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American Journal of Advanced Drug Delivery

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Review Article Intra Vaginal Drug Delivery System: An Overview

Chinmaya Keshari Sahoo* 1, Prakash Kumar Nayak 2, Deepak Kumar Sarangi 3, Tanmaya Keshari Sahoo 4

1Research Scholar, Osmania University College of Technology, Osmania University,Hyderabad, A.P. - 500007 2Norwich clinical Services Pvt. Ltd., Clinical Research co-ordinator cum Pharmacist, Sahakara Nagar, Banglore- 560092 3Omega College of Pharmacy, Edulabad, Ranga Reddy-501301 4Institute of Pharmacy and Technology, Salipur, Cuttack, Odisha-754202

Date of Receipt - 17/04/2013 ABSTRACT Date of Revision- 17/04/2013 Date of Acceptance- 22/04/2013 The human represents a potential, accessible space that offers a valuable route for drug delivery through the use of specifically designed carrier systems for both local and systemic applications. Intra-vaginal drug delivery is particularly appropriate for drugs associated with women's health issues but may also have applications in general drug delivery within the female population. Vagina is one of the best routes for drugs administration like contraceptive steroids, metronidazole, anti-retroviral, etc. An intra-vaginal controlled-release drug delivery system is an effective means for achieving a continuous delivery of therapeutic agents, not only the systemically active drugs, such as contraceptive steroids, but also the locally active drugs, such as metronidazole and other drugs like Zidovudine, Lamivudine, etc. Address for This continuous “infusion” of drugs through the vaginal mucosa can Correspondence prevent the possibility of hepato-gastrointestinal first-pass Osmania University metabolism gastric irritation of drugs and fluctuation of dosing College of Technology, interval. The advantage of intra-vaginal controlled drug Osmania administration over conventional/traditional is the drug absorbed systemically, because due to the presence of dense University,Hyderabad, network of blood vessels in vaginal wall. A range of drug delivery A.P.-500007 platforms suitable for intra-vaginal administration are hydro-, vaginal tablets, /, particulate systems, and E-mail: intra-vaginal rings. sahoo.chinmaya83@g mail.com Keywords : Vagina, First pass metabolisim, Intra vaginal drug delivery, pessaries.

American Journal of Advanced Drug Delivery www.ajadd.co.uk Sahoo et al______ISSN-2321-547X

INTRODUCTION Vagina is route for administration for ‹ Variability in drug related with contraceptives, anti-fungal, and menstrual cycle, and antimicrobials. It is used for the pregnancy, achievement of local or for systemic ‹ Influence with sexual intercourse 4. absorption. The vaginal wall is very well ‹ Personal hygiene. suited for the absorption of drugs for ‹ Some drugs are sensitive at vaginal pH systemic use. As it contains a vast network of blood vessels 1. VAGINAL ANATOMY AND This route offers certain advantages, PHYSIOLOGY WITH RESPECT TO such as avoidance of gut and hepatic first DRUG DELIVERY pass metabolism, reduction in The vagina is a fibro-muscular gastrointestinal and hepatic side effects, and approximately 10 cm in length comprised of local targeting of drugs to the reproductive three distinct layers namely; organs. Vaginally administered agents and ‹ an outer adventitial layer, formulations are mainly being developed to ‹ a middle muscularis layer and provide “dual prophylaxis” for contraception ‹ An innermost mucosal layer 5 and protection against microbial infections 2 The vaginal rugae and micro-ridges on including Acquired Immune Deficiency the epithelial cell surface permit the vagina Syndrome(AIDS) and other sexually to expand, allow the placement of vaginal transmitted diseases (STDs). Drug delivery formulations and increase the surface area of technologies that have been used for vaginal the vagina thus enhancing drug absorption 6. drug delivery include the intra-vaginal ring The vagina has remarkable features in (IVR) and Vaginal Site bio- terms of vaginal secretion, pH, enzyme technology. activity and micro-flora. These factors affect formulation spreading and retention as well Advantages of intra vaginal drug delivery as absorption and drug release in vagina. system ‹ Prolonged release, Vaginal Secretions ‹ Minimal systemic side effects, The vaginal discharge is a of ‹ An increase in bioavailability, multiple secretions that collect in the vagina ‹ Use of less total drug than an oral dose, from peritoneal, follicular tubal, uterine, ‹ First-pass metabolism can be avoided, Bartholin's and Skene's glands 7. In presence ‹ Self medication is possible. of moisture, dosage formulations should ‹ Contact with digestive fluid is avoided ideally disperse in the vaginal canal and degradation of drug is minimized 3. immediately after insertion to avoid ‹ Nausea, vomiting, emesis induced inconvenience to the users. through oral administration is avoided. ‹ Quick onset of action. Enzyme Activity The specific enzymatic activity of Disadvantages four different amino peptidases in vaginal ‹ Gender specificity, homogenates decreases in the order: sheep > ‹ Patient incompliance, guinea pig > rabbit ≥ human ≥ rat 8 . The ‹ Only a few drugs are administered by this human genital tract has lower enzymatic route, activity leading to less degradation of protein

