Rectal Drug Delivery I

Circulation Route

  • Inferior (bottom) → systemic circulation

  • Middle → systemic circulation

  • Superior (top) → portal circulation

Physiological Factors

  • Fluid Quantity

  • Mucus Properties

  • Rectum Contents

  • Circulation Route

Physicochemical Factors

  • Water/Vehicle Solubility (Ionization)

    • water → drug concentration

    • vehicle → drug release & type

  • Surface Properties

    • Hydrophilic + Lipophilic → good

    • Lipophilic + Lipophilic → bad (remains within the base)

  • Particle Size → affects sedimentation (big >150) and (small >50)

  • Drug Concentration

    • Higher Conc → More Drug → Higher agglomeration rate → reduced absorption

    • agglomeration → collection/gathering of disparate elements/particles into a single cluster/mass

  • Molecular Size

Dosage Forms:

  • Suppositories: Solid dosage forms designed for rectal insertion, melt, soften or dissolve to exert systemic or localized effects

    • Cylindrical (easier for insertion) → 4 cm, both or one end tapered

    • Weight (adult: 2g & 1g)

    • Suspensions or Emulsions

  • Enemas: injections of fluid (solution/suspension) into rectum AND colon.

    • micro (1-20 ml)

    • macro (> 50 ml)

Use Cases:

Unable to use the Oral Route

  • GI Disorders

  • N/V

  • Postoperative → cannot consume by mouth due to inability or unconscious)

  • Pediatrics and/or Geriatrics (Child or Elderly)

  • Seizures

  • Mentally Unstable → lead to suicide (choking) or other cases.

Drug Unsuitable for Oral Administration

  • Gi S.E (e.g. diclofenac)

  • Unstable in GIT pH

  • Enzyme Degradation

  • First Pass Elimination

  • Taste Bad

Local Effect Desirable

  • stay in rectal cavity

  • constipation

  • hemorrhoids

  • anal fissure

Advantages:

  • Accommodates relatively large dosage volume

  • Safe and Convenient ROA

  • Minimize Drug Dilution

  • Less degradative enzymes → more gets in the blood

  • Easy Discontinuation

  • Partially Bypass FP

Disadvantage

  • Not widely accepted

  • Absorption Rate dependent on presence of feces

  • Difficult to Administer

Formulation of Suppositories

  • vehicles

  • active ingredients (drug)

  • excipients (additives)

Requirements

  • non-toxic/non-irritation → bowel movement can occur due to irritation of mucous membrane → diarrhea

  • compatibility of drug → ensure no interactions that can cause adverse effects

  • physically and chemically stable during storage before expiry date → efficacy is maintained

    • melting range → melt in insertion or dissolve in rectal fluid

    • small enough to allow solidification after preparation

    • big enough for industrial scale → easy to manufacture consistently

  • Volume contraction → allow for easy removal w/o breaking from the mold

  • Viscosity → thick enough to have good flow into mold (even/consistent distribution and dosing per suppository) → low sedimentation rate → gradual drug release and able to spread evenly over mucosal surface for absorption

Bases

  • fatty

    • cocoa butter (smell like chocolate, yellowish-white, non-irritant, melting point (30-35 degrees) → keep in the fridge.

    • Disadvantage: Polymorphism (overheating → structural change and unstable) → new melting point (25-30 degree) — melts too early at room temperature

    • solution: increase melting point (e.g. beeswax) or decrease melting point (phenols)

    • Synthetic Triglycerides: hydrogenated fatty acids of vegetable oils (e.g. coconut oil) → more expensive & melting point varies based on its combination with other drugs

    • Advantage: does not experience polymorphism.

  • water-soluble

    • Glycerinated Gelatin → translucent yellow tint, hygroscopic (water content), dissolves slower (prolonged release) → administered by dipping in water first (difficult to administer dry) → store in cool, dry place/in containers.

    • Disadvantage: more prone of bacterial/microbial growth

    • Solution: Add preservatives for longer shelf-life and prevent growth.

    • Must be lubricated before placing into the mold (sticky) → e.g. mineral oil

    • PEG polymers → translucent white, chemically stable, non-irritant, combined with others, doesn’t melt at body temp, dissolve slower

    • can vary in solubility and chemical properties when combined with other excipients.

Fatty → melts in the rectum for drug release + PEG polymers.

W.S.B → dissolve in the rectal mucus/fluid for drug release.

  • opposite compared to other concepts → because main goal of making suppositories is for the drug to be suspended in the suppository and not dissolved within in.

Common Excipients used

  • Surfactants → mainly surface-active agents → reduce surface tension

  • Thickeners → increase viscosity → gel-like system to prolong release → transit time (longer)

  • Melting Point Altering Agents → phenol

    s (decreased), beeswax (increased)

Methods to Make Suppositories