Name: Pharmaceutical Dosage Chapter 12: Suppositories and Inserts Suppositories y From the Latin word, supponere meaning

to place under y Semisolid dosage forms for insertion into the body orifices y Melt, soften, or dissolve and exert localized or systemic effects y Types  Rectal suppository  Cylindrical and tapered at one end  Bullet-shaped  1 gram for infants and 2 grams for adult  Vaginal suppository  Pessaries  Globular oviform or conical in shape  3 to 5 grams in weight  Urethral suppository  Bougies  Pencil-shaped: 4 to 5nm  For males: weigh 4 grams, 100 to 150mm long  For females: 2 grams, 60 to 70mm long Advantages of Suppositories y Taken when a drug:  Cannot be tolerated: cause to vomit orally  Cannot be swallowed: cause choking  Decomposed or inactivated by pH or enzymes in the GIT  Destroyed in the liver (oral administration) Disadvantages of Suppositories y Inconvenient, absorption is irregular and difficult to predict Local Action y Suppository base melts distributing the medicaments to the tissue of the region y Rectal suppository: relieves constipation or pain, irritation, itching and inflammation like hemorrhoids and other anorectal conditions y Glycerin suppositories: laxative action by irritating the mucous membranes through its dehydrating action y Vaginal suppository for localized effects: contraceptives (Nonoxynol 9) and antiseptic in feminine hygiene and specific agents to combat invading pathogens (Trichomonas vaginalis, Candida [monilia] albicans, Hemophilus vaginalis) y Urethral suppository: antibacterial and local anesthetic prepared to urethral examination, contraceptive agents Systemic action y Mucous membrane of the rectum and vagina: permits absorption of many soluble drugs Examples of Rectal Suppository for Systemic Effects y Aminophylline and theophylline: relief of asthma y Prochlorperazine and chlorpromazine: nausea and vomiting and as tranquilizers y Chloral hydrate: sedative and hypnotic y Oxymorphone HCl: narcotic analgesic y Ergotamine tartrate: migraine syndrome y Aspirin: analgesic and antipyretic Advantages over Oral Therapy of the Rectal Route of Administration for Achieving Systemic Effects y Drugs  Destroyed or inactivated by the pH or enzymatic activity of the stomach or intestines need not to be exposed to these destructive environments

 
y

Destroyed by portal circulation: may bypass the liver after rectal absorption Irritating to the stomach may be given without causing such irritation

Route is:  Convenient for administration of drugs to adult or pediatric patients who may be unable or unwilling to swallow medications  Effective in the treatment of patients with vomiting episodes Some Factors of Drug Absorption from Rectal Suppositories y Physiologic factors  Colonic contents  Drug have greater absorption in the absence of fecal matter  Other conditions (diarrhea, colonic obstruction due to tumor growths and tissue dehydration) influence rate and degree of drug absorption  Circulation route  Drugs rectally absorbed: bypass the portal circulation, thus enable drugs (destroyed in the liver) to exert systemic effects  Lymphatic circulation also assists in the absorption of rectally administered drug.  pH and lack of buffering capacity of the rectal fluids  Rectal fluids neutral in pH and have no effective buffer capacity therefore drugs do not chemically changed y Physicochemical factors of the drug  Drug  Relative solubility of the drug in lipid and in water  Particle size of the dispersed drug  Suppository base  Ability to melt, soften, and dissolve at body temperature  Ability to release the drug substance  Its hydrophilic or hydrophobic character For Systemic Drug Action Using Cocoa Butter Base y Preferable to incorporate ionized form (salt form) to maximize bioavailability Physicochemical Factors of Suppository Base y Lipid-water solubility  A lipophilic drug distributed in a fatty suppository base in low concentration has lesser tendency to escape to the surrounding aqueous fluids than a hydrophilic substance in fatty base. y Particle size  Influences released and dissolved amount in absorption  The smaller, the readily the dissolution and greater chance for rapid absorption. Suppository Base y Capable of melting, softening, or dissolving to release its drug components for absorption Undesirable Characteristics of a Base y Interacts with the drug, inhibiting its release: drug absorption prevented or delayed y Irritating to the mucous membrane of the rectum, initiating a colonic response and prompt to a bowel movement: negating drug release and absorption