AJADD1[1][2013]043-055 Sahoo et al______ISSN-2321-547X and peptide drugs in the vagina than the following factors: 9. Physiological Factors Vaginal pH ‹ changes in the thickness of The pH of the healthy female genital layer, tract is acidic (pH 3.5–4.5) and is maintained ‹ cyclic changes, within that range by bacterial conversion of ‹ changes in the hormones level, glycogen from exfoliated epithelial cells to ‹ volume of vaginal fluid, lactic acid 10 . ‹ alteration of vaginal pH and ‹ Sexual arousal can potentially affect drug Ideality of intra vaginal drug delivery release from any intravaginal delivery system system and also alter its rate of ‹ Component should melt at vaginal absorption. temperature i.e. at 36 °C, For e.g. ‹ Intra-vaginal drug delivery device 1. Vaginal absorption of steroids is affected should be non-toxic and non irritating, by the thickness of 11 . ‹ It should not have any meta-stable form, 2. Vaginal absorption of shows ‹ The preparation should have wetting and high in post menopausal women emulsifying properties. compare to premenopausal women 12 . ‹ It should have proper , so avoid The high volume of vaginal fluid the leakage of preparation from vagina may increase the absorption of poorly water (in case of semisolid ), soluble drugs; however the same condition ‹ The preparation should have proper bio- again responsible to remove the drug from adhesive/muco-adhesive properties, so the vaginal cavity and subsequent reduction increase the contact time between the of drug absorption. membrane and Preparation. Further cervical , a glycoprotein can possibly be exploited for drug delivery. However at FACTORS AFFECTING ABSORPTION the same time it may serve as a permeability OF DRUGS barrier for different drug candidates 13 . Again changes in the pH of vagina will alter degree The drug transport across vaginal of ionization of weak electrolytic drugs and membrane mainly takes place by three major affect the release profile of pH sensitive ways; drugs 14 . ‹ Transcellularly- via concentration dependent diffusion through the cells, Physicochemical Factors ‹ Paracellularly- mediated via tight ‹ Lipophilicity, junctions and ‹ Ionization, ‹ Vesicular or receptor mediated transport. ‹ Molecular weight, Drug absorption from vaginal delivery ‹ Surface charge and system is mainly takes place in two main ‹ Chemical nature can influence the vaginal steps: drug absorption. ‹ Drug dissolution in vaginal lumen and In consideration to permeability the ‹ Membrane penetration. lipophilic steroids like progesterone and The rate and extent of drug absorption estrone having better permeability than the after intra-vaginal administration may vary depending on

