Vaginal Drug Delievery systems, - A writeup

1. AADS Suraj C.
Vaginal Drug Delivery System
Prepared by: Salwa
Re-Edited by: Suraj C.
• The vagina, unlike other systems like buccal or gastrointestinal, is highly dynamic with respect to its physiology, which renders the vaginal environment an uncertainty factor with respect to
 retention of vaginal dosage forms,
 absorption of drugs, their metabolism and their elimination from the vagina.
• The vaginal cavity is an important area of the reproductive tract and acts as a favorable site for drug administration
 due to avoidance of first pass effect,
 large permeation area,
 rich vascularization and
 relatively low enzymatic activity.
• The vaginal cavity has a potential for
 Non-invasive,
 controlled transmucosal delivery of both local and systemic therapeutically active compounds .
Anatomy & Physiology of Vagina
• The vagina in the adult premenopausal female is approximately 7-8 cm in length and 2 cm wide, shrinking in the postmenopausal female to approximately 4.5-6 cm in length and 1-1.5 cm in width.
• Normal pH of the vagina in premenopausal women ranges from 4 to 5, and rises to almost 7 in the post-menopausal female.
• The vagina is characterized by an exceptional elasticity and the surface area of the vagina is increased by numerous folds by microridges covering the epithelium cell surface.
• The vaginal wall consists of three layers:
 the epithelial layer
 the muscular coat
 the tunica adventia.
• 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. 1

2. AADS Suraj C.
• The network of blood vessels that supply blood to the vagina include a plexus of arteries extending from the internal iliac artery, uterine, middle rectal and internal prudential arteries.
• Drugs absorbed from the vagina does not undergo first-pass metabolism because blood leaving the vagina enters the peripheral circulation via a rich venous plexus, which empties primarily into the internal iliac veins.
• The vaginal epithelium has a high activity of enzymes that could potentially affect short- and long-term stability of intra-vaginal delivery systems and devices.
Absorption mechanism
• Like other mucosal routes of administration, drugs administered via the vaginal route are absorbed :
 transcellularly via concentration dependent diffusion through the cells,
 paracellularly mediated by tight junctions and
 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.
Vaginal ointments, Creams and gels 2

3. AADS Suraj C.
• Ointments, creams and gels are used for topical delivery of contraceptives and antibacterial drugs.
• These vaginal dosage forms are messy to apply, uncomfortable and sometimes embarrassing when they leak into the undergarments.
• They may not provide an exact dose because of non-uniform distribution and leakage.
• The desirable properties of vaginally administered ointments, cream or gel against microbicides are acceptability and feasibility.
• They must be easy to use, non-toxic and non-irritating to the mucus membrane.
• Hydrogel shave been developed for controlled release of drug.
• These hydrogels, when placed in an aqueous environment, swell and retain large volumes of water in their swollen structure and release drug in a controlled fashion.
• Hydrogels are hydrophilic polymers that have been cross linked by means of covalent bonds.
Suppositories and vaginal tablets
• A large number of vaginal medications are available in the form of tablets or suppositories.
• These vaginal formulations are designed to melt in the vaginal cavity and release the drug for several hours.
• Suppository systems are now most commonly used to administer drugs for cervical ripening prior to childbirth and local delivery of drugs.
• Drugs that are administered as suppository include dehydroepi-androsterone sulfate for ripening effect on the uterine cervix, miconazole for vaginal candiasis and progesterone for hormonal replacement therapy.
• Vaginal tablets may contain binders, disintegrant and other excipients that are used to prepare conventional oral tablets.
• It has the advantage of ease of manufacture and insertion.
• Drugs that are administered as vaginal tablets include itraconazole, clotrimazole and prostaglandins.
Vaginal rings
• Vaginal rings are circular ring type drug delivery devices designed to release the drug in a controlled fashion after insertion into the vagina.
• Advantages of vaginal ring are that it is user controlled, does not interfere with caution, does not require a daily intake of pills and allows continuous delivery of low dose Steroids. 3

