sandri G, Rossi S, Ferrari F, Gibin S, Caramella C (2008) Chitosan citrate as multifunctional polymer for vaginal delivery. Evaluation of penetration enhancement and peptidase inhibition properties. Eur J Pharm Sci 33:166–176PubMedCrossRefGoogle Scholar
  21. Braunstein S, van de Wijgert J (2005) Preferences and practices related to vaginal lubrication: implications for microbicide acceptability and clinical testing. J Womens Health 14:424–433CrossRefGoogle Scholar
  22. Buckheit RW, Watson KM, Morrow KM, Ham AS (2010) Development of topical microbicides to prevent the sexual transmission of HIV. Antiviral Res 85:142–158PubMedCrossRefGoogle Scholar
  23. Burns RN, Hendrix CW, Chaturvedula A (2015) Population pharmacokinetics of tenofovir and tenofovir-diphosphate in healthy women. J Clin Pharmacol 55:629–638PubMedPubMedCentralCrossRefGoogle Scholar
  24. Burruano BT, Schnaare RL, Malamud D (2002) Synthetic cervical mucus formulation. Contraception 66:137–140PubMedCrossRefGoogle Scholar
  25. Carati D, Zizza A, Guido M, De Donno A, Stefanizzi R, Serra R, Romano I, Ouedraogo C, Megha M, Tinelli A (2016) Safety, efficacy, and tolerability of differential treatment to prevent and treat vaginal dryness and vulvovaginitis in diabetic women. Clin Exp Obstet Gynecol 43:198–202PubMedGoogle Scholar
  26. Caruso S, Cianci S, Amore FF, Ventura B, Bambili E, Spadola S, Cianci A (2016) Quality of life and sexual function of naturally postmenopausal women on an ultralow-concentration estriol vaginal gel. Menopause 23:47–54PubMedCrossRefGoogle Scholar
  27. Caswell M, Kane M (2002) Comparison of the moisturization efficacy of two vaginal moisturizers: Pectin versus polycarbophil technologies. J Cosmet Sci 53:81–87PubMedGoogle Scholar
  28. Ceschel GC, Maffei P, Lombardi BS, Ronchi C, Rossi S (2001) Development of a mucoadhesive dosage form for vaginal administration. Drug Dev Ind Pharm 27:541–554PubMedCrossRefGoogle Scholar
  29. Cevher E, Sensov D, Taha MA, Araman A (2008) Effect of thiolated polymers to textural and mucoadhesive properties of vaginal gel formulations prepared with polycarbophil and chitosan. AAPS PharmSciTech 9:953–965PubMedPubMedCentralCrossRefGoogle Scholar
  30. Chang JY, Oh YK, Kong HS, Kim EU, Jang DD, Nam KT, Kim CK (2002) Prolonged antifungal effects of clotrimazole-containing mucoadhesive thermosensitive gels on vaginitis. J Control Release 82:39–50PubMedCrossRefGoogle Scholar
  31. Chatterjee A, Bhowmik BB, Thakur YS (2011) Formulation, in vitro and in vivo pharmacokinetics of anti-HIV vaginal bioadhesive gel. J Young Pharm 3:83–89PubMedPubMedCentralCrossRefGoogle Scholar
  32. Chivate AA, Poddar SS, Abdul S, Savant G (2008) Evaluation of Sterculia foetida gum as controlled release excipient. AAPS PharmSciTech 9:197–204PubMedPubMedCentralCrossRefGoogle Scholar
  33. Clark MR, Peet MM, Davis S, Doncel GF, Friend DR (2014) Evaluation of rapidly disintegrating vaginal tablets of Tenofovir, Emtricitabine and their combination for HIV-1 prevention. Pharmaceutics 6:616–631PubMedPubMedCentralCrossRefGoogle Scholar
  34. Coggins C, Elias CJ, Atisook R, Bassett MT, Ettiègne-Traoré V, Ghys PD, Jenkins-Woelk L, Thongkrajai E, VanDevanter NL (1998) Women’s preferences regarding the formulation of over-the-counter vaginal spermicides. AIDS 12:1389–1391PubMedCrossRefGoogle Scholar
  35. Cohen JA, Steele MS, Urena FI, Beksinska ME (2007) Microbicide applicators: understanding design preferences among women in the dominican republic and South Africa. Sex Transm Dis 34:15–19PubMedCrossRefGoogle Scholar
  36. Cone RA (2009) Barrier properties of mucus. Adv Drug Deliv Rev 61:75–85CrossRefPubMedGoogle Scholar
  37. Contó Rigante K (2008) Modificación química de almidones mediante el uso de sales cuaternarias de amonio. PhD thesis, Simón Bolívar University, VenezuelaGoogle Scholar
  38. Cunha L, Grenha A (2016) Sulfated seaweed polysaccharides as multifunctional materials in drug delivery applications. Mar Drugs 14:42PubMedCentralCrossRefPubMedGoogle Scholar
  39. Darroch JE, Frost JJ (1999) Women’s interest in vaginal microbicides. Fam Plann Perspect 31:16–23PubMedCrossRefGoogle Scholar
  40. Davaatseren M, Hong GP (2014) Effect of NaCl, gum arabic and microbial transglutaminase on the gel and emulsion characteristics of porcine myofibrillar proteins. Korean J Food Sci Anim Resour 34:808–814PubMedPubMedCentralCrossRefGoogle Scholar
  41. Delgado JL, Estevez J, Radicioni M, Loprete L, Moscoso Del Prado J, Nieto Magro C (2016) Pharmacokinetics and preliminary efficacy of two vaginal gel formulations of ultra-low-dose estriol in postmenopausal women. Climacteric 19:172–180PubMedCrossRefGoogle Scholar
