Routes of administration - Rectal/Vaginal

Question 1

Describe local action for rectal drug delivery.

Answer 1

– For local treatment of pain and itch e.g. haemorrhoids.
– Drugs include antiseptics, local anaesthetics, anti-inflammatory.

Question 2

Describe systemic action of rectal drug delivery.

Answer 2

– Drug should be absorbed through the mucous membranes of the
rectum.
– Most commonly used are anti-inflammatories, analgesics, anti-asthmatics.

Question 3

What are the advantages of the rectal route?

Answer 3

• 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.

Question 4

State the disadvantages of the rectal route.

Answer 4

• 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.

Question 5

Describe rectal drug absorption.

Answer 5

• 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.

Question 6

Describe quantity of rectal fluid (physiological factors of rectal absorption)

Answer 6

• 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

Question 7

Describe the properties of rectal mucus (physiological factors of rectal absorption)

Answer 7

• 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

Question 8

Describe contents of the rectum (physiological factors of rectal absorption)

Answer 8

• 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

Question 9

Describe motility of the rectal wall (physiological factors of rectal absorption)

Answer 9

• Rectal wall muscle activity may influence rate of dissolution within the rectum

Question 10

Describe circulation route (physiological factor of rectal absorption)

Answer 10

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

Question 11

State the factors influencing rectal drug delivery.

Answer 11

• 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

Question 12

State the rectal preparations available.

Answer 12

– Suppositories,
– Foams,
– Solutions,
– Suspensions,
– Emulsions,
– Rectal capsules,
– Rectal tablets,
– Tampons

Question 13

Describe rectal creams, gels and ointments.

Answer 13

• 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.

Question 14

What does the drug include in rectal cream, gels and ointments?

Answer 14

• astringents (zinc oxide)
• protectants and lubricants (cocoa butter, lanolin)
• local anesthetics (pramoxine HCl)
• antipruritic and anti-inflammatory agents(hydrocortisone)

Question 15

What are suppositories formed from?

Answer 15

• Composed of fatty bases (slow-melting) or water soluble bases (dissolving)

Question 16

Describe the base of suppositories.

Answer 16

• 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

Question 17

What are the two types of suppository base?

Answer 17

1. Glyceride-type fatty bases
2. Water-soluble bases

Question 18

What is used for fatty bases?

Answer 18

• 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

Question 19

What are the issues with hydrophilic bases.

Answer 19

• 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

Question 20

Which drugs are incompatible with hydrophilic bases?

Answer 20

Phenols and sulphonamides

Question 21

State the different excipients

Answer 21

• Surface-active agents
• Hygroscopicity reducing agents
• Melting point controlling agents
• Diluents
• Adsorbents
• Lubricants
• Preservatives
• Colouring

Question 22

Why are drugs unsuitable for very hydrophilic/low water-soluble compounds?

Answer 22

• due to limited fluid available
• drug with a high base-to-water partition coefficients means lower tendency to leave the dosage form

Question 23

What base is recommended for drugs?

Answer 23

A readily water-soluble drug dispersed in a fatty base - W/O emulation type suppositories are not recommended

Question 24

Describe vaginal drug delivery.

Answer 24

• 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

Question 25

State the advantages of vaginal administration.

Answer 25

• 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.

Question 26

What are the disadvantages of vaginal administration?

Answer 26

• 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.

Question 27

Describe intravaginal drug absorption.

Answer 27

• Transcellularly via concentration dependent diffusion through the cells
• Paracellularly mediated by tight junctions
• Vesicular or receptor mediated transport

Question 28

What are the two main steps of drug absorption? (intravaginal drug absorption)

Answer 28

1. drug dissolution in vaginal lumen
2. membrane penetration

Question 29

What are the physiological factors influencing intravaginal drug absorption?

Answer 29

• volume, viscosity and pH of vaginal fluid
• the stage of menstrual cycle
• age
• sexual activity

Question 30

What are the drug related factors influencing absorption?

Answer 30

• Drug solubility, ionisation behaviour
• molecular weight
• Release characteristics from the formulation
• Dosage form

Question 31

What are the important characteristics for vaginal routes?

Answer 31

• 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

Question 32

What are semi-solid vaginal formations?

Answer 32

Creams, ointments and gels

Question 33

Describe semi-solid vaginal formulations - gel hydroxypropyl methylcellulose

Answer 33

• 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

Question 34

Describe carbomers (gel)

Answer 34

• Polyacrylic acid
• Adhere strongly to mucosal membranes without causing irritation
• Polyacrylic acid
• Bioadhesive polymer alone served as moisturizer for dry vagina

Question 35

What filler is commonly used for vaginal tablets and what does It do?

Answer 35

• Lactose: converts lactose into lactic acid

Question 36

What are vaginal rings?

Answer 36

Solid formulations that provide a controlled release of drug over a period of time

Question 37

Describe the two drug-release mechanisms for vaginal route.

Answer 37

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.

Question 38

State the problem with vaginal absorption.

Answer 38

• Low retention time - also due to the self-cleansing action of the vaginal tract

Question 39

How can we improve vaginal absorption?

Answer 39

• 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

Question 40

State the advantages of much/bioadhesive polymers.

Answer 40

• 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.