Vagina: An Ideal Site for Drug Delivery

Patel Geeta M^1*and Patel Madhabhai M²

¹Dept. of Pharmaceutics and Pharmaceutical Tech. , S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Kherva-382711. Gujarat, India.

²Kalol Institute of Pharmacy, Kalol . Gujarat, India

*Corresponding Author E-mail: geekhappy2002@yahoo.co.in

ABSTRACT

Exhaustive efforts have been made toward the administration of drugs, via alternative routes, that are poorly absorbed after the oral administration. However, successful delivery of drugs through the vagina remains a challenge, primarily due to the poor absorption across the vaginal epithelium. Modern technology has yielded vaginal drug-delivery systems that provide optimized pharmacokinetic profiles. These characteristics make the vagina an excellent route for drug administration. The vagina allows women to self-administer medication continuously for weeks or months at a time with a single application. The purpose of this communication is to provide the reader with a summary of advances made in the field of vaginal drug delivery.

KEYWORDS: Vagina, Vaginal defense, Drug delivery system, First pass effect, Self-administer medication

INTRODUCTION:

Technologic advancement in drug delivery has led to a wider choice of sites for drug administration. Traditionally, the routes most commonly used were oral for systemic effects and topical for local effects. By the 1980s and 1990s, attention had shifted to sub dermal and intrauterine routes, which allowed a single intervention by a healthcare provider to provide sustained therapy. Modern technology has yielded vaginal drug-delivery systems that provide optimized pharmacokinetic profiles. These characteristics make the vagina an excellent route for drug administration.¹

Currently, there is a huge interest in the scientific community and drug industry to exploit various mucosal routes of delivering drugs, which are poorly absorbed after oral administration. Over the last decade, it is apparent that the human vagina remains to be a relatively unexplored route of drug delivery despite its potential as a non-invasive route of drug administration. The presence of dense network of blood vessels has made the vagina an excellent route of drug delivery for both systemic and local effect.²

WHY IS THE VAGINA AN IDEAL SITE FOR DRUG DELIVERY?

Anatomy:

In the pharmaceutical literature, human vagina is often described as slightly S-shaped fibro muscular collapsible tubes (Figure-1) ³ between 6 and 10 cm long extending from cervix of the uterus.^4,5

The vaginal wall consists of three layers: the epithelial layer, the muscular coat and the tunica adventia.⁶ During the menstrual cycle, the thickness of the vaginal epithelial cell layer changes by approximately 200– 300 Am.⁷ The surface of the vagina is composed of numerous folds, which are often called rugae. The rugae provide distensibility, support and an increased surface area of the vaginal wall.

The vagina has an excellent elasticity because of the presence of smooth elastic fibers in the muscular coat. Loose connective tissue of tunica adventia further increases the elasticity of this organ. The vascular supply consists of an extensive network of arteries that encompass the vagina from multiple sources, including the uterine artery, the pudendal artery, and the middle and inferior hemorrhoidal arteries. The venous system is just as complex. The primary venous drainage occurs via the pudendal veins.The vaginal, uterine, vesical, and recto sigmoid veins from the middle and upper vagina provide drainage to the inferior vena cava, which bypasses the hepatic portal system.⁸ Because of the extensive vascular connections between the vagina and uterus, a “first uterine pass effect” has been hypothesized when hormones are administered vaginally.⁹

Histology:

The vaginal histology is composed of four distinct layers shown in Figure-2.³ Nonsecretory stratified squamous epithelium forms the most superficial layer. The next is the lamina propria, or tunica, made of collagen and elastin, which contains a rich supply of vascular and lymphatic channels. The muscle layer is third, with smooth muscle fibers running in both circular and longitudinal directions. The final layer consists of areolar connective tissue and a large plexus of blood vessels. Vaginal tissue does not contain fat cells, glands, or hair follicles. Secretions from the vaginal wall are transudate in nature and are produced by the engorgement of the vascular plexus that encompasses the vagina.¹⁰

Figure-1: The female reproductive system

Physiology:

