Intravaginal Drug Delivery Systems
Prepared by: Gami Mukesh M.Pharm (P cuetics)
Guided by: Prof. P.K.Patel Dr.Rishad Jivani
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Contents :
Introduction Anatomy and Physiology of vagina Advantages Disadvantages Factors affecting absorption of drugs Vaginal dosage form Different delivery systems Novel concepts Applications Conclusion References
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Introduction :
Vagina is route for administration for contraceptives , antifungals, antimicrobials. It is used for the achievement of local or for systemic absorption. The vaginal wall is very well suited for the absorption of drugs for systemic use. As it contains a vast network of blood vessels.
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 3.5 to 4.9, and rises to almost 7 in the post menopausal female.
The vagina is normally collapsed on itself and can hold between 2-3 g fluid or gel without leakage to the outside. 4
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 itself consists of three layers:
The epithelial layer (lamina and lamina propria), The tunica adventitia (elastic fibers and collagenous fibers) The muscular coat (smooth muscles and elastic fibers)
The vagina is encompassed by a vascular supply of arteries, veins and lymph capillaries, as well as sensory and autonomous nerves.
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Age related changes associated with menopause cause reduction in vaginal size, loss of elasticity, decrease in vascularity and a thinning of the mucosa. This thinning of the vaginal epithelium leads to a substantial increase in permeability of this tissue. These structural changes would influence vaginal absorption, and must be taken into account as a significant factor in vaginal application of drugs, e.g. It was found that the vaginal absorption of insulin was varied by changes in the thickness of the vaginal epithelium.
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Advantages :
Prolonged release. Minimal systemic side effects. An increase in bioavailability. Use of less total drug than an oral dose. First-pass metabolism can be avoided. Self medication is possible.
Disadvantages :
Patient incompliance. Only a few drugs are administered by this route. Variability in drug absorption related with menstrual cycle, menopause and pregnancy, can also limit vaginal drug delivery route usage. Influence with sexual intercourse.
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Ideality of intra-vaginal DDS: component should melt at vaginal temperature i.e. at 36 C. should be non-toxic and non irritating. should not have any meta-stable form. The preparation should have high water number. The preparation should have wetting and emulsifying properties. The preparation should be non-sensitized on vaginal pH (i.e. 3.5-4.9). It should be stable on storage.
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Cont
The preparation should have small interval between melting and solidification point. The preparation should have proper viscosity, so avoid the leakage of preparation from vagina (in case of semisolid dosage form). The preparation should have proper bioadhesive/mucoadhesive properties, so increase the contact time between the membrane and Preparation.
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Absorption of Drugs from Vagina:
Absorption of a wide range of drugs from the vagina has been studied. A detailed review describes studies on the vaginal absorption of steroids, prostaglandins, antimicrobials, antivirals, proteins and nonxynol-9. The drug transport across the vaginal membrane may occur by a number of different mechanisms: a) Diffusion through the cell due to a concentration gradient (transcellular route) b) Vesicular or receptor-mediated transport mechanism, or c) Diffusion between cells through the tight junctions (intercellular route).
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Factors affecting absorption of drugs :
1) Physiological Factors: Factors related to the vaginal physiology include pH of vagina (3.5 to 4.9) Effect of the menstrual cycle on the permeability of the vaginal mucosa thickness of vaginal epithelium Vaginal fluid volume chemical composition of fluid viscosity of fluid surface tension and the pressure exerted on the dosage form by the rectal wall, play a vital role in vaginal drug absorption mucociliary clearance (MCC) vaginal obstruction etc.
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2) Physico-chemical Factors: Factors related to the dosage forms are physicochemical characteristics of the active ingredients pH and mucosal irritancy osmolarity viscosity (solution, gels) density(powder, tablet) concentration and volume administration type of dosage forms particle size of the molecule of drug hydrophilicity or lipophilicity of drug molecule molecular weight of drug molecule chemical nature ionization surface charge, etc. 14
3)Formulation factors: Drug release The effective area of contact Contact time Concentration 4) Factors Related to the Administration Device: It includes the viscosity of the semi-solid dosage forms (creams, gels, etc), size of th solid dosage form (vaginal tablet, etc) adhesive property of the dosage form.
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Improvement of vaginal absorption :
Use of penetration enhancers e.g. PEG. By increasing the contact time between the dosage form and the vaginal membrane by using mucoadhesive polymers e.g. Carbopol. By increasing vaginal blood flow, thereby raising the concentration gradient across the vaginal mucosa. By the use of pro-drugs enhances drug permeability through modification of the hydrophilicity or lipophilicity of the drug
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By the use of chelating agents as a penetration enhancers in vaginal formulations. E.g Vaginal administration of the protein leuprolide is much more effective when enhancers, such as carboxylic acids with chelating ability are coadministered By the use of gel formulation is an extreme case of viscosity enhancement through the use of viscosity enhancers. So the dosing frequency can be decreased to once or twice a day. Example of vaginal gel is metronidazole gel. It is most popular vaginal gel. Mostly hydrogels are used for the intravaginal gel drug delivery system
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Vaginal dosage forms :
In the development of vaginal dosage forms, several considerations should be addressed as:
Maintenance of an optimal pH for vaginal epithelium Ease of application Even distribution of the drug Retention time in the vagina Compatibility with co-administered medicines
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Formulation
Many different types of formulations have been applied vaginally as, tablets, vaginal suppositories or pessaries, foams, douches, sprays, gels, creams and vaginal rings. Creams, gels, sprays and foams are used as vehicles for drugs such as anti-infective or contraceptive agents. Douches are aqueous solutions that are administered into the vagina for cleansing purpose. Vaginal suppositories, also called pessaries, are usually globular, oviform or cone-shaped, and weighing about 5 g each.
