D3. Drug delivery to the vagina Flashcards
structure of the vagina?
-S-shaped fibromuscular tube 6-10cm in length.
-Connects the uterus (starting at the cervix) to the external environment
ONE NOTE
the vaginal wall consists of what four layers?
the epithelial layer, lamina propria, the muscular layer and the tunica adventitia
ONE NOTE
How does the thickness of the vaginal epithelial cell layer change during the menstrual cycle?
During the menstrual cycle, the thickness of the vaginal epithelial cell layer changes by approximately 200–300 μm.
vagina surface?
Surface is covered in rugae which provide distensibility, support, and an increased surface area.
where does fluid arise in vagina?
The vagina does not possess a gland; fluid arises from cervical secretion, transudation from the blood vessels, and secretion from the endometrium and fallopian tubes
how does the vaginal fluid change?
-Women of reproductive age produce fluid at a rate of 3–4 g/ h, while the discharge produced by postmenopausal women is reduced by 50 %.
-the quantity and composition of the vaginal fluid also changes throughout the menstrual cycle
what can the vaginal fluid contain?
The human vaginal fluid may contain enzymes, enzyme inhibitors, proteins, carbohydrates, amino acids, alcohols, and aromatic compounds.
how can sexual activity affect vaginal drug delivery?
Sexual activity can alter drug release patterns from a vaginal drug delivery system since this will affect the volume and composition of fluid.
Lactobacillus acidophilus is present in the vagina…
Lactic acid is produced from glycogen from the epithelial cells, maintaining the pH between 3.8 and 4.2.
when can pH of vaginal fluid change?
-During menstruation, the pH of vaginal fluid increases.
-Frequent acts of coitus may also cause an increase in the vaginal pH.
-pH tends to rise in presence of local infection and in the post-menopausal stage.
vaginal drug delivery can be used for?
both local and systemic effects but the use of this route for local effects is much more common
Describe drug delivery used for local action
-Treatments for infections, dryness and irritation, for contraception and induction of labour and abortion.
-Vaginal administration allows the use of smaller doses with reduced systemic delivery and toxicity, for example, in the case of miconazole for the treatment of vaginal infections.
Describe vaginal drug delivery in systemic action
-Dense network of blood vessels. 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…
-Drugs delivered via the intravaginal route may exhibit higher bioavailability compared with the oral route since first-pass metabolism is avoided.
-Suitable for patients where oral administration is restricted e.g. in the case of severe vomiting.
-The vaginal route has the potential for preferential delivery to the uterus, known as the ‘first uterine pass effect’
-It is possible to self-administer and remove the dosage form.
challenges of vaginal drug delivery?
-Gender specificity
-Local irritation
-Cultural sensitivity
-Influence of sexual intercourse (and many other factors)
-Variability in epithelium thickness, fluid volume, and pH
-Leakage of the dosage form is inherent
Describe vaginal systemic delivery
-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
cons of vaginal systemic delivery?
can only be used by 50% of population therefore development is for female related conditions only
Absorption in vaginal systemic delivery?
Hormones, prostaglandins given vaginally have demonstrated absorption. Greater plasma concentration achieved with oestrogen by vaginal than oral delivery
Cyclic changes in fluid volume may have either a negative or positive effect on drug absorption…
-For drugs that display poor water solubility, increases in fluid volume may result in greater absorption.
-On the other hand, increase fluid may remove the drug from the vaginal cavity and limit absorption.
-Overly viscous cervical mucus may present an extra barrier.
how can changes in pH affect 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.
how do changes in vaginal epithelium thickness impact drug absorption?
Changes in the vaginal epithelium thickness impact absorption. For example, the vaginal absorption of steroids is decreased by increase thickness
how does the menstrual cycle pose challenges to drug absorption?
-Mucus secretion varies throughout the menstrual cycle.
-In the cervix, secretion is considerably increased by oestrogen (to produce a favourable medium for spermatozoa).
-Oestrogen causes cornification of cells and enlargement of nuclei, with increased deposits of glycogen.
-Luteal phase: fluid thin and less acidic. Ovulation: Jelly-like (resembling egg-whites)
-At ovulation pH is lowest and epithelium thickest
-Vaginal pH increases during menstruation.
-Use of oral contraceptives eliminates cyclic variations
how does pregnancy pose a challenge for drug absorption?
-The vaginal mucosa becomes thicker.
-Increased desquamation of the superficial vaginal mucosal cells with increased vaginal discharge
how does age pose a challenge for drug absorption?
Pre-puberty:
Mucosal epithelium thin.
Vaginal pH ~ 5.
Post- menopause & after hysterectomy:Oestrogen deficiency means…
Epidermis much thinner ( 4 cell layers).
Reduced elasticity and vascularisation.
Reduced secretions.
Reduced glycogen – pH can return to pH 7.
Consequences are: patients are more prone to dryness, irritation, infection (Menopausal Atrophic Vaginitis). Even if not sexually active, patients may need lubrication.
vaginal therapy for infections and STDs?
Antibacterials, antifungals, antiseptics, acidifying agents
vaginal therapy for induction of labour and abortion?
Prostaglandins, oxytocins
other indications for vaginal therapy?