AJADD1[1][2013]043-055 Sahoo et al______ISSN-2321-547X hydrophilic one like hydrocortisone and shape of number 7 Copper is released by a . combination of ionization and chelation from a copper wire wrapped around the Vaginal & Uterine Route for vertical limb. This is effective for up to 40 Sustained/Controlled Release drug m. Delivery Application of prostaglandin containing vaginal rings for induction of labor or Sustained and controlled-release pregnancy termination. Anti-fungals have devices for drug delivery in the vaginal and been important drug candidates for the uterine areas are most often for the delivery treatment of gynecological conditions. of contraceptive steroid hormones. One such The vaginal delivery of azole anti- application is the medicated vaginal ring. gungals as clotrimazole, miconazole, Medicated vaginal rings fabricated from econazole, itraconazole and sertaconazole is silastic 382 medical grade elastomer. These effective in the topical treatment of vaginal are of ‘doughnut-shaped’. Also known as candidiasis. intra-vaginal rings or V-Rings. Vaginal rings provide a means of delivering a drug to the systemic circulation Novel concepts in vaginal drug delivery at a controlled release rate. Several vaginal ring products are currently NVDDS are designed with desirable available, including:- distribution, bio-adhesion, retention and release characteristics. The conventional ‹ Estring - a low-dose -releasing VDFs, such as suppositories, gels, creams ring, manufactured from silicone and foams can meet some but not all of elastomer, for the treatment of vaginal these requirements. Achieved by the use of atrophy. ‹ Bio-adhesive and ‹ Femring - a low-dose estradiol-acetate ‹ Other novel delivery systems. releasing ring, manufactured from silicone elastomer, for the relief of hot flashes and vaginal atrophy associated Bio-adhesive delivery systems with menopause. Bio-adhesive vaginal formulations ‹ NuvaRing - a low-dose contraceptive that are capable of delivering the active vaginal ring, manufactured from poly agent for an extended period at a predictable (ethylene-co-vinyl acetate), and rate. Bio-adhesive formulations have been releasing etonogestrel (a progesterone) found to reduce the conventional treatment ethinylestradiol (an estrogen). NuvaRing time of fungal infections by at least 25%. A - NuvaRing is inserted into the vagina bio-adhesive formulation might not and left in place for three weeks, after necessarily contain a therapeutic agent and which it is removed for a 'ring-free' can be used as a moisturizer for the week to allow to occur. treatment of dry vagina. Tablets that are A more common contraceptive device is the placed directly between the vaginal mucosal (IUD). Two types of surfaces have been demonstrated to be medicated IUD are generally used; excellent bio-adhesive formulations. For ‹ Contraceptive metals and example, chitosan and sodium alginate ‹ Steroid hormones. based bio-adhesive tablets were found to The metal device is exemplified by the release 100 % of metronidazole over a CU-7, a polypropylene plastic device in period of 8 h in a buffer at pH 4.8 17 .Bio-

