Chapter Notes: Semisolid Dosage Forms - Suppositories and Pessaries

Suppositories

Suppositories are solid dosage forms of medicaments intended for insertion into body cavities other than the mouth - most commonly the rectum, vagina or urethra, and occasionally the nasal cavity or ear. After insertion, the suppository base either melts, dissolves or disperses in the cavity fluids to release the active drug. Suppositories are manufactured in a variety of shapes, sizes and weights and are used to produce local, systemic or mechanical effects.

Advantages

• Useful for patients who cannot swallow (children, elderly, unconscious patients).
• Produce local effects at the site of application (for example, local anaesthesia or astringent action in the rectum or vagina).
• Can provide a rapid local action when inserted in the rectum.
• Can promote evacuation of the bowel (e.g., laxative suppositories).
• Unit dose form - convenient and accurate dosing.
• Bypass or reduce oral irritant effects and avoid gastric destruction of acid-sensitive drugs.
• Slow absorption from some bases gives sustained action.

Disadvantages

• Irritant drugs are unsuitable for suppository administration because they can damage mucous membranes.
• Administration can cause embarrassment for some patients.
• Many suppositories require cold storage (commonly 10°-20° C); refrigeration increases cost and complicates storage for some patients.
• Preparation of suppositories can be more complex than simple oral dosage forms.

Types of suppositories

• Rectal suppositories: Intended for insertion into the rectum for local or systemic effects. Typical weight about 1-2 g; common shapes are cone or torpedo.
• Vaginal suppositories (pessaries): Intended for vaginal use; larger than rectal suppositories (commonly 4-8 g), shapes include conical, rod-shaped or wedge-shaped. Mainly used for local vaginal therapy.
• Nasal suppositories (nasal bougies): Thin, cylindrical forms intended for nasal cavity insertion; typically prepared with glycero-gelatin bases and about 9-10 cm long.
• Urethral suppositories (urethral bougies): Thin, long cylinders rounded at one end for urethral insertion; weights vary but these are rarely used.
• Ear cones (aurinaria): Thin, long cylinders for aural use; rarely used nowadays and commonly prepared in theobroma oil or suitable bases.

Recent developments and alternative forms

• Compressed (tablet) suppositories: Suppositories formed by compression, similar to tablets. Compressed pessaries are often almond-shaped for easier insertion and rapid disintegration.
• Layered suppositories: Different drugs or materials placed in separate layers to avoid incompatibility or to control release rates; prepared by sequential partial filling and solidification.
• Capsule suppositories: Soft gelatin capsules containing liquid, semi-solid or solid fills for rectal or vaginal insertion.
• Coated suppositories: Suppositories coated with materials such as polyethylene glycol or cetyl alcohol to provide lubrication, protection or modified release.
• Disposable moulds: Moulds made from plastic or aluminium foil allow direct moulding into packaging; cheaper and convenient for small-scale dispensing.

Suppository bases

An ideal suppository base should:

• Either melt at body temperature or dissolve/disperse in body fluids to release the drug.
• Retain shape and firmness during handling and storage.
• Release the medicament readily.
• Be non-toxic and non-irritant to mucous membranes.
• Be stable on storage and compatible with a wide range of drugs.
• Be easily moulded and not adhere to the mould.
• Have acceptable appearance and be amenable to manufacturing processes (pouring or cold compression).

Classification of suppository bases

Suppository bases are broadly classified into three categories:

1. Fatty (oleaginous) bases
2. Water-soluble and water-miscible bases
3. Emulsifying (synthetic) bases

1. Fatty bases

Theobroma oil (cocoa butter)

Theobroma oil is a yellowish-white solid obtained from cocoa seeds and consists of a mixture of glyceryl esters of stearic, oleic, palmitic and other fatty acids. Melting point about 30-35° C. It melts at body temperature and releases the active ingredient for rapid absorption. Theobroma oil is a suitable base for rectal suppositories but less suitable for pessaries, nasal and urethral bougies because it can leak from cavities after melting and is immiscible with mucous secretions.