  42. Demirci ZO, Yılmaz I, Demirci AŞ (2014) Effects of xanthan, guar, carrageenan and locust bean gum addition on physical, chemical and sensory properties of meatballs. J Food Sci Technol 51:936–942PubMedCrossRefGoogle Scholar
  43. Dittgen M, Durrani MJ, Lehmann K (1997) Acrylic polymers: a review of pharmaceutical applications. STP Pharma 7:403–437Google Scholar
  44. Dodane V, Vilivalam VD (1998) Pharmaceuticals applications of chitosan. J Pharm Sci Technol 1:246–253CrossRefGoogle Scholar
  45. Doggett EG, Lanham M, Wilcher R, Gafos M, Karim QA, Heise L (2015) Optimizing HIV prevention for women: a review of evidence from microbicide studies and considerations for gender-sensitive microbicide introduction. J Int AIDS Soc 18:20536PubMedPubMedCentralCrossRefGoogle Scholar
  46. Duchene D, Ponchel G (1992) Principle and investigation of bioadhesion mechanism of solid dosage forms. Biomaterials 13:709–714PubMedCrossRefGoogle Scholar
  47. Edwards D, Panay N (2016) Treating vulvovaginal atrophy/genitourinary syndrome of menopause: how important is vaginal lubricant and moisturizer composition? Climacteric 19:151–161PubMedCrossRefGoogle Scholar
  48. El-Kamel A, Sokar M, Naggar V, Al Gamal S (2002) Chitosan and sodium alginate-based bioadhesive vaginal tablets. AAPS PharmSci 4:E44PubMedCrossRefGoogle Scholar
  49. Ferguson LM, Rohan LC (2011) The importance of the vaginal delivery route for antiretrovirals in HIV prevention. TherDeliv 2:1535–1550Google Scholar
  50. Forbes CJ, Lowry D, Geer L, Veazey RS, Shattock RJ, Klasse PJ, Mitchnick M, Goldman L, Doyle LA, Muldoon BC, Woolfson AC, Moore JP, Malcolm RK (2011) Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc. J Control Release 156:161–169PubMedPubMedCentralCrossRefGoogle Scholar
  51. Forbes CJ, McCoy CF, Murphy DJ, Woolfson AD, Moore JP, Evans A, Shattock RJ, Malcolm RK (2014) Modified silicone elastomer vaginal gels for sustained release of antiretroviral HIV microbicides. J Pharm Sci 103:1422–1432PubMedPubMedCentralCrossRefGoogle Scholar
  52. Forsberg JG (1996) A morphologist’s approach to the vagina. Acta Obstet Gynecol Scand Suppl 163:3–10PubMedGoogle Scholar
  53. Fuongfuchat A, Jamieson AM, Blackwell J, Gerken TA (1996) Rheological studies of the interaction of mucins with alginate and polyacrylate. Carbohydr Res 284:85–99PubMedCrossRefGoogle Scholar
  54. García-Ochoa F, Santos VE, Casas JA, Gómez E (2000) Xanthan gum: production, recovery, and properties. Biotechnol Adv 18:549–579PubMedCrossRefGoogle Scholar
  55. Garg S, Vermani K, Kohli G, Kandarapu R, Tambwekar KR, Garg A, Waller DP, Zaneveld LJ (2002) Survey of vaginal formulations available on the Indian market: physicochemical characterization of selected products. Int J Pharmaceut Med 16:141–152Google Scholar
  56. Garg S, Tambwekar KR, Vermani K, Kandarapu R, Garg A, Waller DP, Zaneveld LJ (2003) Development pharmaceutics of microbicide formulations. Part II: formulation, evaluation, and challenges. AIDS Patient Care STDS 17:377–399PubMedCrossRefGoogle Scholar
  57. Granström M (2009) Cellulose derivatives: synthesis, properties and applications. Academic dissertation, University of Helsinki, FinlandGoogle Scholar
  58. Guo JH, Skinner GW, Harcum WW, Barnum PE (1998) Pharmaceutical applications of naturally occurring water-soluble polymers. Pharm Sci & Technol Today 1:254–261CrossRefGoogle Scholar
  59. Gupta S, Kaur IP, Prabha V (2016) Evaluation of antifertility effect of gel formulation containing sperm immobilizing factor: in vitro and in vivo studies. Eur J Pharm Sci 81:67–74PubMedCrossRefGoogle Scholar
  60. Hanson S, Lalor P, Niemi S, Northup S, Ratner B, Spector M, Vale BM, Willson J (1996) In Biomaterials science, Academic Press, 215Google Scholar
  61. Hardy E, Jiménez AL, de Padua KS, Zaneveld LJD (1998) Women’s preferences for vaginal antimicrobial contraceptives III: Choice of a formulation, applicator, and packaging. Contraception 58:245–249PubMedCrossRefGoogle Scholar
  62. Hedén P, Sarfati I, Clough K, Olenius M, Sellman G, Trevidic P (2016) Safety and efficacy of stabilized hyaluronic acid gel for breast enhancement. Plast Reconstr Surg Glob Open 3:e575PubMedPubMedCentralCrossRefGoogle Scholar
  63. Hintzen F, Hauptstein S, Perera G, Bernkop-Schnürch A (2013) Synthesis and in vitro characterization of entirely S-protected thiolated pectin for drug delivery. Eur J Pharm Biopharm 85:1266–1273PubMedCrossRefGoogle Scholar