AJADD1[1][2013]043-055 Sahoo et al______ISSN-2321-547X adhesive micro-particles have also been plasticized nylon, plasticized polyethylene- investigated for the vaginal delivery of terephthalate, polyethylene, salmon calcitonin using HYAFF as bio- polyacrylonitrile, polytrifluoro adhesive polymer where microspheres chloroethylene, poly-4,4'-isopro- showed increased bio-availability of drug. pylenediphenylene carbonate, polyethylene- Water dispersible films are being used to vinyl esters and polyvinylchloride-diethyl deliver drugs directly to mucosal surfaces to fumarate. A novel medicating system based form close contact with mucosal membrane on thermoplastic polymeric materials 18 . releases effective amounts of progestational Controlled release drug delivery and estrogenic steroids, which produce a systems can be achieved by the addition of desired anti-fertility effect over a prolonged time-release additives. Bio-adhesive period. Chang et al. have recently reported a formulations based on carbomers and muco-adhesive thermo-sensitive gel that polycarbophil give satisfactory drug exhibited increased and prolonged delivery within the vaginal cavity following antifungal activity of clotrimazole in the application of a single dose. For comparison with conventional PEG-based example, Prochieve TM is a bio-adhesive formulation 20 . gel used in hormone replacement therapy. Replens® is a muco-adhesive gel based on polycarbophil designed to be retained in the Vaginal Dosage Forms genital cavity for 3-4 days 19 . In the development of vaginal Other novel delivery systems dosage forms, several considerations should be addressed as:- Phase change polymers such as ‹ Maintenance of an optimal pH for poloxamers exhibit sol–gel transition in vaginal epithelium, response to body temperature, pH and ‹ Ease of application, specific ions and they prolong the residence ‹ Even distribution of the drug, time of the dosage form in the vagina. ‹ Retention time in the vagina, Formulations based on a thermoplastic graft ‹ Compatibility with co-administered copolymer have been developed to provide medicines. the prolonged release of active ingredients Many different types of formulations such as nonoxynol-9, progestins, , have been applied vaginally as- peptides and proteins in a vaginal ‹ Vaginal Tablets, environment. ‹ Vaginal suppositories or pessaries, An intravaginal therapeutic system ‹ Vaginal Foams, (are aqueous made from certain vaginally acceptable that are administered into the thermoplastic polymeric materials that are vagina for not absorbable can be used for the ‹ Cleansing purpose), sprays, gels, controlled release of drug. One preferred creams(as vehicles for drugs such as example of a thermoplastic polymer is anti-infective or contraceptive agents) styrene-butadiene block copolymer. and Additional thermoplastic polymers that can ‹ Vaginal rings be used for manufacturing novel vaginal delivery systems include polymethylacrylate, polybutylmeth- acrylate, plasticized polyvinylchloride,

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Tablets and Suppositories Creams and Gels

A large number of intravaginal A number research work has been delivery systems are also available in the done on creams and gels as an intravaginal form of tablets and suppositories. Some delivery system. They are mainly used for authors use the terms pessaries and topical delivery of contraceptives and anti suppositories interchangeably and consider bacterial drugs. These delivery systems are vaginal as a separate dosage messy to use, uncomfortable, may not form.These formulations are designed to provide an exact dose because of non- melt in vaginal cavity and release the active uniformity and leakage.Metronidazole and constituent over prolong period of vaginal creams for the time.Vaginal suppositories intended for treatment of bacterial vaginosis already localized effects are employed mainly as proved them as efficacious as oral contraceptives, antiseptics and anti-fungal. delivery.Recently a gel microemultion based systems are most formulation of spermicide with anti HIV commonly used to administer drugs like effect of zidovudine has been developed dehydroepiandrosterone sulphate for 28 .Literature shows that minocaprin ripening effect on uterine , formulations possess potent miconazole for vaginal candiasis and microbicidal activity against HIV, HSV, progesterone for hormonal replacement Chlamydia trachomatis and Neisseria therapy.Normal vaginal tablets contain gonorrhea , which is less cytotoxic than similar components as like conventional oral nonoxynol-935 29 .Cellulose acetate phthalate tablets, they are easy to manufacture and (CAP) used the pharmaceutical industries as insertion.Drugs that are administered as enteric coating agent but recent study vaginal tablets include itraconazole, focused that it’s having an potency to absorb clotrimazole, metronidazole and and inactivate HIV-1, HSV and other STIs prostaglandins. Mucoadhesive polymers are 30 . Further utilizing this ability of CAP a sometimes used in vaginal tablet potential anti-HIV vaginal gel formulation formulation to increase the vaginal has been formulated that are under phase II residence time.The polystyrene sulfonate clinical trials 31 .An Intravaginal vaccine (PSS) is also shows superior antimicrobial delivery by means of vaginal gel is also activity against HIV and HSV, therefore it is reported, even intravaginal delivery of formulated in the form of vaginal tablet, cholera vaccine showed a greater mucosal which will not immobilize sperm, not response in female genital tract compare to cytotoxic and did not inhibit normal vaginal oral administration of the vaccine 32 .Further flora, so as proved as potential delivery oxytoscin, dinoprostone and misoprostol system 27 . Literature shows that presence of commonly used for cervical ripening and hydrophobic and release retarding materials induction of labor are also available in may decrease the absorption of a drug from vaginal gel form. a vaginal formulation and too hydrophobic drugs may not be suitable for vaginal tablets. Further presence of penetration Vaginal Rings enhancers such as surfactants, bile salts can significantly enhance absorption. Vaginal rings are circular ring type drug delivery devices designed to release drug in a controlled release fashion after insertion in the vagina.

