Vaginal Absorption

Introduction :

The vagina, in addition to being a genital organ with functions related to conception it serves as a potential route for drug administration. Mainly used for local action in the vaginal region.

It has the potential of delivering drugs for systemic effects and uterine targeting

Anatomy of Vagina

human vagina is often described as slightly S-shaped fibromuscular tubes between 6-10 cm long and 2 cm wide extending from cervix of the uterus to the vestibule

The vaginal wall consists of three layers: the epithelial layer, the muscular coat and the tunica adventia

Normal pH of the vagina in premenopausal women ranges from 4 to 5, and rises to almost 7 in the post menopausal female.

Vaginal secretions

The vaginal secretion is a mixture of several components such as proteins/peptides, glycoproteins, lactic acid, acetic acid, glycerol, glycogen and ions such as Na++, Ca++ and Cl-

Types of vaginal dosage forms

vaginal semisolids: Creams Gels

Ointments

Suppositories vaginal liquids : Solutions Suspensions vaginal aerosols vaginal controlled release formulations Vaginal rings

Advantages of vaginal drug delivery

Vaginal administration permits use of prolonged dosing, with continuous release of medicaments

Avoiding the fluctuations resulting from daily intake may also lower the incidence of side effects.

Alleviating the inconvenience caused by pain, tissue damage and probable infection, it serves as a better alternative to parenteral route.

Vaginal route can be used for local as well as systemic effect

Advantages of vaginal drug delivery

avoidance of first pass effect avoidance of enzymatic deactivation in GIT large permeation area ,rich vascularization

and relatively low enzymatic activity. Non-invasive self-insertion and removal of the dosage

form like vaginal films, gel, pessaries, etc.

Disadvantages of vaginal drug delivery

cultural sensitivity personal hygiene gender specificity local irritation influence of sexual intercourse Menstrual cycle-associated vaginal changes Sometimes leakage of drugs from vagina and

wetting of under garments

Absorption mechanism

Drugs administered via the vaginal route are absorbed

Transcellularly via concentration dependent diffusion through the cells.

Paracellularly mediated by tight junctions. Vesicular or receptor mediated transport.

• Absorption of drugs from vaginal delivery systems occurs in two main steps:

1. drug dissolution in vaginal lumen 2. membrane penetration.

Factors affecting the vaginal absorption of drugs

1- Physiological factors cyclic changes affect in thickness of vaginal

epithelium fluid volume, viscosity and composition pH sexual arousal

Effect of pH changes on absorption

pH may change degree of ionization of drug and affect their the absorption

Factors affecting the vaginal absorption of drugs

2- Physicochemical properties of drugs Molecular weight lipophilicity ionization surface charge chemical nature

Ex : low molecular weight lipophilic drugs are likely to be absorbed more than large molecular weight lipophilic or hydrophilic drugs.

3- Vaginal enzymes

proteases are likely to be the prominent barrier for the absorption of intact peptide and protein drugs into the systemic circulation

The human genital tract has lower enzymatic activity leading to less degradation of protein and peptide drugs in the vagina than the gastrointestinal tract

sheep > guinea pig > rabbit ≥ human ≥ rat

Strategies to improve vaginal absorption

A- Penetration Enhancers Penetration enhancers are capable of

promoting absorption and penetration of drug through the vaginal mucosa by decreasing the penetration barrier

Currently, the most preferred penetration enhancers include non-ionic surface active agents, bile salts, benzalkonium chloride, hyaluronic acid , polyethylene glycol.

Strategies to improve vaginal absorption

B- Solubility Modifiers:The poor solubility of drugs in 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.

The most commonly used solubilizing agents include citric acid, sorbitan, tween 80, polyoxyethylene and sodium meta-phosphate.

Strategies to improve vaginal absorption

C- Mucoadhesive agents: - Mucoadhesive agents permit a close contact of

formulation with the vaginal mucosal surface by promoting adherence .

