Physiology of the Vagina

INTRODUCTION

Vagina is a fibro muscular tube that extends 6-12 cm from cervix of the uterus. The surface of the vagina is composed of numerous folds, often called rugae. These folds keep distensability, support and provide an increased surface area of the vaginal wall. The vaginal wall is comprised of three layers: the epithelial layer, tunica adventia and the muscular coat. The epithelial layer creates the superficial layer, which is about 200 μm thick. The smooth muscular fibres of the muscular coat are running along in both circular and longitudinal directions. This gives the vagina an excellent elastic character. Further, the connective tissue of the tunica adventia also increases the flexibility of the vagina [1].

Fig1: Female reproductive system showing vagina.

Blood Circulation in Vagina

The vaginal wall compromises of a dense network of blood vessels and extends from internal iliac artery, uterine, middle rectal and internal pudental arteries. The blood enters systemic circulation via rich venous plexus which empties primarily into internal iliac vein. The vagina lacks the direct release of mucus because it does not contain any goblet cells. But still it discharges a large amount of fluid. The fluid has its origin from transudates through the epithelium, cervical mucus, exfoliating cells, and leukocytes, endometrial and tubal fluids. The vaginas nerve supply comes from two sources. The peripheral, which primarily supplies the lower quarter of the vagina, makes it a highly sensitive area: the autonomic primarily supplies upper three quarters. Autonomic fibers respond to stretch and are not very sensitive to pain or temperature. The upper vagina is a very insensitive area because of few sensory fibers. This is why women rarely feel localized sensations or any discomfort when using vaginal rings, and are often unaware of the presence of such items in vagina [2].

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The physiological changes in vagina would affect the absorption of drugs and must be taken into consideration in the development of formulations. The thickness of epithelial layer could affect the permeability, where thinner epithelium causes increased absorption. Amount of fluid is important because drugs must be in solution before absorption. For bio adhesive systems, wetting of the tablet is crucial for bio adhesion and increasing the residence time. Viscosity may present as a barrier for drug absorption and continuous secretion can result in removal of the dosage form [3].

Micro flora of Vagina

The state of a normal healthy vagina is largely a function of the bacterial community which is an important first line of defence for the body. Lactobacillus species, mainly L. crispatus, L. gasseri, L. iners and L. jensenii are dominant constituents in most women’s vagina worldwide and defends the vagina by e.g. producing several compounds with antimicrobial activity and thereby creating an inhospitable environment against pathogens.Despite several vaginal defence mechanisms the vaginal microbiota is sometimes disturbed and there is a change in the normal balance causing symptoms like abnormal or increased vaginal discharge, redness and itching. Irritation of vagina caused by inflammation or infection is called vaginitis. Vaginitis is a very common disease for women of reproductive age all over the world but children and postmenopausal women could also be affected [4,5].

Vaginal Infections

The major and common causes of vaginitis are bacterial vaginosis, trichomonas and Candida vaginitis. Vaginal yeast infection occurs approximately in 75% of all women once in their life time. Bacterial vaginosis is caused by a decrease of lactobacilli concurrent with overgrowth of several fastidious bacterial species which normally could be present in low concentrations in the vagina. Candida vaginitis is a vaginal yeast infection where Candida albicans is commonly the cause of the disorder. Bacterial vaginosis and Candida vaginitis are extremely common infections in women whose epidemiology and pathogenesis are not clarified [6].

The symptoms of vaginitis vary with physiological conditions of women and bacterial vaginosis and Candida vaginitis are diagnosed based on each patient and it depends on the accuracy and knowledge of the clinician handling the patient. Women should not assume that a new infection is the same as previous and use e.g. over the counter treatment, but rather reconsider the diagnosis and do a thorough examination [7]. Generally vaginal infection and its symptoms greatly affect women’s health conditions leading to serious health disorders therefore it is necessary to treat this condition efficiently [8].

Bacterial Vaginosis

The micro biota of normal healthy vagina comprises of certain bacteria which forms a critical defense layer against harmful pathogen. The normal micro biota of vagina comprises of bacteria namely lactobacillus mainly in the lower genital tract. The bacterial vaginosis (BV) occurs most commonly among pregnant women and women who are sexually active. Bacterial Vaginosis is the condition wherein the normal lactobacillus species are replaced with harmful anaerobic microorganisms such as Gardnerella vaginalis and Bacteroides species. Incidence of Bacterial Vaginosis makes the female vagina highly prone to infection such HIV [9].

The most Symptoms and signs can be commonly diagnosed by the vaginal discharge which is highly homogenous and appears to be white gray with an unpleasant odor (especially after sexual intercourse), though the gray discharge coats the walls of the vagina, it does not lead to any kind of irritation. Itching, soreness and redness around the vagina vulva and vagina becomes more alkaline pH [10, 11].