  64. Hladik F, Burgener A, Ballweber L, Gottardo R, Vojtech L, Fourati S, Dai JY, Cameron MJ, Strobl J, Hughes SM, Hoesley C, Andrew P, Johnson S, Piper J, Friend DR, Ball TB, Cranston RD, Mayer KH, McElrath MJ, McGowan I (2015) Mucosal effects of tenofovir 1% gel. Elife 4Google Scholar
  65. Holt BY, Morwitz VG, Ngo L, Harrison PF, Whaley KJ, Pettifor A, Nguyen AH (2006) Microbicide preference among young women in California. J Womens Health 15:281–294CrossRefGoogle Scholar
  66. Huszar G (1986) The physiology and biochemistry of the uterus in pregnancy and labor. CRC Press Inc, Boca Raton, pp 239–260Google Scholar
  67. Hwang MR, Kim JO, Lee JH, Kim YI, Kim JH, Chang SW, Jin SG, Kim JA, Lyoo WS, Han SS, Ku SK, Yong CS, Choi HG (2010) Gentamicin-loaded wound dressing with polyvinyl alcohol/dextran hydrogel: gel characterization and in vivo healing evaluation. AAPS PharmSciTech 11:1092–1103PubMedPubMedCentralCrossRefGoogle Scholar
  68. Illum L (1998) Chitosan and its use as pharmaceutical excipient. Pharm Res 15Google Scholar
  69. Jain A, Kumar L, Kushwaha B, Sharma M, Pandey A, Verma V, Sharma V, Singh V, Rawat T, Sharma VL, Maikhuri JP, Gupta G (2014) Combining a synthetic spermicide with a natural trichomonacide for safe, prophylactic contraception. Hum Reprod 29:242–252PubMedCrossRefGoogle Scholar
  70. Jarrett AM, Gao Y, Hussaini MY, Cogan NG, Katz DF (2016) Sensitivity analysis of a pharmacokinetic model of vaginal anti-HIV microbicide drug delivery. J Pharm Sci 105:1772–1778PubMedCrossRefGoogle Scholar
  71. Jensen M, Hansen PB, Murdan S, Frokjaer S, Florence AT (2002) Loading into electro-stimulated release of peptides and proteins from chondroitin 4-sulphate hydrogels. Eur J Pharm Sci 15:139–148PubMedCrossRefGoogle Scholar
  72. Jespers VA, Van Roey JM, Beets GI, Buve AM (2007) Dose-ranging Phase I study of TMC120, a promising vaginal microbicide, in HIV-negative and HIV-positive female volunteers. J Acquir Immune Defic Syndr 44:154–158PubMedCrossRefGoogle Scholar
  73. Johnson TJ, Gupta KM, Fabian J, Albright TH, Kiser PF (2010) Segmented polyurethane intravaginal rings for the sustained combined delivery of antiretroviral agents dapivirine and tenofovir. Eur J Pharm Sci 39:203–212PubMedCrossRefGoogle Scholar
  74. Jokar A, Davari T, Asadi N, Ahmadi F, Foruhari S (2016) Comparison of the hyaluronic acid vaginal cream and conjugated estrogen used in treatment of vaginal atrophy of menopause women: a randomized controlled clinical trial. Int J Community Based Nurs Midwifery 4:69–78PubMedPubMedCentralGoogle Scholar
  75. Kaddam L, FdleAlmula I, Eisawi OA, Abdelrazig HA, Elnimeiri M, Lang F, Saeed AM (2015) Gum Arabic as fetal hemoglobin inducing agent in sickle cell anemia; in vivo study. BMC Hematol 15:19PubMedPubMedCentralCrossRefGoogle Scholar
  76. Kamoun EA (2016) N-succinyl chitosan-dialdehyde starch hybrid hydrogels for biomedical applications. J Adv Res 7:69–77PubMedCrossRefGoogle Scholar
  77. Karamisheva V, Nachev A (2015) Saforelle—a new approach to treat vaginitis. Akush Ginekol 54(Suppl 2):22–24Google Scholar
  78. Kast CE, Valenta C, Leopold M, Bernkop-Schnürch A (2002) Design and in vitro evaluation of a novel bioadhesive vaginal drug delivery system for clotrimazole. J Control Rel 81:347–354CrossRefGoogle Scholar
  79. Katz DF (1986) Human cervical mucus: research update. Am J Obstet Gynecol 165:1984–1986CrossRefGoogle Scholar
  80. Kehl S, Weiss C, Wamsler M, Beyer J, Dammer U, Heimrich J, Faschingbauer F, Sütterlin M, Beckmann MW, Schleussner E (2016) Double-balloon catheter and sequential vaginal prostaglandin E2 versus vaginal prostaglandin E2 alone for induction of labor after previous cesarean section. Arch Gynecol Obstet 293:757–765PubMedCrossRefGoogle Scholar
  81. Khanna N, Dalby R, Tan M, Arnold S, Stern J, Frazer N (2007) Phase I/II clinical safety studies of terameprocol vaginal ointment. Gynecol Oncol 107:554–562PubMedCrossRefGoogle Scholar
  82. Khanna N, Dalby R, Connor A, Church A, Stern J, Frazer N (2008) Phase I clinical trial of repeat dose terameprocol vaginal ointment in healthy female volunteers. Sex Transm Dis 35:577–582PubMedCrossRefGoogle Scholar
  83. Kim KW, Thomas RL, Lee C, Park HJ (2003) Antimicrobial activity of native chitosan, degraded chitosan and O-carboxymethylated chitosan. J Food Prot 66:1495–1498PubMedCrossRefGoogle Scholar
  84. Kocatürk T, Gençgönül A, Balica F, Özbağcivan M, Çakmak H (2015) Combined eye gel containing sodium hyaluronate and xanthan gum for the treatment of the corneal epithelial defect after pterygium surgery. Clin Ophthalmol 9:1463–1466PubMedPubMedCentralCrossRefGoogle Scholar