Disadvantages of cocoa butter

• Polymorphism: solidifies in different crystalline forms depending on cooling conditions.
• Prone to rancidity and melting in warm climates.
• Tendency to stick to mould surfaces.
• Possible leakage from cavities on melting.
• Relatively costly.
• Immiscible with body fluids; certain drugs (e.g., chloral hydrate, lactic acid) may cause liquefaction when mixed with cocoa butter.

Emulsified theobroma oil

Prepared by adding emulsifying agents (for example glyceryl monostearate, cetyl alcohol, beeswax, spermaceti) to increase the capacity to incorporate aqueous solutions.

Hydrogenated vegetable oils

Hydrogenated oils (from arachis, cottonseed, coconut, palm, etc.) are used as substitutes for cocoa butter. Advantages include resistance to oxidation, no need for mould lubrication, improved appearance (colourless, odourless), and better water absorption. Disadvantages include brittleness on rapid cooling and greater fluidity on melting which can increase sedimentation of added substances; addition of thickening agents (bentonite, magnesium stearate) can help.

2. Water-soluble and water-miscible bases

Glycero-gelatin base

Mixture of glycerin and water gelled with gelatin. Produces translucent suppositories that dissolve or disperse slowly in cavity fluids and thus provide prolonged release. Especially useful for pessaries and for medicaments such as boric acid, chloral hydrate, bromides, iodoform and opium derivatives.

Two types of gelatin bases are commonly used to avoid incompatibilities:

• Type A (Pharmagel A): acidic in nature - used for some acidic drugs.
• Type B (Pharmagel B): more alkaline - used for some alkaline drugs.

Disadvantages of glycero-gelatin base include variable solution time depending on gelatin quality, incompatibilities with some drugs (tannic acid, ferric chloride, gallic acid), susceptibility to microbial growth (preservatives needed), hygroscopicity (special containers required), some physiological activity (glycerol suppositories are laxative) and more difficult handling.

Soap-glycerin bases

Here gelatin is replaced by curd soap or sodium stearate to stiffen the glycerin base. Soap also contributes to the evacuation action. These bases are very hygroscopic and require protection from atmospheric moisture (waxed paper or tin foil wrapping).

Polyethylene glycols (macrogols/carbowaxes)

3. Emulsifying (synthetic) bases

Proprietary synthetic bases that combine desirable properties of fatty and water-soluble bases.

Examples

• Witepsol - triglycerides of saturated vegetable acids with partial esters; a small amount of beeswax may be added for hot climates. Avoid rapid cooling to prevent brittleness.
• Massa estarinum (adeps solidus) - mixture of mono-, di- and triglycerides of saturated fatty acids (mp 33.5-35.5° C); grade B is commonly used.
• Massuppol - mainly glyceryl esters of lauric acid with added glyceryl monostearate to improve water-absorbing capacity.

Advantages of these synthetic/emulsifying bases over theobroma oil include rapid solidification, non-irritancy, no need for mould lubrication in many cases, resistance to overheating effects, ability to absorb water, attractive appearance and less tendency to rancidity. Disadvantages include sensitivity to rapid cooling (brittleness) and relatively low viscosity on melting so that incorporated medicaments may sediment.

Methods of preparation

Suppositories may be prepared by any of the following methods:

1. Rolling method - historically used but largely obsolete.
2. Hot process (fusion) method - commonly used in dispensing and manufacturing.
3. Cold compression method - useful for thermolabile or insoluble drugs.