Vaginal Trichomoniasis

Trichomoniasis is caused by protozoan namely Trichomonas vaginalis which leads to vaginitis in female. T. vaginalis is considered to be the most common cause of sexually transmitted infection. In male Trichomonas are detected in prostatic tissue in benign prostatic hyperplasia, prostatitis, and in men having prostate cancer. Trichomoniasis may also increase the transmission of human immunodeficiency virus (HIV) by two- to three folds both in male and female [12, 13]. Trichomonas infects both male and female however only female shows symptoms male remain asymptomatic. Growth of Trichomonas on vaginal membrane could result in vaginal discharge that smells fishy, and appears to be frothy and yellow colored. The severity of this condition is observed when blood starts to ooze out from vagina and post coital [14].

Vaginal Candidiasis

Vaginal candidiasis is caused by Candida microorganisms and it is responsible for causing yeast vaginitis in female. Of all the species of candida, Candida albicans tends to cause major vaginal disorders. Candida glabrata is another species that could be a cause of vaginal disorders. The disease condition can be treated either with topical azoles or systemic azole (fluconazole or ketoconazole). The major problem in treating patients with Candida vaginitis is that this organism develops resistance to topical and systemic azoles [15].

Diagnosis of Vaginitis

Generally patients affected by vaginitis can be diagnosed by Amsel’s criterion [10] which is a highly significant. According to Amsel’s criteria, the vaginal discharge is homogenous (color and amount varied from normal discharge). Addition of potassium hydroxide to vaginal secretion produces amine odor (WHIFF TEST). Microscopic examination of vaginal fluid reveals clue cells. Generally there is a Notable change in pH of vagina higher than 4.5 [5].

Vaginal Dosage Forms

The majority of commercially available vaginal delivery systems are usually targeting topical administration. Pessaries (tablets or suppositories) are among the most widely used systems. The principle of their action is that they provide sustained release of the drug as they gradually dissolve or melt. However, this mechanism has a drawback and can result in low bioavailability if the formulation melted faster than intended, thereby giving shorter residence time in the vagina. Conventional oral tablets intended for vaginal treatment comprises of disintegrants, binders and other excipients. Formulating very hydrophobic drugs as vaginal tablets may not be an ideal approach. However, it was suggested that by adding penetration enhancing agents such as surfactants can significantly enhance the drug absorption. Moreover, attempts have been carried out to use mucoadhesive polymers in vaginal tablet formulations in order to increase the residence time. Polyacrylic acid (PAA) is among the bioadhesive polymers that have been utilized for vaginal formulations due to its high bioadhesive strength which allows a longer contact time with vaginal surface [16, 17].

Creams and gels are another type of delivery systems frequently used. Creams are normally emulsions whereas gels are usually hydrophilic polymers that utilize covalent bonds to create cross-linked three-dimensional structures [18].

Some formulations such as antifungal emulsion-based formulations seem to have greater advantage over many suppository formulations. An example of gel product is the progesterone gel formulation that is based on a loosely cross-linked poly acrylic acid (Noveon AA1®). This formulation was found to remain on vaginal tissue for 3-4 days, thus allowing dosing intervals of twice a week. However, a disadvantage that can be associated with the use of creams and gels is that they may not provide an exact dose, thus compromising the efficacy of the drug therapy. Ideally, vaginal drug delivery system that is designed for local effect should distribute uniformly throughout the site of action. However, the distribution and coverage of formulation within the vaginal cavity varies with the properties of the delivery system. It was reported that disintegrating tablet show low coverage whereas solution, suspension and emulsions display greater distribution profile [19].

In-situ Gelling System

Over the past 30 years greater attention has been focused on development of controlled and sustained drug delivery systems, of which development and design of polymeric drug delivery systems has been focused a lot and major research has been carried out in this field. There is a major attention in the area of design and development of in-situ gelling systems in recent times; this is evident from the increase in number of studies being carried out in in-situ gel forming systems for various applications. This is widely due to the advantages that polymeric system can form in-situ gel that can be administered easily and frequent dosing can be avoided, also the improved patient compliance and comfort makes it a useful drug delivery system.

In-situ gel forming drug delivery is a type of mucoadhesive drug delivery system. In-situ gel forming drug delivery systems are a revolution in topical drug delivery. These in-situ gelling systems are generally in the form of sol but forms gel at the desired site due to various factors such as pH, temperature and other external stimuli [20].

Method of preparation of in-situ gelling system

There are three broadly defined mechanisms involved in formation of in-situ gel: Physiological stimuli (e.g., temperature and pH), physical changes in biomaterials (e.g., solvent exchange and swelling), and chemical reactions (e.g., enzymatic, chemical and photo-initiated polymerization) [21].

IN-SITU GEL FORMATION BASED ON PHYSIOLOGICAL STIMULI

Thermally triggered system

Temperature sensitive in-situ gel is another class of polymeric delivery system and considered to be the most commonly studied class in drug delivery research. The use of polymer solution having capacity to form gel with changes in temperature is an attractive approach in drug delivery system. Such system undergoes change at ambient at physiologic temperature such that clinical manipulation is facilitated and no external source of heat other than that of body is required for triggering gelation [22]. A useful system should be able to account for small differences in local temperature, which might be encountered in appendages at the surface of skin or in the oral cavity. There are three main strategies used in formulation of thermo responsive sol gel polymeric system they are classified as negatively thermo sensitive, positively thermo sensitive and thermally reversible gel [23].

pH triggered system

Sol to gel transition based on change in physiological pH is another approach in insitu gel formation. There are many polymers used to achieve this process. Cellulose acetate phthalate latex is a polymer that is widely used for sustained ophthalmic drug delivery since the latex remains as solution at pH of 4.4 and undergoes gelation when the pH is raises to 7.4 by the tear fluid but the lower pH of the preparations can lead to discomfort in some patients [24].

