Road Map 4 Rectal and Vaginal Drug Delivery

Question 1

Proctitis

Answer 1

inflammation of the rectum

Question 2

Retention enema

Answer 2

rectal solution/suspension enema intended for local absorption; may have polymers to increase viscosity and contact time

Question 3

Evacuation enemas

Answer 3

rectal solution/suspension intended to create osmotic or irritant effects that result in the evacuation of lower bowel contents

Question 4

Insert

Answer 4

solid dosage forms that are inserted into a naturally occurring (nonsurgical) body cavity other than the mouth or rectum (i.e. vaginal dosage forms…suppositories/tablets/capsules)

Question 5

Intrauterine device (IUDs)

Answer 5

small T-shaped devices inserted into the uterus by a healthcare professional
i. Two types: hormonal (levonogestrel), copper
ii. Inserted using a long slender, plastic tube through the cervix
iii. Can remain in place for up to 10 years

Question 6

Reasons for choosing rectal route

Answer 6

i. GI disorder, N/V, unconsciousness, the very young, the very old
ii. Drugs not suited for oral use
1. Large first pass metabolism
2. Drugs that degrade in the stomach
3. Drug is a GI irritant (NSAIDs)
iii. Large doses of medications can be given
iv. When local treatment is required

Question 7

Limitations of rectal route

Answer 7

i. Patient acceptance
ii. Liquids difficult to retain at the absorption site
iii. Absorption is slow with a large amount of inter- and intra- subject variability
iv. Long term use of rectal drug delivery has been associated with proctitis

Question 8

Blood flow of the rectum and first pass loss

Answer 8

a. Rate and extent of rectal drug absorption are often lower than with oral absorption (likely due to limited surface area)
b. For drugs with a large first pass loss following oral administration, rectal absorption may exceed oral adsorption
i. Partial avoidance of first pass metabolism in the liver
1. Blood flow from upper third of rectum goes to portal vein (susceptible to first pass loss and lowers bioavailability)
2. Blood flow from lower two-thirds of rectum goes to systemic circulation (avoids first pass loss and increases bioavailability)

Question 9

Suppositories

Answer 9

i. Solid dosage forms that are available in a range of shapes and sizes (usually 1 to 4 grams in size)
ii. Drug may be dispersed or dissolve in the suppository base
iii. Two types: fatty bases and water-miscible bases

Question 10

Enemas

Answer 10

i. Rectal solutions or suspensions (retention and evacuation enemas ** defined above)
ii. Drugs in liquid dosage forms can move as far as the splenic flexure (possible to treat conditions of the descending colon)

Question 11

Foams

Answer 11

i. Dispersions of propellant (gas) in liquid (contain surfactants to help stabilize)
ii. Better retention than liquids because they are more viscous
iii. Can spread into and treat conditions of the descending colon

Question 12

Creams/Ointment

Answer 12

i. Used mainly for local treatment
ii. Contain oil and water phases stabilized by emulsifying agent
iii. May apply around the rectum for local treatment
iv. May insert into the rectum (requires applicator; steroid creams inserted into rectum can spread towards the descending colon to provide local anti0inflammatory actions)

Question 13

Gels

Answer 13

i. Provide local or systemic drug delivery
ii. Gels are colloidal, aqueous dispersions of hydrophilic polymers
iii. Do not contain oil
iv. Some designed to have thicker viscosity at warmer body temperatures

Question 14

Fatty bases

Answer 14

i. Designed to melt at body temperature (melts quickly within 3-7 minutes)
ii. Usually needs to be refrigerated
iii. Patient should minimize handling to prevent melting before administration

Question 15

Theobroma oil fatty bases (cocoa butter)

Answer 15

i. Once commonly used
ii. Has multiple polymorphic forms (ability of the material to exist in different crystalline forms)
iii. Results in stability issues if heated above 95F

Question 16

Semi-synthetic fatty vehicles

Answer 16

i. Mixtures of natural or synthetic vegetable oils
ii. Combinations of components can yield different melting points
iii. Fattibase, Wecobee bases, Witepsol bases

