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Unformatted text preview: PHCY 6100 SUPPOSITORIES & INSERTS SUPPOSITORIES (supponere = place “under” the body) i) Def. Solid dosage forms used to administer medications through the rectum, vagina or urethra, where they melt or soften and dissolve to exert localized or systemic effect. ii) Advantages of suppositories Avoid gastric pH and enzymes Avoid irritation of stomach Bypass liver = avoid first pass effect (partially) Useful for patients unwilling or unable to swallow Useful for patients that are vomiting Alternative route if parenteral route is unsuitable Fast acting iii) Some regularly compounded suppositories: For severe nausea & vomiting: metoclopramide, haloperidol, dexamethasone, diphenhydramine and benztropine Long-term prophylactic treatment of asthma: salbutamol For chronic pain: prolonged-release morphine alkaloid iv)Factors affecting drug absorption from suppositories For rectal suppositories: (A) COLONIC CONTENT: empty rectum will allow maximal absorption; diarrhea, rectal tumors, dehydration may affect rate and degree of absorption. (B) CIRCULATION ROUTE: lower hemorrhoidal veins and lymphatics surrounding the colon receive most of the absorbed drug and initiate its circulation, bypassing the liver. (C) PH and BUFFERING CAPACITY: rectal fluid pH is ~ neutral, so no buffering capacity and no chemical changes of drug happen at the site. For all suppositories: (A) LIPID-WATER SOLUBILITY: partition coefficient of drug is important for decision on suppository base to be used. (B) (C) PARTICLE SIZE: smaller have faster dissolution and absorption. NATURE OF THE BASE: a good supp. base must i. Melt at body temperature /soften and dissolve in body fluids; ii. Be able to release the drug for absorption (principle of opposite characteristics: watersoluble drugs in oil-soluble base and vice-versa). iii. Be non-irritating to mucous membranes (exception if for laxative purposes). RECTAL SUPPOSITORIES a) Cylindrical, torpedo, bullet or little finger. b) Adult: ~ 1 ½inch long; ~2g (cocoa butter base) c) Pediatric: half weight and size. d) Application: with fingers. e) Uses PHCY 6100-Teixeira 1 PHCY 6100 SUPPOSITORIES & INSERTS i) Local Effect: relief of constipation and hemorrhoids or anorectal discomforts. Ex: glycerin suppositories: used as cathartic (=laxative) ii) Systemic Effect: for administration of antiemetics, tranquilizers, anti-inflammatories, treatment of asthma, etc. Absorption occurs through the mucous membranes of the rectum into the hemorrhoidal veins and lymphatic circulation. f) Patient counseling Handwashing Packaging material Insertion depends on shape Half suppository If suppository is stored in refrigerator, allow to warm at room temperature or rotate between the palms of hands for a while. Cocoa butter suppositories should be rubbed gently with fingers to melt surface and provide lubrication during insertion. Glycerinated gelatin and PEG suppositories should be moistened with warm water to enhance lubrication and help dissolution (PEG supp.w/ <20% water should be dipped into water to prevent dehydration of rectal mucosa and stimulation of peristalsis) Wrapped suppositories: auxiliary label “Unwrap & Insert”. Suppositories should never be frozen. VAGINAL SUPPOSITORIES: pessaire (= tampon, Fr.) a) Globular, oviform, cone-shaped. b) Size: variable, similar to rectal supps. c) Weight varies widely (up to 5g, cocoa butter base). d) Application: plastic/paper insertion device, which allows proper placement high within the vaginal tract. e) PEG and glycerinated gelatin are the preferred bases: minimize leakage f) Some vaginal suppositories are actually compressed tablets: Inserts g) Uses i) Local Effect: To combat infections of genitourinary area (vaginitis) caused by common pathogenic organisms such as: (A) Trichomonas vaginalis: flagellate protozoan; povidone-iodine is used for treatment. (B) Candida albicans: fungus; causes Moniliasis or Candidiasis; nystatin, miconazole, clotrimazole, terconazole are used for treatment. (C) Haemophilus vaginalis: treated with sulfathiazole, sulfacetamide. To restore vaginal mucosa to normal state: some estrogenic substances. For contraception: local application of spermicidal agents, such as Nonoxynol-9 and Octoxynol. ii) Systemic Effect: not commonly used. Some preparations of progesterone are available to treat PMS and luteal phase defect. h) Patient counseling Written instructions