AN EXHAUSTIVE STATISTIC ON CURRENT MUCOADHESIVE INTRAVAGINAL DRUG DELIVERY METHODOLOGIES

The vaginal course of medication conveyance offers many focal points because of its huge permeation range, rich vascularization, avoidance of first pass metabolism and relatively low enzymatic activity. A few examinations have demonstrated that for sedate organization the vaginal pit is a viable course which expected for the most part for neighborhood activity and conveying drugs for foundational impacts with uterine focusing on. It was first Sobrero who endeavored the vaginal mucosa for tranquilize assimilation, from that point forward much research has been done on the organization of medications through this course. As of late, for vaginal dose frame, different plan and application has expanded impressively. It is fundamentally the conveyance of medications inside or through the vaginal mucosa for neighborhood or foundational pharmacological activity. Degree of medication ingestion and its rate after organization may shift contingent upon vaginal physiology, age of the patient, arrange in the menstrual cycle, neurotic conditions and detailing factors. Here in this audit, there's a feature, the advantages and confinements of vaginal medication conveyance, philosophy in assessment of vaginal medication conveyance frameworks, pharmaceutical viewpoints and an outline of late advances made in the bailiwick of vaginal medication conveyance. Advancement of measurements frame in various stages and in the market, are likewise audited.


INTRODUCTION
Novel researchers have shown their interest on mucoadhesive drug delivery systems among them; vaginal drug delivery system offers a thoroughfare for the release of different antifungal, antibacterial and contraceptive drugs. To improve the vaginal therapy, the formulation administered via the vagina should have more residence time in the vaginal cavity. Conventional vaginal dosages forms have pros and cons both, like they avoid the first pass metabolism, easy to formulate, self-administration, and are economical whereas it produces itching, irritation of vagina, messy to apply, and low residence time respectively. Therefore, to overcome nano drug delivery systems are being formulated. Recently nano drug delivery systems like vaginal liposomes, vaginal niosomes, nano suspensions, nano emulsions, nanofibres, have evoked more interest to deliver the drugs via the vaginal route. They offer increased residence time, cellular targeting, localization of formulation to specific sites and mucoadhesion. Various mucoadhesive polymers like hydroxylpropyl methylcellulose (HPMC), chitosan, sodium alginate, eudragit, polycarbophil, carrageenan, hydroxypropyl cellulose, ethylene (vinyl acetate) co-polymer among others have been used for developing novel vaginal formulations. For prevention of HIV and other sexually transmitted diseases (STDs) 1 topical delivery of microbicides is also being investigated as an alternative option. Merits of bioadhesive systems over the existing conventional preparations:  Excellent accessibility 2  Avoidance of aqueous or organic solvents,  Easy of self-administration 3  Gel like consistency in the activated state or at the body temperature 4  No irritation ISSN: 2456- 8058 84 CODEN (USA): UJPRA3  Rapid bioadhesion, prolonged residence time in the vaginal cavity even in absence of physiological secretions 5 .  Extended dosing interval 6 .  Improved chemical and physical stability 7 . Mucoadhesive vaginal delivery systems have both synthetic and natural polymers. Most commonly used mucoadhesive polymers that are capable of forming hydrogels are synthetic polycarbophil, chitosan, cellulose derivatives (hydroxyethycellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose), pectin, hyaluronic acid derivatives, polyacrylates, tragacanth, carrageenan and sodium alginate. New mucoadhesive molecules are thyolated polymers. There bioadhesive properties are cinched by polyacrylic acid-based polymers, known as Carbomers. Mercantilelycarbomers are available in different grade, molecular weight, residual component or degree of cross-linked structure. Among these polymers, polycarbophil and polyacrylic acid are cross-linked with divinylglycol and are more preferred also. These water insoluble polymers have an apparent pKa of approx 4 and picks up 61-100 times its weight in water [8][9][10] .

Disadvantages
 Gender specificity,  Patient incompliance,  Only a few drugs are administered by this route 11 .  Variability in drug absorption related with menstrual cycle, menopause and pregnancy,  Influence with sexual intercourse 12 .  Personal hygiene.  Some drugs are sensitive at vaginal pH 13 .