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This type of device having several hormonal replacement therapy, release advantages like, estrogen. ‹ It can be controlled by the user, ‹ Does not interfere with coitus and Literature reported that dapivurine, ‹ Allows continuous delivery of which is also known as TMC120, is a potent microbicidal compounds. non-nucleoside reverse transcriptase They are 5.5 cm in diameter with a inhibitor that is the only vaginal ring system circular cross section diameter of 4-9 mm, used as an intravaginal microbicide delivery where drugs are homogeneously dispersed. system for preventing the transmission of Drugs at the surface of the ring release faster STIs and HIV 36 . than the drug in the inner layer. The key Plastic insertion devices are usually used challenge behind the development of this to hold the vaginal suppository during type of device is finding the optimum dose insertion for proper placement within the that will deliver the least amount of drug vagina.Design of a delivery necessary to ensure protection. To obtain system for vaginal administration of constant release of drug from vaginal ring acyclovir was investigated, to provide sandwich or reservoir types of system have sustained release and improve been developed. bioavailability of the encapsulated drug for Sandwich type devices consist of a the local treatment of genital herpes. narrow drug containing layer located below the surface of the ring and positioned EVALUATION OF VAGINAL between a non medicated central core and a FORMULATIONS non-medicated outer band. In reservoir type of rings, drugs are A vaginal formulation must be dispersed in a central core, which is than evaluated by performing both in vitro and in encapsulated by a drug free layer. The vivo studies. Depending on the dosage form, materials introduced to fabricate vaginal additional tests for vaginal drug products ring are mainly polymeric in nature. may include appearance, viscosity, pH, As per literature most commonly used particle size analysis, dissolution rate, polymers for vaginal ring are ploy content uniformity and microbial limits 37 . (dimethylsiloxane) or silicon devices, other elastomeric polymers such as ethylene vinyl acetate have been tested in recent years 33 . In vitro studies Clinical acceptability of ring made up of In vitro studies include the determination of ethylene vinyl acetate is very high because drug release and bio-adhesive characteristics of its increase flexibility, improved optical in addition to various physical and chemical properties, greater adhesion and increased properties of formulations .The release impact and punch resistance 34 .Vaginal rings characteristics of a drug from a vaginal mainly used for contraceptive and hormonal formulation can be determined in simulated replacement therapy. For most contraceptive vaginal fluid (pH 4.2) and in various application the ring is placed in vagina for dissolution media (pH range 2–12) by 21 days followed by a week of ring free different types of diffusion cells with certain period. Nuvaring is one of the examples of modifications and a vaginal dissolution contraceptive ring available in US market tester .The bio-adhesive strength of the 35 .Further Femring and Estring are the vaginal formulation can be measured by example of vaginal ring intended for various techniques (like Wilhelmy plate surface technique) 38 .