  85. Kuklinski C (2000) Farmacognosia, estudio de las drogas y sustancias medicamentosas de origen natural. Ed OmegaGoogle Scholar
  86. Lacey CJ, Woodhall S, Qi Z, Sawant S, Cowen M, McCormack S, Jiang S (2010) Unacceptable side-effects associated with a hyperosmolar vaginal microbicide in a phase I trial. Int J STD AIDS 21:714–717PubMedCrossRefGoogle Scholar
  87. Laeyendecker O, Redd AD, Nason M, Longosz AF, Karim QA, Naranbhai V, Garrett N, Eshleman SH, Abdool Karim SS, Quinn TC (2015) Antibody maturation in women who acquire HIV infection while using antiretroviral preexposure prophylaxis. J Infect Dis 212:754–759PubMedPubMedCentralCrossRefGoogle Scholar
  88. Lamont RF, Sobel JD, Akins RA, Hassan SS, Chaiworapongsa T, Kusanovic JP, Romero R (2011) The vaginal microbiome: new information about genital tract flora using molecular based techniques. BJOG 118:533–549PubMedPubMedCentralCrossRefGoogle Scholar
  89. Larsen B, Monif GR (2001) Understanding the bacterial flora of the female genital tract. Clin Infect Dis 32:69–77CrossRefGoogle Scholar
  90. Levendosky K, Mizenina O, Martinelli E, Jean-Pierre N, Kizima L, Rodriguez A, Kleinbeck K, Bonnaire T, Robbiani M, Zydowsky TM, O’Keefe BR, Fernández-Romero JA (2015) Griffithsin and carrageenan combination to target herpes simplex virus 2 and human Papillomavirus. Antimicrob Agents Chemother 59:7290–7298PubMedPubMedCentralCrossRefGoogle Scholar
  91. Li L, Ben Y, Yuan S, Jiang S, Xu J, Zhang X (2012) Efficacy, stability, and biosafety of sifuvirtide gel as a microbicide candidate against HIV-1. PLoS ONE 7:e37381PubMedPubMedCentralCrossRefGoogle Scholar
  92. Liu Y, Zhu Y, Wei G, Lu W (2009) Effect of carrageenan on poloxamer-based in situ gel for vaginal use: improved in vitro and in vivo sustained-release properties. Eur J Pharm Sci 37:306–312PubMedCrossRefGoogle Scholar
  93. Luessen HL, de Leeuw BJ, Langemeyer MW, de Boer AB, Verhoef JC, Junginger HE (1996) Mucoadhesive polymers in peroral peptide drug delivery: VI. Carbomer and chitosan improve the intestinal absorption of the peptide drug Buserelin in vivo. Arch Pharm Res 13:1668–1672CrossRefGoogle Scholar
  94. Lupo Pasin B (2015) Estudio de gelificación de alginatos para encapsulación: caracterización, preparación y aplicaciones en alimentos funcionales. PhD thesis, University of Barcelona, SpainGoogle Scholar
  95. Lyra MAM, Soares-Sobrinho JL, Brasileiro MT, de la Roca MF, Barraza JA, Viana OS, Rolim-Neto PJ (2007) Hydrophilic matrix and mucoadhesive systems for drug controlled release. Lat Am J Pharm 26:784–793Google Scholar
  96. Madan M, Bajaj A, Lewis S, Udupa N, Baig JA (2009) In Situ forming polymeric drug release systems. Indian J Pharm Sci 71:242–251PubMedPubMedCentralCrossRefGoogle Scholar
  97. Mamani PL, Ruiz-Caro R, Veiga MD (2015) Pectin/anhydrous dibasic calcium phosphate matrix tablets for in vitro controlled release of water-soluble drug. Int J Pharm 494(1):235–243Google Scholar
  98. Masoudi M, Miraj S, Rafieian-Kopaei M (2016) Comparison of the effects of Myrtus Communis L, Berberis Vulgaris and metronidazole vaginal gel alone for the treatment of bacterial vaginosis. J Clin Diagn Res 10:QC04–QC07Google Scholar
  99. Mármol Z, Páez G, Rincón M, Araujo K, Aiello C, Chandler C, Gutiérrez E (2011) Chitin and chitosan friendly polymer. A review of their applications. Revista Tecnocientífica URU 1:53–58Google Scholar
  100. Marras-Márquez T, Peña J, Veiga-Ochoa MD (2014) Agarose drug delivery systems upgraded by surfactants inclusión: Critical role of the pore architecture. Carbohyd Polym 103:359–368CrossRefGoogle Scholar
  101. Marrazzo JM, Ramjee G, Richardson BA, Gomez K, Mgodi N, Nair G, Palanee T, Nakabiito C, van der Straten A, Noguchi L, Hendrix CW, Dai JY, Ganesh S, Mkhize B, Taljaard M, Parikh UM, Piper J, Mâsse B, Grossman C, Rooney J, Schwartz JL, Watts H, Marzinke MA, Hillier SL, McGowan IM, Chirenje ZM (2015) Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med 372:509–518PubMedPubMedCentralCrossRefGoogle Scholar
  102. Martínez Palau M (2008) Síntesis, estructura y aplicaciones de poliésteres secuenciales derivados de ácido glicólico y w-hidroxiácidos. PhD thesis, Polytechnic University of Catalonia, SpainGoogle Scholar
  103. Masteiková R, Chalupová Z, Sklubalová Z (2003) Stimuli-sensitive hydrogels in controlled and sustained drug delivery. Medicina (Kaunas) 39(Suppl 2):19–24Google Scholar
