SUPPOSITORIES & PESSARIES ASMA BASHIR LECTURER INSTITUTE OF PHARMACEUTICAL SCEINCES JSMU. . . . . OBJECTIVES Upon completion of this chapter, you should be able to know about : Ideal suppository bases Types of base Suppository moulds and mould calibration Displacement values Methods of preparation of suppositories and pessaries Containers, labelling and patient advice for suppositories and pessariesSuppositories * The British Pharmacopoeia (BP) defines suppository as: “Suppositories are solid, single-dose preparations. The shape, volume and consistency of suppositories are suitable for rectal administration. They contain one or more active substances dispersed or dissolved in suitable basis which may be soluble or dispersible in water or may melt at body temperature. Excipients such as diluents, adsorbents, surface-active agents, Iubricants, antimicrobial preservatives and colouring matter, authorised by the competent authority, may be added if necessary.”Box 11.1 Advantages and disadvantages of suppositories as dosage forms Advantages Can exert local effect on rectal mucosa Used to promote evacuation of bowel Avoids any gastrointestinal irritation Can be used in unconscious patients (e.g. during fitting) Can be used for systemic absorption of drugs and avoids first-pass metabolism Disadvantages May be unacceptable to certain patients May be difficult to self- administer by arthritic or physically compromised patients Unpredictable and variable absorption in vivoThe British Pharmacopoeia (BP) defines Pessaries as: “Pessaries are solid, single-dose preparations. They have various shapes, usually ovoid, with a volume and consistency suitable for insertion into the vagina. They contain one or more active substances dispersed or dissolved in a suitable basis that may be soluble or dispersible in water or may melt at body temperature. Excipients such as diluents, adsorbents, surface-activea gents, Jubricants, antimicrobial preservatives and colouring matter authorised by the competent authority may be added, if necessary.”Pessaries * The larger size moulds are usually used in the preparation of pessaries, such as 4 g and 8 g moulds. * Pessaries are used almost exclusively for local medication, the exception being prostaglandin pessaries that do exert a systemic effect. * Common ingredients for inclusion in pessaries for local action include: * antiseptics * contraceptive agents * local anaesthetics * various therapeutic agents to treat trichomonal, bacterial and monilial infections.Anumber of criteria can be identified as desirable in an ideal base, including: e Melt at, or just below, body temperature or dissolve in body fluids e Solidify quickly after melting e Easily moulded and removed from the mould e Chemically stable even when molten @ Release the active ingredient readily e Easy to handle @ Bland, i.e. non-toxic and non-irritant. No base meets all these requirements, so a compromise is required. There are two groups of materials, the fatty bases and the water- soluble or water-miscible bases.THE FATTY BASES. Theobroma oil Theobroma oil, a naturally occurring oil, has a melting point range of 30-36°C and so readily melts in the body. It liquefies easily on heating but sets rapidly when cooled. It is also bland, therefore no irritation occurs. The main technical difficulty is the ease with which lower melting point polymorphic forms of theobroma oil are formed. The stable B-form has a melting point of 34.5°C and forms after melting at 36°C and slowly cooling. If it is overheated, the unstable a-form (melting point 23°C) and y-form (melting point 19°C) are produced. These forms will eventually return to the stable form but this may take several days. The melting point is a problem in hot climates and can be reduced further by the addition of a soluble drug. The latter effect can be counteracted by adding beeswax (up to 10%), but care must be taken not to raise the melting point too high, as the suppository would not melt in the rectum. In addition, theobroma oil is prone to oxidation. Theobroma oil shrinks only slightly on cooling and therefore tends to stick to the suppository mould; thus requiring a mould lubricant.SYNTHETIC FATS hydrogenated vegetable ails Synthetic fatty bases have many of the advantages but there are a few potential problems. The viscosity of the melted fats is lower than that of theobroma oil. As a result there is a greater risk of drug particles sedimenting during preparation leading to a lack of uniform drug distribution. This problem is partly compensated for in that these bases set very quickly These bases become brittle if cooled too rapidly, so should not be refrigerated during preparation These bases are produced in series of grades, each with different hardness and melting point ranges. These can be used to compensate for melting point reduction by soluble drugs. However, release and absorption of the drug in the body may vary depending on the base being used.WATER-SOLUBLE AND WATER-MISCIBLE BASES Giyceral-gelatin bases These bases are a mixture of glycerol and water stiffened with gelatin. The commonest is Glycerol Suppositories Base BP, which has 14% (w/w) gelatin and 70% w/w glycerol. In hot climates, the gelatin content can be increased to 18% w/w. Pharmaceutical grade gelatin is a pathogen free, purified protein produced by the hydrolysis of the collagenous tissue, such as skins and bones, of animals. Some people may have ethical problems with the use of such a product.Two types of gelatin are used for pharmaceutical purposes: Type A, which is prepared by acid hydrolysis and is cationic , is