Suppositories

Question 1

Difference between a suppository and an insert

Answer 1

Suppositories are inserted into the rectum for local or systemic effects
Inserts are inserted into body cavities, such as the urethra, vagina, or eye (does not include the rectum)

Question 2

Examples of local effect suppositories

Answer 2

Hydrocortisone for hemorrhoids

Glycerin for laxative effects

Question 3

Examples of systemic effect suppositories

Answer 3

Chloropromazine as a tranquilizer
Oxymorphone HCl as a narcotic
Ergotamine tartarate as a migraine treatment

Question 4

Rationale for using suppositories

Answer 4

GI, side effects, stability, avoids first past effect
Enters systemic circulation and bypasses portal circulation (bypasses the liver) - leads to better circulation and bioavailability
Person may not be able to swallow medication

Question 5

How is rectal tissue different from GI tract?

Answer 5

No microvilli (lower surface area) but has high vascularization of submucosal membrane

Question 6

Describe rectal suppositories (e.g., length, weight, form of drug etc.)

Answer 6

Rectal suppositories weigh 2g and are 2-3cm long
The rectum has a neutral pH and holds around 2-3mL with no buffer capacity
Suppositories use the salt form of the unionized drug

Question 7

Describe the vagina and vaginal suppositories
Vagina length, blood flow, fluid (composition and pH)
Vaginal suppository target, shape, weight, compounding materials

Answer 7

The vagina is a fibromuscular tube around 7.5cm long
Blood supply bypasses hepatic portal system
Suppositories are usually used for targeted drug administration
Vaginal fluid is composed of proteins and polysaccharides, with a low pH (~3, depending on age) (pre-puberal and menopause - pH is slightly alkaline)
Vaginal suppositories are ovoid/globular in shape, weigh 3-5g
Often compounded with water-soluble bases like polyethylene glycol or glycerinated gelatin to minimize leakage (pH = 4.5)
Some suppositories are compressed tablets called “inserts”
Contain fatty bases

Question 8

Describe urethral suppositories (length and weight for males and females)

Answer 8

Urethral suppositories are ~5mm in diameter
Men: 125mm long and weigh 4g
Women: 50mm long and weigh 2g

Question 9

What are some desirable properties of suppository bases?

Answer 9

Stable under normal conditions
Must be compatible with drug and auxiliary agents
No odour, aesthetically pleasing
Non-toxic, non-irritating
Shrinks on cooling with a suitable viscosity
Melts/dissolves in intended orifice
Mixes with or absorbs some water
Some wetting/emulsifying properties

Question 10

Which suppository bases should melt and which should dissolve?

Answer 10

Melt: Fatty bases (also called oleaginous), like cocoa butter (AKA theobroma oil)
Dissolve: Water soluble/miscible bases (PEG, glycerin)

Question 11

Describe polymorphism

Answer 11

Refers to the ability for a crystalline substance to exist in two different forms that have different arrangements of molecules in crystal lattice

Question 12

In regards to cocoa butter, what does polymorphism refer to?

Answer 12

Cocoa butter cannot be heated above 35C because it will form a metastable structure that changes its properties to melt at room temperature (25-30C)
See energy graph in notes with alpha and beta melting points/energy values

Question 13

What are the three factors to consider when preparing a suppository base?

Answer 13

1. Base must not be heated above 35C
2. There may be a change in melting point by adding certain drugs to cocoa butter (e.g., phenol tends to decrease MP, beeswax tends to increase MP)
3. Cocoa butter has no surfactant (cannot emulsify water)

Question 14

With cocoa butter, what does the release of drug into an aqueous medium depend on?

Answer 14

The water/base partition coefficient
Salt forms of drugs have a higher water/base partition coefficient and should be used in cocoa butter as they will dissolve better and will have stronger systemic effects

Question 15

What are two drugs that you should not use with cocoa butter (which is a fatty base) in a suppository?

Answer 15

Acetaminophen (there is no water soluble form, therefore cannot use CB as a base)
Diazepam

Question 16

What are synthetic triglyceride bases? What are their advantages? Disadvantages? Give two examples of synthetic triglyceride bases and a brief description

Answer 16

Hydrogenated vegetable oils (palm, kernel, coconut oils)
Advantage: Do not exhibit polymorphism, have better contraction after cooling, contain self-emulsifying glycerol monostearate and polyoxyl stearate
Disadvantage: Expensive
E.g., fattibase (single entity base with triglycerides) and wecobee (series of bases with varying MP)

Question 17

What is an example of a water soluble/miscible base? What would it be used for?