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In vivo studies local and systemic therapeutically active In vivo studies are conducted in compounds.Novel vaginal delivery systems different animal models to assess efficacy, overcome some of the key limitations distribution, spreading and retention of associated with conventional delivery of formulations in the vagina 39 .Gamma vaginal drugs. Vaginal drug delivery is a scintigraphy and colposcopy 40 are desirable promising area for continued research on the techniques for assessing the distribution, delivery of microbicides that can prevent spreading and retention of vaginal transmission of sexually transmitted diseases formulations in sheep and humans. and HIV. However, the significance of these findings is debatable. REFERENCES Two imaging techniques are being developed to measure the degree of 1. Kamel A.E., Sokar M., Nagger V. & Gamal coverage in the : magnetic S.A., Chitosan and sodium alginate based resonance imaging (MRI) and an bioadhesive vaginal tablets, AAPS Pharm intravaginal optic probe 41 . Several animal Sci., 2002, 4(4): 1-7. model such as sheep, rats, rabbits, rhesus 2. Hall R., Gardea D.M. & Harlan F., Oral versus vaginal misoprostol for labor monkeys, macaque monkeys, dogs and mice induction. Obstet. Gynecol , 2002, 99: 1044- have been used in different studies in the 42 48. development of vaginal formulations . 3. Francois M., Snoeck E., Putteman P., White rabbits are used for primary irritation Wouter F., Proost E.D., Deluet U., Peeter J. and subchronic toxicity testing. Recently & Brewster M.E., A mucoadhesive, developed vaginal-ectocervical (VEC) tissue cyclodextrin based vaginal models will serve as useful, highly formulation itraconazole, AAPS Pharm Sci ., reproducible, non-animal tools to assess the 2003, 5: 1-5. irritation due to vaginal care product 43. 4. Chang J.Y., Oh V.K., Kong H.S., Kim E.J., Jang D.D., Nan K.T. & Kim C.K., Prolonged Antifungal effect of clotrimazole- APPLICATIONS OF INTRA VAGINAL containing mucoadhesive thermosensitive DRUG DELIVERY SYSTEM gels on vaginitis, J. control. Release , 2002, 82: 39-50. ‹ This route of drug administration is 5. Kamel A.E., Sokar M., Nagger V. & Gamal useful for vaginal immunization, S.A., Chitosan and sodium alginate based ‹ Multi-cycle administration of vaginal bioadhesive vaginal tablets, AAPS Pharm contraceptive rings, Sci., 2002, 4(4): 1-7. 6. Hall R., Gardea D.M. & Harlan F., Oral ‹ Effective route for the treatment of HIV versus vaginal misoprostol for labor infection, induction. Obstet. Gynecol , 2002, 99: 1044- ‹ Effective route for the treatment of local 48. fungal infection, 7. Francois M., Snoeck E., Putteman P., ‹ Effective for the delivery of hormones. Wouter F., Proost E.D., Deluet U., Peeter J. & Brewster M.E., A mucoadhesive, cyclodextrin based vaginal cream CONCLUSION formulation itraconazole, AAPS Pharm Sci ., 2003, 5: 1-5. The vaginal route has been used for 8. Chang J.Y., Oh V.K., Kong H.S., Kim E.J., the local application of drugs, but is now Jang D.D., Nan K.T. & Kim C.K., becoming a potential route for noninvasive, Prolonged Antifungal effect of clotrimazole- controlled trans-mucosal delivery of both containing mucoadhesive thermosensitive