ANATOMY AND PHYSIOLOGY OF VAGINA
The human vagina is a fibro muscular tube which is capable of collapsing. It is a passageway that connects the cervix, which is the opening of the uterus, to the outside of the body. It is also known as the birth canal. The length of the vagina is 6-10 cm which widens from the cervix 14 . The wall of human vagina comprises of three layers such as:  An outer adventia layer.  Middle muscular layer.  The tunica adventia. It has contours called rugae at the walls of vagina in close juxtaposition to each other which form a collapsible tube. The epithelium portion does not contain any glands, but its surface is kept moist due to cervical secretion, whose composition and volume varies with age, stage of menstrual cycle and degree of sexual excitement. Drug absorbed via the vaginal route which avoids first pass metabolism because the blood leaving from human vagina directly enter into peripheral system through different veins. The normal human vagina lumen has an acidity of around pH 4-5. This vaginal pH is due to the active secretion of ovarian hormones and is also invariantly maintained by the sloughing of mature cells in the upper layers of vaginal mucosa. Due to the influence of estrogen, these cells contain a content of glycogen, which is metabolized to lactic acid in the vaginal canal which maintain the vaginal pH on the acidic side, whereas, the acyclic luteal influence on the vaginal mucosa significantly increases the pH value.

VAGINAL ANATOMY AND PHYSIOLOGY WITH RESPECT TO DRUG DELIVERY
The vaginal secretion, pH, enzyme activity and microflora makes the vagina remarkably linguistics. These factors affect formulation spreading, retention, absorption and drug release in vagina. Vaginal Secretions: The release is a blend of numerous emissions that is gathered in the vagina from peritoneal, follicular tubal, uterine, Bartholin's and Skene's organs. 15 Here in nearness of dampness, strong dose plans ought to be in a perfect world scattering in the vaginal trench instantly after inclusion to maintain a strategic distance from bother to the clients. Catalyst Activity: The particular enzymatic action diminishes arranged by four diverse amino peptidases in vaginal homogenates i.e.: sheep > guinea pig > rabbit ≥ human ≥ rodent. 16 The human genital tract has bring down enzymatic action which prompts less debasement of protein and peptide sedates in the vagina than the gastrointestinal tract. Vaginal pH: The pH of the healthy female genital tract is acidic (pH 3.5-4.5) and is maintained within that range by conversion of glycogen from exfoliated epithelial cells to lactic acid through bacteria 17 . Changes in the pH are with age, stage in the menstrual cycle, infections, estrogen levels and variations in the levels of cervical mucus. A successful vaginal drug delivery is a critical factor for controlling the vaginal ph 18 . The change in hormone levels with age, during intercourse and various phases of the menstrual cycle leads to alteration in vaginal secretion, pH, enzyme activity as well as changes in the thickness and permeability of the epithelium all of which complicate the problem of achieving consistent drug delivery [19] .