  104. Matsuda T (2002) Device-directed therapeutic drug delivery systems. J Control Release 78:125–131PubMedCrossRefGoogle Scholar
  105. Melis GB, Marotto MF, Orrù MM, Pilloni M, Zedda P, D’Alterio M, Paoletti AM (2016) Bacterial vaginosis: efficacy of a local treatment with a gel containing a fraction derived from propinibacterium acnés. Minerva Ginecol 68:1–8PubMedGoogle Scholar
  106. Meunier L, Garthoff JA, Schaafsma A, Krul L, Schrijver J, van Goudoever JB, Speijers G, Vandenplas Y (2014) Locust bean gum safety in neonates and young infants: an integrated review of the toxicological database and clinical evidence. Regul Toxicol Pharmacol 70:155–169PubMedCrossRefGoogle Scholar
  107. Mohamed RE, Gadour MO, Adam I (2015) The lowering effect of Gum Arabic on hyperlipidemia in Sudanese patients. Front Physiol 6:160PubMedPubMedCentralCrossRefGoogle Scholar
  108. Mughal MA, Iqbal Z, Neau SH (2011) Guar gum, xanthan gum, and HPMC can define release mechanisms and sustain release of propranolol hydrochloride. AAPS PharmSciTech 12:77–87PubMedCrossRefGoogle Scholar
  109. Nel AM, Coplan P, van de Wijgert JH, Kapiga SH, von Mollendorf C, Geubbels E, Vyankandondera J, Rees HV, Masenga G, Kiwelu I, Moyes J, Smythe SC (2009) Safety, tolerability, and systemic absorption of dapivirine vaginal microbicide gel in healthy, HIV-negative women. AIDS 23:1531–1538PubMedCrossRefGoogle Scholar
  110. Nel AM, Smythe SC, Habibi S, Kaptur PE, Romano JW (2010) Pharmacokinetics of 2 dapivirine vaginal microbicide gels and their safety vs. Hydroxyethyl cellulose-based universal placebo gel. J Acquir Immune Defic Syndr 55:161–169PubMedCrossRefGoogle Scholar
  111. Nishikawa M, Onuki Y, Isowa K, Takayama K (2008) Formulation optimization of an indomethacin-containing photocrosslinked polyacrylic acid hydrogel as an anti-inflammatory patch. AAPS PharmSciTech 9:1038–1045PubMedPubMedCentralCrossRefGoogle Scholar
  112. Notario-Pérez F, Martín-Illana A, Cazorla-Luna R, Ruiz-Caro R, Peña J, Veiga MD (2018) Improvement of Tenofovir vaginal release from hydrophilic matrices through drug granulation with hydrophobic polymers. Eur J Pharm Sci 117:204–215Google Scholar
  113. Notario-Pérez F, Martín-Illana A, Cazorla-Luna R, Ruiz-Caro R, Bedoya LM, Tamayo A, Rubio J, Veiga MD (2017) Influence of Chitosan Swelling Behaviour on Controlled Release of Tenofovir from Mucoadhesive Vaginal Systems for Prevention of Sexual Transmission of HIV. Mar Drugs 15(2):50Google Scholar
  114. Obara K, Ishihara M, Ishizuka T, Fujita M, Ozeki Y, Maehara T, Saito Y, Yura H, Matsui T, Hattori H, Kikuchi M, Kurita A (2003) Photocrosslinkable chitosan hydrogel containing fibroblast growth factor-2 stimulates wound healing in healing-impaired db/db mice. Biomaterials 24:3437–3444PubMedCrossRefGoogle Scholar
  115. Ozyazici M, Gökçe E, Hizarcioglu SY, Taner MS, Köseoglu K, Ertan G (2006) Dissolution and vaginal absorption characteristics of metronidazole and ornidazole. Pharmazie 61:855–861PubMedGoogle Scholar
  116. Pacheco de Delahaye E, Techeira N (2009) Chemical and functional properties of native and modified yam (dioscorea alata) starch. Interciencia 34:280–285Google Scholar
  117. Pawar S, Pande V (2015) Oleic acid coated gelatin nanoparticles impregnated gel for sustained delivery of zaltoprofen: formulation and textural characterization. Adv Pharm Bull 5:537–548PubMedPubMedCentralCrossRefGoogle Scholar
  118. Pedersen C, Slepenkin A, Andersson SB, Fagerberg JH, Bergström CA, Peterson EM (2014) Formulation of the microbicide INP0341 for in vivo protection against a vaginal challenge by Chlamydia trachomatis. PLoS ONE 9:e110918PubMedPubMedCentralCrossRefGoogle Scholar
  119. Pendergrass PB, Reeves CA, Belovicz MW, Molter DJ, White JH (1996) The shape and dimensions of the human vagina as seen in three-dimensional vinyl polysiloxane casts. Gynecol Obstet Invest 42:178–182PubMedCrossRefGoogle Scholar
  120. Pendergrass PB, Reeves CA, Belovicz MW, Molter DJ, White JH (2000) Comparison of vaginal shapes in Afro-American, caucasian and hispanic women as seen with vinyl polysiloxane casting. Gynecol Obstet Invest 50:54–59PubMedCrossRefGoogle Scholar
  121. Pendergrass PB, Belovicz MW, Reeves CA (2003) Surface area of the human vagina as measured from vinyl polysiloxane casts. Gynecol Obstet Invest 55:110–113PubMedCrossRefGoogle Scholar
  122. Perioli L, Ambrogi V, Pagano C, Massetti E, Rossi C (2008) Chitosan and a modified chitosan as agents to improve performances of mucoadhesive vaginal gels. Colloids Surf B Biointerfaces 66:141–145PubMedCrossRefGoogle Scholar
