Name: Destroyed by portal circulation: may bypass the Pharmaceutical Dosage liver after rectal absorption Chapter 12: Suppositories and Inserts Irritating to the stomach may be given without Suppositories causing such irritation y y From the Latin word, supponere meaning ³to place under´ Route is: y Semisolid dosage forms for insertion into the body orifices Convenient for administration of drugs to adult or y pediatric patients who may be unable or Melt, soften, or dissolve and exert localized or systemic unwilling to swallow medications effects y Effective in the treatment of patients with Types vomiting episodes Rectal suppository Some Factors of Drug Absorption from Rectal Suppositories Cylindrical and tapered at one end y Physiologic factors Bullet-shaped Coloniccontents 1 gram for infants and 2 grams for adult Drug have greater absorption in the Vaginal suppository absence of fecal matter Pessaries O ther conditions (diarrhea, colonic Globular oviform or conical in shape obstruction due to tumor growths and 3 to 5 grams in weight tissue dehydration) influence rate and Urethral suppository degree of drug absorption Bougies Circulationroute Pencil-shaped: 4 to 5nm Drugs rectally absorbed: bypass the For males: weigh 4 grams, 100 to portal circulation, thus enable drugs 150mm long (destroyed in the liver) to exert For females: 2 grams, 60 to 70mm long systemic effects Advantages of Suppositories Lymphatic circulation also assists in y Taken when a drug: Cannot be tolerated: cause to vomit orally the absorption of rectally administered Cannot be swallowed: cause choking drug. Decomposed or inactivated by pH or enzymes in pH and lack of buffering capacity of the rectal fluids the GIT Rectal fluids neutral in pH and have no Destroyed in the liver (oral administration) effective buffer capacity therefore Disadvantages of Suppositories drugs do not chemically changed y Inconvenient, absorption is irregular and difficult to predict y Physicochemical factors of the drug Local Action y Drug Suppository base melts distributing the medicaments to the Relative solubility of the drug in lipid tissue of the region and in water y Rectal suppository: relieves constipation or pain, irritation, Particle size of the dispersed drug itching and inflammation like hemorrhoids and other Suppositorybase anorectal conditions Ability to melt, soften, and dissolve at y Glycerin suppositories: laxative action by irritating the body temperature mucous membranes through its dehydrating action Ability to release the drug substance y Vaginal suppository for localized effects: contraceptives Its hydrophilic or hydrophobic (Nonoxynol 9) and antiseptic in feminine hygiene and character specific agents to combat invading pathogens For Systemic Drug Action Using Cocoa Butter Base (Trichomonas vaginalis, Candida [monilia] albicans, y Preferable to incorporate ionized form (salt form) to Hemophilus vaginalis) maximize bioavailability y Urethral suppository: antibacterial and local anesthetic Physicochemical Factors of Suppository Base prepared to urethral examination, contraceptive agents y Lipid-water solubility Systemic action A lipophilic drug distributed in a fatty y Mucous membrane of the rectum and vagina: permits suppository base in low concentration has lesser absorption of many soluble drugs tendency to escape to the surrounding aqueous Examples of Rectal Suppository for Systemic Effects fluids than a hydrophilic substance in fatty base. y Aminophylline and theophylline: relief of asthma y Particle size y Prochlorperazine and chlorpromazine: nausea and vomiting Influences released and dissolved amount in and as tranquilizers absorption y Chloral hydrate: sedative and hypnotic The smaller, the readily the dissolution and y Oxymorphone HCl: narcotic analgesic greater chance for rapid absorption. y Ergotamine tartrate: migraine syndrome Suppository Base y Aspirin: analgesic and antipyretic y Capable of melting, softening, or dissolving to release its Advantages over Oral Therapy of the Rectal Route of Administration drug components for absorption for Achieving Systemic Effects Undesirable Characteristics of a Base y Drugs y Interacts with the drug, inhibiting its release: drug Destroyed or inactivated by the pH or enzymatic absorption prevented or delayed activity of the stomach or intestines need not to y Irritating to the mucous membrane of the rectum, initiating be exposed to these destructive environments a colonic response and prompt to a bowel movement: negating drug release and absorption
