1. B. pharm degree program PH 201 Pharmaceutics Suppositories and pessories M. A. Siriwardhene B. Pharm (Honors). M. Phil (Pharmacology) Faculty of Medical Sciences University of Sri Jayewardenepura 6/28/2017M. A. Siriwardhene FMS USJP

2. Introduction Administration of drugs to the rectum and vagina may be performed to treat local disorders, e.g. infection and inflammation or to achieve systemic absorption of the therapeutic agent in situations where alternative routes of drug administration are inappropriate. Suppositories are the main class of rectal dosage forms; however, creams, gels and foams are also used for this purpose.

3. Introduction Pessaries, creams and gels are commonly used for the delivery of therapeutic agents to the vagina. Suppositories and pessaries are semisolid or solid dosage forms that are inserted into the rectum and vagina, respectively. Advice must be given to patients regarding their administration. Rectal and vaginal dosage forms are non-sterile formulations.

4. Suppositories Suppositories are dosage forms prepared for drug delivery via the rectum. They consist of an active medicament dispersed throughout an inactive base. The bases used in these products can be broadly classified into two groups: Fatty bases. These may be of natural origin, such as Theobroma oil (cocoa butter), or synthetic fats such as Witepsol. Hydrophilic bases. The most commonly used hydrophilic base is composed of a solid glycerol/gelatin mixture.

5. Advantages of rectal dosage forms Rectal dosage forms may be successfully employed to provide a local effect for the treatment of infection and inflammation, e.g. haemorrhoids, proctitis. Rectal dosage forms are used to promote evacuation of the bowel (by irritating the rectum), to relieve constipation or to cleanse the bowel prior to surgery. Rectal dosage forms may be employed to provide systemic drug absorption in situations where oral drug absorption is not recommended. Rectal dosage forms may be employed to provide local treatment of diseases of the colon, e.g. Crohn’s disease, ulcerative colitis. Following advice from the pharmacist, the administration of the rectal and vaginal dosage forms may be easily performed by the patient.

6. Disadvantages of rectal dosage forms In certain countries, especially the USA and the UK, the rectal dosage forms are generally unpopular, especially for systemic administration of therapeutic agents, whereas the opposite is true in European countries. Specialist advice is required concerning the administration of dosage forms. The absorption of therapeutic agents from the rectum is slow and prone to large intrasubject and intersubject variability. The presence of faeces within the rectum considerably affects both the rate and extent of drug absorption. Rectal administration of therapeutic agents may result in the development of local side-effects, in particular proctitis. The industrial manufacture of suppositories is more difficult than for other common dosage forms.

7. Physiology of the rectum Following absorption from the rectum, the therapeutic agent enters the haemorrhoidal veins. Blood from the upper haemorrhoidal vein enters the portal vein, which flows into the liver, where drug metabolism occurs. Conversely, blood in the middle and lower haemorrhoidal veins enters the general circulation

8. Diagrammatic representation of blood flow into and from the rectum

9. Significance of rectal absorption When empty the rectum contains circa 3 ml of mucus, spread over a rectal surface area of approximately 300 cm 2. The pH within the rectum is essentially neutral with minimal buffering capacity. Therefore, due to the inability of the fluids within the rectum to alter the degree of ionisation, the salt form of the drug is an important determinant of the resulting local efficacy and/or systemic absorption. The presence of faecal matter will markedly affect both the dissolution of the drug in the rectal fluids and the subsequent absorption of the drug into the systemic circulation.

10. Significance of rectal absorption absorbed drug is dependent on the area of the rectum from which absorption has occurred. Drugs that are absorbed into the inferior and middle haemorrhoidal veins will enter the circulation via the inferior vena cava and will subsequently avoid direct exposure of the drug to, and hence metabolism by, the liver. Absorption into the upper (superior) haemorrhoidal vein will result in entry into the liver (and subsequent metabolism) via the portal vein. There are no esterases or peptidases in the rectal fluid. Local muscle activity within the rectal wall may influence the rate of dissolution of solid dosage forms within the rectum, i.e. suppositories.

11. Factors affecting the rectal absorption of therapeutic agents Site of absorption within the rectum The partition coefficient and degree of ionisation of the therapeutic agent The particle size of the dispersed active agent The physicochemical properties of the formulation base

12. Displacement values Suppositories are prepared by dissolving or dispersing an active medicament in a molten base and pouring the mixture into a suppository mould. Suppository moulds are normally available in 1 g, 2 g and 4 g sizes. The mould capacity is the approximate weights of theobroma oil suppositories that are produced from them The volume of the suppository mould will be constant.