compatible with substances such as boric acid and lactic Type B, which is prepared by alkaline hydrolysis and is anionic , is compatible with substances like ichthammol and zinc oxide The ‘jelly strength’ or ‘bloom strength’ of gelatin is important, particularly when it is used in the preparation of suppositories or pessaries. Glycerol-gelatin bases have a physiological effect which can cause rectal irritation because of the small amount of liquid present. As they dissolve in the mucous secretions of the rectum, osmosis occurs producing a laxative effect. The solution time depends on the content, quality of the gelatin and the age of the suppository. Because of the water content, microbial contamination is more likely than with the fatty bases. Preservatives may be added to the product, but can lead to problems of incompatibility. In addition, glycol-gelatin bases are hygroscopic and therefore require careful storage.MACROGOLS polyethylene glycols These PEGs can be blended together to produce suppository bases with varying melting points, dissolution rates and physical characteristics. Drug release depends on the base dissolving rather than melting (the melting point is often around 50°C). Higher proportions of high molecular weight polymers produce preparations which release the drug slowly and are also brittle. Less brittle products which release the drug more readily can be prepared by mixing high polymers with medium and low polymers. USEFUL PROPERTIES absence of a physiological effect not prone to microbial contamination high water-absorbing capacity ‘As they dissolve, a viscous solution is produced which means there is less likelihood of leakage from the body. DISADVANTAGES. They are hygroscopic, which means they must be carefully stored, and this could lead to irritation of the rectal mucosa. This latter disadvantage can be alleviated by dipping the suppository in water prior to insertion. They become brittle if cooled too quickly and also may become brittle on storage.Incompatibility with several drugs and packaging materials, e.g. benzocaine and plastic, may limit their use. Crystal growth occurs, with some drugs causing irritation to the rectal mucosa and may prolong dissolution times. Table 37.1 Lubricants for use with suppository bases Base Lubricant Theobroma oil Soap spirit Glycerol-gelatin base Almond oil, liquid paraffin Macrogols No lubricant requiredMETHODS USED IN THE PREPARATION Suppositories are made using a metal or plastic suppository mould. Traditional metal moulds are in two halves which are clamped together with a screw. The internal surface is normally plated to ensure that the suppositories have a smooth surface. Before use the mould should be completely cleaned by washing carefully in warm, soapy water and thoroughly dried, taking care not to scratch the internal surface. The exact shape can vary slightly from one mould to another. The preparation of suppositories /Pessaries invariably involves some wastage and therefore it is recommended that calculations are made for excess.PREPARATION OF SUPPOSITORIES CONTAINING AN ACTIVE INGREDIENT WHICH IS INSOLUBLE IN THE BASE The bases used, most commonly, for extemporaneous preparation of suppositories and pessaries are the synthetic fats and glycerol-gelatin base. 1. When calculating the quantity of ingredients it is necessary to prepare excess due to unavoidable wastage. Usually, an excess of two should be calculated for, e.g. to prepare 12 suppositories, calculate for 14. 2. The mould should be carefully washed and dried. 3. Ensure that the two halves fit together correctly. This is necessary to ensure that there is no leakage of material. They usually have code letters and/or numbers which should match.4. For some bases the mould will need to be lubricated. 5. If a lubricant is necessary, apply it carefully to the two halves of the mould using gauze or other non-fibrous material. Do not use cotton wool as fibres may be left on the mould surface and become incorporated into the suppositories. 6. Invert the mould to allow any excess lubricant to drain off. 7. Accurately weigh the required amount of base. If large lumps are present the material should be grated.8.Place in a porcelain basin and warm gently using a water bath or hot plate. Allow approximately two-thirds of the base to melt and remove from the heat. The residual heat will be sufficient to melt the rest of the base. 9. Reduce the particle size of the active ingredient, if necessary. Either grinding in a mortar and pestle or sieving . 10. Weigh the correct amount of medicament and place on a glass tile (ointment slab). 11. Add about half of the molten base to the powdered drug and rub together with a spatula, 12. Scrape the dispersion off the tile using the spatula and place it back in the basin. 13. If necessary, put the basin back over the water bath to remelt the ingredients. 14. Remove from the heat and stir constantly until almost on the point of setting. If the mixture is not stirred at this stage the active ingredient will sediment and uniform distribution of the drug will not be achieve15. Quickly pour into the mould, slightly overfilling each cavity to allow for contraction on cooling. Do not start pouring the suppositories while the mixture is still very molten. If this is done, a suspended drug will sediment to the bottom of the mould and the base shrinks excessively so that the tops become concave.* 16. Leave the mould and its contents to cool for about 5 min and then, using a spatula, trim the tops of the suppositories. Do not leave the suppositories too long before trimming, as they will be too hard and trimming becomes very difficult. 