Suppositories: Dosage Forms & Applications

• Suppositories are solid dosage forms inserted into body orifices to melt, soften, or dissolve, exerting local or systemic effects.
• They are commonly used rectally, vaginally, and occasionally urethrally, delivering both systemic and local medications.

Suppository Shapes

• Suppositories have various shapes and weights to facilitate easy insertion and retention without causing undue distension.
• Rectal suppositories are inserted with fingers, while some vaginal suppositories may require an appliance for high placement.

Rectal Suppositories

• Rectal suppositories are typically cylindrical, about 32 mm long, with tapered ends, shaped like a bullet, torpedo, or little finger.
• Adult rectal suppositories weigh about 2 g when using cocoa butter as the base.
• Rectal suppositories for infants and children are about half the weight and size of adult suppositories and have a more pencil-like shape.

Vaginal Suppositories

• Vaginal suppositories, also called pessaries, are usually globular, oviform, or cone-shaped, weighing about 5 g with a cocoa butter base.

Urethral Suppositories

• Urethral suppositories, or bougies, are slender, pencil-shaped for insertion into the male or female urethra.
• Male urethral suppositories are 3 to 6 mm in diameter and approximately 140 mm long.
• Female urethral suppositories are about 70 mm long, weighing about 2 g when made of cocoa butter.
• Urethral suppositories can be antibacterial or local anesthetics for urethral examinations.

Fate of Suppositories

• Once inserted, the suppository base melts, softens, or dissolves, distributing medicaments to the tissues.
• Medicaments can be retained for local effects or absorbed for systemic effects, offering immediate or sustained release.
• Slow-release suppositories, like morphine sulfate with alginic acid, prolong drug release over several hours.

Local Rectal Suppositories

• Rectal suppositories for local action relieve constipation, and pain, irritation, itching, and inflammation from hemorrhoids or other anorectal conditions.
• Anti-hemorrhoidal suppositories often include local anesthetics, vasoconstrictors, astringents, analgesics, emollients, and protective agents.
• Glycerin suppositories promote laxation by locally irritating mucous membranes, likely through dehydration.

Local Vaginal Suppositories

• Vaginal suppositories or inserts intended for local effects are employed mainly as contraceptives using drugs like nonoxynol-9, also antiseptics for feminine hygiene, trichomonacides for Trichomonas vaginalis, antifungals to treat Candida albicans, and anti-infectives/antibiotics for other microorganisms.

Systemic Effect of Rectal Suppositories

• For systemic effects, the rectum and vagina's mucous membranes permit the absorption of many soluble drugs, though the vaginal route is less common.
• Advantages of the rectal route over oral therapy include avoiding drug destruction by stomach pH or enzymes, preventing stomach irritation, partially bypassing the liver, ease of administration for those unable or unwilling to swallow medication, and effectiveness for patients with vomiting.
• Examples of drugs administered rectally for systemic effect include prochlorperazine, indomethacin (NSAIDs), and ondansetron for nausea and vomiting.

Factors Affecting Drug Absorption from Rectal Suppositories

• The dose of a drug administered rectally may be greater or less than the oral dose based on the physicochemical nature of the drug, its ability to traverse physiologic barriers, and the suppository vehicle's capacity to release the drug.

Rectal Absorption - Physiological Factors

• The human rectum is approximately 15 to 20 cm long, with only 2 to 3 mL of inert mucous fluid when empty.
• The rectum lacks motility and villi, but has abundant vascularization in the submucosal region.
• Physiological factors affecting drug absorption from the rectum include colonic contents, and the pH and lack of buffering capacity of rectal fluids.

Colonic Content

• Greater systemic absorption occurs when the rectum is void of fecal matter for better drug contact with the absorbing surface.
• Evacuation enemas may be used before suppository administration.
• Conditions like diarrhea, colonic obstruction, and tissue dehydration can influence drug absorption rates.