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gels on vaginitis, J. control. Release , 2002, 22. Johnson V.E. & Masters W.H., Intravaginal 82: 39-50. contraceptive study phase-I anatomy. West. 9. Paavonen J, Scand. J. Infect. Dis . 1983, 40: J. Surg. Obstet. Gynecol ., 1962, 70: 202-07. 31-35. 23. Ceschel G.C., Maffei P. and Rossi S., Drug 10. Nelson A.L., The vagina: New Options for Dev. Ind. Pharm., 2001;27 :541-547. the Administration of Medications, 24. Pavelie Z. and Jalsenjak I., J. Control. Rel ., Medscape Today. 2004, Section 6 of 10. 2005; 106 : 34-43. 11. Hwang S., Owada E., Suhardja L.H.U., 25. Neurath A.R., Strick N.and Y. Li, BMC Flynn G.L. & Higuchi W.I., Systems Infectious Diseases, 2003; 3 27 approach to Vaginal delivery of drug: 4 26. Vermani K., Garg S. and. Zaneveld L, Drug methodology for determination of Dev. Ind. Pharm. , 2002; 28 :1133-1146. membrane surface pH., J Pharm Sci ., 1977, 27. Alam A.M., Ahmad J.F., Khan I.Z., Khar 66: 778 K.R. & Ali M., Development and evaluation 12. Katz D.F. & Duna E.N., Cervical mucus: of acid buffering bioadhesive vaginal tablet problems and opportunities for drug delivery for mixed vaginal infections. AAPS Pharm via the vagina & cervix, Adv.Drug Deliv. Sci. Tech ., 2007, 8(4): E1-E8. Rev . 1993, 11: 385-401. 28. Dcruz U.J., Zhu Z.H., Yiv S.H., Chen C.L., 13. Johnson T.A., Greer I.A., Kelly R.W. & Waurzyniak B. & Uckun F.M., WHI-05, a Calder A.A., The effect of pH on release of novel bromi-methoxy substituted phenyl PGE2 from vaginal & endocervical phosphate derivative of zidovudine, is a dual preparation for induction of labour: and in- action spermicide with potent anti HIV vitro study, Br. J. Obstet.Gynaecol ., 1992, activity. Contraception , 1999, 59: 319-31. 99: 877-80. 29. Fichora R.N., Zhou F., Ratnan V., 14. Owen D.H., Dunmire E.N., Planys A.M. & Atanassova V., Giang S., Strick N.& Katz D.F., Factors influencing nonoxynol-9. Neurath A.R., Anti human immune J control release , 1996, 39: 93. deficiency virus. Type I microbicides 15. Moghissi K.S, Vaginal Fluid Constituents. cellulose acetate 1, 2 benzene dicarboxylate In The Biology of the Fluids of the Female in a human in-vitro model of vaginal Genital Tract, Elsevier, North Holland.1979, inflammation, Antimicrobial Agents pp. 13-23. Chemother. , 2005, 49(1): 323-25. 16. Acartürk F., and. Parlatan Z.I, J Pharm. 30. Mayer K.H., Karim S.A. & Kelly C., The Pharmacol ., 2001. 53 1499-1504. safety and tolerability of a novel vaginal 17. Richardson J.L, and. Illum L, Adv. Drug microbicides. PRO 2000/5 gel in sexually Deliv. Rev. , 1992. 8; 341-366. active HIV uninfected and abstinent HIV 18. Boskey E.R., Cone R.A. and Whaley K.J., infected women, AIDS , 2003, 17: 321 Hum. Reprod ., .2001,16, 1809-1813. 31. Manson K.H., Wyand M.S., Miller C. & 19. Hwang S., Owada E., Suhardja L.H.U., Neurath A.R., Effect of cellulose acetate Flynn G.L. & Higuchi W.I., Systems phthalate topical cream on vaginal approach to vaginal delivery of drug: 4 transmission of simian immunodeficiency methodology for determination of virus in rhesus monkey, Antimicrob Agents membrane surface pH., J Pharm Sci ., 1977, Chemither, 2000, 44(11): 3199-3302. 66: 778. 32. Wassen K.S., Holngren L., Jerborn M. & 20. Johnson T.A., Greer I.A., Kelly R.W. & Lycke N., Local intra vaginal vaccination of Calder A.A., The effect of pH on release of the female genital tract. Scand. J. Immunol, PGE2 from vaginal & endocervical 1996, 44: 408- 14. preparation for induction of labour: and in- 33. Sharma G., Jain S., Tiwary A.K. & Kaur G, vitro study, Br. J. Obstet. Gynaecol ., 1992, Once daily bioadhesive vaginal clotrimazole 99: 877-80. tablet: design and evaluation, Acta Pharm ., 21. Owen D.H., Dunmire E.N., Planys A.M. & 2006, 56: 337-45. Katz D.F., Factors influencing nonoxynol-9. 34. Novak A., Loge C., Ebetz L. & Maulen J control release , 1996, 39: 93. E.A., The combined contraceptive vaginal