  123. Perioli L, Amrogi V, Pagano C, Massetti E, Rossi C (2011) New solid mucoadhesive systems for benzydamine vaginal administration. Colloids Surf B Biointerfaces 84:413–420PubMedCrossRefGoogle Scholar
  124. Podual K, Doyle FJ III, Peppas NA (2000) Dynamic behavior of glucose oxidase-containing microparticles of poly(ethylene)-grafted cationic hydrogels in an environment of changing pH. Biomaterials 21:1439–1450PubMedCrossRefGoogle Scholar
  125. Pradeep AR, Agarwal E, Bajaj P, Naik SB, Shanbhag N, Uma SR (2012) Clinical and microbiologic effects of commercially available gel and powder containing Acacia arabica on gingivitis. Aust Dent J 57:312–318PubMedCrossRefGoogle Scholar
  126. Prajapati VD, Jani GK, Moradiya NG, Randeria NP, Nagar BJ (2013) Locust bean gum: A versatile biopolymer. Carbohydr Polym 94(2):814–821Google Scholar
  127. Rabasco A (1997) Nuevas formas de administración de medicamentos. In Tecnología Farmacéutica, Vol. II: Formas Farmacéuticas 8:379–445Google Scholar
  128. Rader M, Marks G, Mansergh G, Crepaz N, Miller LC, Appleby PR, Murphy S (2001) Preferences about the characteristics of future HIV prevention products among men who have sex with men. AIDS Educ Prev 13:149–159PubMedCrossRefGoogle Scholar
  129. Rajan SS, Turovskiy Y, Singh Y, Chikindas ML, Sinko PJ (2014) Poly(ethylene glycol) (PEG)-lactic acid nanocarrier-based degradable hydrogels for restoring the vaginal microenvironment. J Control Release 194:301–309PubMedCentralCrossRefPubMedGoogle Scholar
  130. Ramanathan S, Block LH (2001) The use of chitosan gels as matrices for electrically-modulated drug delivery. J Control Release 70:109–123PubMedCrossRefGoogle Scholar
  131. Ravel J, Gajer P, Fu L, Mauck CK, Koenig SS, Sakamoto J, Motsinger-Reif AA, Doncel GF, Zeichner SL (2012) Twice-daily application of HIV microbicides alter the vaginal microbiota. MBio 3(6):e00370-12.Google Scholar
  132. Rehman K, Mohd Amin MC, Zulfakar MH (2014) Development and physical characterization of polymer-fish oil bigel (hydrogel/oleogel) system as a transdermal drug delivery vehicle. J Oleo Sci 63(10):961–970PubMedCrossRefGoogle Scholar
  133. Rencher WB (2001) Vaginal microbicide formulations workshop. Arlington, VA: Lippincott-RavenGoogle Scholar
  134. Rençber S, Karavana SY, Şenyiğit ZA, Eraç B, Limoncu MH, Baloğlu E (2016) Mucoadhesive in situ gel formulation for vaginal delivery of clotrimazole: formulation, preparation, and in vitro/in vivo evaluation. Pharm Dev Technol 7:1–11Google Scholar
  135. Richardson BA, Kelly C, Ramjee G, Fleming T, Makanani B, Roberts S, Musara P, Mkandawire N, Moench T, Coletti A, Soto-Torres L, Karim SA (2013) Appropriateness of hydroxyethylcellulose gel as a placebo control in vaginal microbicide trials: a comparison of the two control arms of HPTN 035. J Acquir Immune Defic Syndr 63:120–125PubMedPubMedCentralCrossRefGoogle Scholar
  136. Richardson JL, Trevor TI (1999) Vaginal delivery of calcitonin by hyaluronic acid formulations. Drugs Pharm Sci 98:563–599CrossRefGoogle Scholar
  137. Robic A, Gaillard C, Sassi JF, Lerat Y, Lahaye M (2009) Ultrastructure of ulvan: a polysaccharide from green seaweeds. Biopolymers 91:652–664PubMedCrossRefGoogle Scholar
  138. Rodríguez IC, Cerezo A, Salem II (2000) Bioadhesive delivery systems. Ars Pharmaceutica 41:115–128Google Scholar
  139. Rohan LC, Sassi AB (2009) Vaginal drug delivery systems for HIV prevention. AAPS J 11:78–87PubMedPubMedCentralCrossRefGoogle Scholar
  140. Rosen RK, Morrow KM, Carballo-Diéguez A, Mantell JE, Hoffman S, Gai F, Maslankowski L, El-Sadr WM, Mayer KH (2008) Acceptability of tenofovir gel as a vaginal microbicide among women in a phase I trial: a mixed-methods study. J Womens Health 17:383–392CrossRefGoogle Scholar
  141. Ruiz-Caro R, Gago-Guillan M, Otero-Espinar FJ, Veiga MD (2012) Mucoadhesive Tablets for Controlled Release of Acyclovir. Chem Pharm Bull 60(10):1249–1257Google Scholar
  142. Sagiri SS, Singh VK, Kulanthaivel S, Banerjee I, Basak P, Battachrya MK, Pal K (2015) Stearate organogel-gelatin hydrogel based bigels: physicochemical, thermal, mechanical characterizations and in vitro drug delivery applications. J Mech Behav Biomed Mater 43:1–17PubMedCrossRefGoogle Scholar
  143. Sánchez R, Damas R, Domínguez P, Cerezo P, Salcedo I, Aguzzi C, Viseras C (2010) Uso de la HidroxiPropilMetilCelulosa (HPMC) en liberación modificada de fármacos. Farmaespaña industrialGoogle Scholar