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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 lose May dehydrating effect and be irritating to the tissues upon insertion o Remedy present Water minimizes these effects is Suppository 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 body¶s fluids Slower release of medication from the base once inserted the Permits convenient storage without need of refrigeration and without danger of softening
y
Miscellaneous bases
excessively in warm weather Do not leak from the orifice Dipped in water before use to avoid irritation of mucous membrane
Mixture
of oleaginous and water-miscible materials Mixture of many fatty acids with emulsifying agents capable of forming without emulsion: also referred as ³hydrophilic´ 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 o o y Melts between 30 to 36 C 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:
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Facilitates
cleaning and easy removal of the Pressure is applied from one end (by turning molded suppository wheel) and the mass is forced out at the other end y Lubricant used: thin coating mineral oil or expressed A movable end plate at the back of the die is removed (die is filled with mass) almond oil applied with the finger to the molding surface y Additional pressure is applied to the mass in the Seldom necessary when the suppository base is cocoa cylinder butter or PEG (contract sufficiently on cooling within the Formed suppositories are ejected mold to separate from the inner surfaces and allow easy Advantages of Preparation by Compression removal) y y Method is simple Necessary when glycerinated gelatine suppositories are y prepared Resulting suppository is more elegant that of hand molding y Calibration of Molds Avoid the possibilities of sedimentation of the insoluble y solids in the suppository base Calibrate each of suppository molds for the suppository Disadvantages of Preparation by Compression bases to have proper quantity of medicament y y Suppositories are weighed and the total weight and average Too slow for large scale operation y weight of each are recorded Triturate in a mortar, then formed in into a ball in the palms y of the hands previously cooled in the ice water Suppositories are carefully melted in a calibrated beaker y A broad bladed spatula or flat board is used to roll it to a (determine the volume of the mold) y cylinder on a pile tile The volume of the melt is determined for the total number y Cut with a spatula into sections and shaped desired as well as the average of one suppository Determination of the Amount of Base Required Compression in a Tablet Press y y Carbon dioxide releasing tablet (compressed rectal First method suppository) Total volume needed: volume of the drug substance Made of dried sodium biphosphate, NaHCO3 and y starch Second method Dipped or sprayed with a coating of water soluble Requires the following steps: PEG to add film for protection of the core for the Weigh the active ingredient for the aid in insertion into rectum preparation of a single suppository y Dissolve or mix it with a portion of Vaginal compressed tablet melted base insufficient to fill one Contains active ingredients and lactose cavity of the mold and/or phosphoric acids for adjusting the acidity of the vagina to pH 5 Place the mixture to the mold Add additional melted base to the Information Patients Need to Know About Suppositories y cavity to completely fill the mold Using half of a suppository should cut it lengthwise with clean razor blade Remove the suppository from the mold y and weigh Dispensed in paper, foil, or plastic wrappings y Total weight of the suppository: Removal of wrapper before insertion Weight of the ingredient = Packaging and Storage amount of the base needed X y Packaging number of suppositories to Glycerin suppository and glycerinated make = total base needed gelatin suppository Preparing and Pouring of the Melt Tightly closed containers to prevent y Weighed suppository base material is melted (least possible moisture change heat0 over water bath Cocoa butter based suppository y Medicinal substance incorporated into a portion of the Individually wrapped or separated in melted base by mixing on a glass or porcelain tile with compartment bases spatula, stir and allowed to cool almost to its congealing Light sensitive drugs point Individually wrapped in opaque y The pouring must be continuous to prevent µlayering¶ material (metallic foil) y which may lead to a product easily broken on handling Storage y When solidified: the excess material is scraped off the top Cocoa butter suppository base of the mold with spatula. The mold is placed in the freezer Below 300°C or 860°F to hasten hardening of the suppository. In a refrigerator: 2o to 80oC or 68o to y 770oF When suppositories are hard, the mold is removed from the freezer and dislodged the suppositories from the mold. Glycerinated gelatin