The vagina acts as a receptacle during coitus, an outlet for menstrual blood, and a birth canal. The physiology of the vagina is influenced by age, hormone status, pregnancy, and pH changes induced by several factors including semen, menstruation, estrogen status, and bacterial colonization. Reproductive hormones control the thickness of the vaginal epithelium, with E2 thickening the epithelium and hypoestrogenism resulting in atrophy. Vaginal fluids originate from a number of different sources. The fluid is mostly transudate from vaginal and cervical cells.¹¹ The composition of fluids is affected by cyclical changes caused by hormonal influences¹² and the state of arousal. When the vagina is in its sexually unstimulated state, vaginal fluid is primarily composed of plasma transudate from the vaginal wall together with secretions from the cervical and vestibular glands.¹³ On sexual arousal, when the vagina becomes engorged, vasoactive peptides are released locally, which increase arteriolar dilatation and suppress venous return.¹⁴ This has the effect of increasing vaginal lubrication, the extent of which will vary from individual to individual, depending on the hormonal milieu and situational factors.

FACTORS AFFECTING THE VAGINAL: ABSORPTION OF DRUGS:

Overall, vast and multifarious factors and processes are involved in drug absorption from the vaginal route.

Figure-2: Histology of the vaginal mucosa

Physiological factors:

As mentioned above, cyclic changes in thickness of vaginal epithelium, fluid volume and composition, pH and sexual arousal could potentially affect drug release from intravaginal delivery systems. For example, the vaginal absorption of steroids is affected by the thickness of the vaginal epithelium.¹⁵ Vaginal absorption of estrogen has been shown to be higher in postmenopausal women compared to premenopausal women.¹⁶

The volume, viscosity and pH of vaginal fluid may have either negative or positive impact on vaginal drug absorption. The absorption of drug that is poorly water-soluble may be increased when the fluid volume is higher. However, the presence of overly viscous cervical mucus may present a barrier to drug absorption and increased fluid volume may remove the drug from vaginal cavity and subsequently reduce absorption. Since many drugs are weak electrolytes, the pH may change their degree of ionization and affect the absorption of drug. Any change in the vaginal pH may affect the release profiles of pH sensitive drugs from vaginal drug delivery systems.¹⁷

Physicochemical properties of drugs:

Physicochemical properties such as molecular weight, lipophilicity, ionization, surface charge, and chemical nature can influence vaginal drug absorption. For example, the vaginal permeability of straight chain aliphatic alcohols increases in a chain length dependent manner.¹⁸ Similarly, vaginal permeability is much greater to lipohilic steroid such as progesterone and estrogen than to hydrophilic steroid such as hydrocortisone and testosterone.¹⁹

However, it is generally accepted that low molecular weight lipohilic drugs are likely to be absorbed more than large molecular weight lipohilic or hydrophilic drugs. A study on vaginal absorption of polyvinyl alcohol suggested that the molecular weight cut-off above

Vaginal secretions:

The vaginal epithelium is usually considered to be a mucosal surface, although it has no goblet cells and lacks the direct release of mucin.Vaginal discharge is a mixture of several components including transudate through the epithelium, cervical mucus, exfoliating epithelial cells, secretions of the Bartholin’s and Skene’s glands, leukocytes, endometrial and tubal fluids ^23,24. The cervical mucus contains inorganic and organic salts, mucins, proteins, carbohydrates, urea and fatty acids (lactic and acetic acids). Estrogens and sexual stimulation increase vaginal fluid secretion.

Vaginal pH:

The vaginal pH of healthy women of reproductive age is acidic (pH = 4–5); this value is maintained by lactobacilli that convert glycogen from exfoliated epithelial cells into lactic acid. The pH changes with age, stages of menstrual cycle, infections and sexual arousal. Menstrual, cervical and uterine secretions, and semen act as alkalizing agents and increase pH.^{25, 26}

Cyclic changes:

The changes in hormone levels (especially estrogen) during the menstrual cycle lead to alterations in the thickness of the

Table–1.1: Formulation systems experimented for vaginal drug delivery using mucoadhesive polymers

