Routes of administration - Rectal/Vaginal Flashcards
Describe local action for rectal drug delivery.
– For local treatment of pain and itch e.g. haemorrhoids.
– Drugs include antiseptics, local anaesthetics, anti-inflammatory.
Describe systemic action of rectal drug delivery.
– Drug should be absorbed through the mucous membranes of the
rectum.
– Most commonly used are anti-inflammatories, analgesics, anti-asthmatics.
What are the advantages of the rectal route?
- Absorption from the lower rectum bypasses portal circulation through the
liver -> avoiding first-pass metabolism. - Useful for drugs for which systemic delivery is desired and in the
following scenarios:
1) The patient is unable to swallow.
2) The drug is inactivated in the stomach acid.
3) The drug undergoes high first-pass metabolism.
4) The drug possesses limited absorption in the upper GI tract.
5) The drug may cause irritation to the gastric mucosa.
6) The drug requires high doses and cannot be easily formulated as oral dosage
form.
State the disadvantages of the rectal route.
- Patient acceptability and compliance is poor.
- Upward movement of the dosage form can increase first-pass
metabolism. - Specialist advice on administration is required.
- Generally, drug absorption is slower than oral route.
- May result in local side effects.
- Manufacture of suppositories is more difficult than for other
common dosage forms.
Describe rectal drug absorption.
- Primarily by passive diffusion.
- Generally lower than the oral route -> small surface area.
- Following absorption, drug enters the haemorrhoidal veins.
- Blood in the inferior and middle haemorrhoidal veins drain into the systemic
circulation directly. - Blood from superior haemorrhoidal vein
enters the portal vein, which flows into the liver -> first-pass metabolism occurs.
Describe quantity of rectal fluid (physiological factors of rectal absorption)
- limited amount of fluid spread in a thin layer
- dissolution for poorly water-soluble drugs can be the rate-limiting step in the absorption process
Describe the properties of rectal mucus (physiological factors of rectal absorption)
- pH 7-8 with minimal buffering capacity leads to inability to control the degree of drug ionisation
- Salt form of the drug is used to effectively control ionisation to provide local efficacy and/or systematic absorption
Describe contents of the rectum (physiological factors of rectal absorption)
- Drug will have greater opportunity to get absorbed when the rectum is empty - enema is given before rectal drug administration
- Presence of faeces affects drug dissolution in rectal fluids and subsequent drug absorption
Describe motility of the rectal wall (physiological factors of rectal absorption)
- Rectal wall muscle activity may influence rate of dissolution within the rectum
Describe circulation route (physiological factor of rectal absorption)
If the drug is absorbed from lower hemorrhoidal veins it will directly take the drug to inferior vena cava so the absorption will be rapid and effective
State the factors influencing rectal drug delivery.
- Drug associated: partition coefficient > solubility > degree of ionisation > particle size
- Formulation associated: liquid > solid > semi-solid
- Pathology associated: inflammatory bowel disease > haemorrhoids > gastro-intestinal infection
- Physiology associated: rectal fluid volume and pH > presence of rectal contents > rectal mucous > motility
State the rectal preparations available.
– Suppositories,
– Foams,
– Solutions,
– Suspensions,
– Emulsions,
– Rectal capsules,
– Rectal tablets,
– Tampons
Describe rectal creams, gels and ointments.
- Used for topical application to the perianal area for
insertion within the anal canal. - To treat local conditions of anorectal pruritis, inflammation and the pain and discomfort associated with hemorrhoids.
What does the drug include in rectal cream, gels and ointments?
- astringents (zinc oxide)
- protectants and lubricants (cocoa butter, lanolin)
- local anesthetics (pramoxine HCl)
- antipruritic and anti-inflammatory agents(hydrocortisone)
What are suppositories formed from?
- Composed of fatty bases (slow-melting) or water soluble bases (dissolving)
Describe the base of suppositories.
- Provides the bulk of the dosage form and should be a solid at storage temp but soften at 37 degrees to allow drug to be released
- Should be non-irritant to the rectal mucosa
- Physically and chemically stable over the shelf life
- Compatible with the drug
- High viscosity to minimise leaking
What are the two types of suppository base?
- Glyceride-type fatty bases
- Water-soluble bases
What is used for fatty bases?
- In the past cocoa butter - less commonly used as it has a low softening point and its chemically unstable
- Now semi- or full synthetic fatty acids are used
What are the issues with hydrophilic bases.
- Can draw water from rectal epithelium: results in dehydrations and painful sensation - moistening prior to insertion helps
- Many drugs are incompatible with hydrophilic bases
- Drug release is slower because of its interaction with the base and may tend to remain in the base
Which drugs are incompatible with hydrophilic bases?