Proper use of applicator: demonstration Compliance even if symptoms disappear: emphasis Genitourinary infections: treat partner Notification of physician: burning, irritation or allergies. PHCY 6100-Teixeira 2 PHCY 6100 SUPPOSITORIES & INSERTS Inserts or tablets: dipping in water before insertion will facilitate administration. Sanitary napkin: protection of nightwear and bed linen. Handwashing before and after administration. URETHRAL SUPPOSITORIES: bougie (= candle, Fr.) a) Slender, pencil-shaped. b) 3-6 mm in diameter and up to 140 mm long. c) For insertion into male or female urethra as antibacterials or anesthetics. d) Example of urethral suppository: Furacin® (Nitrofurazone, antibacterial) MUSE® (Alprostadil, treatment of erectile dysfunction). SUPPOSITORY BASES a) Stable, nonirritating, chemically and physiologically inert, compatible with a variety of drugs, stable during storage, esthetically acceptable. b) Base should melt or dissolve in rectal fluids. c) Should allow drug(s) to be released and not interfere with its absorption. d) Base regulates drug bioavailability. e) Other desirable characteristics depend upon the drugs: Drugs that lower melting points of base or formulations for use in tropical climates (e.g. camphor, menthol, phenol, chloral hydrate, thymol, volatile oils): use bases with high melting points. Addition of drugs or other ingredients that will raise melting points or addition of large amounts of solids: use bases with low melting points. Base Composition Cocoa butter Mixed triglycerides of oleic, palmitic, stearic acids Partially hydrogenated cottonseed oil Cotomar Dehydag I, II or III Fattibase Hydrokote 25, 711, SP Polybase Suppocire OSI, OSIX, A, B, C, D, DM, H, L Tween 61 Wecobee FS, M, R, S, SS, W PHCY 6100-Teixeira Hydrogenated fatty alcohols and esters Triglyc. From palm, palm kernel & coconut oils w/self-emulsifying glyceryl monostearate and polyoxyl stearate Higher melting fractions of coconut and palm kernel oil Homogeneous blend of PEGs & polysorbate 80 Mixtures of mono-, di-, tri-glycerides from natural vegetable oils; each type having slightly different properties Used alone or in combo w/PEG sorbitan monostearate Triglycerides derived from coconut oil+ palm kernel +emulsifiers Melting point range (C) 34-35 35 33-39 35.5-37 31.1-44.5 60-71 33-45 35-49 31.7-40.5 3 PHCY 6100 SUPPOSITORIES & INSERTS TYPES OF SUPPOSITORY BASES 1) Fatty, oleaginous or oil soluble bases a) Melt at body temp. and release drug for absorption. b) Lubricant effect. c) COCOA BUTTER or theobroma oil i) Most frequently employed base ii) Triglyceride mixture (liquid + crystalline solid) from roasted seeds of Theobroma cacao iii) Yellowish solid with chocolate-like odor iv) Softens at 30 C and melts at 34 C v) Melted slowly in water bath: polymorphism beta forms are preferred metastable crystalline forms: solidification of product very slow vi) Phenol, Menthol, Thymol and Chloral hydrate lower the melting point of cocoa butter use stiffening agents: beeswax and cetyl ester wax vii) Water-soluble drugs: incorporate using an emulsifier (drug readily absorbed after melting of base). viii) Fat-soluble drugs: remain dissolved in the oil after base is melted and are not soluble in physiologic fluids (low or erratic absorption). ix) Very sticky to molds if overheated; molds must be clean and dry. d) SUPPOCIRE 2) Hydrogenated vegetable oils (emulsions) a) FATTIBASE i) Pre-blended mixture of triglycerides of palm, palm kernel and coconut oils + emulsifying and suspending agents; ii) Uniform in composition iii) Free of suspended matter iv) No special storage v) Excellent mold release (no lubrication) vi) Solid with melting point of 35-37C. b) WECOBEE: palm kernel and coconut oils + emulsifying agents; similar characteristics to Fattibase. 