Suppositories & Inserts

Question 1

Definition of suppositories

Answer 1

Solid dosage forms intended for insertion into body orifices where they melt, soften or dissolve and exert either local/systemic effects

Question 2

Reasons for suppositories

Answer 2

1. Patient may not be able to use the oral route:
   - very young, old/mentally disturbed
   - patients with GI tract problems
   - severely debilitated (weak)
2. Drug is less suited for oral administration:
   - GI tract side effects
   - drug stability: effect of pH or enzymes
   - unacceptable drug taste/smell
3. Parenteral route might be unstable

Question 3

Advantages of suppositories

Answer 3

• Self administration
• Avoidance of oral and parenteral routes and their problems
• Drug causes nausea/drug restrictions
• Patient suffering from severe vomiting
• Can be targeted delivery system: localized action, get to the site at a lower dose -> reduce systemic toxicity

Question 4

Disadvantages of suppositories

Answer 4

• Mucosal irritation
• Slow, erratic and incomplete absorption
• Diarrhea and disease states affect absorption
• Installation may trigger defecation reaction
• High cost and problems with large scale manufacturing
• Stringent storage conditions
• Development of proctitis - inflammation of the rectum

Question 5

Route of administrations

Answer 5

Rectum, vagina and urethra

Question 6

Factors affecting rectal absorption: The dosage of the drug given rectally may be greater than/less than the dose of the same drug given orally depending on:

Answer 6

1. Physicochemical factors
   - lipid-water solubility - partition coefficient
   - particle size
   - nature of base/release
2. Physiologic factors
   - Colonic content
   - pH/buffer capacity
   - circulation route
   - Part of rectum at which absorption is taking place

Question 7

Physiology of rectum

Answer 7

Hollow with a relatively flat wall surface without villi, which secretes mucous.
Surface area of 300 cm^2
Rectal fluids are neutral - pH 7.5 without buffering capacity

Question 8

Drug is usually applied at which part of the rectum

Answer 8

Lower part. Middle hemorrhoidal vein and inferior hemorrhoidal vein’s blood flow to lliac vein which flows to inferior vena cava (goes directly into general circulation, avoiding the liver)

Question 9

Physiology of vagina

Answer 9

Vaginal fluids are a mixture of proteins and polysaccharides, protective mucus originate in cervix and pH is low.
Blood supply from vaginal artery and return avoids the hepatic portal system

Question 10

Physiology of urethra

Answer 10

Short straight tube connecting the bladder to the outside; Poorly perfused by blood

Question 11

Ideal suppository bases/vehicles

Answer 11

• Cause no irritation/inflammation - biocompatibility
• Remains solid at room temp. but melts, dissolves, softens at 37 degree celcius
• Chemically stable and inert
• Physically stable
• Melting range should be ideal for rapid solidification
• Does not affect the bioavailability of the drug
• Suitable viscosity when melted, does not leak from rectum/vagina

Question 12

Classification of suppository bases

Answer 12

• Fatty/oleaginous - Cocoa butter, adeps solidus
• Water-soluble/water-miscible - glycerinated gelatin, polyethylene glycol
• Misc - mix of lipophilic and hydrophilic bases, mix of fatty bases and emulsifying agents
• Non-base - tablets, soft gelatin capsules

Question 13

Characteristics of cocoa butter base

Answer 13

• Naturally occurring triglyceride
• Yellowish-white solid, mp 30-36C
• Poor water absorptive properties
• Show polymorphism (alpha - 22C, beta’ - 28-31C, beta - 34-35C, gamma - 18C)
• Beta is the most stable and desired form - mp 34-35. All forms can be converted to beta form: need beta seed crystals to get the required beta form
• Dont heat above 34.5 for long time

Question 14

Disadvantages of cocoa butter base

Answer 14

• Insufficient contraction at cooling
• Low softening point
• Poor chemical stability
• Poor water adsorptive power
• Bad for high speed manufacture

Question 15

Cocoa butter replacements

Answer 15

• Vegetable oils
• Wax
• Triglycerides of fatty acids
• Fatty alcohols C12- C18

Question 16

Characteristic of water-soluble/water-miscible bases

Answer 16

May result in some irritation and dehydration as they take up water and dissolve

Question 17

Examples of water-soluble/water-miscible bases

Note: these bases suppositories should be protected from moisture as they are hygroscopic

Answer 17

Glycerinated Gelatin - mix of glycerin and gelatin in water
Polyethylene glycol (PEG) - polymers of varying MW, base properties change with MW, water-soluble: dissolve in body fluids, stable, must not store in polystyrene vials, ratio of low to high MW PEGs can be altered to prepare a base with a specific m.p., controlled release, no leaking.