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ring, nuva ring: an international study of 38. Bouckaert S., J. Pharm. Pharmacol ., 1995; user acceptability, Contraception , 2003, 67: 47 :970-971. 187-94. 39. Ceschel G.C., Maffei P. and Rossi S., Drug 35. Priet J., Lamontagne J., Bestman-smith J., Dev. Ind. Pharm. , 2001; 27: 541-547 Roy S., Gourde P., Desormeaur A., Omar 40. Pavelie Z. and Jalsenjak I., J. Control. Rel ., R.F., Juhasz J. & Bergeron M.G., Invitro 2005 ;106: 34-43. and invivo evaluation of sodium lauryl 41. Pekka L. and Harri J., British Medical sulfate and dextran sulfate as microbicides Bulletin, 2000; 56 : 739-748. against herpes simplex and human 42. Neurath A.R and Strick N., U.S. Patent, immunodeficiency viruses, J. Clin. 2003; 6:572,875, Microbiol, 2000, 38: 110-19. 43. Alam A.M., Ahmad J.F., Khan I.Z., Khar 36. Richardson J.L. & Armstrong T.I., Vaginal K.R. & Ali M., Development and evaluation delivery of calcitonin by of acid buffering bioadhesive vaginal tablet formulations, in Bioadhesive drug delivery for mixed vaginal infections. AAPS Pharm systems: fundamentals, novel approaches Sci. Tech. ,2007, 8(4): E1-E8. and development, (E. Mathiowitz, D.E. 44. Hussain A. & Ahsan F., The vagina as a Chickering III, C.M. Lehr, eds.) Marcel route of systemic drug delivery, J Dekker, New York, 1999, pp.563-99. Controlled Release , 2005, 103: 301-13. 37. Chang J.Y.,Oh Y.K,. Kim Y.B and. Kim C.K, Int. J. Pharm ., 2002;241: 155-163.

Table 1. Influence of Age on the variation of pH, Length, and Width of human Vagina 15, 16

pH Length of vagina Width of Changes of vagina (cm) vagina(cm)

Before puberty 7 4.5-6 1-1.5

Reproductive age 4-5 2.5 10

Adult pre - 4-5 2 7-8 menopause

Post-menopause 4-7 4.5-6 1-1.5

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Table 2. Various dosage forms in vaginal drug delivery system

Drug Formulation Polymers Purpose of Investigation Ref

Increased absorption from HYAFF microsphere compared Insulin HYAFF Microspheres to aqueous of the 21

drugs

Chitosan, Sodium Tablet (Bioadhesive) Mucoadhesive dosage form Metronidazole Alginate 22

Polycarbophyl, HPMC Good adhesion properties Hyaluronic sodium Clotrimazole Pessaries and capacity to hold the 23 salt dosage form in the target site

Sustained release and Liposomal hydrogel Acyclovir Carbopol 974P improved (Bioadhesive) 24 bioavailability

Advanced delivery system of Progesterone Vaginal ring Polydimethylsiloxane hormone replacement in 25 females

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Table 3. Commonly used marketed vaginal products 44

Therapeutic Drug Intended Use Dosage Form Comments Company (Brand Name)

Contraceptive Bioadhesive in Columbia Nonoxynol-9 Vaginal gel Nature. Laboratories.

Commonly reported Etonogestrel, adverse events are ethinyl estradiol Contraceptive Vaginal ring Organon vaginitis, weight (NuvaRing ®) gain

Clotrimazole Taro Anti-fungal Cream Minor skin irritation (Trivagizole®) Pharmaceuticals

Metronidazole 3M (Metrogel Bacterial vaginosis Vaginal gel Vaginal discharge. Pharmaceuticals Vaginal®)

Estradiol Mild allergic Atropic vaginitis Vaginal tablet Novo Nordisk (Vagifem®) Reaction.

Can increase the Pharmacia and Estradiol (Estring®) Hormone therapy Vaginal ring vaginal secretion Upjohn

Possible side effects Tioconazole Tioconazole Bristol Myers Vaginal ointment are swelling of face, (Trivagizole®) (Trivagizole®) Squibb Lips, tongue.

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Figure.1. Structure of female reproductive system

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