D3 Drug delivery to the vagina Flashcards
describe the anatomy of the vagina
- S-shaped fibromuscular tube
- 6-10cm in length
- connects the uterus (starting at the cervix) to the external environment
how many layers does the vaginal wall consist of and what are they?
4 layers:
- epithelial layer
- lamina propria
- muscular layer
- tunica adventitia
what happens to the epithelial layer of the vaginal wall during the menstrual cycle?
its thickness changes by approximately 200-300 micrometers
describe and explain an adaptation of the epithelial layer of the vaginal wall
- surface is covered in rugae
- these provide distensibility, support and an increased surface area
other than the thickness of the vaginal epithelium, what else changes during the menstrual cycle?
the quantity and composition of the vaginal fluid
the vagina doesn’t possess a gland itself. where does its fluid arise from?
- cervical secretion
- transudation from the blood vessels
- secretion from the endometrium and fallopian tubes
compare vaginal fluid production of a woman of childbearing age to a postmenopausal woman
- reproductive aged women produce vaginal fluid at a rate of 3-4 g/h
- postmenopausal women’s discharge production is reduced by 50%
what may the human vaginal fluid contain?
enzymes
enzyme inhibitors
proteins
carbohydrates
amino acids
alcohols
aromatic compounds
what can alter drug release patterns from a vaginal drug delivery system and how?
- sexual activity
- the volume and composition of vaginal fluid will be affected which affects drug release pattern
how is the acidic pH of 3.8-4.2 maintained in the vagina?
lactic acid is produced from glycogen from the epithelial cells
what happens to the pH of the vagina during menstruation?
it increases / becomes more alkaline
other than menstruation, what may cause an increase in vaginal pH?
- frequent acts of coitus (sexual intercourse)
- presence of infection
- being postmenopausal
why may vaginal drug delivery be used for local drug action?
- treatments for infections, dryness and irritation
- contraception
- induction of labour
- abortion
- vaginal administration also allows the use of smaller doses with reduced systemic delivery and toxicity (eg. miconazole for the treatment of vaginal infections)
why may vaginal drug delivery be used for systemic drug action?
- dense network of blood vessels
- for patients where oral administration is restricted (eg. severe vomiting)
why is the dense network of blood vessels in the vagina good for systemic drug delivery via the vagina?
- vaginal vein form venous plexuses along the side of the vagina and blood from the vaginal vein moves into the inferior vena cava, avoiding the hepatic portal system
- this means drugs delivered via the intravaginal route may exhibit higher bioavailability compared with the oral route since first-pass metabolism is avoided
what does the vaginal drug delivery route have the potential for?
- preferential delivery to the uterus
- this is known as the ‘first uterine pass effect’
challenges of vaginal drug delivery
- gender specificity
- local irritation must be kept in mind
- cultural sensitivity
- influence of sexual intercourse (and many other factors)
- variability in epithelium thickness, fluid volume and pH can make absorption unpredictable
- leakage of the dosage form is inherent
describe how drugs may be absorbed in systemic delivery via the vagina. detail higher molecular weight drugs and what is avoided
- similar to other mucosal routes of delivery, drugs may be absorbed transcellularly, paracellularly or via receptor-mediated routes
- good vascularisation provides the potential for maintaining a concentration gradient for passive diffusion
- avoids first pass metabolism
- higher molecular weight drugs absorbed well compared to other mucosae
what physiological challenges are there that affect absorption of drugs in the vagina?
- cyclic changes in fluid volume may have either a negative or positive effect on drug absorption
- cyclic changes in pH and changes in pH due to disease state or menopausal status may change the degree of ionisation and alter absorption characteristics of weak electrolyte drugs
- changes in the vaginal epithelium thickness impact absorption
cyclic changes in vaginal fluid volume may have either a negative or positive effect on drug absorption. explain this
- for drugs that display poor water solubility, increases in fluid volume may result in greater absorption (greater volume for API to dissolve in and can only be absorbed if dissolved)
- on the other hand, increased fluid may remove the drug from the vaginal cavity and limit absorption
- overly viscous cervical mucus may present an extra barrier
changes in the vaginal epithelium thickness impact absorption. give an example of a drug group that is affected by this
the vaginal absorption of steroids is decreased by increased thickness of the vaginal epithelium
describe secretion during the menstrual cycle
- mucus secretion varies throughout the menstrual cycle
- in the cervix, secretion is considerably increased by oestrogen
why is secretion increased by oestrogen in the cervix?
to produce a favourable medium for spermatozoa
describe the vaginal secretions during the luteal phase
fluid thin and less acidic
describe the vaginal secretions during ovulation
jelly-like (egg white resemblance)
describe the pH and epithelium thickness at ovulation
- pH is lowest
- epithelium is thickest
other than increased secretion, what else does oestrogen cause in the menstrual cycle?