Hot process (fusion) method - typical procedure

1. Clean and lubricate the mould (unless using an emulsifying or synthetic base that does not require lubrication).
2. Heat the base gently in a suitable container over a water bath until most of it is melted; avoid overheating.
3. Mix the powdered medicament with a portion of the melted base on an ointment tile to form a uniform paste, then return the mixture to the melting vessel and thoroughly homogenise.
4. Warm the mixture until pourable, then pour into the moulds kept on ice; fill slightly above the cavity to allow for contraction on cooling.
5. Allow to cool and set (often 10-15 minutes on ice), remove excess material with a blade, open the mould and eject the suppositories.
6. Wipe, wrap individually (wax paper or aluminium foil) and package in suitable containers.

Cold compression method

Useful for thermolabile ingredients because heating of the bulk base is avoided.

1. Grate a solid fatty base (for example cocoa butter) and mix thoroughly with the powdered medicament.
2. Place the mixture in a cold compression cylinder and compress it through a narrow opening into a chilled mould using a piston. The extruded threads are compressed and cut to form individual suppositories.
3. This method requires specialised hand or power-operated compression machines and chilling of the mass and cylinder to avoid heat of compression making the mass too fluid.

Suppository moulds and lubrication

Moulds for dispensing commonly have 6-12 cavities and are manufactured from stainless steel, nickel-copper alloy, brass, aluminium or plastic. Mould surfaces must be clean and free of scratches to produce smooth suppositories. Lubrication is essential for some bases (for example cocoa butter, glycero-gelatin) and is applied with a brush or gauze swab; cotton wool should not be used because fibres may detach. Excess lubricant is drained by inverting the mould. Emulsifying and some synthetic bases may not require lubrication.

Calibration of the mould and displacement value

Although the cavity volume of a given mould is constant, the weight of a finished suppository varies with the density of the base and any incorporated medicament. Calibration is therefore necessary for each base-drug combination so that correct weights are obtained.

Displacement value is defined as the amount of drug that displaces one part of the base. It is used to calculate how much base is displaced when a given quantity of drug is added so that the final suppository weight is accurate.

Typical method to determine displacement value experimentally:

1. Prepare and weigh a set (e.g., six) of plain suppositories made from the base and determine their average weight; denote this as a grams per suppository.
2. Prepare and weigh a set of suppositories containing a known percentage of drug (for example, 40% w/w drug in the mass) and determine the average weight; denote this as b grams per suppository.
3. Calculate the amount of base present in the medicated suppository: base present = (100 - %drug) × b / 100 = c grams.
4. Amount of drug present = %drug × b / 100 = d grams.
5. Amount of base displaced by d grams of drug = a - c.
6. Displacement value = d / (amount of base displaced) = d / (a - c).

Displacement values (reference table)

The displacement value for a particular drug and base combination should be used when calculating quantities of base required for a given strength of medicated suppositories.

Practical notes on pouring: Always keep the mass in gentle motion while pouring to ensure uniform distribution of medicament in all cavities; fill the cavities slightly above brim because many fatty bases contract on cooling, producing hollows at the surface.

Packaging and storage

Suppositories are usually packed in shallow partitioned card boxes to keep them upright and separated. Commercial products may be individually wrapped in aluminium foil or manufactured in sealed mould-packaging. Glycero-gelatin suppositories are often stored in tightly closed glass containers. Suppositories should be stored in a cool place (often refrigerated if required) to maintain shape and stability.

Use of suppositories for drug absorption

Suppositories are useful when oral administration is not possible or when a drug is destroyed by gastric acidity. Rectal absorption takes place through a rich vascular supply in the anorectal region; absorption from the lower rectum drains to systemic veins and can partially bypass hepatic first-pass metabolism, giving more direct systemic availability. For effective systemic action the drug must be finely subdivided and uniformly distributed in the base. Suppositories are used for local treatment of rectal and vaginal conditions and for systemic delivery of analgesics, hormones, antibiotics, steroids and local anaesthetics.

Example: preparation of suppositories and clinical dispensing

Example 9.1 Calculate the displacement value of zinc oxide in theobroma oil suppositories containing 40% of zinc oxide and prepared in a 1 g mould. The weight of 8 suppositories is 11.74 g.