4. AADS Suraj C.
• They are approximately 5.5 cm diameter with a circular cross section diameter of 4–9 mm and the ring are inserted in the vagina.
• In simple vaginal rings, drug is homogeneously dispersed within a Polymeric ring.
• Drug at the surface of the ring is released faster than drug in the inner layer of the ring.
• Sometimes, drugs in the outermost layer provide an initial burst release.
• To obtain a constant release of a drug from vaginal ring, sandwich or reservoir type rings has been developed.
• Sandwich type devices consist of a narrow drug containing layer located below the surface of the ring and positioned between non-medicated central core and a non-medicated outer band.
• In reservoir type rings, drugs are dispersed in a centralized core, which is then encapsulated by a drug free layer of polymer.
• In a single ring, it is possible to have several cores of different drugs and thereby allowing administration of several drugs from the same device.
• The rate of drug release can be modified by changing the core diameter or thickness of the non- medicated coating.
• The material for making vaginal ring is usually polymeric in nature.
• Commonly used polymer are poly(dimethylsiloxane) or silicone devices, although other elastomeric polymers such as ethylene vinyl acetate and styrene bartender block copolymer have been tested in recent years.
• The addition of vinyl acetate units in the polyethylene provides the following advantages:
 increased flexibility,
 improved optical properties,
 greater adhesion,
 increased impact and puncture resistance.
• The clinical acceptability of rings made of ethylene vinyl acetate is very high.
BENEFITS OF VAGINAL DRUG ADMINISTRATION
1. In the vagina, arteries and veins form a dense network which provides a rich blood supply and consequently the vagina is well suited for the rapid and steady uptake of hormones.
2. Drugs administered via the vagina are not subject to the first-pass effect and gastrointestinal interferences with absorption of medication are avoided. 4

5. AADS Suraj C.
3. Vaginal administration often minimizes side effects associated with the oral route. An example is the administration of bromocriptine vaginally in treatment of hyperprolactinemia in women who suffer from nausea and vomiting following oral administration.
Bioadhesive delivery systems
• 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.
• Bioadhesive vaginal delivery systems have several advantages when compared to conventional dosage forms:
 Firstly, the bioadhesive vaginal formulations are readily localized in the region of application thus improving the bioavailability of drugs. Greater bioavailability of insulin, calcitonin, progesterone and estrogen was observed from bioadhesive vaginal formulations.
 Secondly, these delivery systems provide intimate contact of the formulation with the underlying absorption surface. This allows for modification of tissue permeability for absorption of macromolecules such as proteins and peptides.
 Thirdly, it permits continuous and prolonged residence of the dosage form at the site of application. Lastly, it reduces side effects due to avoidance of repeated administration of the drug.
• The main advantages of the bioadhesive systems over the existing solid and semi-solid preparations are as follows :
 Low production costs,
 Avoidance of aqueous or organic solvents,
 Ease of self-administration with no need to use applicators,
 Gel-like consistency in the activated state,
 Avoidance of local irritation phenomena,
 Rapid bioadhesion, prolonged residence time in the vaginal cavity even in absence of physiological secretions associated with a controlled drug delivery, extended dosing interval,
 Improved chemical and physical stability.
Mucoadhesive polymers
1. Mucoadhesion is usually obtained by using both synthetic and natural bioadhesive polymers.
2. The most commonly used mucoadhesive polymers that are capable of forming hydrogels are synthetic polyacrylates, polycarbophil, chitosan, cellulose derivatives (hydroxyethycellulose, 5