- cornification of cells
- enlargement of nuclei
- increased deposits of glycogen
what 3 general factors can influence drug dissolution and membrane transport and, therefore, influence drugs’ absorption profiles?
- menstrual cycle
- pregnancy
- age
explain how pregnancy is a factor that can affect drug absorption in the vagina
- the vaginal mucosa becomes thicker during this time
- increased desquamation of the superficial vaginal mucosal cells with increased vaginal discharge can present an extra barrier
explain how age is a factor that can affect drug absorption in the vagina, in particular, pre-puberty
- mucosal epithelium is thin
- vaginal pH is higher (around 5)
explain how age is a factor that can affect drug absorption in the vagina, in particular, post-menopause or after hysterectomy
oestrogen levels drop which means:
- epidermis is much thinner (4 cell layers)
- reduced elasticity and vascularisation
- reduced secretions
- reduced glycogen (used by lactobacillus) - pH can return to pH 7
what are the consequences of the drop in oestrogen in postmenopausal women or women that have had a hysterectomy?
- patients are more prone to dryness, irritation and infection
- even if they’re not sexually active, patients may need lubrication
indications for vaginal therapy
- infections and STDs
- induction of labour and abortion
- spermicide
- prevention of STD transmission
- vaginal dryness in postmenopausal women
- contraceptives
what things may be used to treat infections and STDs via vaginal therapy?
antifungals
antibacterials
antiseptics
acidifying agents
what may be used in vaginal therapy to induce labour or abortion?
prostaglandins
oxytocins
intended use of a bioadhesive vaginal gel containing the therapeutic drug: progesterone
- infertility
intended use of a gel containing the therapeutic drug: metronidazole
- bacterial infection
intended use of a pessary containing the therapeutic drug: dinoprostone
induction of labour
intended use of a veginal ring containing the therapeutic drug: etonogestrel and ethinyl estradiol
contraception
intended use of a vaginal ring containing the therapeutic drug: estradiol
hormone therapy
intended use of an ointment containing the therapeutic drug: tioconazole
anti fungal, vaginal candida infection
intended use of a vaginal cream containing the therapeutic drug: clotrimazole
antifungal
intended use of a tablet containing the therapeutic drug: estradiol
atrophic vaginitis
what considerations in formulation design are there for vaginal drug delivery?
- non-irritating, non-drying
- must not burn or itch
- easy to insert / apply
- should not cause leaking
- should not stain or discolour undergarments
- formulation should not adversely affect sexual activity
- should be discreet enough to be used without knowledge of male partner
- should be compatible with vaginal environment
why should vaginal drug delivery systems by compatible with the vaginal environment?
- changing pH or microflora gives opportunities for pathogens to grow
describe NuvaRing
- vaginal ring containing drug entrapped in a polymer network
- contains etonogestrel and ethinyl estradiol
state examples of polymers that can be used in vaginal rings and why?
- polysiloxanes
- ethylene vinyl acetate copolymers
- both of these are flexible, inert and non-irritating
why do vaginal rings lower the incidence of side effects compared to contraceptive methods with daily intake? what does this help with?
- avoids fluctuations in drug concentration
- lowering the incidence of side effects will increase the acceptability of a product and thus enhance patient compliance
what is ‘Replens’?
- bioadhesive gel based on polycarbophil (an insoluble but water-swellable polymer)
what does ‘Replens’ do?
- binds and rehydrates vaginal epithelium via release of purified water to underlying cells
- forms moist film over vaginal tissue, which remains attached to epithelial cell surfaces
- treats vaginal dryness by lubricating vaginal wall
- increases blood flow and restores acidic pH
what can vaginal dryness be caused by?
menopause
breastfeeding
cancer treatment
diabetes
and other factors
what does the rehydration of the vaginal epithelium mean for those suffering with vaginal dryness?
reduces incidence of vaginal itching, irritation and dyspareunia (genital pain before, during or after sex)
can Replens be used by breast cancer patients? why / why not?