Answer 17

Glycerinated gelatin (mainly for vaginal suppositories)
Are hygroscopic, therefore must wet before applying
Must add preservatives
Hygroscopicity can cause stinging and might affect drug passage in mucosa

Question 18

Describe glycerinated gelatin as a suppository base (drug release, storage, preservatives, instructions for use, incompatibilities, classification of glycerin)

Answer 18

Translucent, disperse slowly, provide prolonged release of API (usually vaginal suppositories, but also urethral, seldom rectal due to slow dissolution)
Must keep in sealed container so that they do not melt from moisture 
Add preservative (e.g., methylparaben)
Dip in water before using
Incompatible with Gelatin A and Gelatin B (A = acidic, B = basic)
Glycerin is classified as a humectant, plasticizer, solvent, and tonicity-adjusting agent

Question 19

Describe polyethylene glycol polymers are suppository bases (characteristics, melting temperature/drug release, storage, use, incompatibilities)

Answer 19

Non-irritating, water miscible, formulated by mold compression in wide range of hardness and MP
Do not melt at body temperature, but provide prolonged release
Can be stored at room temperature in a sealed container
Must be moistened with water before use
Incompatible with PEG, drugs prone to oxidation (phenol, tannic acid, benzocaine), interacts with plastics (wrap in foil)

Question 20

Cocoa butter - criteria for selecting this base

Answer 20

Melts quickly at body temperature, immiscible with body fluids, inhibits diffusion of fat-soluble drugs to target site, NOT for vaginal preparations as it has a non-absorbable residue (oleaginous)

Question 21

PEG - when to use this base

Answer 21

For antiseptics

Question 22

Fatty base vs. PEG in:
Patient comfort
Compatibility and stability
Route of administration
Systemic effect
Local effect

Answer 22

Patient comfort: Fatty base = more comfortable, non-irritating; PEG = stinging sensation, defecate reflex
Compatibility and stability: Fatty base = less reactive, melt on storage; PEG = more reactive, don’t melt on storage
RoA: Fatty base = rectal; PEG = vaginal
Systemic effect: Fatty base = poor release of hydrophobic drugs; PEG = better release of hydrophobic drugs
Local effect: Fatty base = emollient effect

Question 23

What are the three methods of preparation for suppositories?

Answer 23

1) Hand rolling (triturate cocoa butter and ingredients, roll in hands to form ball, roll out in cylinder, cut and shape)
2) Fusion method (melt base, disperse drug, pour in mold, congeal, remove)
3) Compression method (mixed mass of suppository base and drug is forced into special compression mold)

Question 24

Advantages and disadvantages of hand rolling suppositories

Answer 24

Advantages: Don’t need special equipment, don’t need to heat cocoa butter
Disadvantages: Need experience and good technique, don’t look nice

Question 25

Advantages and disadvantages of fusion method

Answer 25

Advantages: Aesthetically pleasing
Disadvantages: Need to be careful when heating, density calculation and mold calibration must be done

Question 26

What is the density replacement factor?

Answer 26

When a drug is placed in a base, it displaces some base as a function of its density
Equal DF = Equal volume of base is displaced
Drug DF > Base DF = Displace smaller weight of base

Question 27

What is the double casting technique? What is this used to determine?

Answer 27

Drug quantity is filled with an inadequate amount of base to fill cavities, it is poured into a mold, then topped up with more base
Suppositories are removed, remelted, recasted to evenly distribute API
Necessary information is amount of base displaced by drug and the DF calculation

Question 28

What is polyoxyl 40 stearate?

Answer 28

Mixture of monostearate and distearate esters of mixed polyoxyethylene diols and free glycols
Average polymer length is equivalent to 40 oxyethylene units
Substance is white to light tan waxy solid, water soluble
MP = 39-45C

Question 29

Biopharmaceutical/Therapeutic questions to ask with suppositories?

Answer 29

Is there adequate absorption through the route of administration?
How much excipient/drug is released?
Allergies?
Contraindications?