Polymer	Drug	Use	Dosage forms	Ref.
1-Poly (acrylates) Polyacrylic acid-starch mixture Polyacrilic acid-Poloxamer Carbopol 974P-cystein conjugate Polyacrilic acid Carbopol 934P Polycarbophil Carbopol 934P 2- Thiolated  chitosan 3 -Cellulose Derivatives NaCMC-MC-HPMC-HPC HPC-Carbopol NaCMC-PVP-HPMC E50 4- Hyluronic acid and derivatives Hyluronic acid Hyluronic acid-HEC Hyluronic acid 5- Pectin 6- Starch Pregelatinised starch	- - - Econazole Metronidazole Clotrimazole LH-RH Insulin Romestron HCl Acetaminophen Nonoxynol-9 Clotrimazole Acyclovir Bleomycin Hydrochloride Ketoconazole Calcitonin - Doederleins bacillus Ketoconazole Insulin Metronidazole	Vaginal dryness Vaginal dryness Vaginal Immunization Vaginal candidiasis Bacterial vaginosis Vaginal candidiasis Ovulation inducer Hypoglycemic Antiemetic Anti- inflammatory Spermicidal Genito urinary infection Antiviral Cervical carcinoma Antifungal Hypocalcemia Vaginal dryness Normalize bacterial flora Fungistatic Diabitis Mellitus Bacterial Vaginosis	Gel Acidform In-situ gel Gel Tablet In-situ gel Tablet Gel Suppository In-situ liquid Suppository Gel Tablet Tablet Disk Tablet Microsphere Paste ,gel - Douche Microsphere Tablet	47 48,49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 25 67

epithelial cell layer, width of intercellular channels, pH and secretions.²⁷ The variations in enzyme activity (endopeptidases and amino peptidases) with hormonal changes further complicate the problem of achieving consistent drug delivery.

VAGINAL ENZYMES:

The external cell layers and the basal cell layers of the vagina retain most of the enzyme activity ^28,29. Among the enzymes present, proteases are likely to be the prominent barrier for the absorption of intact peptide and protein drugs into the systemic circulation. It has also been reported that the rat vaginal smears have trypsin-like activity, which reaches a maximum level during the proestrus stage.³⁰ Lee ³¹ has suggested that most of the exopeptidases and endopeptidases, which digest the peptides and proteins are present in the vaginal epithelium. The various enkephalins studied in rabbit vaginal epithelium suggest the presence of at least three peptidases viz. amino peptidase, dipeptidyl peptidase and dipeptidyl carboxypeptidase, which play a vital role in metabolism of enkephalins.³² Among these enzymes, amino peptidase were the main enzymes responsible for methionine and leucine enkephalin metabolism, while dipeptidyl carboxypeptidase was the main enzyme for d-ala-met-enkephalin metabolism. Sayani et al. reported the existence of amino peptidases in rabbit nasal, rectal and vaginal extracts.³³

ADVANTAGES OF VAGINAL DRUG ADMINISTRATION:

The advantages of the vaginal route of administration are:

· The avoidance of hepatic first-pass metabolism – this has been reflected by the greater bioavailability of propranolol after vaginal administration compared with oral delivery.³⁴

· A reduction in the incidence and severity of gastrointestinal side effects, as observed during the vaginal delivery of bromocriptine.³⁵

· A reduction in hepatic side effects of steroids used in hormone replacement therapy or contraception.³⁶

· It overcomes the inconvenience caused by pain, tissue damage and probable infection by other parenteral routes.

· The self-insertion and removal of the dosage form is possible.³⁷

· Like some other non-oral drug-delivery methods, vaginal systems (e.g., suppositories, gels, vaginal rings) aim to provide not only a localized effect, but through drug absorption, sustained therapeutic levels compared with the traditional oral route.

· Longer intervals between doses are generally welcomed by patients as a more convenient alternative to daily intake, and this can enhance regimen compliance.

Figure-5: Vaginal dosage forms

Figure-3: C. albicans                   Figure-4:T. Vaginalis

• Vaginal drug delivery can also allow for selective regional therapeutic administration, that is, local drug

· exposure where needed, producing little or no change in exposure throughout the rest of the body.

LIMITATIONS:

In addition to being gender specific, the vaginal route is less preferable in terms of convenience. The permeability of the vagina is strongly influenced by the estrogen concentration, which can influence the pharmacokinetics of drugs designed for systemic action.

COMMON CONDITIONS AFFECTING THE VAGINA³:

The epithelium of the vagina contains glycogen, which is broken down enzymes and bacteria into acids such as lactic acid. This maintains a low vaginal pH which is normally between 4 and 5. Such a pH is desirable because it makes the vagina inhospitable to pathogens. Decreased levels of glycogen in the vagina leads to an increase in vaginal pH and makes the vagina more susceptible to infection. 

Common vaginal infections:

• Vaginitis : Vaginitis means inflammation of the vagina and it creates discharge, odour, irritation or itching. It has many causes which includes infection with Trichomonas vaginalis, dietary deficiency or poor hygiene.

