Rectal Drug Absorption and Circulation

Rectal blood circulation

• Superior rectal vein drains into the hepatic portal vein
• The portal vein leads to the “first-pass hepatic metabolism” of drugs
• Middle and inferior rectal veins drain directly into general systemic circulation
• Little “first-pass hepatic metabolism” of the drug occurs in the middle and inferior rectal veins

Rectal Drug Absorption

• Hydrophobic base suppositories melt into a very thin layer of mucous that allows the drug to be passively diffused
• Hydrophilic base suppositories dissolve and mix with the mucous layer where the drug is then passively diffused

Factors affecting rectal absorption

• The type of base used
• The type of drug
• The solubility of the drug in the vehicle (surfactant may be needed)
• The concentration of the drug
• The particle size of the drug

Hydrophilic Base: Glycogelatin

• Glycogelatin is made up of: Glycerin + Gelatin + Water (e.g. 70:20:10)
• It is not used as much as cocoa butter or PEG bases
• Glycogelatin is good for laxative suppositories
• Used for vaginal suppositories (e.g.paracetamol, morphine)
• It can also deliver: anti-inflammatories, anti-emetics and anti-nausea drugs, sedatives/tranquilisers, antihaemorrhoidals, hormones, antibacterials, antifungals, contraceptives

Advantages of suppositories and pessaries

• Ease of administration by a professional or by the user
• Easy to remove or flush out if necessary
• Useful for young children and the elderly
• Provides rapid, targeted drug delivery when systemic delivery is unsuitable
• Limits systemic exposure to the drug
• Partially avoids first-pass intestinal and hepatic metabolism allowing > 30% of the dose to reach systemic circulation unchanged
• Allows for large doses to be delivered

Advantages of suppositories and pessaries (cont’d)

• Can be used in unconscious and disabled patients
• Can be used in infants and young children
• Avoids problems with oral administration:
  • Taste or smell
  • Drug degradation in the stomach acid
  • Nausea and vomiting
  • Pre-surgical need to keep stomach empty

Disadvantages of suppositories and pessaries

• Drug absorption is slower vs. oral or IV administration
• Percentage absorption is variable and unpredictable
• Not suitable for drugs with a narrow therapeutic range
• Potential for mucosal irritation
• Potential for triggering defecation and loss of product from the rectum
• Diarrhoea and GI disease reduce absorption

Disadvantages of suppositories and pessaries (cont’d)

• Menstruation can affect vaginal absorption
• Leakage of melted product
• Can be difficult for arthritics to self-administer
• Cost of production is high

Drug release rates from different bases

• Oily bases promote slow drug release for oil-soluble drugs, and rapid release for water-soluble drugs
• Water-miscible bases produce a moderate drug release for oil-soluble drugs, and slow to fast release for water-soluble drugs

Preparing cocoa butter suppositories

• Wash hands, wear rubber or vinyl gloves
• Remove the suppository from its wrapping
• Moisten the suppository if necessary
• Lubricate the mould if required
• Pour the stirred melt into the mould quickly in one movement
• Allow the suppository to cool and congeal slowly
• Trim excess if needed
• Carefully remove the suppository from the mould
• Wrap and put into a container
• Label and dispense

Formulating suppositories

• Suppositories have a fixed volume determined by the volume of the mould
• When formulating suppositories with >5% w/w drug, we need to allow for the volume of the base “displaced” by the drug and reduce the quantity of the base in the mixture accordingly

Displacement Values

• Drugs have a “displacement value” (DV) or “density factor”
• The DV is the number of grams of active ingredient that displaces 1 gram of base
• DV = Density of drug / density of cocoa butter
• Reference books usually list DVs relative to cocoa butter base which has a density of 0.9 g/mL

Examples of DVs

• Boric acid: 1.5
• Codeine phosphate: 1.1
• Hydrocortisone: 1.5
• Morphine HCl: 1.6
• Paracetamol: 1.5
• Phenobarbital: 1.2
• Zinc oxide: 4.0

Displacement Values relative to PEG bases

• PEG bases have a density of 1.09 g/mL (about 1.20 times the density of cocoa butter)
• To calculate the DV relative to PEG, divide the DV relative to cocoa butter by 1.2
• For example, boric acid DV vs. cocoa butter 1.5, DV vs. PEG 1.5 / 1.2 = 1.25

Examples of Vaginal Pessaries

• Hormone replacement pessary: Progesterone 200 mg (active), Silicon dioxide 35 mg (suspending aid), Polyethylene glycol base qs (base)
• Antibiotic for vaginal vaginosis: Metronidazole 500 mg (active), Glycerinated gelatin base qs (base)

Summary

• Suppositories and pessaries are solid dosage forms designed to deliver drugs to the rectum or vagina.
• Some suppositories are designed to deliver drugs locally, while others are designed to deliver drugs systemically.