Vaginal drug delivery

What is the anatomy?

Approx. 8-10cm in length (cervix to vestibule)

Low pH (pH4-5 derived from organic acids) therefore slows/stops microbial growth

Anatomy enables secure retention of delivery system (tablet/pessaries)

Vast network of blood vessels = blood supply direct to the systemic circulation

Disadvantages of vaginal drug delivery

gender specificity

local irritation

compliance

limited number of products

variable absorption

Benefits of vaginal drug delivery

Avoidance of first pass metabolism as drug enters systemically from blood vessels

Less pain and tissue damage cf. parenteral

Less systemic side effects

General, but particularly applicable to steroid hormones:

• Controlled release device (longer dosage intervals)

• Easy insertion / removal of MR device

• Low doses needed (10% oral dose – as no 1st pass) which can reduce side effects

• Local effects (to treat infection)

How does menopause affect absorption of drugs from vagina?

1. thinner vaginal epithelial

   but still reduced SA and permeability for drug absorption

2. decreased vascularity

   decreased systemic absorption

3. reduced vaginal secretions (of mucus)

   affects dissolution

4. increased pH

   affects drug ionisation, solubility and stability

due to reduced mitosis in the basal epithelial layers and a decline in small blood vessels the vaginal epithelium becomes extremely thin, leading to a considerable

increase in permeability of this tissue

What factors cause variable drug absorption?

surface area of vaginal rugae

epithelial barrier

mucus

enzymatic activity

arterial supply and venous drainage

absorption route

How does surface area affect absorption variability?

High Surface area (vaginal rugae)

Length and width changes post-menopausal

How does epithelial barrier affect absorption variability?

thickness (200-300mm) depends on age

• thinner pre-pubertal and post-menopausal

and cycle

• thicker at mid-cycle (follicular phase) due to changes in oestrogen

non-cornified stratified squamous epithelial cells

pores in barrier can appear mid-cycle which increase absorption

How does mucus affect absorption variability?

pH varies between 4-5 (from decomposition of glycogen)

pH increases post-menopausal (to 7) - important as affects drug ionisation

Viscosity varies with

1. age

2. stage of cycle

   increased viscosity pre-ovulation

   decreased viscosity post-ovulation

3. during sexual arousal (also affects pH)

Changes in viscosity and pH will both significantly affect release and absorption of drugs.

How does enzymatic activity affect absorption variability?

May degrade drugs

e.g. polypeptides - but enzyme activity is still lower than GI tract

Affected by cycle

Activity of certain enzymes vary pre- and post-menopause

• e.g. beta-glucuronidase, acid phosphatase, alkaline phosphatase and esterase

How does arterial supply and venous drainage affect absorption variability?

Vagina abundant with arteries, blood vessels and lymphatic vessels as well as sensory and autonomous nerves

Extensive absorption of drug into systemic circulation

NO FIRST PASS METABOLISM = very good for oestrogens delivery as 95% is metabolised in the liver through GI absorption route

How does absorption route affect absorption variability?

Transport can be paracellular and transcellular

Hydrophilic compounds favour the paracellular route

How does the menstrual cycle affect drug absorption?

Follicular phase (after menstruation): the epithelium is thick and cohesive
due to the proliferation of the cells in the basal layers
stimulated by oestrogen
There is a parallel increase in the number of desmosomes.
The number of intercellular junctions also increase
so narrow intercellular channels
so the epithelium more cohesive.

 

Luteal phase (end of cycle): the epithelium is thin, loose and porous with increased permeability
desquamation of the superficial epithelial layer,
the epithelium becomes loose and porous,
loosening intercellular grooves
and widening the intercellular channels. 
There is increased possibility of absorption of even high MW hydrophilic drugs during this phase

How are physico-chemical properties considered in formulation?

Solubility (low mucus volume), dissolution rate, charge, molecular weight and aggregation all important factors

low volume of mucus = decreased drug release

permeability increased for non-ionised lipophilic drugs and steroids

How are contact area and time considered in formulation?

depends on size of dosage form and spreading

bio adhesion can prolong contact time with epithelium for prolonged absorption

How are steroids absorbed from vagina? local/systemic? pros/cons?