• Bacterial vaginosis: The causal organism often implicated in this infection is Gardnerella vaginalis, although other bacteria present in the vagina also contribute to the cause. The infection arises due to the overgrowth of these bacteria. About 50% of patients will have a thin white discharge with a strong fishy odour.

Candidiasis (Thrush): Is a common yeast infection caused by the organism Candida albicans (Figure-3). The signs and symptoms of thrush are a white cheesy discharge that itches and irritates the vagina.

• Trichomoniasis: Is a sexually - transmitted infection caused by the organism Trichomonas vaginalis (Figure-4). The symptoms in women include vaginal itching as well as a frothy, foul-smelling, greenish-yellow discharge.

VAGINAL DOSAGE FORMS:

Traditionally creams, gels, tablets, capsules, pessaries, foams, ointments, films, tampons, vaginal rings and douches are the most commonly used VDFs ^38,39 is shown in Figure-5. Vaginal formulations are also used in traditional medicine systems, for example, V-gel which is an ayurvedic vaginal formulation for the treatment of candidiasis, trichomoniasis, bacterial and senile vaginitis. In addition, polyherbal microbicides are under development.⁴⁰ Intravaginal systems are also available for controlled drug delivery in animals.⁴¹

NOVEL CONCEPTS IN VAGINAL DRUG DELIVERY:

Several aesthetic and functional qualities must be incorporated into VDFs. The composition of vaginal dosage forms will be the focus of interest in the future novel forms are liposomes, vaginal rings ^42,43 cubic gels ⁴⁴, formulations based on polystyrene⁴⁵ and formulations based on silicone elastomers. One interesting group of auxiliary agents is the mucoadhesive polymers, which are basis of new designed systems.^46,47 Novel vaginal drug delivery system needs to be designed with desirable distribution, bioadhesion, retention and release characteristics.

Mucoadhesive delivery systems:

Bioadhesive vaginal formulations that are capable of delivering the active agent for an extended period at a predictable rate have been developed and studied recently. Conventional vaginal formulations are associated with disadvantages of low retention to the vaginal epithelium, leakage and messiness thereby causing inconvenience to the user. To circumvent these problems, bioadhesive drug delivery systems are being propagated. Many drug delivery systems are based on mucoadhesive polymers (Table-1).⁶⁸

Mucoadhesive delivery systems have been developed both for the local and the systemic administration of drugs through different mucosal routes: buccal ,^69,70 nasal,^71,72 and vaginal.⁷³ The development of a mucoadhesive vaginal dosage form permits the drug to maintain a certain level locally, to extend drug residence time at the administration site, and to reduce dosing frequency and the amount of drug administered.⁷⁴ Therefore, a mucoadhesive vaginal delivery system represents a good alternative to the numerous applications typical of conventional dosage forms.

Vaginal mucoadhesive formulations:

· The intravaginal route has been used to deliver contraceptives as well as anti-infective agents such as antifungal drugs to exert a local effect. Agents targeted for the vaginal route have been formulated into various dosage forms including creams, gels and vaginal tablets.

· Localised application of vaginal formulations enables the spread of these formulations over the target area, which allows an effective therapy.

· Bioadhesive polymers are incorporated into vaginal formulations to aid the adhering of the dosage form to its target site. Polymers also increase the retention of the active drug in the vagina and also optimise the spread of the formulation over the vaginal epithelium.

Sol–gel transition system:

Recently, in situ-gelling liquid dosage forms have been investigated in other fields of topical delivery where a liquid type application is more convenient than other forms.⁷⁵ The liquids applied to topical areas turn into gels as a result of a chemical/ physical change induced by the physiological environments. This transition is induced by a shift in the pH as for cellulose acetate phthalate , the concentration of calcium ions as for Gelrite,⁷⁶ or temperature as for poloxamers.⁷⁷ Poloxamer, a block copolymer made of polyoxyethylene and poly-oxypropylene, is known for its excellent compatibility with other chemicals, and high solubility capacity for various drugs.⁷⁸

Gel-microemulsion:

