Chapter 34 Suppositories and pessaries
Introduction
Drug administration by the rectum can be used for local or systemic action. Dosage forms used include suppositories, rectal tablets, capsules, ointments and enemas. Vaginal administration can also be for both local and systemic action, using dosage forms which include pessaries and vaginal formulations of tablets, capsules, solutions, sprays, creams, ointments and foams. This chapter gives details of how suppositories and pessaries are prepared extemporaneously, the substances and equipment used in their preparation, the calculations involved and patient advice. Details about the formulation, manufacture and biopharmacy can be found in Aulton (2007).
Suppositories and pessaries are drug delivery systems where the drug is incorporated into an inert vehicle. The vehicle is referred to as the base. They are formed by melting the base, incorporating the drug and then allowing them to set in a suitable mould (made of metal or plastic).
Suppository bases
A range of materials is available for use as bases. A number of criteria can be identified as desirable in an ideal base, including the following:
No base meets all these requirements, so a compromise is usually required. There are two groups of materials, the fatty bases and the water-soluble or water-miscible bases.
The fatty bases
These bases, which melt around body temperature, are the naturally occurring theobroma oil and synthetic fats.
Theobroma oil, which has been used as a suppository base for over 200 years, 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. However, for a number of reasons the newer synthetic bases have now largely superseded it. The main technical difficulty is the ease with which lower melting point polymorphic forms of theobroma oil are formed. The stable β-form has a melting point of 34.5°C and forms after melting at 36°C and slowly cooling. However, if it is overheated, the unstable α-form (melting point 23°C) and γ-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 also 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 then not melt in the rectum. In addition theobroma oil is prone to oxidation, and in common with many naturally occurring substances, may vary from batch to batch. Theobroma oil shrinks only slightly on cooling and therefore tends to stick to the suppository mould. For this reason the mould must be lubricated before use.
Synthetic fats
These are prepared by hydrogenating suitable vegetable oils. They have many of the advantages of theobroma oil but fewer disadvantages. However, there are a few potential problems:
Further information on these bases can be found in the Pharmaceutical Codex (1994).
Water-soluble and water-miscible bases
Glycerol-gelatin bases
These bases are a mixture of glycerol and water stiffened with gelatin. The commonest is Glycerol Suppositories Base BP, which has 14% weight in weight (w/w) gelatin, and 70% w/w glycerol. In hot climates the gelatin content can be increased to 18% w/w. Gelatin is a purified protein produced by the hydrolysis of the collagenous tissue, such as skins and bones, of animals. Grades of gelatin for pharmaceutical use must be heat treated during their preparation to ensure that the product is pathogen free. Some people may have ethical problems with the use of material from an animal source.
Two types of gelatin are used for pharmaceutical purposes: Type A, which is prepared by acid hydrolysis and is cationic, and Type B, which is prepared by alkaline hydrolysis and is anionic. Type A is compatible with substances such as boric acid and lactic acid while Type B 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. In addition they are also hygroscopic and therefore require careful storage. They are much more difficult to prepare and handle than other bases and the solution time depends on the content and quality of the gelatin and also 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 incompatibilities.
Macrogols
These polyethylene glycols 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. Details of combinations which are used are found in the Pharmaceutical Codex (1994, p. 172). Macrogols have several properties which make them useful as suppository bases including the absence of a physiological effect, are not prone to microbial contamination and have a high water-absorbing capacity. As they dissolve, a viscous solution is produced which means there is less likelihood of leakage from the body.
There are, however, a number of 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, penicillin and plastic, may limit their use. In addition crystal growth occurs, with some drugs causing irritation to the rectal mucosa and, if the crystals are large, prolonged dissolution times.
Preparation of suppositories
Suppositories are made using a suppository mould which may be made of metal or plastic. Traditional metal moulds for extemporaneous dispensing (Fig. 34.1) 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 it is important to ensure that the mould is completely clean and it should be washed 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.
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.
When preparing suppositories where the active ingredient is 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.
Table 34.1 Lubricants for use with suppository bases
| Base | Lubricant |
| Theobroma oil | Soap spirit |
| Glycerol-gelatin base | Almond oil, liquid paraffin |
| Synthetic fats | No lubricant required |
| Macrogols | No lubricant required |
Moulds are made in four sizes: 1 g, 2 g, 4 g and 8 g. 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 (see Example 34.1).
Example 34.1
A 1 g 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 overfilling to allow for shrinkage. They are trimmed after about 5 minutes and left to set for a further 10–15 minutes. 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 5.05 g. The mould calibration figure is therefore 5.05/5 = 1.01 g. This is the value which should be used for that particular combination of mould and base.
Example 34.2
Prepare six suppositories each containing 250 mg bismuth subgallate.
Not all material can be removed from the evaporating basin, so quantities are calculated for an excess of two suppositories. Therefore calculate for eight suppositories.
DV of bismuth subgallate = 2.7 (Pharmaceutical Codex), i.e. 2.7 g of bismuth subgallate displaces 1 g of base.
A 1 g mould will be used with mould calibration = 0.94.
To calculate the amount of base required, a simple equation is used:
where N is the number of suppositories to be made, y is the mould calibration, D is the dose in one suppository, DV is the displacement value.
Using the terms in the equation for this example:
Using the equation:
Example 34.3
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 = 6 g.
Weight of six suppositories containing 40% drug = 8.8 g.
Weight of base is then = 60% = 60/100 × 8.8 = 5.28 g.
Weight of drug in suppositories = 40% = 40/100 × 8.8 = 3.52.
Weight of base displaced by drug = 6 × 5.28 = 0.72g.
If 0.72 g of drug is displaced by 3.52 g of base, then 1 g of base will be displaced by 3.52/0.72 g = 4.88 g.