Question 17

Water-miscible/soluble bases

Answer 17

i. Designed to be miscible with and dissolve in rectal fluids
ii. Dissolve slowly over 30-40 minutes (they don’t melt)

Question 18

Two types of water-miscible/soluble bases

Answer 18

1. glycerinated gelatin (rarely used for rectal suppositories)
2. Polyethylene glycol (PEG)

Question 19

Polyethylene glycol (PEG)

Answer 19

i. Consist of polymer chains of different lengths
ii. When MW is greater than 1000, it will be wax-like solid
iii. As MW increases, melting point increases
iv. PEG bases are hygroscopic and will attract water after administration resulting in stinging (counsel to moisture suppository with water prior to insertion)

Question 20

Fusion molding

Answer 20

i. Most common approach
ii. Base is melted over a water bath. Drug is incorporated and poured into molds. Allowed to cool and harden before removing from molds.
iii. Requires mold calibration (need to determine weight of drug mixture that will fit in the volume of the suppository mold)

Question 21

Hand molding

Answer 21

i. Made from cocoa butter
ii. Instead of melting the base it is grated into small pieces and then mixed with the drug in mortar and pestle
iii. The mass is formed into a ball, then rolled into a uniform cylinder, and then cut into the appropriate number of suppositories

Question 22

Compression molding

Answer 22

i. Base is grated, mixed with drug in mortar and pestle, and put into a cold compression mold
ii. Pressure is applied to force mixture into the shape of the mold

Question 23

Advantages of vaginal drug delivery

Answer 23

i. Local or systemic delivery of drugs
ii. Suitable for patients that cannot take medication orally
iii. Avoid first pass metabolism
iv. Prolonged retention is possible with some dosage forms (i.e. rings)
v. Ease of administration

Question 24

Limitations of vaginal drug delivery

Answer 24

i. Gender specific
ii. Menstrual cycle and hormone changes can alter the rate and extent of drug absorption
iii. Leakage of dosage form will likely occur
iv. Can see systemic absorption of drugs intended for local treatment
v. Some delivery systems may cause local irritation
vi. User preference may not favor use

Question 25

Vaginal inserts

Answer 25

i. Provide a precise dose ii. Designed to melt at body temp or disintegrate upon insertion iii. Design of the dosage form should take into consideration: fluid volume, minimize the potential to cause local irritation, ensure retention at the site of administration

Question 26

Vaginal suppositories

Answer 26

i. Solid dosage forms made using a suppository base 1. Fatty bases i. Designed to melt at body temperature ii. Rarely used for vaginal use 2. Water-soluble bases i. Designed to dissolve in vaginal fluids (types: glycerinated gelatin and polyethylene glycol)

Question 27

Vaginal tablets/capsules

Answer 27

i. Similar to oral tablets/capsules (may be coated or uncoated) Ideally should disintegrate and dissolve in a small amount of fluid to release drug ii. Can be designed to include bioadhesive polymers (hold to minimize leakage)

Question 28

Vaginal creams and ointments

Answer 28

i. Semi-solid dosage forms made of oil and water dispersions 1. Cream = oil in water emulsion 2. Ointment = water in oil emulsion ii. Supplied in tubes and applied with applicator iii. Messy iv. If applicator is not pre-filled, leads to a less precise dose v. Soothing vi. Faster release if the drug is dissolved in the continuous phase

Question 29

Vaginal gels

Answer 29

i. Semi-solid dosage form made of a colloidal, aqueous dispersion of hydrophilic polymers ii. Supplied in tubes and applied with an applicator iii. Messy iv. If applicator is not pre-filled, leads to a less precise dose v. Soothing

Question 30

Vaginal rings

Answer 30

i. Flexible, circular devices containing drug entrapped through a polymer ii. Provide zero-order controlled release of the medication iii. Can be used for local or systemic effects iv. Placed in the upper third of the vagina where it is retained v. Non-erodible = must be removed by the patient

Question 31

Explain proper counseling points for the use of vaginal dosage forms

Answer 31

a. Wash hands before and after use b. If in packaging, need to unwrap c. Suppositories and tablets often come with applicator (some applicators are reusable. Some are disposable) d. Suppositories that are moistened before they are inserted are less likely to sting