Microemulsion is thermodynamically stable, isotropically clear dispersions of two immiscible liquids, such as oil and water, stabilized by an interfacial film of surfactant molecules.⁷⁹ The surfactant may be pure, a mixture, or combined with other additives. The microemulsion has an oil in- water (o/w), a water-in-oil (w/o), or a bicontinuous structure. In this kind of microemulsion, (a) the hydrophilic component is dispersed as colloidal droplets in the lipophilic component, (b) the lipophilic component is dispersed as colloidal droplets in the hydrophilic component, or (c) the hydrophilic and the lipophilic component form a microemulsion with bicontinuous structure wherein said components form elongated adjacent channels. The droplet size is typically in the range of 1–100 nm. Microemulsions have great potential as intravaginal/rectal drug delivery vehicles for lipophilic drugs, such as microbicides, steroids, and hormones, because of their high drug solubilization capacity, increased absorption, and improved clinical potency. However, the use of microemulsions for intravaginal or intrarectal administration imposes rigorous demands on the nontoxicity of the formulation and its bioavailability.

Liposomes:

Liposomes, a novel drug delivery system, are widely applied in topical treatment of diseases, especially in dermatology. Phospholipid vesicles enhance the penetration of compounds incorporated and/or encapsulated in them. Topically applied lipid vesicles can be considered as one type of the so called ‘‘percutaneous penetration enhancer’’.⁸⁰ Liposomes have the potential to be applied vaginally, but up to now, only a few papers report the application of liposomes in vaginal therapy.⁸¹

Cubic phase gel:

Glyceryl mono oleate–water system was studied for vaginal delivery of antimuscarinic drugs, propantheline bromide and oxybutynin hydrochloride to treat urinary in incontinence.⁸² The incorporated drug induced the formation of lamellar phase, which upon water uptake formed cubic phase with equilibrium water content of 40% (w/w). The cubic phase would also be retained in the vaginal cavity due to its bioadhesive characteristics. As previously observed by Ericsson et al.,⁸³ both drugs were release by diffusion following square root of time kinetics over a period of 18 h. Thus, a unique application of vaginal drug delivery with in situ formed cubic phase was demon- started, however no in vivo results were presented without which it will be difficult to know if cubic phase would form rapidly in the vaginal environment to sustain drug release for the desired duration.

IN VITRO AND IN VIVO EVALUATION OF VAGINAL FORMULATIONS:

A vaginal formulation must be evaluated by both in vitro and in vivo experimentation for various functional requirements.

In vitro studies include the determination of release and bioadhesive characteristics in addition to various physical and chemical properties of formulations. The release characteristics of a drug from a vaginal formulation can be determined by membrane diffusion studies, microbiological methods⁸⁴ and a vaginal dissolution tester.⁸⁵ Disintegration or dissolution tests, uniformity of content or weight are some of the official tests for pessaries.⁸⁶ The in vitro bioadhesive strength, swelling and stability studies, viscosity of the base in case of passeries are also some of the in vitro evaluation tests.

In vivo studies are carried out for the assessment of efficacy, distribution, spreading and retention of formulations in the vagina. The rate and extent of drug release can be determined by: (1) monitoring quantities of systemically absorbed materials, for example, peptides and proteins,⁸⁷ (2) measuring the pharmacological activity and (3) analysis of vaginal lavage.⁸⁸ Gamma scintigraphy is a valuable method for assessing the distribution, spreading and retention of vaginal formulations in sheep and human females. Colposcopy has also been used for direct in vivo visualization and analysis.

In the process of the development of a vaginal formulation, various animal models such as sheep, rat, rabbit, rhesus monkey, macaque monkey, dog and mice have been used. The rabbit is the recommended model for vaginal irritation studies. There is significant species variability in the anatomy and physiology of the vagina of different animals. Because of interspecies differences, the evaluation of vaginal formulations in human subjects is desirable.

CONCLUSION:

The vaginal route has been traditionally used for the local application of drugs, but is now gaining importance as a possible site for systemic delivery. The safety and efficacy of vaginal administration have been well established through its long and well-studied history. Drugs are easily and rapidly absorbed through the vaginal epithelium into the systemic circulation. Novel developments such as bioadhesive systems and liposomes overcome some of the major limitations of conventional vaginal products. The consideration of women’s opinions on vaginal products is also important for the development of acceptable dosage forms and better compliance. In these review we summarized the continuing interest, and discussed the current research in this field. Nonetheless, future work is required in order to optimize pharmaceutical performance of vaginal dosage forms and allow excellence of clinical outcome.

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Received on 08.02.2009       Modified on 12.05.2009

Accepted on 21.09.2009      © RJPT All right reserved

Research J. Pharm. and Tech.2 (3): July-Sept. 2009,;Page 426-432