Suppositories and Pessaries (PDF)

SUPPOSITORIES AND PESSARIES Prof Thiru Govender Discipline of Pharmaceutical Sciences Suppositories Definition: solid, uniformly medicated, conical or torpedo-shaped dosage form for rectal administration. They melt slightly below body temperature so that after insertion the mass...

SUPPOSITORIES AND PESSARIES Prof Thiru Govender Discipline of Pharmaceutical Sciences Suppositories Definition: solid, uniformly medicated, conical or torpedo-shaped dosage form for rectal administration. They melt slightly below body temperature so that after insertion the mass melts and the medicament is liberated into contact with the rectal mucosa. Applications - Used for 3 reasons: 1. To exert a local effect on the rectal mucosa 2. To promote evacuation of the bowel 3. To provide systemic effect Release process of a drug from a suspension suppository Advantages § Can be administered to very ill or unconscious patients. § Can be administered to patients who are nauseous or vomiting. § Several categories of patients may use the rectal route more easily than the oral route e.g. very young / old, mentally impaired. § Can be used to administer drugs which are sensitive to gastric juices. § Drugs that cause GIT side-effects may be administered rectally. § Unpleasant taste and smell becomes insignificant when administered rectally. § Can be used to administer drugs destroyed by the 1st pass effect. § Drugs that are candidates for abuse e.g suicide may be formulated as suppositories. Disadvantages § Slow and sometimes incomplete absorption has been reported, as well as considerable inter and intra-subject variation in absorption rates. § Discomfort to the patient may be experienced. § Leakage of suppository may occur. § Problems with large scale manufacture and achieving suitable shelf life may occur. Absorption of Drug from the Rectum  1. Location of the Suppository in the Rectum ž Venous drainage → there are 3 separate veins: — Lower and middle haemorrhoidal veins drain directly into the general circulation via the inferior vena cava. — Upper superior rectal vein drains into the portal vein which flows to the liver. ž Therefore 50-70% of all rectal dosage forms are first to carried into the systemic circulation before reaching the liver. 2. Quantity of Fluid Available ž Fluid volume available for drug dissolution is very small (approx. 3mL spread in a layer of approx. 100µm thick over the organ). ž Volume enlarged only under non-physiological circumstances e.g. osmotic attraction by water soluble vehicles or diarrhea. 3. Properties of Rectal Mucosa ž Effect of composition, viscosity, surface tension of rectal fluids unknown. ž Estimated from data available for other parts of the gi tract. 4. Contents of the Rectum ž Rectum usually empty except temporarily when faecal matter arrives from higher parts of colon. ž Material is either expelled or transported back into the colon, depending on the voluntary control exhibited on the sphincter of the anus. ž Rectal wall exerts pressure on the suppository - abdominal organs may simply press on to rectum especially when body is in upright condition - may stimulate spreading and thus promote absorption. 5. Motility of the Rectal Wall ž Second source of pressure is motility of muscle of the rectal wall - originates from the normally occurring colonic motor complexes. ž These are waves of contractions running over the wall of the colon and are associated with the presence of food residues in the colon.  Properties of an Ideal Suppository Base Melting range must be lower than approx. 37°C Non-toxic, non-irritating, non-sensitizing Compatible with a wide variety of drugs and promotes optimal drug release Must not have metastable intermediates Must shrink on cooling → easily removed from mould Must have wetting and emulsifying properties Chemically and physically stable during storage Easily moulded or manufactured Economical Classification of Suppository Bases 1. Fatty bases a) Theobroma oil b) Synthetic Hard Fat 2. Water-soluble and water miscible Bases a) Glycero-gelatin b) Macrogols 3. Miscellaneous 4. Xerogels 1. Fatty Bases ž Designed to melt at body temperature a) Theobroma Oil Yellowish – white solid with an odour of chocolate. Mixture of glycerol esters of stearic, palmitic, oleic and other fatty acids. Advantages: 1. Melting pt. 30-36°C 2. Readily melted on warming, rapid setting on cooling. 3. Miscible with many ingredients. 4. Bland and non-irritating. Disadvantages: 1. Polymorphism 2. Adherence to the mould 3. Softening point too low for hot climates 4. Melting point ↓ by soluble ingredients 5. Poor water-absorbing ability 6. Leakage 7. Expense b) Synthetic Hard Fat Prepared by hydrolyzing the vegetable oil, then hydrogenating the resulting fatty acid and then re-esterifying the acids by heating with glycerol. Advantages of Synthetic hard fats over Theobroma oil: 1. Their solidifying points are unaffected by overheating. 