Pharmacology of Rectal Drug Delivery

Rectal Fluid pH

• Rectal fluids have a pH of 7-8, which is nearly neutral.
• This means that drugs are not chemically altered by rectal fluids.

Systemic Drug Action

• The ionized form of drugs is preferred for formulations using cocoa butter bases.
• Cocoa butter melts quickly at body temperature, but releases the drug slowly because it is immiscible with body fluids.
• The barrier separating the colon lumen from the blood is more permeable to unionized forms of drugs.
• Unionized forms of drugs can easily pass through lipid membranes.

Physicochemical Factors of Drugs and Bases

• Drug solubility and its lipid-water partition coefficient determine the type of base and drug release.
• Lipophilic drugs have a slower release into aqueous fluids than hydrophilic drugs.
• Particle size affects drug absorption.
• The base must melt, soften, or dissolve to release the drug, but it should be solid at room temperature.
• Avoid reactions between the base and drug that inhibit drug release, as this could lead to decreased absorption.
• Interactions between the base and drug can affect the drug's stability and bioavailability.
• A base that irritates the rectum may accelerate bowel movement, potentially affecting drug release and absorption.

Suppository Bases

• The role of suppository bases is to maintain shape and solidity after insertion into the body cavity.
• Bases are selected for their ability to dilute the drug to a non-irritating level, control drug release rate, and present the drug in an appropriate form for use.

Ideal Suppository Base Characteristics

• Stable during storage and melts at body temperature or dissolves in body fluids.
• Non-toxic and non-irritating.
• Compatible with any medication.
• Easily molded and removed from the mold.

Types of Suppository Bases

• Oily Bases:

  • Cocoa Butter (Theobroma Oil): The most widely used base, melts at a suitable temperature, stable at room temperature, liquefies readily upon heating and solidifies upon cooling.
    • Disadvantages:
      • Polymorphism: Can exist in different crystalline forms with varying melting points.
      • Can adhere to the mold.
      • Softening point is too low in hot climates.
      • Melting point can be reduced by the addition of substances like phenol and chloral hydrate.
      • Susceptible to rancidity during storage.
      • Poor water-absorbing ability, although this can be improved with emulsifiers.
      • Can leak from the body.
      • Expensive.
    • Advantages:
      • Melts at body temperature.
      • Maintains solidity at room temperatures.
      • Liquefies readily on heating and solidifies on cooling.

• Hydrophilic Bases:

  • Glycerinated Gelatin: A mixture of glycerin and water, combined with gelatin to form a stiff jelly.
    • Advantages:
      • Slow dissolution in body fluids, providing a slow and continuous release of the drug.
      • Does not become rancid.
      • Suitable for all types of suppositories.
    • Disadvantages:
      • Laxative effect due to osmosis: can irritate the rectum.
      • Inconsistent dissolution times.
      • Hygroscopic, requiring storage in airtight containers.
      • Can dehydrate rectal and vaginal mucosa.
      • Susceptible to microbial contamination.
      • Preparation is time-consuming.
  • PEG Macrogols: Mixtures of polyethylene glycols with varying molecular weights.
    • Advantages:
      • Wide range of melting points available.
      • Rapid release of drug.
      • Compatible with many drugs.
    • Disadvantages:
      • Can irritate the rectum.
      • Hygroscopic, requiring storage in airtight containers.
  • Soap-Glycerin Base: A combination of soap, glycerin, and water. - Advantages: - Dissolves slowly in body fluids. - Stable on storage. - Suitable for both rectal and vaginal suppositories. - Disadvantages: - Requires a strong, sealed container. - Can irritate the rectum. - Dissolution time can be unpredictable. - May contain water, increasing the likelihood of microbial contamination.

• Miscellaneous Bases:

  • Emulsified Theobroma Oil: Used for incorporating large quantities of aqueous solutions.
  • Synthetic Hard Fats (Hydrogenated Oils): Derived from vegetable oils, often with a wider range of melting points than cocoa butter.
    • Advantages:
      • Overheating does not affect the solidifying point.
      • Resistant to oxidation.
      • Do not require mold lubrication.
    • Disadvantages:
      • Brittle upon rapid cooling.
      • Lower viscosity when melted, resulting in greater drug sedimentation.

Addressing Polymorphism of Cocoa Butter

• Partial Melting: Melting only a portion of the cocoa butter, leaving solid crystals to prevent the formation of unstable crystalline forms.

• Seeding: Adding small amounts of stable crystals to the melted base accelerates the transformation from unstable to stable crystalline forms..

• Controlled Cooling: Melting the base and then solidifying it, followed by storing the solidified base between 28-32°C for an extended period, promotes the formation of stable crystals.

Formulation of Suppositories

• Bases
• Antioxidants: Protect against oxidation and degradation of drugs and bases. Examples include ethyl or propyl gallate, ascorbic acid, BHA, BHT, hydroquinone, tocopherol.
• Emulsifying Agents: Increase the water-absorbing capacity of fatty bases. Examples include polysorbates (Tweens), wool alcohol, wool fats.
• Hardening Agents: Increase the melting point of bases to compensate for drugs that decrease it. Examples include beeswax, high-molecular weight macrogols.
• Preservatives: Prevent microbial growth in water-soluble bases. Examples include chlorocresol, methyl paraben, propyl paraben.
• Thickening Agents: Increase viscosity of molten bases and prevent sedimentation of suspended solids. Examples include aluminum monostearate, colloidal silica, magnesium stearate, stearyl alcohol.
• Plasticizers: Improve base flexibility and reduce brittleness. Examples include castor oils, glycerin, glycol, Tween 80, Tween 85.

This quiz covers the physicochemical properties of drugs utilized in rectal formulations, focusing on the role of pH, solubility, and drug release mechanisms. Understand how factors like drug ionization and base formulation impact systemic drug action. Test your knowledge on how these elements work together to optimize drug delivery through rectal routes.