suppository y Below 350°F Generally, little pressure is required to let fall the Controlled room temperature suppository of their mold. 20o to 250°C or 68o to 770°F Preparation by Compression y PEG suppository base Prepared by forcing the mixed mass of the suppository base Room temperature and the medicament into special molds using suppository Stored of high humidity molding machines y Absorbs moisture and becomes spongy On a small scale a mortar is heated in warm water before Extremedryness use and then dried, the softening of the base and the mixing Lose moisture and becomes brittle process are greatly facilitated forming a paste-like V aginal Inserts ( V aginal T ablets) consistency y More widely used than the vaginal suppositories Suppository mass is placed in the cylinder
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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
Oinments, creams, and aerosol forms
y
Jellies and gels
Protofoam
y
Table 12.1: Examples of Rectal Suppositories
Suppository Bisacodyl
Commercial Product Dulcolax (Ciba)
Active Constituent
y y
y y
y
y
Contraceptive sponge Intrauterine progesterone drug delivery system Progestasert Powders Solutions Vaginal douches Enemas Retention and evacuation enemas Suspensions Barium sulfate suspension
Type of
10 mg
Effect Local
Chlorpromazine
Thorazine (SmithKline Beecham)
25, 100 mg
Systemic
Hydrocortisone
Anusol-HC (Warner-Lambert)
25 mg
Local
Hydromorphone Mesalamine Oxymorphone
Dilaudid (Knoll) Canasa (Axcan Scandipharm) Numorphan (Endo)
3 mg 500 mg 5 mg
Systemic Local Systemic
Prochlorperazine
Compazine (SmithKline Beecham)
2.5, 5, 25 mg
Systemic
Promethazine
Phenergan (Wyeth-Ayerst)
12.5, 25, 50 mg
Systemic
Category and Comments
Cathartic. Base: hydrogenated vegetable oil Antiemetic; tranquilizer. Base: glycerin, glyceryl monopalmitate, glyceryl monostearate, hydrogenated fat acids of coconut and palm kernel oils Pruritus ani, inflamed hemorrhoids, other inflammatory conditions of the anorectum. Base: hydrogenated glycerid 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 p kernel oils Antihistamine, antiemetic, sedative: used to manage aller conditions; preoperative sedation or nausea and vomitin motion sickness. Base: cocoa butter, white wax.
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 Antifungal for local Monistat 7 Miconazole nitrate vulvovaginal Suppositories 200mg candidiasis (Advanced Care Products) (moniliasis) Clotrimazole 500mg Vulvovaginal yeast Mycelex-G Vaginal (Candida) infections Tablets (Bayer) Semicid Vaginal Nonoxynol-9 100mg Nonsystemic Contraceptive Inserts reversible birth (Robins Healthcare) control
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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
Choices:
Questions:
Questions:
1. ___ Protofoam 2. ___ Globular oviform or conical in shape 3. ___ Rectal suppository: relieves constipation or pain, irritation, itching and inflammation like hemorrhoids and other anorectal conditions 4. ___ For males: weigh 4 grams, 100 to 150mm long 5. ___ Vaginal tablet and inserts 6. ___ Cylindrical and tapered at one end 7. ___ For females: 2 grams, 60 to 70mm long 8. ___ Mucous membrane of the rectum and vagina: permits absorption of many soluble drugs 9. ___ Progestasert 10. ___ Glycerin suppositories: laxative action by irritating the mucous membranes through its dehydrating action 11. ___ Barium sulfate 12. ___ Retention and evacuation 13. ___ Vaginal douches Choices: A. Aminophylline and theophylline B. Prochlorperazine and chlorpromazine C. Chloral hydrate D. Oxymorphone HCl E. Ergotamine tartrate F. Aspirin G. Wecobee bases H. Witepsol bases I. Cocoa butter J. Cocoa butter suppository base K. Glycerinated gelatin suppository
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
1. 2. 3.
4. 5. 6. 7. 8. 9. 10.
___ Some factors of drug absorption from rectal suppositories ___ Drug has greater absorption in the absence of fecal matter ___ Irritating to the mucous membrane of the rectum, initiating a colonic response and prompt to a bowel movement: negating drug release and absorption ___ Lymphatic circulation also assists in the absorption of rectally administered drug. ___ Rectal fluids neutral in pH and have no effective buffer capacity therefore drugs do not chemically changed ___ Preferable to incorporate ionized form (salt form) to maximize bioavailability ___ Cold compression ___ Made from stainless steel, aluminium, bass or plastic ___ Weigh the active ingredient for the preparation of a single suppository ___ Total volume needed: volume of the drug substance
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 350°F ___ In a refrigerator: 2o to 80oC or 68o to 770oF
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