Increased bioavailability as steroids (e.g. oestrogen) have extensive first-pass metabolism following oral route

Local or systemic

Used for urogenital atrophy (reduction in oestrogen), contraception, premenstrual syndrome, post-natal depression, HRT

Oestrogens

• Oestrone – rapidly and efficiently absorbed

• 17-b-oestradiol – rapidly absorbed (extent of absorption > oral)

Progestogens

• Progesterone – rapidly absorbed (extent of absorption 50-100% more than IM absorption)

• Medroxyprogesterone acetate – rapidly absorbed, used in CR products

• Norgestrel – rapidly absorbed

Steroids usually formulated as creams or hydrogels

What other drugs are absorbed from vagina? examples?

Prostaglandins – labour induction, pregnancy termination

 Antimicrobials

• Metronidazole

• Sulphanilamide for Candida albicans

• Some imidazoles e.g. econazole, miconazole, clotrimazole for Candida

 

 Potentially: proteins / peptides

• Insulin

• TSH/ Parathyroid hormone

• Chemical enhancement required for good absorption across barrier

Describe pessary formulation

prepared by moulding or direct compression

microbial contamination must be minimised (more than rectal)

bases containing gelatin must be heated at 100ºC for 1 hour

base must melt/dissolve at/slightly below 37ºC

glycerinated gelatin bases preferred as well tolerated

PEG’s can be irritant

fatty bases not widely used

auxillary application device = counselling required

Describe vaginal tablets formulation

similar to uncoated tablets but larger and heavier

major constituent is lactose

• converted to lactic acid in situ

• further reduces vaginal pH

manufactured in the same way as tablets

must disintegrate in situ

• use of disintegrants as low fluid volume

Describe vaginal capsules formulation

soft gelatin capsules

not common

Describe microspheres formulation

Potential for peptide/protein delivery (e.g. calcitonin)

Microspheres can be made bio adhesive with polymers

used for non-hormonal treatment for vaginal atrophy

Improved retention

E.g. Replens used to increase moisture

• bio adhesive polycarbohil gel

Describe intravaginal rings formulation

Flexible, doughnut-shaped silicon drug delivery system that can be inserted into the vagina

Slowly releases hormones that are absorbed into the bloodstream

Controlled release of hormonal contraceptives, spermicidals, HRT

One year combined ring (progestin and ethynylestradiol) or progestin-only ring for lactating women

Inserted for three weeks, then removed for one week to allow menstruation, the ring works like other hormonal methods by preventing the ovaries from releasing an egg each month

Releases hormone(s) at a constant rate

the daily dose required is lower than that contained in oral contraceptives

so decreased long- and short-term side effects as no peaks/troughs

the ring can deliver agents that are inactive when used orally

What are the different types of drug dispersion in rings?

Matrix = contraception dispersed through whole ring

Reservoir = drug must first permeate through the biocompatible polymer before exiting = stops burst release

Sandwich = core is filled with polymer for quicker release of drug into body by diffusion

Describe semi-solid formulation, uses

o/w creams, gels, ointments

anti-infectives, estrogenic hormones, spermicidals

Describe aerosol foam formulation, uses

water miscible o/w emulsions

estrogenic and contraceptive agents

Describe douches formulation

for delivery of solutions

Describe contraceptive devices formulation

IUD’s containing progesterone (Progestasert®) – lasts 1 year

contraceptive sponge (impregnated with nonoxynol-9) – lasts 1 day

What is an annovera vaginal system? uses? pros?

Contraceptive vaginal ring (CVR)

Ring body: composed of soft silicone elastomer

Core technology: One core with Segesterone Acetate (SA) only and one with SA and ethinyl estradiol (EE)

Releases 150 µg of SA, 15 µg EE daily

A single ring can be used for up to 12 months (13 cycles).

Use: a woman inserts the CVR for 3 weeks in and then 1 week out, for 13 consecutive cycles

No physician intervention is required for insertion or removal

First long acting method of BC that is completely under a woman’s control

No refrigeration required

What is a future potential of vaginal drug delivery in HIV infections?

Vaginal gel containing antiviral agents have been shown to be effect in reducing HIV infections