17. Allow cooling for another 10-15 min until the suppositories are completely firm and set. Do not try to speed up the cooling process by putting the mould in a refrigerator. Synthetic fats in particular are inclined to become brittle and break if cooled too quickly. 18. Unscrew the mould and remove the suppositories. 19. Each perfect suppository should then be wrapped in greaseproof paper and packed in an appropriate container and labelled.When preparing suppositories where the active ingredient is either a semi-solid, is soluble in the base or is a liquid which is miscible with the base, the melting point of the base will be lowered. In these situations, a base with a higher than normal melting point should be used if available. The base is melted as normal and the active ingredient is added directly to the base and incorporated by stirring. Moulds are made in four sizes: 1 g, 2g, 4g and 8g. Unless otherwise stated, the 1 g size is used for suppositories. The same moulds are used to prepare pessaries, when the two larger sizes are generally used. A suppository mould is filled by volume, but the suppository is formulated by weight. The capacity of a suppository mould is nominal and each mould will have minor variations. Therefore, the weight of material contained in different moulds may be different and will also depend on the base being used. It is therefore essential that each mould be calibrated for each different base.. . MOULD CALIBRATION The capacity of the mould is confirmed by filling the mould with the chosen base. The total weight of the perfect suppositories is taken and a mean weight calculated. This value is the calibration value of the mould for that particular baseA1g suppository mould is to be used to prepare a batch of suppositories. The base to be used is a synthetic fat. Some base is melted in an evaporating basin over a water bath or hot plate. When about two- thirds of the base has melted the basin is removed from the heat. The contents of the basin are stirred and the remaining base melts with the residual heat. Continue stirring the base until it is almost on the point of setting (it starts to thicken, becomes slightly cloudy and small crystals can be seen on the surface). The base is then poured into the mould cavities, slightly overiilling to allow for shrinkage. They are trimmed after about 5min and left to set for a further 10-15min. ‘The mould is then opened and the suppositories, removed. Only the perfect products should be weighed. Any which are chipped or damaged should be discarded. From the above exercise, five perfect suppositories were obtained. The total weight was 5.05g. The mould calibration figure is therefore 5.05/5 = 1.01g. This is the value which should be used for that particular combination of mould and base.SUPPOSITORIES & PESSARIES ASMA BASHIR LECTURER INSTITUTE OF PHARMACEUTICAL SCEINCES JSMUOBJECTIVES Upon completion of this lecture , you should be able to know about : Displacement values Methods of preparation of suppositories and pessaries Containers, labelling and patient advice for suppositories and pessariesDISPLACEMENT VALUES The volume of a suppository from a particular mould is uniform but its weight can vary when a drug is present because the density of the drug may be different from that of the base. Allowance must be made for this by using displacement values (DV). The displacement value of a drugis the number af parts by weight of drug which displaces | part by weight of the base. Displacement values in the literature normally refer to values for theobroma oil. These values can also be used for other fatty bases. With glycerolgelatin suppository base, approximately 1.2 g occupies the same volume as 1 g of theobroma oil. Using this information, the relevant displacement values can be calculated. There may be occasions when information on the DV of a drug is not available. In these situations the DV must be determinedHydrocortisone BP has a displacement value of 1.5 This means that 1.5 g Hydrocortisone BP displaces 1 g of the suppository base Table 37.2 Displacement values with respect to fatty bases Medicament Displacement value Aspirin a Bismuth subgallate 27 Chloral hydrate 1.4 Cinchocaine hydrochloride 1.0 Codeine phosphate 11 Hamamelis dry extract 15 Hydrocortisone 15 Ichthammo! 1.0 Liquids 1.0 Metronidazole 17 Morphine hydrochloride 1.6 Paracetamol 15 Pethidine hydrochloride 1.6 Phenobarbital 141 Zinc oxide 47ee Example 11.2 Prepare six codeine phosphate suppositories 60 mg For one For 10 suppository suppositories Codeine 60mg 600mg Phosphate BP Hard Fat BP sufficient to fill sufficient to fill 1 x 1g size mould 10 x 1g size moulds Displacement value for codeine phosphate is 1.1. Hence 1.1 g of codeine phosphate displaces 1 g of base. Therefore 0.6 g displaces (1 x 0.6 g) + 1.1=0.55 g of base. Therefore the amount of fatty base needed is 10— 0.55g=9.45g.To calculate the DV of a drug: A batch of unmedicated suppositories is prepared and the products weighed. A batch of suppositories containing a known concentration of the required drug is prepared and the products are weighed. Weight of six unmedicated suppositories = 6g Weight of six suppositories containing 40% drug = 8.8g Weight of base is then = 60% = 60/100x8.8 = 5.28g Weight of drug in suppositories = 40% = 40/100 x 8.8= 3.52 Weight of base displaced by drug = 6 — 5.28 =0.72g. If 0.72g of \baseis displaced by 3.52g of drug, then 1g of base wili be displaced by 3.52/0.72g = 4.88g. Therefore displacement value of drug = 4.9 (rounded to one decimal place). os