3) Mixtures of glycerin + high mol. wt. fatty acids a) Palmitic and stearic acid: fatty acids b) Bases: GLYCERYL MONOPALMITATE and GLYCERYL MONOSTEARATE 4) Water-soluble and water miscible bases a) Drug dissolves and mixes with aqueous body fluids. b) May cause some irritation: slight dehydration of rectal mucosa. c) POLYETHYLENE GLYCOL BASES or PEGs i) Most popular water soluble base ii) Polymers of ethylene oxide + water iii) Dissolve slowly in body fluids (does not melt) PHCY 6100-Teixeira 4 PHCY 6100 SUPPOSITORIES & INSERTS iv) Exist in several physical states and molecular weights (MW> 1000 are solids (waxtype) and MW = 200, 400, 600 are clear colorless liquids). v) Modification of ratios of low: high molecular weights= final base with desired specific melting point. vi) Incompatible with aminopyrine, quinine, ichthammol, aspirin, benzocaine, sulfonamides. vii) Sodium barbital, salicylic acid and camphor crystallize out of PEG suppositories. viii) No need for refrigeration ix) Dipping in water before use is recommended to avoid irritation of rectal mucosa. x) Should be dispensed in glass or cardboard containers (PEG interacts adversely with polystyrene). d) POLYBASE i) Preblended homogeneous mixture of PEGs and polysorbate 80 ii) Water miscible, stable at RT iii) Does not require mold lubrication e) GLYCERINATED GELATIN i) Gelatin (20%) + Glycerin (70%) + 10% water (in steam bath) + solution or suspension of medication. ii) Vaginal suppositories (also urethral w/ 60% gelatin and 20% glycerin) iii) Softens and mixes slowly with body fluids providing more prolonged release. iv) Molds need to be lubricated v) Stored in tight containers: hygroscopic nature of glycerin. vi) Not recommended for systemic rectal suppository: osmotic effect and defecation reflex. 5) Miscellaneous bases: hydrophilic bases a) Mixtures of the above bases (fatty + water-soluble/miscible) = w/o emulsions b) Polyoxyl 40 stearate: mixture of stearates and glycols; has surface active action. PREPARATION OF SUPPOSITORIES a) HAND MOLDING i) Requires considerable skill ii) Preparation without heat iii) Generally uses cocoa butter iv) Cocoa butter is grated, mixed with active ingredient (mortar & pestle or ointment slab), pressing of mix until resolidification, shaping into a long cylinder with desired diameter, cutting into desired length. b) FUSION i) Base is melted ii) Medicinal agents are incorporated iii) Melt is poured into molds iv) Cooling and congealing v) Trimming, removal from mold (or disposable molds) vi) Packaging PHCY 6100-Teixeira 5 PHCY 6100 SUPPOSITORIES & INSERTS c) COMPRESSION (cold compression) i) For bases that can be formed into suppositories under pressure ii) Preferred method for heat-sensitive medicinal agents and substances insoluble in the suppository base. iii) Typical base: 6% hexanetriol-1,2,6 + PEG 1450 + 12% polyethylene oxide polymer 4000 iv) Base + medicinal substances are combined and triturated in a mortar with pestle (mortar can be warmed under hot water). The friction will soften the base to a pastelike consistency. It can also be prepared using suppository machines similar to tablet machines. SUPPOSITORY MOLDS a) Several sizes, shapes, materials (stainless steel, aluminum, brass, plastic). b) Calibration of molds: difference in densities of the materials_ METHOD 1 i) Confirm cavities are clean and dry ii) Obtain and melt sufficient base to fill 6-12 molds iii) Pour base, cool, trim iv) Remove suppositories and weigh v) Divide total weight by number of blank suppositories prepared = average weight of each suppository vi) Use this weight as a calibrated value for that specific mold and that specific base. vii) OR: the volume of the mold can be determined by melting the suppositories and measuring the volume of the melt. The volume for total number as well as for the average of one suppository is determined. viii) The amount of base required to prepare medicated suppositories has to consider the required amount of drug needed in each suppository. Since the volume of the mold is known, the volume of the drug subtracted from the total volume of the mold will give the volume of base required. ix) Because suppository bases are solids at RT, the volume of base has to be converted to weight from the density of the material. Ex: If 12 ml of a base is required to fill a suppository mold and if the drugs in the formula have a volume of 2.8 ml, then 9.2 ml of base will be required. By multiplying 9.2 ml of base times the density of the base, 0.86g/ml, it will be determined that 7.9 g of the base are required (METHOD 1). c) Another practical method to calibrate molds _ METHOD 2 i) Ex: Make 15 suppositories containing 2 ml of 5% solution of drug. 10 ml base is the volume to make one suppository (previously determined for that specific mold and base). Total base + medicinal agents to fill prescription (+ 1 or2 extra) = (15 + 2 supp.) x 10 ml/sup = 170 ml total mixture. Amount of medicinal agent needed = 2 ml/10 ml x 100 % = 20% is medicinal agent and 80% is base. Then, 170 ml x 0.20 = 34 ml drug and 170 ml x 0.80 = 136 ml of base. d) Another