Ans:

Weight of 8 plain suppositories made from base alone (1 g mould) = 1.0 g × 8 = 8.00 g.

Weight of 8 medicated suppositories (40% zinc oxide in final mass) = 11.74 g.

Amount of base present in the medicated suppositories = (100 - 40) × 11.74 / 100 = 60 × 11.74 / 100 = 7.044 g.

Amount of medicament present in the medicated suppositories = 40 × 11.74 / 100 = 4.696 g.

Amount of theobroma oil displaced by 4.696 g of medicament = plain base weight - base present = 8.000 - 7.044 = 0.956 g.

Displacement value = amount of drug / amount of base displaced = 4.696 / 0.956 ≈ 4.912 ≈ 4.9 (approx. 5.0).

Therefore the displacement value of zinc oxide with reference to theobroma oil ≈ 5.0.

Example 9.2 Prepare and dispense iodoform suppositories.

Given: Iodoform 0.9 g per suppository. Suppositories to be 2 g each. Make and send 8 suppositories of 2 g each. Displacement value of iodoform = 4.0.

Ans:

Calculate for two extra suppositories to allow wastage: total number to prepare = 8 + 2 = 10 suppositories.

Total weight required for 10 suppositories = 2 g × 10 = 20.0 g (this is the total final mass).

Total drug required for 10 suppositories = 0.9 g × 10 = 9.0 g.

Let the quantity of base required be X grams. The total final mass must equal base + drug: X + 9.0 = 20.0 → X = 11.0 g. However, because drug displaces base, we must account using the displacement value.

Using displacement value D = 4.0, the effective base required = total mass - (drug / D).

Drug displacement in terms of base = drug / D = 9.0 / 4.0 = 2.25 g.

Thus base required = total mass - (drug / D) = 20.0 - 2.25 = 17.75 g cocoa butter.

Therefore formula for 10 suppositories:

• Iodoform: 9.0 g (0.9 g per suppository)
• Cocoa butter: 17.75 g

Procedure (fusion method):

1. Clean and lightly lubricate the mould with a suitable lubricant (e.g., liquid paraffin or arachis oil) where required; place mould on ice to drain excess lubricant.
2. Melt most of the cocoa butter on a water bath until about two-thirds has melted; remove from bath and stir to promote uniform melting without overheating.
3. On an ointment tile mix the powdered iodoform with about half of the melted cocoa butter to form a smooth paste; then return this to the main melt and homogenise.
4. Warm until pourable and pour into chilled moulds kept on ice, filling each cavity slightly above the brim while stirring the mass to maintain uniform drug distribution.
5. Allow to set on ice for 10-15 minutes, trim excess, open mould and remove suppositories.
6. Wipe lightly, wrap each suppository in wax paper or foil and pack appropriately; label and dispense eight suppositories of 2 g each with directions for use.

Pessaries (Vaginal suppositories)

Pessaries are suppositories intended for intravaginal use. They are larger than rectal suppositories (commonly 4-8 g or more) and may be conical, wedge-shaped or rod-shaped. Specially shaped pessaries are sometimes supplied with applicators to facilitate insertion. Vaginal preparations are often formulated as glycero-gelatin bases; vaginal tablets and capsules are also commonly used as alternatives.

Pessaries are often supplied in containers or in individually wrapped form. Because many pessaries are hygroscopic or may sting on insertion, labels sometimes advise moistening before insertion. Pessaries should be stored in a cool place.

Example 9.3 Prepare and dispense 8 lactic acid pessaries B.P.C.

Given: Lactic acid 5% in final pessary. Use glycero-gelatin (glycerin suppository mass) base. Pessary mould size = 8 g. Prepare and send 8 pessaries.

Ans:

Standard approach: Calculate for 10 pessaries (8 required + 2 extra for wastage) because the example uses 10 as the working quantity.

