Unit 2 - Vaginal delivery Flashcards
Describe the vaginas anatomy
- approximately 8-10 cm in length (cervix to vestibule)
- low pH (pH 4-5 derived from organic acids) therefore retards microbial growth
- anatomy enables secure retention of delivery system
- vast network of blood vessels
- blood supply direct to the systemic circulation
What are the drawbacks of using the vagina for drug delivery?
- gender specificity
- local irritation
- compliance
- limited number of products
- variable absorption
What are the benefits of vaginal drug delivery?
- avoidance of first pass metabolism
- controlled release (longer dosage intervals)
- easy insertion / removal of MR device
- low doses needed (10% of oral dose - no first pass metabolism)
- local effects (to treat infection
- less pain and tissue damage (compared with parenteral)
- less systemic side effects
What factors allow for absorption of drugs from vagina?
- surface area
- epithelial barrier
- mucus
- enzymatic activity
- arterial supply and venous drainage
- absorption route
How does the surface area of the vagina change over time?
Length and width changes post-menopausal
Describe the epithelial barrier of the vagina?
Thickness (200 - 300um) depends on age
- thinner pre-pubertal and post-menopausal
Thickness depends on cycle
- thicker at mid-cycle due to changes in oestrogen
Non-cornified stratified squamous epithelial cells
Pores in barrier can appear mid-cycle
Describe the mucus of the vagina?
- pH varies between 4 and 5 (from decomposition of glycogen)
- increases post-menopausal
- viscosity varies with age, stage of cycle (increases pre-ovulation, decreases post-ovulation) and during sexual arousal (also affects pH)
- changes in viscosity and pH will both significantly affect release and absorption of drugs
How does enzyme activity in the vagina affect drug delivery?
May degrade drugs - e.g. polypeptides but enzyme activity lower than GI tract Affected by cycle Activity of certain enzymes varies pre- and post-menopause - beta-glucuronidase - acid phosphatase - alkaline phosphatase - esterase
Describe the blood vessels around the vagina
Vagina abundant with arteries, blood vessels and lymphatic vessels as well as sensory and autonomic nerves
NO FIRST PASS METABOLISM
How are drugs absorbed from the vagina?
Paracellular - hydrophilic compounds favour this route
But transport can be Transcellular too.
What are the two main phases in the menstrual cycle in humans?
Follicular phase
Luteal phase
Describe the follicular phase of the menstrual cycle
- increase in the epithelial thickness due to the proliferation of the cells in the basal layers, stimulated by oestrogen
- parallel increase in the number of desmosomes
- number of intercellular junctions also increase with narrow intercellular channels, rendering the epithelium more cohesive
- the epithelium is thick and cohesive
Describe the luteal phase of the menstrual cycle
Characterised by desquamation of the superficial epithelial layer, with the epithelium becoming loose and porous
- loosening of the intercellular grooves and widening of the intercellular channels
- epithelium is thin, loose and porous with increased permeability
- increased possibility of absorption of even high molecular weight hydrophilic drugs during this phase
What effect does the menopause have on the permeability of the epithelial tissue?
Due to reduced mitosis in the basal epithelial layers and a decline in some blood vessels the vaginal epithelium becomes extremely thin, leading to a considerable increase in permeability of this tissue
What physico-chemical properties need to be considered when designing a vaginal drug delivery system?
- solubility
- dissolution rate
- charge
- molecular weight
- aggregation
- low volume of mucus
- permeability increased for lipophilic drugs and steroids
Why is drug release the rate limiting step in vaginal drug delivery?
Low volume of mucus
What factors affects contact area and time in vaginal drug delivery?
- depends on size of dosage form and spreading
- bioadhesion can prolong contact time
What are the advantages of administering steroids vaginally rather than orally?
Increased bioavailability as extensive first-pass metabolism following oral route
What are prostaglandins used for when administering them vaginally?
- labour induction
- pregnancy termination
Which antimicrobials can be administered vaginally?
Metronidazole Sulphanilamide - Candida albicans Some imidazoles e.g. econazole, miconazole, clotrimazole - Candida
Which proteins or peptides could potentially be delivered vaginally?
- insulin
- thyroid stimulating hormone / parathyroid hormone
Chemical enhancement required
What indications are steroids administered vaginally?
- urogenital atrophy
- contraception
- premenstrual syndrome
- post-natal depression
- hormone replacement therapy
Give two examples of oestrogens that can be delivered vaginally?
- oestrone (rapidly and efficiently absorbed)
- 17-B-oestradiol (rapidly absorbed; extent of absorption > oral)
Give examples of progestogens that can be delivered vaginally?
- progesterone (rapidly absorbed; extent of absorption 50 - 100% compared with IM)
- medroxyprogesterone acetate (rapidly absorbed, used in CR products)
- norgestrel (rapidly absorbed)
What types of vaginal dosage forms are there?
- pessary
- vaginal tablet
- vaginal capsule
- microsphere
- intravaginal rings
- semi-solids
- aerosol foams
- douches
- contraceptive devices
Describe pessaries
- prepared by moulding or direct compression
- microbial contamination must be minimised
- bases containing gelatin must be heated at 100C for 1 hour
- base must melt/dissolve at, or slightly below, 37C
- glycerinated gelatin bases preferred as well tolerated; PEGs can be irritant; fatty bases not widely used
- auxillary application device
Describe vaginal tablets
- similar to uncoated tablets but larger and heavier
- major constituent is lactose (converted to lactic acid in situ)
- manufactured in the same way as tablets
- must disintegrate in situ (use of disintegrants)
What are vaginal capsules made from?
Soft gelatin
Describe microspheres for vaginal drug delivery
- potential of peptide/protein delivery (calcitonin)
- can be made bioadhesive with polymers
- improved retention
- Replens: bioadhesive polycarbohill gel
What is an intravaginal ring?
Flexible, doughnut shaped silicon drug delivery system that can be inserted into the vagina where it slowly releases hormones that are absorbed into the bloodstream
What is the function of an intravaginal ring?
For controlled release of hormonal contraceptives, spermicidals or HRT
Which two hormones are used in the combined intravaginal ring?
- progestin
- ethynylestradiol
Which hormone is used in an intravaginal ring for lactating women?
- progestin
How is the intravaginal ring used?
- inserted for three weeks
- removed for one week to allow for menstruation
The ring works like other hormonal methods by preventing the ovaries from releasing an egg each month
What are the advantages of using an intravaginal ring?
- the ring releases hormone(s) at a constant rate
- the daily dose required is lower than that in oral contraceptives
- decreased long and short term side effects
- the ring can deliver agents that are inactive when used orally
Give three examples of semi-solids that can be administered vaginally
- o/w creams
- gels
- ointments
Give some uses of semi-solids that are administered vaginally
- anti-infectives
- estrogenic hormones
- spermicidals
Give an example of an aerosol foam that can be administered vaginally
Water miscible o/w emulsions
Give two uses of aerosol foams that can be administered vaginally
Estrogenic and contraceptive agents
What is the function of a douche?
Delivery of solutions
Give two examples of contraceptive devices that can be administered vaginally
- IUDs (containing progesterone (Progestasert) - lasts 1 year
- contraceptive sponge (impregnated with nonoxylnol-9) - lasts 1 day
