Exhaustive University Study Notes: Suppositories and Pessaries Formulation and Pharmacology

Learning Objectives for Suppositories and Pessaries

• Definition: Understand and define suppositories and pessaries.

• Classification: Identify the various classifications of suppositories.

• Clinical Evaluation: List the advantages and disadvantages of using suppositories.

• Pharmacokinetics: Identify factors affecting drug absorption from rectal suppositories.

• Formulation Science: Discuss various suppository bases, excipients, and their properties.

• Manufacturing: Describe methods of preparation including pour molding, compression, and hand molding.

• Logistics: Describe packing, labeling, and storage requirements.

Anatomy and Physiology of Body Orifices

The Rectum

• Terminal Portion: The rectum begins at the sigmoid colon and ends at the anal canal.

• Dimensions: It is approximately $15$ to $20\,cm$ long.

• Function: Acts as a temporary storage site for solid waste.

• Mucous Fluid: Contains approximately $2$ to $3\,ml$ of mucous fluid.

  • pH: Approximately $7.4$.

  • Buffering Capacity: Very little buffering capacity.

• Vascular Supply: Primarily supplied by three arteries with blood return via three veins:

  • Superior Hemorrhoidal/Rectal Vein (leads to the portal vein and then the liver).

  • Middle Hemorrhoidal/Rectal Vein.

  • Inferior Hemorrhoidal/Rectal Vein.

The Anal Canal and Anus

• Terminal Section: The last $2$ to $3\,cm$ of the rectum.

• Sphincter Control:

  • Internal Sphincter: Composed of smooth muscle.

  • External Sphincter: Composed of skeletal muscle.

The Urethra

• Structure: A muscular tube connecting the bladder to the external environment.

• Length (Female): Approximately $4\,cm$.

• Length (Male): Approximately $20\,cm$.

• Blood Supply: Provided by the urethral artery.

Introduction to Suppositories

• Etymology: Derived from the Latin word supponere.

  • sub: Meaning "under."

  • ponere: Meaning "to place."

  • Literal meaning: "To be placed under the body."

• General Definition: Solid dosage forms intended for insertion into body orifices (other than the mouth) where they melt, soften, or dissolve to release therapeutic agents for local or systemic effects.

• Common Sites of Insertion: Rectum, vagina, and (occasionally) the urethra.

• Design Characteristics: Available in various sizes and shapes to allow easy insertion without causing undue distension and to ensure retention for the necessary duration.

Classification and Physical Characteristics

Rectal Suppositories

• Shape: Typically shaped like a bullet, a little finger, or tapered at one or both ends (frequently wider in the middle).

• Weight (Adult): Typically ranges from $1$ to $4\,g$, depending on the density of the base and medicaments.

• Pediatric Uses: Suppositories for infants and children are approximately half the weight and size of adult versions and assume a more pencil-like shape.

Vaginal Suppositories (Pessaries)

• Shapes: Frequently globular, oviform, or cone-shaped (also pear, rod, or cone variations).

• Weight: Ranges widely, usually between $3$ and $5\,g$.

Urethral Suppositories (Bougies)

• Shape: Slender, pencil-shaped units.

• Male Urethral Suppositories: Typically weigh approximately $4\,g$.

• Female Urethral Suppositories: Approximately half the weight ($2\,g$) and length of the male version.

Other Classifications

• Nasal Suppositories: Also known as nasal bougies or buginaria.

• Ear Cones: Known as aurinaria.

Advantages and Disadvantages of Suppositories

Advantages

• Self-Administration: Easily performed by the patient.

• Stability: Avoids inactivation of drugs by the low pH or enzymatic activity of the gastric lumen.

• Gastric Tolerance: No stomach irritation.

• Metabolism: Can avoid first-pass metabolism by the liver (depending on placement).

• Patient Compliance Factors: Ideal for patients who are vomiting, unable to swallow, unwilling to take oral meds, or post-operative.

Disadvantages

• Physiological Reaction: Risk of mucosal irritation.

• Compliance: Some patients find the administration route unpleasant.

• Absorption Variability: The gastrointestinal state (e.g., diarrhea or fecal matter) significantly affects absorption.

• Manufacturing Costs: High cost due to special formulations and packaging requirements.

• Data Scarcity: A perceived lack of comparative data and research compared to oral dosage forms.

Factors Affecting Drug Absorption

I. Physiologic Factors

• Colonic Contents: Fecal matter, diarrhea, and tissue dehydration can slow down rectal drug absorption. Systemic effects are achieved more effectively when the rectum is void (empty).

• Site of Absorption: The fate of the drug depends on where it is absorbed in the rectum.

