L55 - Formulation of Suppositories

• What are suppositories?


  Solid dosage forms for rectum/vaginal/urethral use that melt, soften or dissolve in the body cavity.
• What are suppositories used for?


  Localapplicationeg itching, infection, haemorrhoids.

  Systematicapplicationeg analgesia, hormones, anti-nauseants.
• What is the bioavailability of suppositories like?


  Varies - due to differences in individuals eg thickness of mucosa and venous drainage.
• What patient groups are suppositories good for?


  - Infants/small children.

  
  

  - Those with difficulty swallowing/dysphagia.

  
  

  - Those with vomiting who can't keep down oral medication.
• Describe the pH of rectal fluid.

  Neutral (pH7-8).

  
• What's the slowest step in rectal absorption?


  Dissolution of slightly soluble substances and absorption.
• How are suppositories prepared?


  Dissolving/dispersing drug in a base at high temps.

  
  

  Mix and pour into a mold.

  
  

  Solidify at room temp.
• Give an example of 2 traditional suppository bases.

  Theobroma oil and glycogelatin.
• Give and example of 2 more modern suppository bases.

  Hydrogenated vegetable bases.

  
  

  Water-soluble PEGs (PolyEthylene Glycol) bases.
• What do we need to consider regarding the drug solubility in the vehicle?


  - Rate at which drug is released and absorbed is directly related to its solubility in the vehicle.

  
  

  - Partition coefficient of drug between vehicle and rectal fluid.
• For drugs highly soluble in vehicle, what is the release rate like?


  Slow, due to low leaving tendency.
• What's the significane of particle size in suppository?

  Influences dissolution rate and availability for absorption in drugs present in undissolved state in suppository.

  
  

  - The smaller the particle, the more rapid the dissolution and absorption.
• Why use bismuth as an excipient?


  To aid absorption. Can be irritant tho.
• When might suppository absorption be impaired?

  - If base interacts with drug/inhibits its release.

  
  

  - If base irritates rectal membrane: could cause bowel movement resulting in incomplete drug release and absorption.
• Describe the ideal properties of a suppository base.


  - Melts/dissolves at body temp.

  
  

  - Non-toxic and non-irritant.

  
  

  - Released API easily.

  
  

  - Easily molded and removed from mold.

  
  

  - Easy to handle.

  
  

  - Stable on storage.
• Describe Theobroma oil.


  - Oleaginous base.

  
  

  - Solidifies in 4x crystalline forms depending on melting temp and boiling range.
• What are the 4x polymorphic forms of theobroma oil?

  
  

  What's the preferred form? Why?

  (image! x axis)

  
  

  Preferred = Beta bc most stable.

  
  

  Forms beta crystals with a normal melting point when melted at max. 36degrees then cooled.

  
  

  
  

  - Lower melting point polymorphs eventually convert to a more stable form over time.

  
• List some disadvantages to a theobroma oil base.


  - Oxidation of unsaturated glycerides make it rancid over time.

  
  

  - Anal leakage (cocoa butter imiscible with body fluids).

  
  

  - Readily melts on warming but doesn't contract on cooling so need lubricant to remove from mold.

  
  

  - Expensive; not suitable for high speed mass production.
• Describe Hydrogenated Vegetable Bases eg Witepsols


  - Solidify rapidly in mold and contract on cooling - no need to lubricate.

  
  

  - Mix high and low MP bases to provide range of melting points.

  
  

  - Contain emulsifiers: may form o/w emulsions in rectal cavity... poor drug release from base.

  
• What are the 2 main purposes of a glycogelatin base?


  Laxative purposes and vaginal therapy.
• List some disadvantages to glycogelatin suppository bases.


  - Hygroscopic: need to pack tightly.

  
  

  - Dehydrating, so irritate mucosa. Wet before inserting.

  
  

  - Long prep time.

  
  

  - Mold lubrication required.
• What's the most popular macrogol used as a base?


  PEG!

  
  

  - Ratios can be altered to create a base with a specific MP.

  
  

  Eg Polybase - preblended base of PEGs and polysorbate 80. Stable at room temp, doesn't need lubrication.
• List some


  advantagesto using PEG mixtures as suppository bases.- Adjust MP to suit warmer temps.

  
  

  - Drug release not dependent on MP.

  
  

  - Improved physical stability on storage.

  
  

  - Readily miscible with rectal fluids.
• List some disadvantages to using PEG mixtures as suppository bases.


  - More chemically reactive than fats, so incompatible w/ many drugs eg Pen-G (benzylpenicillin).

  
  

  - Care needed in processing to avoid contraction holes.

  
  

  - Rate of water-soluble drug release decreases with increasing Mw of PEG used.

  
  

  - PEGs more irritating to mucus mebranes than fatty bases.
• How can suppositories be stored? (packaging material)?

  
  

  Where are cocoa butter and glycogelatin suppositories stored? What about PEG?

  Tin, Al, paper, plastic.

  
  

  Theobroma oil/glycogelatin = fridge.

  
  

  PEG = room temp.
• Why do we need to calibrate suppository molds?

  Bc some bases have different densities.
• How do we calibrate suppository molds?


  By weighing several suppositories of base to be used.
• Why are displacement values important for suppositories?

  - Adding drug alters density, increasing final suppository weight.

  
  

  Need to account for this!