2. Display good resistance to oxidation because their unsaturated fatty acids have been reduced. 3. Difference between melting and setting points is small (±1.5 - 2°C), therefore set quickly → ↓ risk of sedimentation and easier to administer. 4. Series of grades with different melting point ranges and degrees of hardness are available. 5. Good water – absorbing capacity. 6. No mould lubrication required → contract significantly on cooling. Disadvantages: 1. Low viscosity → allows for sedimentation. 2. Brittle if cooled rapidly therefore avoid refrigeration during preparation.  2. Water-soluble & Water Miscible Bases a) Glycero-gelatin Mixture of glycerol and H2O gelled by the addition of gelatin. Glycerol suppository mass usually contains 70% glycerol and a minimum of 14% gelatin. High concentrations of gelatin are required for hot countries. Disadvantages: 1. Physiological effects → laxative action. 2. Unpredictable solution time → inter-batch variation. 3. Hygroscopic → requires protection from heat and moisture and has dehydrating effect on mucosa. 4. Microbial contamination is likely to occur. 5. Long preparation time and requires lubrication. b) Macrogols Consists of mixtures of polyethylene glycols of different molecular weight. Melting point well over body temp.- mixes with rectal fluid. Because of high melting point - suited for application in tropical climates. Advantages: 1. No laxative effect. 2. Microbial contamination less likely. 3. Contracts on cooling → no lubricant required. 4. Produces high viscosity solutions. 5. Good solvent properties. 6. Gives products with smooth, clean appearance. Disadvantages: 1. Hygroscopic – irritates mucosa - painful sensation for patient. 2. Poor availability of medicament → good solvent properties → retention of drug. 3. Incompatible with some drugs e.g. Benzocaine ( bismuth salts- ↓ activity of QAC’s & parabens). 4. Brittleness. 5. Crystal growth of certain drugs may occur. 3. Miscellaneous Bases ž Mixtures of oleaginous & water-soluble bases. ž Melt at body temp. & form an emulsion with rectal fluids e.g. Tween 60. ž Suppositories using soap as a base are also included. 4. Xerogels ž Solutions of active in methylcellulose or PEG. ž Can be used in body orifices with a small amount of body fluids.  The Drug Solubility § Drug solubility indicates type i.e. solution suppository or suspension suppository to be prepared. § Drug solubility in rectal fluid determines the maximum attainable concentration and thus driving force for absorption. § If drug has a high vehicle water partition coefficient – will be in solution greatly in the vehicle – therefore tendency to leave vehicle will be small – thus release rate will be low and hence unfavourable for rapid absorption. § Lipid solubility required for drug penetration through rectal membranes – hence a balance needs to be achieved. Surface Properties § Important as particles will be transferred from one phase to another. § Happens when drug is brought into contact with the vehicle and air has been displaced from its surface. If not achieved, agglomerates may form. Adversely affects final drug content uniformity. § If wetting by vehicle has taken place, displacement by rectal fluid will be required to let the drug go into solution- this is prerequisite for absorption. This is reason why surfactants may be added. Particle Size § Important technologically & biopharmaceutically. Particle size should be limited to prevent undue sedimentation during or after preparation. § Smaller the particle size - the less the possible mechanical irritation to the patient and higher the dissolution rate. Amount of Drug § If number of particles increases, it will increase rate to form agglomerates and also affects viscosity of the molten base. Therefore drug amount needs to be optimized.  Other Additives 1. Antioxidants → if base/medicaments is susceptible to oxidation. 2. Preservatives → for water soluble and water- miscible bases. 3. Emulsifiers → may be used to facilitate the incorporation of aqueous solutions or polar liquids. 4. Hardening agents → may be required to ↓ sedimentation rate.  Specific Problems in Formulating Suppositories 1. Water → combination of H2O & natural oils or fats → following problems: i. ↑ oxidation of fat → include antioxidant. ii. H2O evaporates → substances crystallizes out. iii. Incompatibilities accelerated. iv. Good growth medium for micro-organisms → include preservative. 