- yes
- it is non-hormonal so can be used
how long does Replens gel last?
3 days
insoluble particles larger than 50 micrometers are likely to cause what in a vaginal formulation?
mechanical irritation after administration
if a fatty base is used in a vaginal formulation, what will happen to lipophilic and hydrophilic drugs?
- lipophilic drug will solubilise in fatty bases
- hydrophilic drug will be suspended
explain what the solubility of a drug in the vehicle and body fluids impacts in a vagina formulation
- solubility of drug in the vehicle and body fluids affects release of the drug from the formulation
- drug tends to reside in the medium which it is more soluble in
other than the solubility of the drug, what else affects the release of drug from a vaginal formulation?
the miscibility of the base with the bodily fluids
what kind of base is preferred for the release of a drug that is highly lipophilic and not hydrophilic?
a water-soluble base is preferred for release
what kind of base is preferred for the release of a drug that is highly hydrophilic and not lipophilic?
a lipid base is preferred for release of hydrophilic drugs
what is a desirable combination for drug release when it comes to vaginal formulations?
- a water-soluble form of a drug dispersed in a lipid base
- this will ensure rapid release of drug and miscibility with vaginal fluids
what vaginal formulation is difficult to optimise with regards to dose?
- fatty pessaries when they contain greater than 10% oily drugs
- hard to maintain the required mechanical strength and melting point (they become very soft)
what are pessaries? how can they be prepared? what do they contain?
- solid, single-dose preparations for vaginal insertion
- can be prepared in various shapes, usually ovoid, with a volume and consistency suitable for insertion into the vagina
- contain one or more active substances dissolved or dispersed in a suitable base that may be soluble or dispersible in water or may melt at body temperature releasing the drug
what should the base be in pessaries?
- non-irritating
- physically and chemically stable
- pharmacologically inert
when is leakage less likely to be a problem with pessaries?
if the viscosity of the vehicle after melting or dispersing is high
describe what happens when drugs from pessaries enter the systemic circulation, when is this an advantage?
- enter without passing through the liver
- advantage if the drug is inactivated by the liver
common bases for pessaries
- hydrophobic waxes, fats, witepsols
- hydrophilic waxes, Macrogols, PEG
- gelatin (hydrophilic), glycerogelatin
what does the choice of pessary base depend on?
drug properties - there is no single ideal suppository base
why is PEG (polyethylene glycol) a versatile pessary base?
various melting points can be achieved by varying the molecular weight:
- low molecular weight (PEG 300 and PEG 600) = liquid at room temperature
- medium molecular weight (1000 Da) = semi-solid
- high molecular weight (>3000 Da) = waxy solid
describe hydrophilic pessary bases
water miscible
mix well with secretions
what characteristics should a pessary base have compared to the drug?
base with opposite characteristics to drug should be used so they partition our easily:
- hydrophilic bases release hydrophobic drugs
- hydrophobic bases release ionised drugs
list some disadvantages of aqueous vehicles in pessaries
- hygroscopic (attracts water leading to a painful sensation)
- there are many incompatible drugs with aqueous vehicles
- drug release may be slow because drugs tend to stay in base
- a water-soluble drug analogue in a hydrophobic base is preferable
what can drugs do to bases in pessaries?
- may reduce melting point and viscosity
- certain drugs can lower the melting point of the base making it necessary to re-optimise the formulation to achieve the melting point close to body temperature
describe the use of surfactants in pessaries
- aid spreading
- may irritate the epithelium
- can create an emulsion system which reduces drug release
describe the use of gelatin in pessaries
- can be a positive or negatively charged molecule depending on pH and gelatin type
- can pose difficulties and must be considered
what is possible if oppositely charged drugs are present in pessaries?
ionic binding of the oppositely charged drugs
state 3 things that lower vaginal pH (make it more acidic)
- high oestrogen levels
- increased glycogen
- lactobacilli presence
list 7 things that increase vaginal pH (make it more alkaline)
- menstruation
- frequent acts of coitus (sex)
- the presence of infection
- age (postmenopausal)
- reduced glycogen
- low oestrogen levels
- hysterectomy