Phenols and sulphonamides
State the different excipients
- Surface-active agents
- Hygroscopicity reducing agents
- Melting point controlling agents
- Diluents
- Adsorbents
- Lubricants
- Preservatives
- Colouring
Why are drugs unsuitable for very hydrophilic/low water-soluble compounds?
- due to limited fluid available
- drug with a high base-to-water partition coefficients means lower tendency to leave the dosage form
What base is recommended for drugs?
A readily water-soluble drug dispersed in a fatty base - W/O emulation type suppositories are not recommended
Describe vaginal drug delivery.
- Less common than to the rectal.
- Primarily, use for local effects e.g. local infection but systemic
action is also possible. - Many of the formulation design approaches are similar to rectal
State the advantages of vaginal administration.
- Can be used for local effects, allowing a smaller dose to be used.
- Permits use of prolonged dosing, with extended release.
- Avoid the fluctuations resulting from daily intake.
- Alleviate the inconvenience caused by pain.
- Large permeation area, rich vascularization and relatively low enzymatic
activity. - Non-invasive dosage form.
- Important route for locally active drugs.
What are the disadvantages of vaginal administration?
- Gender specific.
- Systemic treatment is not widely popular.
- Menstruation cycle and hormonal variations affect systemic
absorption. - Vaginal fluid volume variations affect local drug absorption.
- The acidic pH of vagina may enhance degradation of some drugs.
- Often require the use of special applicators.
Describe intravaginal drug absorption.
- Transcellularly via concentration dependent diffusion through the cells
- Paracellularly mediated by tight junctions
- Vesicular or receptor mediated transport
What are the two main steps of drug absorption? (intravaginal drug absorption)
- drug dissolution in vaginal lumen
- membrane penetration
What are the physiological factors influencing intravaginal drug absorption?
- volume, viscosity and pH of vaginal fluid
- the stage of menstrual cycle
- age
- sexual activity
What are the drug related factors influencing absorption?
- Drug solubility, ionisation behaviour
- molecular weight
- Release characteristics from the formulation
- Dosage form
What are the important characteristics for vaginal routes?
- Long acting, easy to apply with infrequent dosing.
- Free from local irritation.
- Colourless, odourless and resistant to leakage.
- Should not affect sexual activity.
- Should not cause staining or discolouring of under garments
What are semi-solid vaginal formations?
Creams, ointments and gels
Describe semi-solid vaginal formulations - gel hydroxypropyl methylcellulose
- a semi-synthetic polymer derived from cellulose
- A nonionic water-soluble polymer
- Its swelling and dissolution properties make it control the drug release
- -OH groups facilitate binding and adherence to mucosal membranes
Describe carbomers (gel)
- Polyacrylic acid
- Adhere strongly to mucosal membranes without causing irritation
- Polyacrylic acid
- Bioadhesive polymer alone served as moisturizer for dry vagina
What filler is commonly used for vaginal tablets and what does It do?
- Lactose: converts lactose into lactic acid
What are vaginal rings?
Solid formulations that provide a controlled release of drug over a period of time
Describe the two drug-release mechanisms for vaginal route.
Melting
– Designed to melt at body temp releasing the drug and the molten mass disperses in the available space.
* Disintegration
– Solid dosage forms release drugs by dissolution or disintegration, followed by dispersion of the contents in the vaginal fluids.
– Semi-solid dosage form release drugs by diffusion or dispersion of contents from formulation to vaginal fluids.
State the problem with vaginal absorption.
- Low retention time - also due to the self-cleansing action of the vaginal tract
How can we improve vaginal absorption?
- Mucoadhesive agents - permit a close contact of drug with the vaginal mucosal surface
- Nanotechnology - Potentiate the action of most active constituents, reducing the required dosage and
side effects and improving the resulting activity - Penetration enhancers - Currently, the most preferred penetration enhancers include non-ionic surface
active agents - Solubility modifiers - Addition of solubilizing agents and co-solvents
State the advantages of much/bioadhesive polymers.
- Flexibility – controls the extent of the interpenetration between polymers and
mucosal/epithelial surface. - Hydrophilicity – polymers are mostly hydrophilic which are able to form strong
adhesive bonds with mucosal membranes. - Hydrogen bond – hydrogen bonds between polymer functional groups (OH and
COOH) and mucosal surfaces facilitate muco-adhesion. Hydrogen binding between
polymer chains help assure sustained release of the drug by diffusion within the
polymer. - High molecular weight – provide more available binding sites, slows down drug
diffusion.
