11. Suppositories and Inserts

1. 11. Suppositories and Inserts

2. Contents • Suppositories • Some factors of drug absorption from rectal suppositories • Suppository bases • Preparation of suppositories • Rectal suppositories • Vaginal suppositories • Packaging and storage • Vaginal inserts

3. 1. Suppositories • Suppositories are solid dosage forms intended for insertion into body orifices where they melt, soften, or dissolve and exert local or systemic effects. • Suppositories are commonly used rectally and vaginally and accasionally urethrally. They have various shapes and weights.

5. The shape and size of a suppository must be such that it can be easily inserted into the intended orifice without causing undue distension, • and once inserted, it must be retained for the appropriate period.

6. 1） Local action • Rectal suppositories intended for localized action are most frequently used to relieve constipation or the pain, irritation, itching, and inflammation associated with hemorrhoids or other anorectal conditions. • A popular laxative, glycerin suppositories promote laxation by the local irritation of the mucous membranes.

7. Vaginal suppositories or inserts intended for localized effects are employed mainly as contraceptives, antiseptics in feminine hygiene, and as specific agents to combat as invading pathogen. • Most commonly, the drugs used are nonoxynol-9（9-壬苯醇醚）for contraception, and trichomonacides（杀滴虫剂）to combat vaginitis caused by Trichomonas vaginalis, Candida (Monilia) albicans, and other microorganisms.

8. 2) Systemic action • For systemic effects, the mucous membranes of the rectum and vagina permit the absorption of many soluble drugs. • Although the rectum is used frequently as the site for the systemic absorption of drugs, the vagina is not as frequently used for this purpose.

9. Among the advantages over oral therapy of the rectal route of administration for achieving systemic effects are these: a) Drugs destroyed or inactivated by the pH or enzymatic activity of the stomach or intestines need not be exposed to this destructive environments; b) Drugs irritating to the stomach may be giving without causing such irritation c) Drugs destroyed by portal circulation may bypass the liver after rectal absorption

10. d) The route is convenient for administration of drugs to adult or pediatric patients who may be unable or unwilling to swallow medication e) It is an effective route in the treatment of patients with vomiting episodes.

11. Examples of drugs administered rectally in the form of suppositories for their systemic effects include • prochlorperazine （丙氯拉嗪）and chlorpromazine（氯丙嗪） • oxymorphone HCl （盐酸羟吗啡酮） • ergotamine tartrate（麦角胺酒石酸盐） • indomethacin • ondansetron

12. 2. Some factors of drug absorption from rectal suppositories 1) Physiologic factors • Colonic content • when deemed desirable, an evacuant enema may be administered and allowed to act before the administration of a suppository of a drug to be absorbed. • Diarrhea, colonic obstruction, and tissue dehydration

13. Circulation route • The lower hemorrhoidal veins surrounding the colon receive the absorbed drug and initiate its circulation throughout the body, bypass the liver. • Lymphatic circulation also assists in the absorption of rectally administered drugs.

14. pH and lack of buffering • Because rectal fluids are essentially neutral in pH and have no effective buffer capacity, the form in which the drug is administered will not generally be chemically changed by the rectal environment. • The suppository base employed has a marked influence on the release of active constituents incorporated into it.

15. 2) Physicochemical factors of the drug and suppository base • Lipid-water solubility • A lipophilic drug that is distributed in a fatty suppository base in low concentration has less of a tendency to escape to the surrounding aqueous fluids than would a hydrophilic substance present in a fatty base to an extent approaching its saturation.

16. Water soluble bases, for example, PEG, which dissolve in the anorectal fluids, release for absorption both water-soluble and oil-soluble drugs. • Naturally, the more drug a base contains, the more drug will be available for potential absorption.

17. Particle size • For drugs present in a suppository in the undissolved state, the size of the drug particle will influence its rate of dissolution and its availability for absorption. • The smaller the particle size, the more readily the dissolution of the particle and the greater the chance for rapid absorption.

18. Nature of the base • The possiblity of chemical and/or physical interactions between the medicinal agent and the suppository base, which could affect the stability and/or bioavailability of the drug. • If the base is irritating to the mucous membranes of the rectum, it may initiate a colonic response and prompt a bowel movement, negating the prospect of complete drug release and absorption.

19. 3. Suppository bases One of the first requisites for a suppository base is that • it remains solid at room temperature • but softens, melts or dissolves readily at body temperature • so that the drug it contains may be made fully available soon after insertion.