Question 18

Advantages of using compressed tablets (not common for rectal suppositories - low moisture environments, but becoming more popular for vaginal use)

Answer 18

• easier to manufacture

- more stable (storage and chemical reaction)

Question 19

SPECIFIC considerations for formulation

Answer 19

• water
• hygroscopicity
• incompatibilities
• viscosity
• brittleness
• density
• volume contraction
• dosage replacement
• weight/volume control

Question 20

Consideration for formulation

Answer 20

• Base selection: composition, melting behaviour, rheological properties
• Drug onset and action: quick, slow, prolonged effect
• Application and use: rectal/vaginal/urethral, systemic/local absorption
• Drug release: dissolve in rectal fluid/melt on the mucous layer

Question 21

Process for drug release

Answer 21

• suppositories with oleaginous bases: melt -> spread
• suppositories with hydrophilic bases: dissolves in fluids -> diffuses from fluids
  1. Melting and spreading
  2. Sedimentation
  3. Wetting
  4. Dissolution

Question 22

Factors to consider for drug release

Answer 22

1. Type of base
2. Solubility in water and vehicle
3. Particle size
4. Amount of drug
5. Other additives

Question 23

Drug release: Oil-soluble drug and oily base

Answer 23

Slow release, poor escaping tendency

Question 24

Drug release: Water-soluble drug and oily base

Answer 24

Rapid release - preferred

Question 25

Drug release: Oil soluble drug and water miscible base

Answer 25

Moderate release rate

Question 26

Drug release: Water soluble drug and water miscible base

Answer 26

Rapid release- based on diffusion

Question 27

How does particle size affect drug release

Answer 27

- Small particles -> better dissolution, less irritation, better sedimentation rate - Suggested: 50 - 100um

Question 28

How does amount of drug affect drug release

Answer 28

No. of particles increase -> chance of agglomerate formation increases Density/dose replacement calculations needed if more than 100mg drug is used in 2g suppository

Question 29

How does other additives affect drug release

Answer 29

May cause depression in the mp or cause deglomeration, which help to prevent cake formation

Question 30

Ways to prepare suppositories

Answer 30

1. Hand rolling and shaping 2. Cold Compression 3. Molding from a melt

Question 31

Describe using hand rolling and shaping to prepare suppositories

Answer 31

1. Weigh ingredients 2. Grate cocoa butter 3. Add active ingredient 4. Mix thoroughly utilizing a mortar/pestle or a pill tile/spatula 5. Shape into long cylinder 6. Cut into desired length, rounding the tips 7. Packaging and labeling

Question 32

Describe using cold compression to prepare suppositories

Answer 32

- Base and medication mixture is forced into special molds using suppository making machines - No heat needed 1. Mix base and other ingredients thoroughly utilizing a mortar/pestle or mechanical mixtures 2. Pressure is applied to the mold -> perfectly molded suppositories with no air bubbles (special equipment needed)

Question 33

Describe using molding from a melt (fusion) to prepare suppositories

Answer 33

- Heat required - Special calculations required - Most common 1. Base material gently heated to melt 2. Active ingredients and excipients are added with mixing 3. Melt is poured into molds (slightly overfill) 4. Allow the melt to cool and congeal into suppositories 5. Trim, package and label suppositories

Question 34

Considerations for the method molding from a melt

Answer 34

1. Suppository molds: plastic, stainless steel, aluminium, bass, etc. -> understand the effect of heat and excipients on the mold 2. Lubrication of mold: For mold release e.g. of lubricants: glycerinated gelatin and mineral oils 3. Amount of base required: 10% extra for mold to be overfilled 4. Calibration of mold 5. Preparation and pouring of melt: Melt over water bath with least possible heat -> homogeneous heating, stir during pouring into chilled mold

Question 35

Calibration of mold

Answer 35

1. Prepare the molds, clean and dry cavities 2. Melt sufficient suppository base to fill 6-12 molds 3. Pour in the mold, cool and trim 4. Remove suppositories and weigh 5. Divide the total weight by the no. of blank suppositories prepared = average weight of each suppository for this particular base 6. Use this weight as the calibrated value for that specific mold using that specific lot of suppository base 7. Put in beaker and melt to get volume 8. Calculate weight and volume of each cell 9. Different bases will have different densities

Question 36

When do you need to calculate for suppositories

Answer 36

If the active drug > 100mg for a 2g suppository weight

Question 37

What if the density factor of a base is not known?

Answer 37

Calculate as the ratio of blank weight of the base and cocoa butter

Question 38

Methods to calculate the quantity of base that active medication will occupy and the quantity of ingredients required

Answer 38

1. Dosage replacement factor 2. Density factor - Paddock method 3. Occupied volume

Question 39

Name some quality control tests

Answer 39

- Melting range test - Liquefaction test - Breaking test - Softening/liquefaction temperature test