MECHANISM
The mechanism of mucoadhesion is generally based into two steps;  Contact stage  Consolidation stage. The first stage is an intimate contact, formed between the mucoadhesive and mucous membrane. Initially its contact with the mucus layer is deep. While in the consolidation stage, presence of moisture activates the mucoadhesive material. System is plasticized by moisture and allowing the mucoadhesive molecules to break free and attached by weak Vander Waals and hydrogen bonds. The diffusion theory and the dehydration theory are the two theories that explain the consolidation step. Mucoadhesive molecules and the glycoproteins of the mucus mutually interact and interpenetration their chains and the building of secondary bonds. This is performed according to diffusion theory. For this to take place, the mucoadhesive device favored both chemical and mechanical interactions. For example, molecules having hydrogen bonding groups (-OH, -COOH), high ISSN: 2456- 8058 85 CODEN (USA): UJPRA3 molecular weight, an anionic surface charge, flexible chains and surface-active properties, which helps in spreading throughout the mucus layer [20][21][22][23][24][25][26][27][28][29] . Theories Mucoadhesive is a complex process having numerous theories; their mechanisms are explained as below: Wetting Theory: The wetting theory is the oldest theory of adhesion. Applied on low-viscosity bio adhesive or liquid systems which present affinity to spread over the surface. Predominantly applicable to liquid bioadhesive systems. The thermodynamic work of adhesion is a function of surface tension of the surface in contact as well as interfacial tension. The interfacial energy is responsible for the contact between the two surfaces and adhesive strength. By using measuring techniques such as the contact angel, liquids are spread over the surface and leads to the greater affinity. There is no contact angle to provide good spread ability. The spread ability coefficient (SAB) can be calculated by the difference between the surface energies γB and γA and the interfacial energy γAB. Hence this theory tells about the importance of contact angle and reduces the surface and interfacial energies to gain good amount of mucoadhesion. S AB = γ B -γ A -γ AB Dispersion Hypothesis: Here the polymer chains and bodily fluid blend to an adequate profundity to make a semipermant cement security. Attachment compels increments with the level of infiltration of the polymer chains and dissemination coefficient have property to improve/diminish the entrance rate of dispersion, adaptability. Nature of the mucoadhesive chains, versatility and contact time likewise rely upon dispersion coefficient. Profundity of interpenetration required to create a productive bioadhesive security lies in the range 0.2-0.5. Given condition is utilized to identify the interpenetration profundity of polymer and mucin chain. l = (tD b ) Where t is the contact time and D expressed asthe diffusion coefficient of the mucoadhesion material in the mucus. To achieve the adhesion strength of polymer, the depth of penetration is approximately equivalent to the chain size of polymers. If components have good mutual solubility then proper diffusion should be occurred. Bio adhesive and the mucus have similar chemical structures. If structural similarity is more than mucoadhesive bond is better. Fracture Theory: The most used theory in studies on the mechanical measurement of mucoadhesion is fractional theory. It attempts to relate the difficulty of separation of two surfaces after adhesion which is used to analyze the force required to separate two surfaces after adhesion is established. This force Sm is calculated in tests of resistance by the ratio of maximal detachment force Fm and the total surface area A0 involved in the adhesive interaction.
S m = F m /A 0 Since the fracture theory is used only for the force required to detach the parts and not used to measure interpenetration or diffusion of polymer chains. It is used to calculate solid or semi-solid bio adhesive materials, in which no penetration of the polymer chain into the mucus layer. Electronic Theory: Hypothesis is used to describe that when when electron exchange between the bodily fluid and the mucoadhesive framework, bond ought to be happened, and through contrasts in their electronic structures is emerge. When electron is transfer between the mucus and the mucoadhesive, double layer of electrical charges at the mucus and mucoadhesive interface is formed. The net result of this process is the formation of attractive forces within the double layer. Adsorption Theory: After an initial contact between two surfaces, the material adheres because of surface forces acting between the atoms in the two surfaces. In this theory, adhesion is the result of various surface interactions (primary and secondary bonding) between the polymer that is adhesive on surface and mucus substrate. Chemisorption required forming primary bonds and ionic, covalent and metallic bonding play an important role in adhesion, which is generally undesirable due to their permanency. Vander walls forces, hydrophobic interactions and hydrogen bonding are responsible for formation of secondary bonds. To break these interactions less energy is required, they are the most well-known from of surface interaction in mucoadhesion process due to having semi-permanent bonds. All these theories are involved in the different stages of the mucus/substrate interaction, rather than individual and alternative theories. These theories are considered as supplementary process. Each and every theory is equally describing the mucoadhesion process. Mucin is initially wetting and then diffusion of the polymer into mucin layer and formation of fractions in the layers, the adhesion or electronic transfer or simple adsorption phenomenon should be affected that finally leads to the perfect mucoadhesion. Formation of mucoadhesive bond is depending on the nature of the mucus membrane, mucoadhesive material, the attachment process and the subsequent environment of the bond.

VAGINAL ROUTES OF DRUG ABSORPTION
The drug is delivered in the vagina mainly via two routes: intravaginally to the vaginal epithelium or transvaginal through the vaginal mucosa to uterus and systemic circulation. Cicinelli et al. reported that the vagina has specific blood flow characteristics, either by a portal type circulation or by venous and lymphatic channels that allow bypassing the gastrointestinal tract absorption and liver detoxification and permit preferential transport of drug molecules from the vagina to the uterus and systemic circulation. [30] Several physical models have been devised to study the vaginal permeability of drugs 31 . Antifungal agents such as tioconazole, clotrimazole and miconazole are topically administered to treat vaginal yeast infections. On the basis of our knowledge of anatomical and physiological features of the vagina, it is likely that many other drugs will be formulated for vaginal administration in the future 32 [40][41] . Cellulose acetate phthalate based sponges and those made from other cellulose derivatives are soft, mechanically resilient and thus ideally suitable as bio-erodible microbicidal vaginal devices 42 . Conceival is a novel non-toxic, nonspermicidal, self emulsifying lipophilic gel with improved solubility of lipophilic anti-HIV microbicides 43 . Another vaginal product under development is a liposome preparation containing monoclonal antibodies that will completely agglutinate sperm in the ejaculate.