Total final mass for 10 pessaries = 10 × 8 g = 80 g. (Note: the example in the source used a factor of 1.2 to allow for handling and evaporative losses when preparing glycero-gelatin base; typical convenient batch mass is 100 g.)

Using the example's convenient batch mass of 100 g (to prepare about 10 pessaries): required lactic acid (5% w/w) = 100 × 5 / 100 = 5.0 g.

Formula:

• Lactic acid: 5.0 g
• Glycero-gelatin base: 100 g

Method (outline):

1. Lubricate the mould with liquid paraffin or arachis oil, invert and cool to drain excess lubricant.
2. Heat glycerin in a china dish on a water bath; add gelatin to water and wet thoroughly, then add hot glycerin and heat until a clear solution (glycero-gelatin base) is formed. Adjust weight to 100 g if necessary by evaporating excess water.
3. Remove an appropriate portion of the base and mix thoroughly with 5.0 g lactic acid to ensure even distribution.
4. Pour the medicated base into chilled mould cavities (which lower setting point due to lactic acid) and allow to set; open mould and remove pessaries while the mass is still firm.
5. Wrap individual pessaries in foil or waxed paper and pack in a well-closed container because lactic acid pessaries are hygroscopic. Label and dispense eight pessaries with directions for use.

Packaging, storage and clinical considerations

Suppositories and pessaries should be individually wrapped or partitioned to avoid contact and moisture uptake. Glycero-gelatin and macrogol bases require airtight containers; fatty bases often require cool storage to retain shape. For systemic delivery via the rectal route, placement in the lower rectum is preferred to reduce hepatic first-pass metabolism; for local therapy, correct insertion and retention at the site are important.

Revision Questions

Very Short Answer Type Questions

1. Define the term 'Pessaries'.

2. Define the term 'Suppository'.

3. What is 'displacement value'?

4. Explain the importance of displacement value.

5. Mention different methods of preparation of suppositories.

6. Name the different types of suppository bases.

7. Mention different types of suppositories which are available in the market.

8. Why is calibration of a mould necessary before using it?

9. Why is cocoa butter not always suitable in the preparation of suppositories?

10. What are the lubricants used to lubricate the mould?

Short Answer Type Questions

11. Write the qualities of an ideal suppository base.

12. Mention the advantages and disadvantages of suppositories.

13. Give in brief the advantages and disadvantages of theobroma oil as a suppository base.

14. Write the advantages and disadvantages of hydrogenated oils as suppository bases.

15. What is displacement value? How will you find the displacement value of a drug?

16. Write the advantages and disadvantages of glycero-gelatin base used for preparing suppositories.

17. Why is glycero-gelatin base preferred in preparing pessaries?

Long Answer Type Questions

18. Define the term 'suppositories'. What are the advantages and disadvantages of suppositories?

19. What do you mean by 'suppositories'? Describe in brief the various types of suppositories.

20. What are 'suppository bases'? Classify different suppository bases used in the preparation of suppositories and describe each briefly.

21. Discuss in brief the various methods of preparation of suppositories.

22. Define the term 'pessaries'. Discuss in brief the method of preparation of pessaries.

23. Write short notes on the following:

(a) Theobroma oil

(b) Displacement value

(c) Pessaries

(d) Fusion method of preparation of suppositories

Objective Type Questions - Completion (fill in the blanks)

24. Suppositories are __________ dosage forms of drugs.

25. Suppositories are used to produce __________, __________ and __________ action.

26. Cocoa butter is a mixture of __________ esters of stearic, palmitic, oleic and other fatty acids.

27. In suppositories, the drug is released either due to __________ of the base or __________ of its contents in body cavity fluid.

28. Compression method is suitable for the preparation of suppositories containing __________ and __________ drugs.

29. Cocoa butter is not a suitable base for __________ and __________ suppositories.

Key

24. unit

25. local, systemic, mechanical

26. glyceryl

27. melting, dissolving, body cavity

28. thermolabile, insoluble

29. pessaries, nasal