6. AADS Suraj C.
hydroxypropylcellulose and hydroxypropylmethylcellulose), hyaluronic acid derivatives, pectin, tragacanth, carrageenan and sodium alginate. Recently, thyolated polymers have been explored as new mucoadhesive molecules.
3. The bioadhesive properties are ensured by polyacrylic acid-based polymers, known as Carbomers.
4. A number of different commercially available Carbomer grades may be used. They vary in their molecular weight, degree of crosslinking structure or residual components.
5. Among the polyacrylic acid polymers, polycarbophil, a polyacrylic acid cross-linked with divinylglycol, is preferred. This water insoluble polymer has an apparent pKa of approximately 4.5 and picks up 60 - 100 times its weight in water.
Classification of Mucoadhesive vaginal drug delivery systems
 Mucoadhesive Gels
 Mucoadhesive Tablets
 Mucoadhesive Films
 Emulsion type mucoadhesive systems
 Pessaries or Suppositories
 Bioadhesive Vaginal Foams
1. Mucoadhesive Vaginal Gels
• The most widely used mucoadhesive vaginal drug delivery systems are gels.
• In particular, for drugs designed for gynaecological use, a bioadhesive gel able to ensure prolonged contact between the active ingredient and the vaginal mucosa, and gradual release of that ingredient over time, provides the ideal solution in terms of efficacy and compliance by patients.
• Among vaginal formulations, gels are easy to manufacture, comfortable, and have the ability to spread onto the surface of mucous and to achieve an intimate contact with vaginal mucosa.
• Moreover, because of their high water content and their rheological properties, they present the further advantage of a hydrating and lubricating action, which is particularly useful in pathological situations characterized by dryness of the vaginal mucosa.
• The employment of mucoadhesive polymers can improve the time of contact with the mucosa, delaying the loss of the formulation and prolonging the effect.
2. Mucoadhesive Vaginal Tablets
• Mucoadhesive polymers such as polycarbophil, cellulose ethers, chitosan and polyvinylpyrrolidine were used for the preparation of tablet formulations. 6

7. AADS Suraj C.
• The manufacturing process of vaginal bioadhesive controlled release matrix tablets consists of the preparation of a matrix mixture comprising the pharmaceutically acceptable excipients.
• The release mechanism is based on drug diffusion through the swollen polymers and progressive erosion /dissolution of the gel matrix.
3. Mucoadhesive Vaginal Films
• Another mucoadhesive solid dosage form is film.
• The film is made from a precursor composition containing a water-soluble or water-swellable thermoplastic polymer, preferably HPC and/or PEO and a bioadhesive polymer.
o The film can also contain a therapeutic agent, preservative, buffering agent, antioxidant, super- disintegrant or absorbent, flavorant, colorant, water-insoluble polymer, organic acid, surfactant, film modifier and/or cross-linking agent.
• A mucoadhesive film formulation which is suitable for delivery of therapeutic agents to vaginal mucosa has been developed.
• Film composition for delivery of pharmacologically effective agents topically to vaginal mucosa comprises polymer which is hydrophilic, hydrophobic or a mixture of both.
• The polymer is selected from the group consisting of hydroxypropyl methylcellulose, gelatin, alginic acid, alginic acid sodium salt, pectin, collagen, poloxamer, carbopol, microcrystalline cellulose, polyacrylic acid, polyethylene glycol and polypropylene glycol.
o The film has a controllable rate of gelling, swelling and degradation and is preformed into a device or is applied as a coating to the surface of a more complex drug delivery system.
• pH-responsive film for intravaginal delivery of a beneficial agent has been prepared for the intravaginal administration of prophylactic and therapeutic agents.
• The invention provides a pH-responsive, biocompatible for intravaginal administration of a beneficial agent, comprising a biocompatible, hydrophilic polymer that is positively charged at a low pH and assumes an electronically neutral form at a higher pH; an effective amount of beneficial agent and optionally at least one film-forming binder.
• The responsive film may also include other additives such as plasticizers, sustained-release polymers, antioxidants and antimicrobial agents.
4. Emulsion Type Mucoadhesive Vaginal Systems
• Emulsion type bioadhesive drug delivery systems offer different approach for vaginal administration.
• The vaginal drug delivery system comprises an essentially pH neutral emulsion having globules with two phases, an internal water-soluble phase and an external water-insoluble phase or film. 7