Circulation Route

• Drugs absorbed rectally bypass the portal circulation during their first pass, allowing drugs destroyed in the liver to exert systemic effects.
• Lower hemorrhoidal veins receive the absorbed drug, bypassing the liver.
• Lymphatic circulation aids in the absorption of rectally administered drugs.

pH and Lack of Buffering Capacity

• Rectal fluids are neutral (pH 7) with no effective buffer capacity, so the drug's form is generally unchanged.
• Cocoa butter melts rapidly but its immiscibility with fluids can hinder the release of fat-soluble drugs.

Physicochemical Factors

• Physicochemical factors of the drug include lipid and water solubility, particle size, surface properties, amount of drug, and pKa.
• Physicochemical factors of the base include its ability to melt, soften, or dissolve, drug release, hydrophilic or hydrophobic character, and rheological properties.

Lipid-Water Solubility of Drug

• The lipid-water partition coefficient is important for suppository base selection and predicting drug release.
• Lipophilic drugs in fatty bases have less tendency to escape to surrounding aqueous fluids than hydrophilic drugs.
• Water-soluble bases release both water-soluble and oil-soluble drugs for absorption.

Drug Solubility and Suppository Formulation

• Fatty bases are suitable for drugs with high water solubility, while aqueous bases are for drugs with high fat solubility; intermediate solubility drugs require a balance.
• The amount of drug determines how much is available for absorption, although absorption rate plateaus beyond a specific concentration.

Particle Size

• For undissolved drugs, smaller particle sizes increase the surface area, promoting dissolution and rapid absorption.

Nature of the Base

• The base must melt, soften, or dissolve to release the drug.
• Interactions between the medicinal agent and the base can affect drug stability or bioavailability.
• Irritation from the base can trigger bowel movements and reduce absorption.

Properties of the Ideal Suppository Base

• The ideal base should be nontoxic, non-irritating, inert, compatible with medicaments, stable during storage, and easily manufactured.
• It should dissolve or disintegrate in mucous secretions or melt quickly at body temperature, remain molten for pouring, solidify rapidly, contract on cooling, and have wetting and emulsifying properties.

Suppository Bases

• Requisites for a suppository base is that it should remain solid at room temperature but soften, melt, or dissolve readily at body temperature so that the drug is fully available soon after insertion.
• Main types of suppository bases include fatty bases, water-soluble bases, and miscellaneous bases.

Fatty or Oleaginous Bases

• Cocoa butter melts quickly at body temperature but is immiscible with body fluids.
• Water-soluble drugs release well from cocoa butter.
• Cocoa butter's emollient action is superior for anorectal disorders.
• Other fatty bases include hydrogenated fatty acids of vegetable oils and fat-based compounds like glyceryl monostearate.

Cocoa Butter

• Cocoa Butter, NF, is a fat from Theobroma cacao seeds.
• It is yellowish-white with a faint chocolate odor.
• Its main constituent is triglyceride from palmitic, stearic, and oleic acids.
• It melts at 30°C to 36°C, but exhibits polymorphism.

Cocoa Butter Polymorphism

• Cocoa butter exhibits polymorphism, existing in several crystalline forms.
• Carelessly melting cocoa butter at high temperatures and quickly chilling it results in a metastable crystalline form (alpha crystals) that melts at a lower point (22°C).
• Slow, even melting is required to retain stable beta crystals for congealing.
• Disadvantages include polymorphism, adherence to molds, low melting point, low water absorbance, stability issues, unsuitability for warm climates, and relatively high cost.

Other Fatty Bases

• Other fatty bases include commercial products like Fattibase, Wecobee bases, and Witepsol bases.

Water-Soluble and Water-Miscible Bases

• The main members of this group are glycerinated gelatin and polyethylene glycols.
• Glycerinated gelatin suppositories are prepared by dissolving granular gelatin (20%) in glycerin (70%) and adding water or a solution or suspension of the medication (10%).
• Glycerinated gelatin is most frequently used in preparation of vaginal suppositories, with which prolonged local action of the medicinal agent is usually desired. The glycerinated gelatin base is slower to soften and mix with the physiologic fluids than is cocoa butter and therefore provides a slower release.
• Disadvantages include moisture absorption and tissue irritation; water can be added before insertion.