- These include polycarbophil, hyaluronic acid, chitosan, sodium alginate, tragacanth, carbomer, acacia,

- Some of these polymers may possess site-specific bioadhesive properties. For example, xanthan gum and sodium alginate show site-specific bioadhesive properties in a simulated vaginal environment

Strategies to improve vaginal absorption

D- Nanotechnological Strategies nanosystems often potentiate the action of most active

constituents, reducing the required dosage and side effects and improving the resulting activity

which use nanoparticles ranging from1 to 100 nm in size.Disadvantage- expensive, and difficulties in some processes.- depending on the size of the anonoparticles produced,

they may be easily inhaled, resulting in dangerous lung diseases

nanotechnological processes

liposomes (LIPs) microemulsions (MEs) hydrogel (HYD) polymeric nanoparticles(PNs) solid lipid nanoparticles (SLNs)

Viginal dosage forms:

Vaginal creams , ointments and gels Vaginal Suppositories Vaginal liquids Vaginal Aerosols sustained/controlled-release drug delivery Vaginal Films Vaginal tablets

Vaginal semisolids:

Vaginal creams , ointments and gels Topical vaginal preparations are used for mainly

conditions like infections, vaginitis, conditions of endometrial atrophy & for contraceptive purposes too.

The vaginal topical preparations are mainly applied by special applicators.

Drugs like anti-infectives,hormones contraceptives

Vaginal Suppositories

Solid suppositories are the most common dosage forms.

the oval shape is more preferred.

The most commonly used base for vaginal suppositories consist of combination of the various molecular weight polyethylene glycols & surfactants & preservatives are added in them.

They are buffered to acidic pH about 4.5.

Vaginal tablets

Tablets are designed to rapidly disintegrate in the vaginal cavity to release the active drug.

The normal vaginal tablets contain similar components as like the conventional oral tablets.

Mucoadhesive polymers are sometimes used in vaginal tablet formulations to overcome the drawback of normal vaginal tablet

Vaginal liquids

The vaginal douches and solutions are also available in market. They are used for cleansing of vagina.

The unit dose douches are prepared which are mixed with warm water and applied by inserters in vagina.

Vaginal Aerosols

Aerosols foams containing estrogenic substances & contraceptive agents are available.

The aerosol container has plunger which apply the foam in the vaginal cavity.

Marketed preparations like povidone-iodine vaginal foam

Vaginal route for sustained/controlled-release drug delivery

are circular ring type drug delivery devices designed to release drug in a controlled fashion after insertion in the vagina.

Contraceptive drugs

IN SITU GELLING

Mucoadhesive formulations prepared using temperature-sensitive and mucoadhesive polymers, poloxamer and polycarbophil.

The water insoluble polymers swells in vagina and form bioadhesive gel on vaginal layer.

This allows continuous release up to 25 to 50 hrs.

Vaginal Films

Vaginal films are polymeric drug delivery systems shaped as thin sheets, usually ranging from 220 to 240 μ m in thickness.

These systems are often square (approximately 5 cm × 5 cm), colorless, and soft, presenting a homogenous surface.

Vaginal films are produced with polymers such as polyacrylates, polyethylene glycol, polyvinyl alcohol, and cellulose derivatives.

ex. VCF vaginal contraceptive films

References:1. The vagina as a route for systemic drug delivery

/Alamdar Hussain, Fakhrul Ahsan /Journal of Controlled Release 103 (2005) 301–313

2. vaginal Mucosa – A Promising Site for Drug Therapy /Vinita Vijay Kale1* and Alok Ubgade2 / British Journal of pharmaceutical Research3(4): 983-1000, 2013

3. Vaginal drug delivery systems: /. DOBARIA1*, R. MASHRU1 AND N. H. VADIA2 / East and Central African Journal of Pharmaceutical Sciences Vol. 10 (2007) 3-13

4. The scope and potential of vaginal drug delivery/Kavita Vermani and Sanjay Garg /3, No. 10 October 2000

5. Nanotechnological Strategies for Vaginal Administration of Drugs / Journal of Biomedical Nanotechnology · September 2015