Pharmaceutical aspects
Many pharmaceutical organizations right now concentrate on the advancement of novel vaginal medication conveyance frameworks for treatment of vaginal contaminations, sexually transmitted diseases, contraception and other gynecological conditions. These innovative delivery systems may lead to extended product shelf life making the products competitive in the market place. The option approach of definitions based pharmaceutical organizations is grow new measurements frames utilizing novel excipients that offer particular preferences over ordinary medication conveyance frameworks. With a specific end goal to accomplish alluring medication attributes diverse methodologies are utilized 44 . The compatibility between the drug and excipients can easily be evaluated by thermal (Differential Scanning Calorimetry) and isothermal (HPLC) stress testing. 45 Penetration Enhancers: Penetration enhancers are capable of promoting absorption and penetration of drug through the vaginal mucosa by decreasing the penetration barrier 9,46 . Currently, the most preferred penetration enhancers include non-ionic surface-active agents, bile salts, benzalkonium chloride, hyaluronic acid 47 , polyethylene glycol, ethoxydiglycol and inter esterified stone oil 5,20 . Solubility Modifiers: The poor solubility of drugs in simulated vaginal fluid may affect the release pattern of a drug from its device, which influences the onset and therapeutic efficacy of the drug. Water-soluble drugs are good candidates for vaginal drug delivery. The aqueous solubility of a drug can be increased by several mechanisms such as addition of solubilizing agents and cosolvency 48 . The most commonly used solubilizing agents include citric acid, ethylenediaminetetraacetate, sodium meta-phosphate, polyvinyl pyrrolidone, sorbitan, tween 80, polyoxyethylene, polyoxyethylene n-alkyl ethers, poloxamers, and cyclodextrin 49 . For example, a novel itraconazole formulation intended for vaginal use is based on hydroxypropyl-β-cyclodextrin, a functional excipient that increases drug solubility 50 . Mucoadhesive agents: Mucoadhesive agents permit a close contact of formulation with the vaginal mucosal surface by promoting adherence 51 . These include polycarbophil, hyaluronic acid, chitosan, sodium alginate, tragacanth, carbomer, acacia, sodium carboxymethyl cellulose or other cellulose derivatives, Carbopol 974P-NF, Carbopol 971P-NF and other copolymers of acrylic acid 52 . Some of these polymers may possess sitespecific bioadhesive properties. For example, xanthan gum and sodium alginate show sitespecific bioadhesive properties in a simulated vaginal environment 53 . Polycarbophil 934P exhibited pH-dependent bioadhesive properties 54 .

CONVENTIONAL
VAGINAL DOSAGE FORMULATIONS Vaginal tablet: Vaginal tablets are prepared in such a way that they will melt, or disintegrate in the vagina and release the medication in the cavity. Vaginal tablet contains all the excipients of a normal conventional tablet. The tablets are prepared by direct compression method and effervescing agents can be incorporated into formulations to enhance the swellabilty and release of the drug 54 . Tablets offer the advantage of ease of manufacture and insertion. Tablets are stable and less messy to handle than creams or ointments. For example, Clotrimazole vaginal tablet have been used to prevent vaginal candidiasis. Ultra-low dose estriol and Lactobacillus acidophilus vaginal tablets (Gynoflor®) were found to be effective in treating vaginal atrophy in postmenopausal breast cancer patients [55][56][57][58] . Bio adhesive vaginal tablets containing cyclodextrin complex of itraconazole were developed to prevent vaginal candidiasis. Vaginal creams are used to deliver the antifungal, antibacterial and contraceptive drugs topically [59][60][61][62] . Vaginal creams are messy to apply, uncomfortable and sometimes embarrassing when they leak into the underclothing. Also, the exact dose is not provided because of the heterogeneous distribution of the formulation when applied into the vagina as they are easy to use, formulate and are easily available. Premarin vaginal cream is indicated for the treatment of patients with refractory endometria 63

NOVEL VAGINAL DOSAGE FORMULATIONS Controlled/sustained release vaginal tablets
Conventional vaginal tablets release the drug immediately and do not offer prolonged or controlled release of the drugs. Many chronic illnesses and recurrent infections may require prolonged therapy. Therefore controlled/sustained release vaginal tablets have been developed. These tablets may employ various rate sustaining polymers such as hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose, sodium alginate, ethyl cellulose, guar gum, xanthan gum, etc. Also, the mucoadhesion of the tablets can be improved by using mucoadhesive agents such as chitosan, polycarbophil, etc. Tenofovir vaginal tablet was investigated to deliver tenofovir as a potential HIV microbicide. 72