The strongest mucoadhesive property is exhibited by the commercial forms of lightly cross-linked poly acrylic acid (Polycarbophil and Carbopol), Carbomer a cross-linked poly acrylic acid polymer (PAA) also undergoes phase transition as the pH is increased above its pKa of about 5.32. Various grades of Carbopol are available commercially in the market. The property of stiffness of gel formation is determined by crosslinking density. The cross linking density of Carbopol 934 is very low, while Carbopol 981 has intermediate cross linking capacity and highest being Carbopol 940 [25, 26].

IN-SITU GEL FORMATION BASED ON PHYSICAL MECHANISM

Swelling

In-situ gel formation may also occur when material tends to absorbs water from external environment and expand. Ex: – Myverol 18-99 which is polar lipid that swells in water to form lyotropic liquid crystalline phase structures. It has some bioadhesive properties and can be degraded in-vivo by enzymatic action [27].

Diffusion

This method involves formation of gel by the diffusion of solvent from the surface of polymer solution into external surface of tissue either by precipitation or by solidification of polymer matrix. N-methyl Pyrrolidone (NMP) has been shown to be useful solvent for such system.

IN-SITU GEL FORMATION BASED ON CHEMICAL REACTION

Chemical reactions that results in-situ gelation may involve precipitation of inorganic solids from supersaturated ionic solutions, enzymatic processes, and photo-initiated processes.

Ionic cross linking

Polymers may undergo phase transition due to the presence of cations and anions. The presence of mono and divalent cations such as Ca2+,Mg2+, K+ and Na+ hinders the formation of gel in case of anionic polymers such as gellan gum, In the same way, alginic acid undergoes gelation in presence of Ca2+ and the interaction with guluronic acid block in alginate chains [28].

Enzymatic cross-linking

Natural enzymes have many advantages over chemical approaches in in-situ gel formation, For example an enzymatic process does not require any monomers and initiators and it operates efficiently under normal physiological conditions. Intelligent stimuli-responsive delivery systems using in-situ gels that can release insulin have been investigated. Cationic pH-sensitive polymers containing immobilized insulin and glucose oxidase can swell in response to blood glucose level releasing the entrapped insulin in a pulsatile fashion. Adjusting the amount of enzyme also provides a convenient mechanism for controlling the rate of gel formation, which allows easier administration of the mixtures prior to gelation [29].

Structure of Foam

Foams are thermodynamically and mechanically unstable systems; they are characterized by a very large interface which has a tendency to reduce itself. Foams are “elastic systems” and the entrapped gas phase can be compressed [30]. Successful foam requires the formation, growth and stabilization of the gas bubbles in the reacting medium. The bubbles in a foam can be more or less homogeneous and vary in size and shape ranging from almost spherical to irregular polyhedral, depending on how the foam was generated and the incorporated excipients. Other parameters include the nature and concentration of the foaming agent, viscosity of the liquid phase, temperature and pH of the system: all these can affect the foam structure [31].

Preparation of Foams

Foams are produced by supersaturating a liquid phase with gas. The type of surfactant and bubble surface mobility greatly influences the foam rheological properties [32]. A typical foaming process involves dissolution of the foaming agent, bubble nucleation, bubble growth, and stabilization. Methods to achieve this include whipping, shaking, bubbling, pressurized aerosols and air spray foam pumps. Whipping, also called beating, is accomplished with different devices that agitate a liquid in order to form an interface with a gas phase. The volume of air incorporated usually increases with an increase in the beating intensity. High viscosity liquids do not produce stable foams [33]. During whipping, each air bubble undergoes severe mechanical stress and a more rapid coalescence happens during foam generation than in standing foam.

Propellants

Pressurized aerosols include both two-phase and three-phase aerosol foams. In the two-phase system, the liquefied propellant is dissolved in the solution of a foaming agent under pressure. In the three-phase system, the propellant is dissolved in a lipid phase, which is emulsified with a water phase using an emulsifier. The foaming agent can also act as an emulsifier [34]. The third phase is the vapor phase of the propellant over the emulsion. Both two and three-phase systems should be shaken prior to use. In these systems, the propellants with low boiling points evaporate rapidly leading to immediate foam generation. Water is most commonly used as a solvent in foam aerosols, as well as ethanol and isopropanol [35]. The most common propellants include n-butane, isobutene, n-propane or mixtures of these. Their concentration is typically in the range of 3-12%. Fluorinated hydrocarbon gases may be liquefied by cooling below their boiling point or by compressing the gas at room temperature. These two features are used in the filling of aerosol containers with propellant [36].