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Plastic insertion devices are usually used to hold the vaginal suppository during insertion for proper placement within the vagina. Vaginal suppositories intended for localized effects are employed mainly as contraceptives, antiseptics and antifungals. Design of a liposome delivery system for vaginal administration of acyclovir was investigated, to provide sustained release and improved bioavailability of the encapsulated drug for the local treatment of genital herpes.
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Different Systems for Delivery :
1. Solid Systems-include tablets, capsules and vaginal suppositories. Semisolid Systemscreams,gels,ointments. 2. Liquid Systems-Vaginal douching with liquids containing antimicrobial drugs like povidine-iodine. 3. Vaginal Foams-It is new vaginal drug delivery systems. In fact, foams containing antimicrobials, local anesthetics, and hormones have the potential to gradually substitute several currently available dosage forms, namely creams and ovules.most foam bases are nonirritating.
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4. Medicated Vaginal Tampons-A medicated vaginal tampon, approved as a medical device by the Food and Drug Administration (FDA), is available (Ela Tampon, Rostam, Israel). This bifunctional tampon contains a polymeric delivery system (strips) that absorb menstrual fluid while gradually releasing lactic acid and citric acid. 5. Vaginal Sponges-A vaginal sponge made of soft polyurethane foam (diameter of 5.5 cm and 2.5 cm thick) and saturated with 1 g of nonoxynol - 9 authorized as a spermicide. 6. Vaginal Rings-Nuva ring of estradiol
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7. Vaginal Films-Vaginal films are polymeric drug delivery systems shaped as thin sheets, usually ranging from 220 to 240 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.
Figure 1 Medicated vaginal rings fabricated from silastic 382 medical grade elastomer.
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Several vaginal ring products are currently available, including: Estring - a low-dose estradiol-releasing ring, manufactured from silicone elastomer, for the treatment of vaginal atrophy. Femring - a low-dose estradiol-acetate releasing ring, manufactured from silicone elastomer, for the relief of hot flashes and vaginal atrophy associated with menopause. NuvaRing - a low-dose contraceptive vaginal ring, manufactured from poly(ethylene-co-vinyl acetate), and releasing etonogestrel (a progesterone) ethinylestradiol (an estrogen). NuvaRing is inserted into the vagina and left in place for three weeks, after which it is removed for a 'ringfree' week to allow menstruation to occur. 24
Novel concepts in vaginal drug delivery NVDDS are designed with desirable distribution, bioadhesion, retention and release characteristics. The conventional VDFs, such as suppositories, gels, creams and foams can meet some but not all of these requirements. 1. Bioadhesive delivery systems : Bioadhesive delivery systems Bioadhesive vaginal formulations that are capable of delivering the active agent for an extended period at a predictable rate. Bioadhesive formulations have been found to reduce the conventional treatment time of fungal infections by at least 25%. A bioadhesive formulation might not necessarily contain a therapeutic agent and can be used as a moisturizer for the treatment of dry vagina. 25
2. Phase change polymers such as poloxamers exhibit sol gel transition in response to body temperature, pH and specific ions and they prolong the residence time of the dosage form in the vagina. Formulations based on a thermoplastic graft copolymer have been developed to provide the prolonged release of active ingredients such as nonoxynol-9, progestins, estrogens, peptides and proteins in a vaginal environment
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3. Recently, effervescent vaginal tablets of nystatin were formulated, their antifungal and therapeutic effect was found higher than that of conventional one. Also,the antifungal activity of effervescent vaginal tablets containing clotrimazole was improved as compared to the conventional one. Moreover, bioadhesive effervescent ketoconazole tablets for vaginal delivery was studied. Therefore, effervescent vaginal tablets can consider as one of vaginal medication dosage forms
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4. Microbicides Microbicides are compounds that can be applied inside the vagina or rectum to protect against sexually transmitted infections (STIs) including HIV. They can be formulated as gels, creams, films, or suppositories. Microbicides may or may not have spermicidal activity (contraceptive effect). At present, an effective microbicide is not available. Despite the knowledge of successful HIV prevention strategies condom use, reduction in the number of sexual partners, diagnosis and treatment of sexually transmitted infections HIV continues to spread at an alarming rate especially among women in developing countries.
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microbicides (e.g Carraguard, Cyanoviran, cellulose sulphate, PRO 2000) provide a physical barrier that keeps HIV and other pathogens from reaching the target cells. Another class of microbicides (e.g. Acidform, BufferGel and Lactobacillus crispatus) act by enhancing the natural vaginal defence mechanisms by maintaining an acidic pH, which protects the vagina. There are 23 microbicide products in various stages of clinical development. Carraguard, a product of the Population Council, is in Phase III effectiveness trial in South Africa and Botswana.
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Applications
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
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Marketed Preparation
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Conclusion
Conclusions 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 alternative to behavioural modifications and the use of condoms. Novel developments such as bioadhesive systems and liposomes overcome some of the major limitations of conventional vaginal products.
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References :
1. References Chein.w.yie , Novel Drug Delivery System 2nd edition,p 529-584. 2. Gad cox shayne , Pharmaceutical Manufacturing Handbook , vaginal drug delivery, p 809-857. 3. Arkendu Chatterjee et al. / Journal of Pharmacy Research 2009, 2(4),698-700. 4. Kavita Vermani and Sanjay Garg, PSTT Vol. 3, No. 10 October 2000 5. The scope and potential of vaginal drug delivery 6. UNAIDS, International Working Group on Vaginal Microbicides, Recommendations for the development of microbicides. AIDS 1996, 10:1-6.
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GTU Question
Discuss in brief intravaginal drug delivery system. Discuss the advantages and disadvantages of vaginal drug delivery system and enlist the factors affecting vaginal absorption.
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