13. Displacement values The density of the medicament may vary considerably from that of the base The weight of the base required to make a suppository will vary depending on the medicament used For example, 2 g of a medicament with twice the density of theobroma oil would occupy approximately the same volume as 1 g of the suppository base

14. Displacement values The displacement values (DVs) of medicaments are required when calculating the weight of suppository base required to prepare medicated suppositories The displacement value of a medicament is the number of parts, by weight, of a medicament that will displace one part of suppository base (normally theobroma oil). Displacement values for various medicaments are given in the Pharmaceutical Codex.

15. Examples Calculate the quantities required to make 10 theobroma oil suppositories (2 g mould) each containing 400 mg of zinc oxide (Displacement value = 4.7) Calculate the quantities required to make six glycerogelatin suppositories (4 g mould), each containing 100 mg aminophylline (Displacement value = 1.3)

16. Medicaments included as a percentage w/w If a medicament is present in a suppository as a percentage w/w, then its displacement value is not required when calculating the respective amounts of medicament and base required to prepare the suppository.

17. Examples What quantities are required to prepare eight theobroma oil suppositories, in a 4 g mould, containing 1% w/w lignocaine hydrochloride?

18. Glycero-gelatin base If a glycero-gelatin base is used, the appropriate correction factor must be used as a 1 g mould for a theobroma oil suppository will actually hold 1.2 g of glycero-gelatin base.

19. Example Prepare 12 glycero-gelatin suppositories, containing 0.5% w/w cinchocaine hydrochloride. Use a 2 g mould How would you prepare 10 theobroma oil suppositories (1 g mould) containing 2.5% w/w bismuth subgallate? Six theobroma oil suppositories (2 g), each containing 125 mg of paracetamol, are to be prepared. The displacement value of paracetamol is 1.5. What quantities of base and medicament are required?

20. Example A prescriber requests fi ve glycero-gelatin suppositories be made, containing 1% w/w hydrocortisone acetate. If a 4 g mould is used, what quantities of base and medicament are needed? Prepare 10 theobroma oil suppositories, each containing 50 mg of bismuth subgallate (DV = 2.5). If a 2 g mould is used, what quantities of base and medicament are required?

21. Vaginal dosage forms The administration of drugs to the vagina is principally performed to achieve a local effect, e.g. for the treatment of infection. However, it is also known that, due to the highly vascular nature of the vaginal wall, systemic absorption of therapeutic agents may occur following administration by this route. Furthermore, absorption into the systemic circulation by this route avoids first-pass metabolism in the liver. The fluid content within the vagina is low under normal physiological conditions

23. Vaginal drug delivery There are ridges (folds) in the vagina, termed vaginal rugae, that increase the surface area of, and hence drug absorption from, the vagina. In addition the vaginal rugae will enhance the retention of the dosage form in the vagina (in particular solid and semisolid systems), thereby facilitating prolonged drug release to this site. The limited volume of fluid within the vagina will limit the dissolution of moderate to highly lipophilic drugs.

24. Vaginal drug delivery The vagina is highly vascular; a plexus of arteries and veins is located round the vagina. The venous blood supply from the vagina does not enter the portal system and therefore first-pass metabolism does not occur. This renders the vagina a useful site for the systemic administration of therapeutic agent.

25. Advantages of vaginal dosage forms Vaginal dosage forms may be successfully employed to provide a local effect for the treatment of infection (fungal and bacterial) and for the treatment of hormone deficiency (topical hormone replacement therapy for the treatment of vaginal atrophy). Vaginal dosage forms may be employed to provide systemic drug absorption of certain therapeutic agents. Examples of these applications include: steroid hormones (e.g. oestradiol acetate) for the treatment of the systemic symptoms of the menopause and for long- term contraception prostaglandins (for cervical ripening).

26. Disadvantages of vaginal dosage forms Whilst the use of topical preparations for the treatment of local disorders is accepted, the use of vaginal dosage forms for systemic drug administration is not as popular. Specialist advice is required concerning the administration of dosage forms to ensure correct placement and hence retention in the vagina. This may often require the use of special applicators. The industrial manufacture of vaginal pessaries (suppositories) is more difficult than for other common vaginal dosage forms.

27. The end Thank you and good luck