Vaginal ring
Vaginal ring is fabricated by dispersing a contraceptive steroid, such as medroxy progesterone acetate, as micronized solid particles in a viscous mixture of silicone elastomer and catalyst and then extruding the steroid polymer dispersion into a mould to form a vaginal ring [73][74][75][76] . They are designed to be inserted into the vagina and position around the cervix for 21 days to achieve a constant plasma progestin level and cyclic intravaginal contraception. Reported problem associated with the use of vaginal rings are erosion of vaginal wall, ring expulsion, interference with coitus, unpleasant ring odour, difficulty with storage and sanitation, premature discontinuation due to vaginal discomfort and device related events, including foreign body sensation. For example, Asilastic vaginal ring impregnated with medroxyprogesterone acetate was used as contraceptive device. A novel contraceptive vaginal ring releasing etonogestrel and ethinylestradiol was used to control the menstrual cycle and the bleeding 78 . Oestradiol releasing vaginal ring has been investigated for the treatment of postmenopausal urogenital atrophy. Novel vaginal danazol ring therapy for pelvic endometriosis has been investigated. Vaginal microspheres are designed as innovative vaginal drug delivery system to impart stability to drug molecules, improve bioavailability and to produce controlled as well as targeted drug release. Bioadhesive micro particles and mucoadhesive microspheres are used for better prevention of different diseases 79 . Vaginal microspheres have several advantages such as constant and prolonged therapeutic effect, mucoadhesion, reduction in dose frequency and better patient compliance. But disadvantages also have been reported like higher drug loading required, batch to batch nonuniformity, variation in release rates and toxicity 80 . Econazole nitrate polymer-lipid based vaginal mucoadhesive microspheres were prepared by using spray congealing method. Hyaluronan ester vaginal microspheres were designed for the release of salmon calcitonin to treat the vaginal infection.

Vaginal nanoparticles
Because of less duration of action and incomplete coverage, the effect of administered drugs via vaginal route reduces. Therefore, to obtain prolonged release, cellular targeting, and for the treatment of several vaginal infectious disorders, vaginal nano particles have been formulated. These nano particles may contain several mucoadhesive polymers such as chitosan, polycarbophil to improve the mucoadhesion so as to achieve better therapeutic efficacy. Example: mucus penetrating nano particles for vaginal drug delivery were used to protect against herpes simplex virus. 81 Vaginal liposomes consisting small interfering RNA were designed to inhibit different vaginal infectious diseases. 82

RECENT DEVELOPMENTS IN VAGINAL DRUG DELIVERY SYSTEM
Vaginal films containing Abacavir, a potent nucleoside reverse transcriptase inhibitor, were designed for the inhibition of sexually transferred diseases 83 . The films were formulated by solvent evaporation method. The resulted films produce extended release of the drugs and they can be applied as novel drug delivery system for the treatment of sexually contagious diseases. Chitosan embedded liposomes incorporating clotrimazole were designed and the results showed it as a promising formulation for vaginal topical therapy.  91 . Double reservoir polyurethane intravaginal rings were prepared to treat sexually transmitted diseases and uncontrolled pregnancy. Dual reservoir vaginal rings were designed in such a way that they will release tenofovir (HIV-1 reverse transcriptase inhibitor) and levonorgestrel (contraceptive) for a prolonged period. Oxybutynin vaginal rings for alleviation of overactive bladder symptoms in women have been developed. From the in vivo test it was revealed that these rings were well tolerated and have the potential to act as a novel drug delivery system for the prevention of overactive bladder symptoms. Lyophilized liposomal gels containing antiviral drug, acyclovir, for the intravaginal delivery were formulated and evaluated. Liposomes were prepared by rotary evaporation method with carbopol and HPMC and subsequently lyophilized. From the evaluation, it was revealed that the carbopol gels showed higher viscosity, spreadability and mucoadhesiveness than the HPMC gels, therefore carbopol liposomal gels were proposed as a promising delivery system of acyclovir via the vaginal route 92  Recently developed tissue model vaginal-ectocervical (VEC) will serve as a useful, highly reproducible, nonanimal tools to assess the irritation due to vaginal care product.

CONCLUSION
Mucoadhesive vaginal drug delivery formulations offer potential improvements in residence time, bioavailability and penetration of drug through mucus membrane of vaginal cavity. It reduces the side effects that are caused by another route of drug administration like avoid first pass metabolism.