Therefore displacement value of drug = 4.9 (rounded to one decimal place).
Example 34.4
Prepare eight suppositories containing 18% zinc oxide.
Calculate for 10 suppositories (2 excess).
Weight of base required to fill mould = 10 × 1 = 10 g.
Example 34.5
Calculate the quantities required to make 15 suppositories each containing 150 mg hamamelis dry extract and 560 mg of zinc oxide.
A 2 g mould, with mould calibration of 2.04, will be used.
Calculate for 17 suppositories (2 excess).
DV of hamamelis dry extract = 1.5 (Pharmaceutical Codex).
DV of zinc oxide = 4.7 (Pharmaceutical Codex).
Weight of hamamelis dry extract = 17 × 0.15 = 2.55 g.
Weight of zinc oxide = 17 × 0.56 = 9.52 g.
Weight of base = 17 × 2.04 − (2.55/1.5 + 9.52/4.7) = 34.68 − (1.7 + 2.03) = 30.95 g.
Example 34.6
Prepare 12 pessaries containing 10% ichthammol.
A 4 g mould (calibration value 4.0) is used.
Calculate for 14 pessaries to allow for wastage. Additional base is required because it is more dense than the oily bases. The density factor is 1.2.
Mould calibration for glycerol-gelatin base is 4.0 × 1.2 = 4.8 g.
A displacement value is not required because the ichthammol is expressed as a percentage.
| Gelatin | 14 g |
| Glycerol | 70 g |
| Water | to 100 g |
| Ichthammol | 10% w/w |
| Glycerol-gelatin base | 90% w/w |
The total weight required to prepare the pessaries is 14 × 4.8 g = 67.2 g. For ease of calculation prepare 70 g. Quantities are therefore:
| Ichthammol | 7 g |
| Base | 63 g |
It is advisable to make a small excess of base, taking care to choose quantities which give easily weighable amounts, i.e. do not try to weigh to several decimal points. In this case 65 g can be prepared.
Using the method described above, prepare 65 g of the base, taking care that the correct type of gelatin is chosen. Because the active ingredient is ichthammol, Type B should be used. When the 65 g of base has been prepared, 2 g should be removed from the basin, leaving the required 63 g. The base is removed from the heat, allowed to cool a little before 7 g of ichthammol is added with careful stirring. The mixture is then poured into the lubricated mould and left to set.
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. For example a drug which has twice the density of the base will occupy half the volume which the same weight of base occupies, and a drug whose density is four times that of the base will occupy a quarter the volume which the same weight of base occupies. Allowance must be made for this by using displacement values (DVs).
The displacement value of a drug is the number of parts by weight of drug which displaces 1 part by weight of the base.
Displacement values for a variety of medicaments are given in Table 34.2. Other reference sources such as the Pharmaceutical Handbook (Wade 1980) and the Pharmaceutical Codex also give information on displacement values. Minor variations may occur in the values quoted so it is always advisable to indicate the source of your information.
Table 34.2 Displacement values with respect to fatty bases
| Medicament | Displacement value |
| Aspirin | 1.1 |
| Bismuth subgallate | 2.7 |
| Chloral hydrate | 1.4 |
| Cinchocaine hydrochloride | 1.0 |
| Codeine phosphate | 1.1 |
| Hamamelis dry extract | 1.5 |
| Hydrocortisone | 1.5 |
| Ichthammol | 1.0 |
| Liquids | 1.0 |
| Metronidazole | 1.7 |
| Morphine hydrochloride | 1.6 |
| Paracetamol | 1.5 |
| Pethidine hydrochloride | 1.6 |
| Phenobarbital | 1.1 |
| Zinc oxide | 4.7 |
Displacement values in the literature normally refer to values for theobroma oil. These values can also be used for other fatty bases. With glycerol-gelatin 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.
Calculation of quantities when the active ingredient is stated as a percentage
A displacement value is not required when calculating quantities stated as percentages.
When there is more than one active ingredient present the quantity of each medicament is calculated and the amount of base is calculated using the displacement value for each ingredient.
Preparation of suppositories using a glycerol-gelatin base
The formula for Glycerol Suppository Base BP is:
| Gelatin | 14% |
| Glycerol | 70% |
| Water | to 100% |
Note: Gelatin which is of a grade suitable for pharmaceutical use should not contain any pathogens, but as a precaution, the base may be heat treated. This is done by heating the base for 1 hour at 100°C in an electric steamer. This should be done before the base is adjusted to weight (at Stage 7 above).
This base is commonly used for the preparation of pessaries, as described in the following example.
Containers for suppositories
Glass or plastic screw-topped jars are possibly the best choice of container for extemporaneously prepared suppositories and pessaries. Cardboard cartons may be used but these offer little protection from moisture or heat. They are therefore not suitable for hygroscopic materials.
Shelf life
Provided they are well packaged and the storage temperature is low, suppositories and pessaries are relatively stable preparations. Unless other information is available, an expiry date of 1 month is appropriate.
Labelling for suppositories
Adequate information should appear on the label so that the patient knows how to use the product. In addition the following information should appear: ‘Store in a cool place’ and ‘For rectal use only’ or ‘For vaginal use only’, whichever is appropriate.
‘Do not swallow’ can be put on the label but do not use ‘For external use only’ – the preparation is being inserted into a body cavity and this instruction is therefore incorrect.
Patient advice
In addition to what appears on the label, patients should be told to unwrap the suppository or pessary (this may appear to be unnecessary advice but there is sufficient evidence to show that it is not always done) and insert it as high as possible into the rectum or vagina. It may be helpful to provide the patient with a diagram and instruction leaflet, such as that produced by the National Pharmaceutical Association. When suppositories are for children it is likely that an adult will have to carry out the insertion.