-Spermicide
-Prevention of STD transmission e.g. Nonoxinol-9
-Vaginal dryness
-Contraceptives
what dosage forms available?
one note
considerations in formulation design?
-Must be non-irritant and non-drying, must not burn, must not itch.
-Should be easy to insert or apply.
-Should not cause leaking.
-Should not stain or discolour under garments.
-The formulation should not adversely affect sexual activity.
-Women should be able to use it without the knowledge of a male partner i.e. should be discreet and comfortable.
-Should be compatible with the vaginal environment as changing pH or microflora gives opportunities for pathogens to grow (conversely, simply restoring the acidic pH can resolve some infections).
what is the contraceptive vaginal ring?
Vaginal rings are flexible circular systems containing the drug entrapped in a polymer network e.g. NuvaRing® containing etonogestrel and ethinyl estradiol.
what polymers are used in the contraceptive vaginal ring?
Polymers such as polysiloxanes and ethylene vinyl acetate copolymers used; both of these materials are flexible, inert, and non-irritating.
Describe side effects from contraceptive vaginal ring?
-Avoiding the fluctuations resulting from daily intake may lower the incidence of side effects
-Lowering the incidence of side effects will increase the acceptability of a product and thus enhance patient compliance
systemic level drug profiles?
one note
what is replens?
Bioadhesive gel based on polycarbophil. The polymer is insoluble, but water swellable
action of Replens?
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 surface.
what can vaginal dryness be caused by?
Vaginal dryness can be caused by menopause, breastfeeding, cancer treatment, diabetes, and other causes.
What does replens do?
-Hydration of epithelium lubricates the vaginal wall.
-Reduces the incidence of vaginal itching, irritation, and dyspareunia
-Increases blood flow.
-Acidic pH is restored.
-Non-hormonal so can be used for breast cancer patients.
-Last for 3 days.
how does drug particle size affect performance?
insoluble particles larger than 50 μm are likely to cause mechanical irritation after administration
how does solubility of a drug affect its performance?
a lipophilic drug will solubilize in fatty bases, while a hydrophilic drug will be suspended. The solubility of a drug in the vehicle and body fluids affects release from the formulation. Because of partitioning, the drug tends to reside in the medium which it is more soluble. The miscibility of a base with body fluids affects release. If the drug is highly lipophilic and poorly hydrophilic, a water-soluble base is preferred (for release). Similarly, if the drug is more hydrophilic, a lipid base will be preferred (for release)…
what is a desirable combination?
A desirable combination is a water-soluble form of drug, dispersed in lipidic base, which will ensure rapid release of drug and miscibility with vaginal fluids.
with regards to dose, why are fatty pessaries difficult to optimize?
With regards to dose, fatty pessaries are difficult to optimize when they contain greater than 10% of oily drugs, while maintaining the required mechanical strength and the melting point…
what are vaginal Suppositories (Pessaries) ?
Pessaries are solid, single-dose preparations for vaginal insertion
How are pessaries prepared?
Can be prepared in various shapes, usually ovoid, with a volume and consistency suitable or insertion into the vagina. Typically, they weigh around one gram.
What do vaginal Suppositories (Pessaries) contain?
-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.
-Base should be non-irritating, physically and chemically stable, and pharmacologically inert.
Leakage in vaginal Suppositories (Pessaries) ?
Leakage is less likely to be problematic if the viscosity of the vehicle after melting or dispersing is high..
livers effect on vaginal Suppositories (Pessaries)?
The drug enters the systemic circulation without passing through the liver; this is an advantage if the drug is inactivated by the liver.
Tablet type pessaries?
Tablet type pessaries are available, and the composition is similar to an immediate release tablet.
common bases in suppository bases?
-Hydrophobic waxes, fats, witepsols
- Hydrophilic Waxes Macrogols, PEG
-Gelatin (Hydrophilic) Glycerogelatin
hydrophilic bases?
Hydrophilic bases are water miscible and mix with secretions.
The choice of base depends on drug properties – there is no single ideal suppository base
PEG?
PEG is versatile because various melting points can be achieved by varying the molecular weight.
Low molecular weight (PEG 300 and PEG 600) = liquid at room temperature
Molecular weight circa. 1000 Da = semisolid
Molecular weight > 3000 Da = waxy solid
Challenges with drug release from suppository bases, don’t want drug retained in base- use a base with opposite characteristics to drug, so that drug partitions out easily :
-Hydrophobic bases release ionised drugs.
-Hydrophilic bases release hydrophobic drugs
Challenges with drug release from suppository bases- Aqueous vehicles have some disadvantages:
-Hygroscopic – attracts water leading to painful sensation
- There are many incompatible drugs.
- Drug release may be slow because drugs tend to stay in base.
- A water-soluble drug analogue in a hydrophobic base is preferable
other challenges with drug release from suppository bases?
-Drugs may reduce melting point and viscosity. Certain drugs can lower the melting point of the base, making it necessary to re-optimize the formulation to achieve the melting point close to body temperature.
-Surfactants will aid spreading but may irritate.
-Can also create an emulsion system which reduces drug release.
-Gelatin can be a + or – charged molecule depending on pH and gelatin type.
-Ionic binding of oppositely charged drugs possible.