Classification of Suppository Base y Fatty or oleaginous bases  Frequently employed since cocoa butter (triglyceride) is a member of other triglycerides  Wecobee bases: derived from coconut oil  Witepsol bases: saturated fatty acids C12 to C18  Other fatty oleaginous materials  Hydrogenated fatty acids of vegetable oils (palm kernel oil and cottonseed oil)  Fat based compounds containing compounds of glycerin HMW fatty acids: palmitic and stearic acids (glyceryl monostearate and glyceryl monopalmitate) y Water-soluble or water-miscible bases  Main members of this group are bases of:  Glycerinated gelatin o Have tendency to absorb moisture due to the hygroscopic nature of glycerin causing the following effect:  May lose their shape and consistency  May lose dehydrating effect and be irritating to the tissues upon insertion o Remedy  Water present minimizes these effects  Suppository is moistened with water prior to insertion (reduce tendency of base to draw water from the mucous membranes and irritates tissue)  Bases of polyethylene glycols o Polymers of ethylene oxide and water prepared to various chain lengths, molecular weight ranges of 200, 400, 600, 1000, 1500, 1540, 3350, 4000, 6000, and 8000 and physical states  Do not melt at body temperature and dissolve slowly in the bodys fluids  Slower release of medication from the base once inserted  Permits the convenient storage without need of refrigeration and without danger of softening

 

excessively in warm weather Do not leak from the orifice Dipped in water before use to avoid irritation of mucous membrane

Miscellaneous bases  Mixture of oleaginous and water-miscible materials  Mixture of many fatty acids with emulsifying agents capable of forming without emulsion: also referred as hydrophilic suppository base  A soap as a base like glycerin suppositories which have sodium stearate Cocoa Butter y A triglyceride (glycerin + one or different fatty acids) primarily of oleopalmitostearin and oleodistearin y Melts between 30o to 36oC y Ideal suppository base, melting just below body temperature maintaining solidity at room temperature y Exhibits marked polymorphism (to exist in several different crystalline forms, with the triglyceride content) y Crystalline form represents a metastable condition ( crystals with lower melting point), slow transition to the more stable form of crystals (greater stability and high melting point) y Slowly and evenly melted on a water bath  Avoid formation of unstable crystalline form  Ensure the retention in the liquid of the more stable crystals y Lowers the melting point when incorporated: phenol and chloral hydrate y Solidifying agents melted with cocoa butter to compensate for the softening effect of the added substances  Cetyl esters wax (20%)  Beeswax (4%) Different Preparations of Suppositories y Molding from melt or fusion (commonly employed in small scale and industrial scale) y Cold compression y Hand molding or rolling and shaping y Compression in a tablet press Preparation of Suppositories y Preparation by molding  Melting of the base preferably in water or stream bath to avoid local overheating  Incorporating the required medicament: either emulsified or suspend in it  Pouring the melt into the cooled metal mold which are usually chrome or nickel plate  Allowing the melt to cool and congeal thoroughly using refrigerator in a small scale or refrigerated air on a larger scale  Removing the formed suppositories from the mold Suppository Molds y Made from stainless steel, aluminium, bass or plastic y Separated into sections (longitudinally), opened for cleaning before and after a batch preparation of suppository y Scratches should be avoided especially the plastic Lubricating the Molds y Before the melt is poured:
y

Facilitates cleaning and easy removal of the molded suppository y Lubricant used: thin coating mineral oil or expressed almond oil applied with the finger to the molding surface y Seldom necessary when the suppository base is cocoa butter or PEG (contract sufficiently on cooling within the mold to separate from the inner surfaces and allow easy removal) y Necessary when glycerinated gelatine suppositories are prepared Calibration of Molds y Calibrate each of suppository molds for the suppository bases to have proper quantity of medicament y Suppositories are weighed and the total weight and average weight of each are recorded y Suppositories are carefully melted in a calibrated beaker (determine the volume of the mold) y The volume of the melt is determined for the total number as well as the average of one suppository Determination of the Amount of Base Required y First method  Total volume needed: volume of the drug substance y Second method  Requires the following steps:  Weigh the active ingredient for the preparation of a single suppository  Dissolve or mix it with a portion of melted base insufficient to fill one cavity of the mold  Place the mixture to the mold  Add additional melted base to the cavity to completely fill the mold  Remove the suppository from the mold and weigh  Total weight of the suppository:  Weight of the ingredient = amount of the base needed X number of suppositories to make = total base needed Preparing and Pouring of the Melt y Weighed suppository base material is melted (least possible heat0 over water bath y Medicinal substance incorporated into a portion of the melted base by mixing on a glass or porcelain tile with spatula, stir and allowed to cool almost to its congealing point y The pouring must be continuous to prevent layering which may lead to a product easily broken on handling y When solidified: the excess material is scraped off the top of the mold with spatula. The mold is placed in the freezer to hasten hardening of the suppository. y When suppositories are hard, the mold is removed from the freezer and dislodged the suppositories from the mold. y Generally, little pressure is required to let fall the suppository of their mold. Preparation by Compression y Prepared by forcing the mixed mass of the suppository base and the medicament into special molds using suppository molding machines y On a small scale a mortar is heated in warm water before use and then dried, the softening of the base and the mixing process are greatly facilitated forming a paste-like consistency  Suppository mass is placed in the cylinder

