Pharmaceutical Science: Suppository Formulation

Compounding of Suppositories & Pessaries

• The rectum is the straight section of the GI tract, extending from the last 150-200 mm of the colon.
• It has a hollow structure with a smooth, flat inner surface.
• Three rectal valves are present inside.
• The anus separates the rectum from the external environment.

Rectal Subdivision

• The rectum is divided into two main parts: the anal canal (taking up 20%) and the ampulla (making up 80%).
• The rectal wall has a single layer of epithelial cells, with cylindrical and goblet cells, including mucus.
• The total surface area of the rectal mucosa is approximately 300 cm², and its volume is roughly 3 mL.
• The pH of the rectum is 7.5, and its buffer capacity is minimal.

Rectal Anatomy

• The rectum is illustrated with sections of anal columns, the pectinate line, external and internal anal sphincters, and the anal canal.

Rectal Drug Delivery Advantages

• Delivering drugs rectally offers both localized and systemic effects.
• Drug absorption occurs primarily through passive diffusion.
• Sterase and peptidase enzymes are absent in the rectal tract.
• Beneficial for patients who can't take oral medications (due to vomiting, unconsciousness, or other factors) or for drugs that are sensitive to stomach acid, enzymes, or the first-pass effect in the liver.
• Useful for drugs with a bad taste.

Rectal Drug Delivery Disadvantages

• Patients often have a strong aversion to rectal administration.
• Absorption is slow and incomplete in the rectal region.
• Poorly absorbed low-solubility drugs are ill-suited for this method.
• Variability occurs in absorption responses between individuals.
• Proctitis (inflammation of the rectum) is a potential complication.
• Production and storage of suppositories can pose challenges due to temperature sensitivity and other issues.

Vaginal Anatomy

• The vagina is a 10 cm fibromuscular tube with an approximate surface area of 60 cm².
• The vagina has three distinct layers: the adventitia, mucosa, and muscularis.
• The presence of rugae and micro-ridges on the epithelial surface increases surface area.
• A substantial network of blood vessels in the vaginal wall enables both local and systemic drug absorption.

Vaginal pH

• The pH of the vagina is maintained at a level of 3.5-4.5 by the bioconversion of lactic acid produced by vaginal microflora.
• Vaginal fluids result from secretions from various glands.
• Peptidase enzymes are present in the vagina and will degrade protein and amino acids but have lower activity compared to the GI tract.
• Vaginal wall thickness, fluid volume and pH are influenced by age, cyclical changes and pregnancy for example a 50-year-old woman may have a less thick vaginal wall.

Intravaginal Delivery Advantages

• The vagina's structure retains drug forms, making drug release prolonged.
• Systemic side effects are minimized.
• High bioavailability.
• Avoidance of first-pass metabolism by the liver.
• Quicker drug onset of action.
• Self-medication is possible.

Intravaginal Delivery Disadvantages

• This delivery method is gender specific.
• Cultural and traditional aversion may lead to non-compliance from individuals receiving treatment.
• A limited selection of drugs is available for this method.
• Variability in drug absorption among individuals.
• Personal hygiene is a concern.
• Some drugs are sensitive to vaginal pH.
• Sexual activity can impact dosage.

Rectal Preparations

• Rectal medications are intended for absorption with optional systemic or topical effect, which can include diagnoses.
• Common types of rectal preparations include suppositories, rectal capsules, solutions, suspensions, powders, tablets, semi-solid preparations (like ointments), enemas, foams, and tampons.

Vaginal Preparations

• Also used for local and systemic effects.
• Dosage forms like pessaries, suppositories, vaginal tablets, capsules, solutions, sprays, ointments, and foams are possible.

Suppository Description

• Typically 32 mm (1.5 inches) long, cylindrical with an optional tapered end, bullet, or torpedo shape for easier insertion.
• Weights vary.

Suppository Drug Types

• Local use as in hemorrhoid treatment, laxatives, or anal pain relief.
• Systemic use for pain relief (e.g. analgesia, like oxymorphone HCl) or nausea and vomiting medication.
• Drug content can vary between 0.1% and 40%.

Suppository Base Characteristics & Release

• Suppository bases must melt, soften, or dissolve at body temperature to release their medication.
• The base type affects release; dissolving in the rectum, melting on the mucus layer, or other actions.
• Dissolution rate is limited by rectal fluid amounts.
• Dissolved drugs enter the mucosal layer while suspended drugs go through the rectal motility or gravity before dissolving.

Suppository Base Types

• Fatty or oleaginous bases are common options, like cocoa butter (classic), hydrogenated fatty acids from vegetable oils, and mixtures to achieve the desired texture and temperature properties.
• Cocoa butter is a fatty base made from Theobroma cacao seed that has a yellowish-white solid consistency.
• A triglyceride of various fatty acids (e.g., oleopamito-stearin and olea-distearin) makes it's melting range 30-36°C.
• It is often combined with other substances to modify its properties.
• Other options include synthetic/semi-synthetic bases produced by hydrogenation of vegetable oils and various mixtures with varying textures and properties. These include ADEPS SOLIDUS, FATBASE, and mixtures from palm, coconut, and/or other oils with self-emulsifying agents. Another option comprises white petrolatum with polyethylene glycol (PEG).

Water-Soluble/Water-Miscible Bases

• Glycerinated gelatin and polyethylene glycols (PEGs) are water-soluble/water-miscible bases.
• Glycerinated gelatin (GG) involves mixing granular gelatin (20%) in glycerin (70%) along with medicine (10%).
• Primarily used for suppositories and medications.
• PEGs are ethylene oxide and water polymers. A variety of molecular weights (300, 400, 600, 1000, 1540, 3350, 4000, 6000, and 8000) yield varied solid or liquid properties. Melting ranges increase with higher molecular weights.

Miscellaneous Bases

• Chemical or physical mixtures of oleaginous and water-soluble substances.
• Preformed emulsions (e.g., polyoxyl 40 stearate) are another option.

Displacement Value of Bases

• Displacement value (DV) determines the weight portions of active ingredient that a base in a suppository displaces.
• DV is often used to calculate the needed weight of base when making suppositories.
• Typical DVs are shown against common medications used in suppositories.

Preparing Suppositories via Moulding

• Melt the base and add the medication
• Pour into a pre-made mold.
• Allow the mixture to solidify.
• Remove the suppositories.
• Moulds made from steel, aluminum, brass, or plastic and lubricated with oils (like liquid paraffin) to ease removal.
• Moulds need calibration and volume specifications, and often an extra amount of suppositories is made to account for losses.

Suppository Size & Content

• Common suppository sizes are 1g and 2g.
• Nominal sizes represent the base weight needed to fill the suppository mold; they don't reflect the actual final weight of the finished product.

Adding Solids/Liquids to Bases

• Adding insoluble solids requires reducing their size (trituration) and including them in a portion of the melted base.
• Stir well to ensure drug dispersal into the base.
• Soluble solids are added directly and stirred well into the molten base.
• Liquids are added to the molten base, followed by mixing until dispersed. If dealing with extracts, allow some cooling.

Suppository Shelf Life, Packaging, and Labeling

• For stable products (suppositories and pessaries), storage at cool temperatures with proper packaging is crucial.
• Typical shelf life is up to 4 weeks.
• Materials like PVC or foil are common packaging materials.
• Clarity in labeling (storage conditions, 'use only as directed', 'do not swallow', 'rectal' or 'vaginal use only', etc) is essential.