Traditionally, vaginally drug delivery was only used for contraceptive agents and also for treatment of local infections. Recently its potential for delivering peptides has been explored since it is vascular, permeable to many drugs5 and drugs absorbed via this route avoid firstpass metabolism.
A major problem with using the vagina as a route for systemic drug delivery is that as the epithelium is highly sensitive to oestradiol and its thickness changes throughout the menstrual cycle, so the extent and rate of drug absorption will also vary. This has been reported for vaginal absorption of steroids10 and vidarabine has been shown to have a 5100 times higher permeability coefficient during the early dioestrus stage than during the oestrus stage in guinea pigs11. Other problems are gender specificity, personal hygiene and the influence of sexual intercourse.
The thick cervical mucosa may aid bioadhesion of drug delivery systems, but it will also act as a diffusional barrier to the drug. The distribution and coverage of materials within the vagina varies considerably with the nature of the delivery system, disintegrating tablets spread the least, whilst solutions, suspensions and foams spread the best. The rupture time of soft jelly capsules containing nonoxynol-9 after its vaginal insertion found to rely on local pH and acidity and level of infection present. Capsules did not rupture when the vaginal pH was alkaline of if the vagina was dry12.
Creams and gels have been the usual methods for delivering contraceptives and drugs for topical delivery. These are generally considered to be messy to apply and uncomfortable when they leak into undergarments; in addition, dosages are imprecise.
An emulsion based system to deliver anti-fungals seems to have great advantages over many current suppository formulations. It is a "multi-phase" liquid, or semi-solid and it does not seep from the vagina. The system is designed to give controlled delivery for 3 or more hours.
Pessaries can be either tablets or suppositories designed for vaginal application. They are usually designed to either dissolve or melt and which utilize a variety of materials. Tablets are often modifications of suppositories used for rectal drug delivery.
Intravaginal inserts consisting of a polyester resin plug or sponge have been tried13, but traumatic manipulation of the sponge, use during menstruation or the puerperium, and prolonged retention of the sponge may increase toxic shock syndrome risk14. The use of osmotic pumps has also been investigated15.
Vaginal ring delivery systems are usually based upon silicone elastomers with an inert inner ring which is coated with another layer of elastomer containing drug. A third, outer rate controlling elastomer layer may be added to prevent an initial burst release which could be observed with newly applied rings.
The rings are approximately 6 cm in diameter with a circular cross-section diameter of 4-7 mm. They are positioned in the vagina around the cervix. For most contraceptive applications, the rings are left in place for 21 days then removed for 7 days to allow menstruation. The main challenge is to deliver enough drug to prevent conception, whilst not producing bleeding irregularities. Since their development in 1970, they have been used to deliver medoxyprogesterone acetate, chlormadinone acetate, norethindrone, norgestrel and levonorgestrel, among others. A low dose oestradiol vaginal ring has been found to be significantly more acceptable than creams for the treatment of urogenital atrophy16. Recently, a contraceptive ring has been developed containing oestrogen and progestin particles dispersed in aqueous polyethylene glycol throughout the ring. It successfully delivers both drugs, at a consistent ratio with approximately zero-order kinetics.
Bioadhesive tablets and microparticles in particular hydrogels such as poly (acrylic acid) and celluloses are currently being utilised for sustained and controlled delivery17. The first bioadhesive tablets contained hydroxypropylcellulose and polyacrylic acid and were used to treat cancerous lesions with bleomycin.
A bioadhesive polycarbophil gel, a lightly cross-linked polyacrylic acid, used to retain moisture and lubricate the vagina has recently been introduced onto the market (Replens, Columbia Laboratories). Clinical assessment of local tissue pH, in postmenopausal women, shows the polycarbophil gel produces a reduction in pH from about 6 to 4 and maintains the acidic pH for about 3-4 days after the last dose. Hydration of the vaginal tissue occurs through an increase in vaginal blood flow as determined by a laser Doppler measurement. In patients with a history of breast cancer who experienced vaginal dryness, vaginal irritation, or dyspareunia, the polycarbophil gel produced a statistically significant reduction in mean vaginal pH and an improvement in vaginal moisture, mucosa secretions, and elasticity scores, as well as significant improvement in vaginal health measures18.
The polycarbophil gel has been shown to remain on vaginal tissue for 3-4 days and hence has the potential to serve as a platform for drug delivery19. It appears to be an effective delivery system for the spermicidal/antiviral agent nonoxynol-9.
Intrauterine devices (IUDs) have been used for many years as a method of contraception. They are first described in 1909 by Richter20 who used a ring made of silkworm gut. In 1930, Graefenberg also used silkworm gut but added an alloy of copper, nickel and zinc21.
As a result of the long history of using IUDs, it is not surprising, therefore that intrauterine delivery has focused upon the use of medicated intrauterine devices. Newer IUDs have been constructed which contain copper or progesterone. Copper containing IUDs release some copper continuously whilst in situ. There was some concern about systemic absorption of copper with long term use, however this was not found to occur. The copper remains mainly in the uterine fluid which is thought to render it unabsorbable and only small quantities are found in the endometrium. Itching or allergic dermatitis, possibly due to absorption of copper into the circulation has been reported some months after insertion of the device. The concept of using conventional IUDs for the long-term delivery of contraceptive steroids is also being researched. The Progestasert IUD delivers progesterone at about 65 pg.day-1 over 1 year. The drug reservoir contains 38 mg of progesterone dispersed in silicone oil surrounded by a release rate controlling mechanism composed of ethylene-vinyl acetate copolymer. The greatest advantage of this system is that it eliminates the need for oestrogen which is required in oral contraceptives. Progesterone's half-life is only a few minutes since the endometrium metabolizes progesterone rapidly and the local delivery allows reduction of the dose and reduction in side effects.
The uterine wall is permeable to negatively charged molecules, high molecular weight drugs and its permeability is not affected by the degree of ionization of the compound22. This observation has lead to speculation that the tight junctions in the uterine wall are more permeable than those in other tissues. The size of the tight junctions in the uterus is between 400 and 700 A, which is about twice that in the intestine or nasal mucosa. Absorption is facilitated by the exceptionally rich blood and lymph supply to the uterus. One possible drawback is that the constant outward flow of cervical secretion can dilute and cause a loss of drug delivered into the uterus.
Intrauterine delivery of insulin, calcitonin and erythrpoietin has been investigated in rats, but no human data is yet available22. It has been suggested that this route may be useful for delivering drugs to treat conditions such as osteoporosis.
Introduction of a foreign body into the uterine cavity results in increased vascular permeability, oedema and stromal infiltration of leucocytes, including neutrophils, mononuclear cells and macrophages. The foreign-body reaction should not be confused with endometritis which is bacterial in origin. Complications which have arisen from IUD use include uterine perforation, abortion of unsuspected pregnancies, uterine cramp and bleeding, menorrhagia and pelvic infections.
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