8. AADS Suraj C.
• The water-soluble interior phase contains a therapeutically active drug or drugs.
• The particle size of the globules are ranging about 0.1 - 100 microns.
5. Vaginal Suppositories
• Suppositories can be easily applied to the vagina.
• Hydrated bioadhesive vaginal suppository formulations are formed of one or more hydrophilic polymers, such as sodium carboxymethyl cellulose, polyacrylic acids or polyacrylates, a pessary or suppository base, water (30 % by weight of the formulation) and an active ingredient.
6. Bioadhesive vaginal foams:
• Advantages of foams in intravaginal administration:
 Ready-to-use formulations with inexpensive disposable applicators.
 Excellent coverage of the intravaginal surface.
 Can incorporate bioadhesives to reduce dosing frequency.
 Easy intravaginal insertion.
 Accurate dosing (using metered dose valves).
 No dripping after treatment.
 Non-irritating excipients
• They can be formulated as:
 Oil-in-water emulsion foam (cream-like).
 Water-in-oil emulsion foam (occlusive-cream-like).
 Petrolatum based foam (ointment-like).
 Waterless hydrophilic foam (hydrophilic-ointment like).
 Oily foam (ointment-like, with or without water).
 Suspension foam.
Advantages of vaginal drug delivery system
• This route is the most preferred and targeted goal of new drugs and dosage forms, vaginal administration can be used as an alternative route in certain cases of therapeutic importance:
1. In cases of nausea and vomiting, the act of taking medication orally may induce emesis so that the drug is vomited before it is absorbed.
2. Irritation to the stomach and small intestine associated with certain drugs can be avoided.
3. Hepatic first pass elimination of high clearance drugs may be avoided partially.
4. Contact with digestive fluid is avoided, thereby preventing enzymatic degradation of some drugs.
5. Drug delivery can be stopped by removing the dosage form e.g. Vaginal rings. 8

9. AADS Suraj C.
6. Drugs, which traditionally are only given parental, may be administered vaginally either as such or in combination with absorption-promoting additives.
7. Rapid drug absorption and quick onset of action can be achieved.
8. Convenient for the patients, especially for those on long-term therapy, when compared with parenteral medication.
9. The vaginal bioavailability of smaller drug molecules is good.
10. The bioavailability of larger drug molecules can be improved by means of absorption enhancer or other approach.
11. Self-medication is possible.
Limitations of Vaginal Drug Delivery Systems
1. Some of the drugs are sensitive at the vaginal pH.
2. Local irritation of some drugs.
3. Influence of sexual intercourses.
4. Gender specificity.
5. Personal hygiene.
6. Sometimes leakage of drugs from vagina and wetting of under garments.
Applications of Vaginal Drug Delivery System
 This route of drug administration is useful for vaginal immunization.
 Multi-cycle administration of vaginal contraceptive rings.
 Effective route for the treatment of HIV infection.
 Effective route for the treatment of local fungal infection.
 Effective for the delivery of hormones.
Evaluation of VDDS
In-vitro and in-vivo evaluation of vaginal formulations:
1. In-vitro studies include:
Release:
1. By membrane diffusion studies
2. Microbiological methods and
3. A vaginal dissolution tester
The bioadhesive strength:
 By measuring tensile strength or shear stress required to separate the formulation from the vaginal mucosa. 9

10. AADS Suraj C.
 Disintegration or dissolution tests, uniformity of content or weight are some of the official tests.
2. In-vivo studies include:
• The bioavailability can be determined by :
 Monitoring quantities of systemically absorbed materials, e.g., peptides and proteins.
 Measuring the pharmacological activity and
 Analysis of vaginal lavage.
• Gamma scintigraphy is a valuable method assessing the distribution, spreading and retention of vaginal formulations.
• Colposcopy has also been used for direct in vivo visualization and analysis.
• (Colposcopy is a medical diagnostic procedure to examine an illuminated, magnified view of the cervix and the tissues of the vagina and vulva.)
Conclusion
• Bioadhesive vaginal formulations are likely to emerge as new vaginal formulations for both local and systemic delivery.
• With the increasing number of novel polymers each year, the challenge remains to design appropriate bioadhesive vaginal formulations.
• Vaginal rings have shown significant promise and are well accepted within female population.
• Several combination vaginal contraceptive rings have been found to provide excellent contraceptive efficacy with little risk of adverse effects.
• 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.
• For the prevention of STDs, AIDS and conception, the use of vaginal products might provide a better path.
• Novel developments such as bioadhesive systems and liposomes overcome some of the major limitations of conventional vaginal products.
REFERENCES
 Y. W. Chien. Novel drug delivery systems, 2012.
 Tapash K. Ghosh, Bhaskara R. Jasti. Theory and practice of contemporary pharmaceutics, 2010.
 N. Dobaria, R. Mashru, N. H. Vadia. Vaginal drug delivery systems: A Review of Current Status.
 Acarturk F. Mucoadhesive Vaginal Drug Delivery Systems.
 Ashok.V, R.Manoj Kumar, D. Murali and Arkendu Chatterjee. A Review on Vaginal Route as a Systemic Drug Delivery. 10