Pressure is applied from one end (by turning wheel) and the mass is forced out at the other end  A movable end plate at the back of the die is removed (die is filled with mass)  Additional pressure is applied to the mass in the cylinder  Formed suppositories are ejected Advantages of Preparation by Compression y Method is simple y Resulting suppository is more elegant that of hand molding y Avoid the possibilities of sedimentation of the insoluble solids in the suppository base Disadvantages of Preparation by Compression y Too slow for large scale operation y Triturate in a mortar, then formed in into a ball in the palms of the hands previously cooled in the ice water y A broad bladed spatula or flat board is used to roll it to a cylinder on a pile tile y Cut with a spatula into sections and shaped desired Compression in a Tablet Press y Carbon dioxide releasing tablet (compressed rectal suppository)  Made of dried sodium biphosphate, NaHCO3 and starch  Dipped or sprayed with a coating of water soluble PEG to add film for protection of the core for the aid in insertion into rectum y Vaginal compressed tablet  Contains active ingredients and lactose and/or phosphoric acids for adjusting the acidity of the vagina to pH 5 Information Patients Need to Know About Suppositories y Using half of a suppository should cut it lengthwise with clean razor blade y Dispensed in paper, foil, or plastic wrappings y Removal of wrapper before insertion Packaging and Storage y Packaging  Glycerin suppository and glycerinated gelatin suppository  Tightly closed containers to prevent moisture change  Cocoa butter based suppository  Individually wrapped or separated in compartment bases  Light sensitive drugs  Individually wrapped in opaque material (metallic foil) y Storage  Cocoa butter suppository base  Below 300C or 860F  In a refrigerator: 2o to 80oC or 68o to 770oF  Glycerinated gelatin suppository  Below 350F  Controlled room temperature  20o to 250C or 68o to 770F  PEG suppository base  Room temperature  Stored of high humidity  Absorbs moisture and becomes spongy  Extreme dryness  Lose moisture and becomes brittle Vaginal Inserts (Vaginal Tablets) y More widely used than the vaginal suppositories

Easier to manufacture, more stable and less messy Avoid accompanied with a plastic inserter for easy placement y Contain same types of anti-infective and hormonal substances as vaginal suppositories y Prepared by tablet compression and formulated with:  Base or filler: lactose  Disintegrating agent: starch  Dispersing agent: PVP  Lubricant: magnesium stearate y Some are capsules of gelatin containing medication to be released intravaginally y Also used rectally, insertion facilitated by lightly wetting with water Other Inserts y Tablet and capsules  Vaginal tablet and inserts
y y

y y y y y y y y

Oinments, creams, and aerosol forms  Protofoam Jellies and gels Contraceptive sponge Intrauterine progesterone drug delivery system  Progestasert Powders Solutions  Vaginal douches Enemas  Retention and evacuation enemas Suspensions  Barium sulfate suspension