2. Hygroscopicity of Common Bases Glycerol- gelatin bases → lose moisture in dry climates and absorb H2O in humid climates- can affect stability. Macrogols absorb moisture in humid climates 3. Incompatibilities Macrogols incompatible with many substances 4. Viscosity Important w.r.t manufacturing & bioavailabilty Melted cocoa butter → has low viscosity Glycerol- gelatin and PEG type bases → have high viscosity 5. Brittleness Theobrama oil suppositories → are elastic, do not fracture easily. Macrogols and synthetic fat with high degree of hydrogenation and high steratae content → causes brittleness. To overcome brittleness: a. The temperature of the melted base and the mould should be as similar as possible. b. Addition of small amounts of Tween 80/85 castor oil, glycerin or propylene glycol. 6. Density Important when the amount of drug per suppository must be calculated. Volume of mould is fixed → therefore mass of individual suppository depends on the density of the base. 7. Volume Contraction There must be good mould release of the suppository. 8. Lubricants Bases with a low volume of contraction require lubricants for rmoval of suppository. Theobroma oil → alcoholic solutions of glycerin, propylene glycol and silicones used. Glycero-gelatin → liquid paraffin and arachis oil used. 9. Rancidity & Antioxidants Fats which oxidize become rancid..Can add antioxidants e.g.: tocopherol, phenol, ascorbic acid, a-naphthol 10. Surface Changes Efflorescence (flowering) → small crystals develop in the form of a powder film on the surface of the suppository. Caused by substance having a melting point close to room temperature. To overcome this problem: i. Store at the recommended temperature ii. Replace raw materials of low melting with substances having higher melting points iii. Use close-fitting packaging e.g. blister packs Hard Moulding ž Base and medicament are cold rolled into a cylindrical rod → lengths containing the correct doses are cut off and one end is pointed → used for small quantities only. ž Labour intensive method.  Compression Moulding ž Blend mass is cold grated and then extruded into a mould → requires special suppository compression machine. Advantages: ž No heating/melting therefore no sedimentation or polymorphic changes → produce elegant suppositories → are perfect shape. ž Suitable for heat labile drugs. Disadvantages: ž Difficult to exclude air → is a slow process. ž Cannot use disposable moulds. Pour Moulding Most common method Re-usable and disposable moulds can be used Involves the following general steps:- Melting the base Incorporating any medicament Pouring melt into mould Allowing melt to cool and set into suppository Removing suppository from the mould Suitable for large scale manufacture → ± 3500 suppositories per hour can be produced on a rotary table - Disposable moulds are used most frequently - Advantage for disposable moulds: i. Most suitable for hot climates ii. Do not require cleaning after use iii. Provide protection from atmosphere  Reusable Metal Moulds Disposable Plastic Moulds Used also as Packaging  Evaluation of Suppositories 1) Appearance → includes odour, colour, surface condition and shape → BP and USP. 2) Weight → BP test – uniformity of weight. Weigh individually 20 suppositories, taken at random and determine the average weight. Not more than 2 of the individual weights deviate from the average weight by more than 5% and none deviates by more than 10%. 3) Disintegration → BP requires that all suppositories comply with the test for disintegration of suppositories 4) Melting behaviour → also known as the liquefaction time test → measure liquefaction time of suppositories in an apparatus that stimulates in vivo conditions. 5) Mechanical strength → designed to measure brittleness of the suppository. Active can affect strength of the base therefore test is important to avoid formulation problems. 6) Content of active ingredient → BP requires all suppositories to pass uniformity of content test. 7) Drug release – in vitro or in vivo  In vitro release rate → 3 methods: i. Place suppository in specific volume of water at 37°C and measure amount of drug released after set intervals. ii. Diffusion of active from moulten suppository into agar gel plate. iii. Diffusion of active through a semi-permeable membrane from the moulten suppository base into an aq. buffered medium.  In vivo determination of release: i. Blood and urine samples. ii. Measuring pharmacological effect after dosing. iii. Active remaining in the rectum after specific time intervals is determined. Pessaries ž Pessaries are solid medicated preparations designed for insertion into the vagina, usually to exert a local effect. ž Mainly for local effect e.g. treatment of Trichomonas and candida infections. ž Can be used for systemic effect → oestrogens and prostaglandin analogues → also progesterone. ž Usually buffered at pH 4.5. ž Usually prepared in a 4-8g mould. ž Glycerol-gelatin bases used → well tolerated and relatively soluble in vaginal secretions. PEG promotes irritation and fatty recipients may result in leakage.