  144. Sánchez-Sánchez MP, Martín-Illana A, Ruiz-Caro R, Bermejo P, Abad MJ, Carro R, Bedoya LM, Tamayo A, Rubio J, Fernández-Ferreiro A, Otero-Espinar Veiga MD (2015) Chitosan and Kappa-Carrageenan vaginal acyclovir formulations for prevention of genital herpes. In vitro and ex vivo evaluation. Mar Drugs 13:5976–5992PubMedPubMedCentralCrossRefGoogle Scholar
  145. Schwartz JL, Kovalevsky G, Lai JJ, Ballagh SA, McCormick T, Douville K, Mauck CK, Callahan MM (2008) A randomized six-day safety study of an antiretroviral microbicide candidate UC781, a non-nucleoside reverse transcriptase inhibitor. Sex Transm Dis 35:414–419PubMedCrossRefGoogle Scholar
  146. Schwebke JR, Marrazzo J, Beelen AP, Sobel JD (2015) A phase 3, multicenter, randomized, double-blind, vehicle-controlled study evaluating the safety and efficacy of metronidazole vaginal gel 1.3% in the treatment of bacterial vaginosis. Sex Transm Dis 42:376–381PubMedPubMedCentralCrossRefGoogle Scholar
  147. Sezer AD, Cevher E, Hatıpoğlu F, Oğurtan Z, Baş AL, Akbuğa J (2008) Preparation of fucoidan-chitosan hydrogel and its application as burn healing accelerator on rabbits. Biol Pharm Bull 31:2326–2333PubMedCrossRefGoogle Scholar
  148. Shah AJ, Donovan MD (2007) Formulating gels for decreased mucociliary transport using rheologic properties: polyacrylic acids. AAPS PharmSciTech 8:E48–E53PubMedCentralCrossRefPubMedGoogle Scholar
  149. Sharma H, Sharma BD, Talukder S, Ramasamy G (2015) Utilization of gum tragacanth as bind enhancing agent in extended restructured mutton chops. J Food Sci Technol 52:1626–1633PubMedCrossRefGoogle Scholar
  150. Sherafudeen SP, Vasantha PV (2015) Development and evaluation of in situ nasal gel formulations of loratadine. Res Pharm Sci 10:466–476PubMedPubMedCentralGoogle Scholar
  151. Shinde UA, Kanojiya SS (2014) Serratiopeptidase niosomal gel with potential in topical delivery. J Pharm 2014:382959Google Scholar
  152. Shokri J, Adibkia K (2013) Application of cellulose and cellulose derivatives in pharmaceutical industries. In cellulose—medical, pharmaceutical and electronic applicationsGoogle Scholar
  153. Singh VK, Anis A, Banerjee I, Pramanik K, Bhattacharya MK, Pal K (2014a) Preparation and characterization of novel carbopol based bigels for topical delivery of metronidazole for the treatment of bacterial vaginosis. Mater Sci Eng C Mater Biol Appl 44:151–158PubMedCrossRefGoogle Scholar
  154. Singh VK, Banerjee I, Agarwal T, Pramanik K, Bhattacharya MK, Pal K (2014b) Guar gum and sesame oil based novel bigels for controlled drug delivery. Colloids Surf B Biointerfaces 123:582–592PubMedCrossRefGoogle Scholar
  155. Sjoberg I (1992) The vagina. Morphological, functional and ecological aspects. Acta Obstet Gynecol Scand 71:84–85PubMedCrossRefGoogle Scholar
  156. Skoler-Karpoff S, Ramjee G, Ahmed K, Altini L, Plagianos MG, Friedland B, Govender S, De Kock A, Cassim N, Palanee T, Dozier G, Maguire R, Lahteenmaki P (2008) Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomised, double-blind, placebo-controlled trial. Lancet 372:1977–1987PubMedPubMedCentralCrossRefGoogle Scholar
  157. Smart JD, Kellaway IW, Worthington HE (1984) An in-vitro investigation of mucosa-adhesive materials for use in controlled drug delivery. J Pharm Pharmacol 36:295–299PubMedCrossRefGoogle Scholar
  158. Smith JM, Srinivasan P, Teller RS, Lo Y, Dinh CT, Kiser PF, Herold BC (2015) Tenofovir disoproxil fumarate intravaginal ring protects high-dose depot medroxyprogesterone acetate-treated macaques from multiple SHIV exposures. J Acquir Immune Defic Syndr 68:1–5PubMedPubMedCentralCrossRefGoogle Scholar
  159. Soppimath KS, Aminabhavi TM, Dave AM, Kumbar SG, Rudzinski WE (2002) Stimulus-responsive “smart” hydrogels as novel drug delivery systems. Drug Dev Ind Pharm 28:957–974PubMedCrossRefGoogle Scholar
  160. Sriamornsak P (2003) Chemistry of pectin and its pharmaceutical uses: a review. Silpakorn Univ Int J 3:206–228Google Scholar
  161. Srinivasan P, Dinh C, Zhang J, Pau CP, McNicholl JM, Lo Y, Herold BC, Teller R, Kiser P, Smith JM (2014) Pharmacokinetic evaluation of tenofovir disoproxil fumarate released from an intravaginal ring in pigtailed macaques after 6 months of continuous use. J Med Primatol 43:364–369PubMedPubMedCentralCrossRefGoogle Scholar
  162. Szekalska M, Winnicka K, Czajkowska-Kośnik A, Sosnowska K, Amelian A (2015) Evaluation of alginate microspheres with metronidazole obtained by the spray drying technique. Acta Pol Pharm 72:569–578PubMedGoogle Scholar
  163. Tasdighi E, Jafari Azar Z, Mortazavi SA (2012) Development and in-vitro evaluation of a contraceptive vagino-adhesive propranolol hydrochloride gel. Iran J Pharm Res 11:13–26PubMedPubMedCentralGoogle Scholar