practical method to calibrate molds _ METHOD 3 i) Place all required medications in a calibrated container ii) Add melted base until the volume reaches the original calibration of the volume of the mold. iii) Melt is prepared using the least possible heat (water bath). iv) Medicinal agents may be first incorporated into a small portion of melted base then added with stirring to the remaining base, which is already cooling. PHCY 6100-Teixeira 6 PHCY 6100 SUPPOSITORIES & INSERTS v) Heat-sensitive ingredients and volatile materials are added at this point with stirring. e) Mold should always be filled in excess to allow contraction and prevent formation of dips in the end of suppository. f) Preparation of the mold i) Clean & dry ii) Lubricants usually NOT needed if prepared and heated properly iii) If using lubricant: Water-soluble base = light mineral oil or vegetable oil Oleaginous base = glycerin and propylene glycol Thin layer on the wall only (excess = distorted suppositories) Spray or wipe molds with a lubricant-treated cloth iv) Mold must be equilibrated at RT for pouring g) Preparation of the base i) Method chosen depends on the type of base. ii) If cocoa butter is used by fusion: should be melted to a pourable liquid, creamy but hazy in appearance (not clear yellow state = unstable alpha polymorph form with low melting point). iii) If PEG bases used by fusion: water bath or direct heat @ 60C. COMPOUNDING SUPPOSITORIES a) In general, the maximum quantity of formulation (excipients + drugs) that can be incorporated is about 30% of the blank weight of the suppository. For example, for a 2g disposable mold, the maximum formulation would be about 600 mg. b) A 10% overage of materials should be calculated _ loss during preparation and overpouring. c) If disposable molds are not marked with lines for reproducible filling, determine extent of fill from the blank. d) Plastic disposable molds: beware of temperature of melt (<60 C). e) To incorporate and distribute evenly vegetable extracts: moisten material by levigation with a small quantity of melted base. f) To incorporate a large amount of powder: dampen with a few drops of a miscible liquid (mineral oil or glycerin). g) To incorporate liquids that are too fluid: mix with a powder such as starch. h) After pouring the melt, the molds should be allowed to set for 15-20 min at RT then refrigerated for an additional 30 min. OTHER RECTAL AND VAGINAL DOSAGE FORMS a) Vaginal tablets or inserts i) More widely used than suppositories: easier to manufacture, more stable, less messy ii) Application with help of a cardboard/plastic applicator. iii) Compressed tablets or capsules b) Ointments, Creams, Aerosol Foams i) Rectal ointments: used for localized anorectal problems (hemorrhoids); special rectal delivery tip is used for administration. ii) Vaginal ointments and creams: for administration of anti-infective agents, estrogenic substances, contraceptive agents (with diaphragm) PHCY 6100-Teixeira 7 PHCY 6100 iii) SUPPOSITORIES & INSERTS Vaginal and Rectal Aerosol Foams: generally oil/water emulsions; administration of anti-inflammatory agents, estrogenic substances and contraceptives. c) Jellies and Gels i) Jellies are gels with a large proportion of water and thickening agents; gels have semisolid consistency. ii) Tubes need to be tightly closed to prevent from drying out. iii) Mostly used during medical examinations and laboratory procedures. d) Vaginal contraceptive sponges i) Contain ~ 1g of Nonoxynol-9 which is activated when moistened with water prior to use. ii) Designed to fit snugly in the upper vagina. iii) Provide contraceptive protection for 24 hr but should remain in place at least 6 hr after intercourse. e) Intrauterine Drug Delivery System: progesterone i) Provide ~ 1 year of contraceptive action, through release of approximately 6 micrograms of drug per day. ii) It is a slow release form with a rate-controlling membrane. f) Powders and Solutions i) Douches: antiseptics for vaginal hygiene (powder for dilution or solutions) ii) Enemas: solutions used rectally for local effect (evacuation or treatment of inflammations) or for systemic absorption (Aminophylline). PHCY 6100-Teixeira 8 ...
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This note was uploaded on 10/15/2010 for the course PHCY 6100 taught by Professor Teixeira during the Fall '10 term at Univeristy of Wyoming- Laramie.

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