20. Classification of suppository bases 1) Fatty or oleaginous base • Cocoa butter • is defined as the fat obtained from the roasted seed of Theobroma cacao. • At room temperature it is a yellowish, white solid having a faint, agreeable chocolate-like odor.

21. Chemically, it is a triglyceride primarily of oleopalmitostearin（油酸棕榈酸硬脂酸三甘油酯）and oleodistearin（油酸二硬脂酸三甘油酯）. • Cocoa butter melts between 30C to 36C, it is an ideal suppository base. • Cocoa butter exhibits marked polymorphism.

22. Hydrogenated fatty acids of vegetable oils (palm kernal oil and cottonseed oil) • Fat-based compounds containing compounds of glycerin with the higher molecular weight fatty acids, such as palmitic and stearic acids (glyceryl monostearate and glyceryl monopalmitate)

23. 2) Water-soluble and water-miscible bases • Glycerinated gelatin • Glycerinated gelatin suppositories may be prepared by dissolving granular gelatin (20%) in glycerin (70%) and adding a solution or suspension of the medication (10%). • Glycerinated gelatin base is most frequently used in the preparation of vaginal suppositories, where the prolonged localized action of the medicinal agent is usually desired.

24. Glycerinated gelatin-based suppositories have a tendency to absorb moisture due to the hygroscopic nature of glycerin. • The suppository may have a dehydrating effect and be irritating to the tissues upon insertion • Urethral suppositories may be prepared from a glycerinated gelatin base (60% gelatin, 20% glycerin and 20% medicated aqueous portion)

25. Polyethylene glycols • PEGs are polymers of ethylene oxide and water, prepared to various chain lengths, molecular weights, and physical states. • They are available in a number of molecular weight ranges. • Various combinations of these PEGs may be combined by fusion, using two or more of the various types to achieve a suppository base of the desired consistency and characteristics. • PEG suppositories do not melt at body temperature but rather dissolve slowly in the body’s fluids.

26. 3) Miscellaneous bases • mixtures of oleaginous and water-soluble or water-miscible materials, • These materials may be chemical or physical mixtures, • some are preformed emulsions, generally of the water/oil type, • or they may be capable of dispersing in aqueous fluids. • E.g. polyoxyl 40 stearate （聚氧乙烯40硬脂酸酯）

27. Polyoxyl 40 stearate is a mixture of the monostearate and distearate esters of mixed polyoxyethylene diols and the free glycols. • The average polymer length being equivalent to about 40 oxyethylene units. • The substance is a waxy, white to light tan solid that is water-soluble. Its melting point is generally between 39C and 45C.

28. 4. Preparation of suppositories 1）Preparation by molding The steps in molding include • melting the base, • incorporating any required medicaments, • pouring the melt into molds, • allowing the melt to cool and congeal into suppositories, • removing the formed suppositories from the mold.

29. Suppository molds • Commercially available molds can produce individual or large numbers of suppositories of various shapes and sizes. • Molds in common use today are made from stainless steel, aluminum, brass, or plastic. • Individual plastic molds may be obtained to form a single suppository.

31. Lubrication of the mold • Depending on the formulation, suppository molds may require lubrication before the melt is poured to facilatate clean and easy removal of the molded suppositories. • Lubrication is seldom necessary when the suppository base is cocoa butter or polyethylene glycol. • Lubrication is usually necessary when glycerinated gelatin suppositories are prepared.

32. Calibration of the mold • Each individual mold is capable of holding a specific volume of material in each of its openings. • The pharmacist should calibrate each suppository mold for the usual base so as to prepare medicated suppositories each having the proper quantity of medicaments.

33. Prepare molded suppositories from base material alone • After removal from the mold, the suppositories are weighted, and the total weight and the average weight of each suppository are recorded. • To determine the volume of the mold, the suppositories are then carefully melted in a calibrated beaker, and the volume of the melt is determined for the total number as well as the average of one suppository.