Table 12.1: Examples of Rectal Suppositories Suppository Bisacodyl Chlorpromazine Hydrocortisone Hydromorphone Mesalamine Oxymorphone Prochlorperazine Commercial Product Dulcolax (Ciba) Thorazine (SmithKline Beecham) Anusol-HC (Warner-Lambert) Dilaudid (Knoll) Canasa (Axcan Scandipharm) Numorphan (Endo) Compazine (SmithKline Beecham) Phenergan (Wyeth-Ayerst) Active Constituent 10 mg 25, 100 mg 25 mg 3 mg 500 mg 5 mg 2.5, 5, 25 mg Type of Effect Local Systemic Local Systemic Local Systemic Systemic Category and Comments Cathartic. Base: hydrogenated vegetable oil Antiemetic; tranquilizer. Base: glycerin, glyceryl monopalmitate, glyceryl monostearate, hydrogenated fatty acids of coconut and palm kernel oils Pruritus ani, inflamed hemorrhoids, other inflammatory conditions of the anorectum. Base: hydrogenated glycerides Analgesic. Base: cocoa butter with silicone dioxide Anti-inflammatory. Base: hard fat Analgesic. Base: Polyethylene glycols 1000 and 3350 Antiemetic. Base: glycerin, monopalmitate, glyceryl monostearate, hydrogenated fatty acids of coconut and palm kernel oils Antihistamine, antiemetic, sedative: used to manage allergic conditions; preoperative sedation or nausea and vomiting; motion sickness. Base: cocoa butter, white wax.

Promethazine

12.5, 25, 50 mg

Systemic

Table 12.2: Examples of Vaginal Suppositories and Tablets Product Active Ingredients Category and (Manufacturer) Comments AVC Suppositories Sulfanilamide 1.05g For Candida albicans (Novavax) infections Monistat 7 Miconazole nitrate Antifungal for local Suppositories 200mg vulvovaginal (Advanced Care candidiasis Products) (moniliasis) Mycelex-G Vaginal Clotrimazole 500mg Vulvovaginal yeast Tablets (Bayer) (Candida) infections Semicid Vaginal Nonoxynol-9 100mg Nonsystemic Contraceptive Inserts reversible birth (Robins Healthcare) control

Multiple choices: Try it! Choices: A. Rectal suppository B. Vaginal suppository C. Urethral suppository D. Local Action E. Systemic action F. Tablet and capsules G. Ointments, creams, and aerosol forms H. Intrauterine progesterone drug delivery system I. Solutions J. Enemas K. Suspensions Questions: 1. 2. 3. ___ Protofoam ___ Globular oviform or conical in shape ___ Rectal suppository: relieves constipation or pain, irritation, itching and inflammation like hemorrhoids and other anorectal conditions ___ For males: weigh 4 grams, 100 to 150mm long ___ Vaginal tablet and inserts ___ Cylindrical and tapered at one end ___ For females: 2 grams, 60 to 70mm long ___ Mucous membrane of the rectum and vagina: permits absorption of many soluble drugs ___ Progestasert ___ Glycerin suppositories: laxative action by irritating the mucous membranes through its dehydrating action ___ Barium sulfate ___ Retention and evacuation ___ Vaginal douches

Choices: A. Colonic contents B. Circulation route C. pH and lack of buffering capacity of the rectal fluids D. Physicochemical factors of the drug E. Undesirable characteristics of a base F. For systemic drug action using cocoa butter base G. Different preparations of suppositories H. Suppository molds I. First method J. Second method Questions: 1. ___ Some factors of drug absorption from rectal suppositories 2. ___ Drug has greater absorption in the absence of fecal matter 3. ___ Irritating to the mucous membrane of the rectum, initiating a colonic response and prompt to a bowel movement: negating drug release and absorption 4. ___ Lymphatic circulation also assists in the absorption of rectally administered drug. 5. ___ Rectal fluids neutral in pH and have no effective buffer capacity therefore drugs do not chemically changed 6. ___ Preferable to incorporate ionized form (salt form) to maximize bioavailability 7. ___ Cold compression 8. ___ Made from stainless steel, aluminium, bass or plastic 9. ___ Weigh the active ingredient for the preparation of a single suppository 10. ___ Total volume needed: volume of the drug substance

4. 5. 6. 7. 8. 9. 10.

11. 12. 13. Choices: A. B. C. D. E. F. G. H. I. J. K.

Aminophylline and theophylline Prochlorperazine and chlorpromazine Chloral hydrate Oxymorphone HCl Ergotamine tartrate Aspirin Wecobee bases Witepsol bases Cocoa butter Cocoa butter suppository base Glycerinated gelatin suppository

Questions: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. ___ Nausea and vomiting and as tranquilizers ___ Relief of asthma ___ Narcotic analgesic ___ Derived from coconut oil ___ Saturated fatty acids C12 to C18 ___ Analgesic and antipyretic ___ Migraine syndrome ___ Sedative and hypnotic ___ Melts between 30o to 36oC ___ Below 350F ___ In a refrigerator: 2o to 80oC or 68o to 770oF