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Vaginal Drug Delivery
By
Puria Rafsanjani Nejad
Communication Problems
A Quick Note
Intro
Localized vs. Systematic
Until recently it was limited to localized treatment
 Anti-infectives
 Estrogens
for after menopause
decline in circulating estrogen->reduction in vaginal blood flow->drying of
vaginal tissue, rise of pH, discomfort
A very low dose is recommended
 targeted drug delivery to the uterus
systemic delivery of drugs, via the mucous membranes
 estrogens, progesterones and prostaglandins (currently)
 delivery of therapeutic peptides and proteins (exploring)
Structure Of The Vagina
vaginal tract
 ~2 cm in width ,anterior wall 8 cm in length, posterior wall 11 cm in length
 can hold between 2–3 g of fluid or gel without leakage
vaginal wall constitutes
 Epithelium: an elaborate system of channels
between the cells
changing width as the hormone levels change
for movement of leukocytes and large proteins
 lamina propria: dense connective tissue
collagen fibers, fibroblasts, macrophages,
mast cells, lymphocytes, Langerhans cells …
blood supply (entry to systemic circulation)
there is also Lymph drainage
Physiological Factors
Cyclical changes in the vaginal epithelium
 estrogens, progesterones, luteinizing hormone
(LH) and follicle-stimulating hormone (FSH)
aging, biphasic sexual cycling and pregnancy
 3 outer parts of 5 part of Ep are highly affected
Follicular phase
 estrogen stimulates mitosis, increase in epithelial
thickness, intercellular channels are narrow
epithelium is thick, tight and cohesive
Luted phase
 shedding occurs on the superficial epithelial layer
epithelium becomes loose and porous
widening of the intercellular channels
Postmenopause
Pregnancy
The vaginal fluids and pH
 Fluids from different sources exist
 It contains antimicrobial substances
 Bioavailability: effective dissolution, the degree of deactivation
 Fluctuations in vaginal bioavailability due to physiological cyclical changes
Ph:
 Controlled primarily by lactic acid or by carbohydrates (vaginal microflora)
 Varies between 4.0 and 5.0 (highest during menstruation)
 During pregnancy (3.8 and 4.4, increase in cellular glycogen)
 Affects degree of ionization of drug
 Lower enzymatic than GI track
Transport routes
 Paracellular and transcellular routes
 For hydrophilic drugs: pore pathway (influenced by the physiological
changes in the thickness of the vaginal epithelium)
thinning of the epithelium and a pore like widening of the intercellular
channels
 Insulin administration (effect of blood sugar level with respect to cyclic
activity)
 Penicillin (high blood levels, sufficient to be, only at permeable stages)
Carrier-mediated transport”
 No receptor-mediated or bulk-fluid mechanisms have been reported
Drug Formulation
Desirable attributes :
 No adverse reactions, such as tissue irritation
 Ease of application
 Even distribution of the drug throughout the vagina, rather than being
concentrated in one spot
 Retention of the drug in the vagina, even when the patient is standing and
walking
 Absence of an offensive odor
 Compatibility with other forms of medication and contraception
 Minimal interference in sexual activity
Pros and Cons
Pros:
 Relatively large surface area (60 cm2)
 Rich blood supply (rapid absorption, sink conditions)
 Low metabolic activity (proteins) , Reduced first-pass effects
 Permeable, relatively easy to administer, Prolonged retention
 When the oral route is unfeasible (patient’s issues or drug’s)
 Potential to achieve zero-order controlled release
Pros and Cons
Cons:
 high molecular weight drugs: limited only to potent drug molecules (ng/mL)
 Adverse effects (low amount of fluids)
 Cyclical changes (fluctuations in bioavailability)
 Leakage
 Not applicable for everyone
Samples
estrogens and progesterones
Oral limitations:
 low oral bioavailability, lack of efficacy, high levels of metabolites (1st pass,
CNS toxicity)
Used:
 as contraceptives, in hormone replacement therapy (HRT), in IVF programs
 Estring (1997, 6.5–9.5 μg/24 h, estradiol, over a 3-month period)
Other samples
 Prostaglandin E2, 10 mg dinoprostone, cervical ripening in the induction of
labor, cross-linked polymer hydrogel, swells in the vaginal fluid, 0.3 mg/h
 Misoprostol, termination of second-trimester pregnancy, 100–200 μg every
12 h, easier to administer, more bioavailability than oral
Newer Technologies
Peptide Delivery
 Large molecular weight peptides, including insulin, TSH, calcitonin, GnRH
analogs, and various antigens have all demonstrated systemic absorption
via the vaginal route
 GnRH analogs: greater elevation of serum LH and FSH levels than oral
Insulin:
 Rapid dose-related changes in the plasma glucose and insulin
 In rats and rabbits and sheep! Clinical trials yet to come
 Cyclic absorption can even be dangerous
Penetration enhancers may be used to promote peptide absorption across
the vaginal epithelium (toxicological issues should be paid attention to)
Other samples
Antivirals and vaccines
 Antiviral vaginal gel, reduce the risk of HIV transmission, Dextrin sulfate,
blocking viral entry into host cells, Phase I
 Antiviral vaginal devices, Nonoxynol-9 approved spermicide with strong
antiviral activity, silicone elastomer matrix system (M ∞ t1/2)
Vaginal mucosal vaccines
 Antigens are taken up by antigen-presenting cells (APCs) in the vaginal
membrane; the APCs move through the lymphatic vessels to the genital
lymph node, where an immune response is initiated.
 Treatment of recurrent urinary tract infections
(non-human primates in 2005, phase 2 clinical trial 2007)
Vaginal drug delivery systems:
A Review of Current Status,
N. DOBARIA1 et al, East and Central
African Journal of Pharmaceutical
Sciences, 2007