34. Determination of the amount of base required • Volume of base=Total volume of the mold-the volume of the drug substances • If 12 ml of cocoa butter are required to fill a suppository mold and if the medicaments in the formula have a collective volume of 2.8 ml, how many gram of cocoa butter required? (the density of cocoa butter is 0.86 g/mL)

35. Weigh the active ingredient for the preparation of a single suppository; • Dissolve it or mix it with a portion of melted base insufficient to fill one cavity of the mold, and add the mixture to a cavity; • Add additional melted base to the cavity to fill it completely • Allow the suppository to congeal and harden • Remove the suppository from the mold and weigh it

36. Preparing and pouring the melt • Using the least possible heat, the weighed suppository base material is melted, generally over a water bath, since no great deal of heat is usually required. • Medicinal substances are usually incorporated into a portion of the melted base by mixing on a glass or porcelain tile with a spatula.

37. After incorporation, this material is stirred into the remaining base, which has been allowed to cool almost to its congealing point. • The melt is poured carefully and continuously into each cavity of the mold, which has been previously equilibrated to room temperature.

38. When the suppositories are hard, the mold is removed from the refrigerator and allowed to come to room temperature. • Then the sections of the mold are separated, and the suppositories are dislodges.

39. The solid materials remain suspended if the pouring is performed just above the conjealing point and not when the base is too fluid. • A small quantity of silica gel can be incorporated into formula to aid in keeping the active drug suspended. • In filling each suppository cavity, the pouring must be continuous to prevent layering, which may lead to a product easily broken on handling. • To ensure a completely filled mold upon congealing, the melt is poured excessively over each opening, actually using above the level of the mold.

40. Density calculations for suppositories • Determination of the dosage replacement factor method f={100(E-G)/GX}+1 where E=the weight of the pure base suppositories G=the weight of suppositories with X% of the active ingredient

41. Example 1 Prepare a suppository containing 100 mg of phenobarbital (f=0.81) using cocoa butter as the base. The weight of the pure cocoa butter suppository is 2.0 g. What will be the total weight of each suppository?

42. Determination of density factor method • Determine the average blank weight, A, per mold using the suppository base of interest • Weigh the quantity of suppository base necessay for 10 suppositories. • Weigh 1.0 g of medication • Melt the suppository base and incorporate the medication, mix, pour into molds, cool, trim, and remove from the molds • Weigh the 10 suppositories and determine the average weight (C).

43. 6）determine the density factor as follows Density factor = B/(A-C+B) where A=average weight of blank B=weight of medication per suppository C=average weight of medicated suppository 7) Take the weight of the medication required for each suppository and divide by the density factor of the medication to find the replacement value of the suppository base

44. 8) Subtract this quantity from the blank suppository weight 9) Multiply by the number of suppositories required to obtain the quantity of suppository base required for the prescription. 10) Multiply the weight of drug per suppository by the number of suppositories required to obtain the quantity of active drug required for the prescription.

45. 药物的重量与同体积基质重量的比值称为该药物对基质的置换价药物的重量与同体积基质重量的比值称为该药物对基质的置换价 DV=W/G-(M-W) 式中， G-纯基质平均栓重；M-含药栓的平均重量；W-每个栓剂的平均含药重量 • 用测定的置换价可以方便地计算出制备这种含药栓需要基质的重量x: x={G-(y/DV)}.n y-处方中药物的剂量； n-拟制备栓剂的枚数

46. Example 2 Prepare 12 acetaminophen 300 mg suppositories using cocoa butter, where the average weight of the cocoa butter blank is 2 g and the average weight of the medicated suppository is 1.8 g.

47. Determination of occupied volume method • Determine the average weight per mold (blank) using the suppository base of interest • Weigh the quantity of suppository base necessary for 10 suppositories • Divide the density of the active drug by the density of the suppository base to obtain a ratio • Divide the total weight of active drug required for the total number of suppositories by the ratio obtained in step 3 (this will give the amount of suppository base displaced by the active drug).

48. Substract the amount obtained in step 4 from the total weight of the prescription to obtain the weight of suppository base required • Multiply the weight of active drug per suppository times the number of suppositories to be prepared to obtain the quantity of active drug required

49. Example 3 Prepare 10 suppositories, each containing 200 mg of a drug with a density of 3.0. The suppository base has a density of 0.9 and a prepared blank weighs 2.0 g. Using the “determination of occupied volume method,” prepare the required suppositories.

50. 2) Preparation by compression • Suppositories may be prepared by forcing the mixed mass of the base and the medicaments into special molds using suppository-making machines. • In preparation of compression into the molds, the base and the other formulative ingredients are combined by thorough mixing, the friction of the process softening the base into a pastelike consistency.