Polyethylene Glycols (PEG)

• Polyethylene glycols are polymers of ethylene oxide and water with varying molecular weights and physical states.
• They can be combined by fusion to achieve desired consistency.
• PEG suppositories dissolve slowly and don't melt at body temperature.
• They allow for slower medication release and convenient storage without refrigeration.
• PEG suppositories do not leak from the orifice since they mix with mucous secretions upon dissolution
• PEG suppositories require at least 20% water or dipping in water before use to avoid irritation.

Miscellaneous Bases

• The miscellaneous group of bases are mixtures of oleaginous and watersoluble or water-miscible materials. These materials may be chemical or physical mixtures.
• Polyoxyl 40 stearate is a surface-active agent used in several commercial suppository bases. Its melting point is generally 39°C to 45°C.
• Mixtures of fatty bases with emulsifying agents can hold water or aqueous solutions.

Preparation of Suppositories

• Suppositories are prepared by molding from a melt, compression, or hand rolling and shaping, with molding being the most frequent method.

Preparation by Molding

• Steps include melting the base, incorporating medicaments, pouring the melt into molds, cooling, and removing the suppositories.
• Cocoa butter, glycerinated gelatin, and polyethylene glycol are suitable for molding.

Suppository Molds

• Molds are made from stainless steel, aluminum, brass, or plastic.
• They should be carefully cleaned to avoid scratches.

Preparation by Compression

• The base and medicaments are forced into molds using suppository-making machines.
• Small-scale preparation uses a mortar and pestle, while large-scale uses mechanical kneading mixers.

Preparation by Hand Rolling and Shaping

• Hand rolling and shaping is a historic part of the art of the pharmacist (it requires considerable practice and skill).

Determination of the Amount of Base Required

• Generally, in preparing suppositories, the pharmacist calculates the amounts of materials needed for the preparation of one or two more suppositories than the number prescribed.
• The volume of drug substances subtracted from the total volume of the mold will give the volume of base required.
• The volume of base may be converted to weight from the density of the material.
• If the added amounts of medicaments are slight, they may be considered to be negligible, and no deduction from the total volume of base may be deemed necessary.
• If the quantity of active drug is less than 100 mg per 2 g suppository weight then the volume occupied by the powder is insignificant and need not be considered
• If considerable quantities of other substances are to be used, the volumes of these materials are important and should be used to calculate the amount of base actually required to fill the mold.

Displacement Value (D.V)

• Displacement value is defined as the quantity of drug that displaces one part of the base.
• If the density of the drug equals the density of the base, the drug will displace the same amount of base.
• If the density of the drug is more than the density of the base the drug will displace low amount of base
• If the density of the drug is less than the density of the base the drug will displaces high amount of base
• DV. for liquids equals 1

Vaginal Suppositories

• The most commonly used base for vaginal suppositories consists of combinations of the various molecular weight polyethylene glycols.
• To this base is frequently added surfactants and preservative agents, commonly the parabens.
• Many vaginal suppositories and other types of vaginal dosage forms are buffered to an acid pH usually about 4.5, consistent with the normal vagina.

Vaginal Inserts

• Vaginal tablets are more widely used, easier to manufacture, more stable, and less messy.
• Vaginal tablets, frequently referred as vaginal inserts, are usually ovoid and are accompanied in their packaging with a plastic inserter, a device for easy placement of the tablet within the vagina.
• They contain anti-infective and hormonal substances, formulated to contain lactose as the base or filler, a disintegrating agent such as starch, a dispersing agent such as polyvinylpyrrolidone, and a tablet lubricant such as magnesium stearate.
• Some vaginal inserts are capsules of gelatin containing medication to be released intravaginally.

Packaging and Storage

• Most commercial suppositories are individually wrapped in foil or plastic to prevent contact and adhesion.
• Suppositories containing light-sensitive drugs are individually wrapped in an opaque material such as a metallic foil.
• Cocoa butter suppositories must be stored below 30°C and preferably in a refrigerator (2°C to 8°C).
• Glycerinated gelatin suppositories can be stored at controlled room temperature (20°C to 25°C).
• Suppositories made from a base of PEG may be stored at usual room temperatures.
• Suppositories stored in high humidity may absorb moisture and tend to become spongy, whereas suppositories stored in places of extreme dryness may lose moisture and become brittle.