  • Upper Hemorrhoidal Vein: Transports the drug to the portal vein and liver, subjecting it to metabolism.

  • Lower/Middle Hemorrhoidal Veins: Direct systemic absorption, bypassing the liver.

• pH of Rectal Fluids: Rectal fluid pH is neutral ($7.4$). Because it lacks buffering capacity, the chemical form of the drug generally remains unchanged by the environment.

II. Physicochemical Factors

• Lipid-Water Solubility: The partition coefficient is critical.

  • A lipophilic drug in a fatty base (at low concentration) has a lower tendency to release into body fluids than a hydrophilic drug in a fatty base.

• Drug Concentration: Generally, more drug in the base leads to more available drug for absorption. However, once the intestinal lumen is saturated, further increases in concentration do not increase the absorption rate.

• Rate-Limiting Step: Usually, the rate-limiting step is the partitioning of the dissolved drug from the melted base, rather than the dissolution of the drug in body fluids.

• Particle Size: Smaller particles increase the rate of dissolution.

• Nature of the Base: Characteristics include the ability to melt/soften/dissolve at body temperature ($37^\circ C$), the ability to release the drug, and its hydrophilic/hydrophobic character.

  • Note: If the base is irritating, it may prompt a bowel movement, eliminating the possibility of complete drug absorption.

Suppository Bases and Formulation

Ideal Properties of a Base

• Melts at body temperature or dissolves in body fluids.

• Non-toxic and non-irritant.

• Compatible with medicaments.

• Releases medicaments readily.

• Easily molded and removed from the mold.

• Stable when heated above its melting point.

• Easy to handle and stable during storage.

Classification of Bases

1. Fatty (Oleaginous) Bases: Most common; melt in the rectum.

2. Water-Soluble or Water-Miscible Bases: Hygroscopic; dissolve in body fluids.

3. Miscellaneous Bases: Combinations of lipophilic and hydrophilic substances.

A. Fatty (Oleaginous) Bases

Cocoa Butter (Theobroma Oil)

• Origin: Fat obtained from roasted seeds of Theobroma cacao.

• Physical State: Yellowish-white solid at room temperature with a chocolate-like odor.

• Chemical Nature: Primarily a triglyceride.

• Melting Point: $30^\circ C$ to $36^\circ C$.

• Polymorphism: Exhibits marked polymorphism. If overheated, it may form a lower-melting polymorph that keeps it liquid at room temperature.

• Advantages: Non-irritating; excellent emollient; available in grate form.

• Disadvantages: Erratic drug release; requires refrigeration; prone to rancidity (oxidation of unsaturated glycerides).

• Additives for Cocoa Butter:

  • Beeswax ($4\%$): Used as a solidifying agent if substances like phenol or chloral hydrate lower the melting point.

  • Emulsifying Agents: Added to improve poor water-absorbing ability.

Synthetic Hard Fat (e.g., Suppocire, Witepsol)

• Composition: Mixtures of triglycerides of higher saturated fatty acids with mono/diglycerides.

• Advantages: Solidifying points are unaffected by overheating; resistant to oxidation (rancidity); available in various melting point grades; no mold lubricant usually required.

• Disadvantages: Can become brittle if cooled too rapidly; lower viscosity than cocoa butter when melted, which may lead to drug sedimentation and lack of uniformity.

B. Water-Soluble and Water-Miscible Bases

Glycero-Gelatin

• Composition:

  • B.P. standard: $14\%\,w/w$ gelatin, $70\%\,w/w$ glycerol, and water quantum satis ($Q.S.$) to $100\%$.

  • U.S.P. standard: $20\%\,w/w$ gelatin, $70\%\,w/w$ glycerol, and water $Q.S.$ to $100\%$.

• Uses: Common for pessaries where prolonged action is needed; provides slow release.

• Drawbacks: Laxative effect; hygroscopic (must be protected from moisture); prone to microbial contamination; requires mold lubrication; requires pre-moistening with water before insertion to avoid tissue irritation.

Macrogols (Polyethylene Glycols / PEG)

• Nature: Polymers of ethylene oxide and water.

• Mechanism: They do not melt at body temperature; they dissolve slowly in body fluids.

• Formulations:

  • Base A (Low Melting): $95\%$ PEG 1000, $5\%$ PEG 4000. Immediate drug release.

  • Base B (High Melting): $75\%$ PEG 1000, $25\%$ PEG 4000. Sustained drug release.

• Advantages: No laxative effect; low microbial contamination; contracts on cooling (easy removal); stable in hot climates (MP > 37^\circ C); high viscosity prevents leakage.