  164. Tien D, Schnaare RL, Kang F, Cohl G, McCormick TJ, Moench TR, Doncel G, Watson K, Buckheit RW, Lewis MG, Schwartz J, Douville K, Romano JW (2005) In vitro and in vivo characterization of a potential universal placebo designed for use in vaginal microbicide clinical trials. AIDS Res Hum Retroviruses 21:845–853PubMedCrossRefGoogle Scholar
  165. Tintori C, Brai A, Dasso Lang MC, Deodato D, Greco AM, Bizzarri BM, Cascone L, Casian A, Zamperini C, Dreassi E, Crespan E, Maga G, Vanham G, Ceresola E, Canducci F, Ariën KK, Botta M (2016) Development and in vitro evaluation of a microbicide gel formulation for a novel non-nucleoside reverse transcriptase inhibitor belonging to the N-Dihydroalkyloxybenzyloxopyrimidines (N-DABOs) family. J Med Chem 59:2747–2759PubMedCrossRefGoogle Scholar
  166. Tuğcu-Demiröz F, Acartürk F, Erdoğan D (2013) Development of long-acting bioadhesive vaginal gels of oxybutynin: formulation, in vitro and in vivo evaluations. Int J Pharm 457(1):25–39PubMedCrossRefGoogle Scholar
  167. Tuğcu-Demiröz F, Acartürk F, Özkul A (2015) Preparation and characterization of bioadhesive controlled-release gels of cidofovir for vaginal delivery. J Biomater Sci Polym Ed 26:1237–1255PubMedCrossRefGoogle Scholar
  168. USP Pharmacopoeia. 39th edn (2016)Google Scholar
  169. Valenta C (2005) The use of mucoadhesive polymers in vaginal delivery. Adv Drug Deliv Rev 57:1692–1712PubMedCrossRefGoogle Scholar
  170. Valore EV, Park CH, Igreti SL, Ganz T (2002) Antimicrobial components of vaginal fluid. Am J Obstet Gynecol 187:561–568PubMedCrossRefGoogle Scholar
  171. Vandamme TF, Lenourry A, Charrueau C, Chaumeil JC (2002) The use of polysaccharides to target drugs to the colon. Carbohydr Polym 48:219–231CrossRefGoogle Scholar
  172. Venugopal V (2011) Polysaccharide from seaweed and microalgae. In Marine Polysaccharides: Food Applications. Taylor and Francis Group, Boca Raton, pp 111–122CrossRefGoogle Scholar
  173. Vermani K, Garg S (2000) The scope and potential of vaginal drug delivery. Pharm Sci Technol Today 3:359–364PubMedCrossRefGoogle Scholar
  174. Vokurka S, Skardova J, Hruskova R, Kabatova-Maxova K, Svoboda T, Bystricka E, Steinerova K, Koza V (2011) The effect of polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair) on oral microbial colonization and pain control compared with other rinsing solutions in patients with oral mucositis after allogeneic stem cells transplantation. Med Sci Monit 17:CR572–CR576Google Scholar
  175. Woolfson AD, Malcolm RK, Gallagher R (2000) Drug delivery by the intravaginal route. Crit Rev Ther Drug Carrier Syst 17:509–555PubMedCrossRefGoogle Scholar
  176. Wu N, Zhang X, Li F, Zhang T, Gan Y, Li J (2015) Spray-dried powders enhance vaginal siRNA delivery by potentially modulating the mucus molecular sieve structure. Int J Nanomedicine 10:5383–5396PubMedPubMedCentralGoogle Scholar
  177. Xiao BB, Zhang D, Chen R, Shi HR, Xin XR, Wang HL, Pang YC, Zhu SN, Yao C, Liao QP (2015) Sucrose gel for treatment of bacterial vaginosis: a randomized, double-blind, multi-center, parallel-group, phase III clinical trial. Beijing Da Xue Xue Bao 47:925–932PubMedGoogle Scholar
  178. Yang KH, Hendrix C, Bumpus N, Elliott J, Tanner K, Mauck C, Cranston R, McGowan I, Richardson-Harman N, Anton PA, Kashuba AD (2014) A multi-compartment single and multiple dose pharmacokinetic comparison of rectally applied tenofovir 1% gel and oral tenofovir disoproxil fumarate. PLoS ONE 9:e106196PubMedPubMedCentralCrossRefGoogle Scholar
  179. Zavos PM, Cohen MR (1980) The pH of cervical mucus and the postcoital test. Fertil Steril 34:234–238PubMedCrossRefGoogle Scholar
  180. Zhou Q, Zhong L, Wei X, Dou W, Chou G, Wang Z (2013) Baicalein and hydroxypropyl-γ-cyclodextrin complex in poloxamer thermal sensitive hydrogel for vaginal administration. Int J Pharm 454:125–134PubMedCrossRefGoogle Scholar
  181. Zhuang H, Bu S, Hua L, Darabi MA, Cao X, Xing M (2016) Gelatin-methacrylamide gel loaded with microspheres to deliver GDNF in bilayer collagen conduit promoting sciatic nerve growth. Int J Nanomedicine 11:1383–1394PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • María-Dolores Veiga
    • 1
  • Roberto Ruiz-Caro
    • 1
  • Araceli Martín-Illana
    • 1
  • Fernando Notario-Pérez
    • 1
  • Raúl Cazorla-Luna
    • 1
  1. 1.Department of Pharmaceutical Technology, Faculty of PharmacyComplutense University of MadridMadridSpain

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