• Disadvantages: Hygroscopic (irritation); potential drug retention (poor bioavailability) due to high solvent properties; incompatibilities with benzocaine, penicillin, and plastics; brittle if cooled quickly.

Soap Glycerin

• Production: Stearic acid + Sodium carbonate in glycerin solution yields stearin soap.

• Advantages: Soap assists the laxative action of glycerin; makes glycerin hard enough for a suppository.

• Disadvantages: Highly hygroscopic (must be wrapped in wax paper or tin foil).

Other Formulation Excipients

• Surfactants: Enhance wetting and drug release (e.g., sorbitan esters, polyoxyethylene sorbitan fatty acid esters).

• Hygroscopicity Reducers: e.g., Colloidal silicon dioxide.

• Melting Point Controllers: White/yellow beeswax, cetyl esters wax, bentonite.

• Antioxidants: Prevent rancidity in fatty bases.

• Emulsifying Agents: Increase water-absorbing capacity.

• Preservatives: Necessary for water-soluble bases.

• Thickening Agents: Prevent sedimentation (e.g., $2\%$ aluminum monostearate, cetyl/stearyl alcohols).

• Plasticizers: Improve flexibility and decrease brittleness (e.g., castor oil, glycerin, propylene glycol).

Preparation Methods

Pour Molding Method

1. Melt the Base.

2. Incorporate Medicaments.

3. Pour into Molds: Molds can be stainless steel, aluminum, brass, or plastic.

4. Cool and Congeal.

5. Remove Suppositories.

• Lubrication: Molds may need a thin coating of mineral oil or soap spirit.

  • Cocoa butter/Glycerol-gelatin molds require lubricant (soap spirit for cocoa butter, liquid paraffin for glycerol-gelatin).

  • Synthetic fats and Macrogols usually require no lubricant.

Calibration of the Mold

• Procedure: Prepare blank suppositories from the base alone, weigh them, and record the average weight. Carefully melt them in a calibrated beaker to determine the volume of the mold.

Displacement Value (DV) or Density Factor (DF)

• Definition: The ratio of the weight of the drug to the weight of the base displaced by that drug. It is the quantity of drug required to displace one unit of base.

• Formula: $DV = \frac{\text{Weight of drug}}{\text{Weight of base displaced}}$ or $DV = \frac{\text{Density of medicament}}{\text{Density of base}}$.

• Example Calculations:

  • Goal: Prepare $10$ suppositories, each with $200\,mg$ drug (density $3.0$), in a base (density $0.9$) where the blank weight is $2.0\,g$.

  • Step 1: Average weight per mold = $2\,g$.

  • Step 2: Total base for $10$ blanks = $2\,g \times 10 = 20\,g$.

  • Step 3: Density ratio = $3.0 / 0.9 = 3.33$.

  • Step 4: Amount of base displaced = $2.0\,g / 3.33 = 0.6\,g$.

  • Step 5: Required base weight = $20\,g - 0.6\,g = 19.4\,g$.

  • Step 6: Total drug needed = $0.2\,g \times 10 = 2.0\,g$.

Preparation by Compression

• Mechanism: Forcing a mixed mass into molds using a machine.

• Advantages: Simple; elegant appearance; prevents sedimentation; good for heat-labile drugs.

• Disadvantages: Potential for air entrapment.

Hand Molding

• Use: Useful for small quantities.

• Steps: Triturate drug into fine powder $\rightarrow$ knead into base $\rightarrow$ roll into rod shapes $\rightarrow$ cut and point one end.

Packaging, Labeling, and Storage

• Packaging: Usually in tin, aluminum, or plastic. Poor packaging leads to staining or deformation.

• Labeling Instructions:

  • "Unwrap and insert through rectum."

  • "Keep the suppositories in a refrigerator" (specifically for cocoa butter/glycerinated gelatin).

• Storage Conditions:

  • Fatty/Glycerinated Gelatin: Preferably refrigerated.

  • Macrogols (PEG): Can be stored at room temperature.

Common Formulation Problems

• Water Content: Avoided because it causes fat oxidation, drug crystallization, and bacterial growth.

• Hygroscopicity: Glycerogelatin/Soap glycerin bases lose or absorb moisture based on humidity.

• Interactions:

  • Salicylic acid and sodium barbital crystallize out of PEG.

  • Salicylic acid softens PEG into an ointment.

  • Penicillin G decomposes in PEG.

• Sedimentation: Prevented by adding $2\%$ aluminum monostearate to increase viscosity.

• Brittleness: Common in synthetic fats; solved by adding Tween 80, castor oil, or glycerin.

• Rancidity: Decomposition of unsaturated fatty acids into aldehydes and ketones. Bases with lower unsaturated fatty acid content are more resistant.