SALMAN BIN ABDULAZIZ UNIVERSITY COLLEGE OF PHARMACY Dr. Mohammad Khalid Anwer e-mail:- [email protected] A suppository is a medicated or non medicated solid dosage form generally intended for use in the rectum, vagina and urethra. Drugs may be administered in suppository form for either local or systemic effects. Such action depends on the nature of the drug, its concentration, and the rate of absorption. Emollients, astringents, antibacterial agents, steroids, and local anesthetics are dispensed in suppository for treating local conditions Analgesics, antispasmodics, sedatives, tranquilizers, and antibacterial agents are dispensed in suppository for systemic action Types and shapes of suppositories 1. Rectal suppositories are tapered to resemble a torpedo shape. weigh about 2 g for adults and 1 g for Children. 2.Vaginal suppositories molded in the globular or oviform shape, or compressed on a tablet press into modified conical shapes. weigh about 3 to 5 g. 3.Urethral suppositories called bougies, are pencil shaped and pointed at one extremity. for males weigh about 4 g each and are 100 to 150 mm long; for females, they are 2 g each and usually 60 to 75 mm in length. Factors Affecting Drug Absorption from Rectal Suppositories Physiologic Factors Many drugs cannot be administered orally Why? Affected by the digestive juices Their therapeutic activity is modified by the liver enzymes after absorption from the small intestine. More than (50 to 70%) of rectally administered drugs can be absorbed from the anorectal area into the general circulation and still retain therapeutic values. Why? 1 The lower hemorrhoidal veins surrounding the colon and rectum enter into the inferior vena cava and thus bypass the liver. The upper hemorrhoidal vein does connect with the portal veins leading to the liver. The lymphatic circulation helps also in absorbing a rectally administered drug and in diverting the absorbed drug from the liver. 2 The pH of the rectal mucosa has a rate-controlling role in drug absorption. The colon has a pH of ≈ 6.8, with no buffer capacity, thus the dissolving drugs determine the pH in the ano-rectal area. Colonic lumen is permeable to the unionized forms of drugs. Thus, weaker acids and bases are more readily absorbed than the stronger, highly ionized ones. Thus, the absorption of a drug would be enhanced by a change in the pH of the rectal mucosa that would increase the proportion of unionized drug. So absorption of acidic drugs can be increased when the pH of the surrounding fluids was lowered. The absorption of salicylic acid rises from 12% at a pH 7 to 42% at pH 4. In contrast, with a basic drug like quinine, which becomes more ionized at the lower pH values, the absorption is decreased from 20% at pH 7 to 9% at pH 4. 3 The diffusion of the drug to the site on the rectal mucosa at which absorption occurs. The diffusivity is influenced by: The nature of the medicament, such as the presence of surfactant or the water-lipoidal solubility of the drug The physiologic state of the colon (the amount and chemical nature of the fluids and solids present). The state of the anorectal membrane. This membranous wall is covered with a relatively continuous mucous blanket, which can act as a mechanical barrier for the free passage of drug through the pore space where absorption occurs. Physicochemical Characteristics o f the Drug Drug in vehicle- Drug in colon fluidsAbsorption through the rectal mucosa drug absorption from the anorectal area 1. Release the drug from the suppository base. 2. Distribute by the surrounding fluids to sites of absorption 3. Dissolve in the fluids 4. Contact of the drug with the lumen walls, and to a large number of absorption sites. Physicochemical Characteristics of the Base For Fatty Bases: • The absorption rate is faster from fatty bases having a lower melting range than from those with higher melting ranges • Since fatty bases may harden for several months after molding, this rise in melting range certainly would affect absorption For Polyethylene Glycol Bases •The absorption rate increases along with hydroxyl values. The absorption rate is faster as the molecular mass of the polyethylene glycols (PEGs) used increased. Specifications for suppository bases 1. Origin and Chemical Composition. Either entirely natural, synthetic or modified natural products. Physical or chemical incompatibilities of the base with the other constituents may be predicted if the exact formula composition is known, including preservatives, antioxidants and emulsifiers. 2. Melting Range. Since fatty suppository bases are complex mixtures of triglycerides and therefore do not have sharp melting points, their melting characteristics are expressed as a range indicating the temperature at which the fat starts to melt and the temperature at which it is completely melted. 3. Solid-Fat Index (SFI). A base with a sharp drop in solids over a short temperature span proves brittle if molded too quickly. This type of base requires a reduced differential between mold temperature and mass temperature for trouble-free molding. Suppository hardness can be determined by the solids content at room temperature. Since skin temperature is about 32°C, one can predict a product that would be dry to touch from a solids content over 30% at that temperature. 4. Hydroxyl Value. This is a measure of unesterified positions on glyceride molecules and reflects the monoglyceride and diglyceride content of a fatty base. The number represents the milligrams of KOH that would neutralize the acetic acid used to acetylate 1 g of fat. 5. Solidification Point. Is the time required for solidifying the base when it is chilled in the mold. If the interval between the melting range and solidification point is 10°C or more, the time required for solidification may have to be shortened by refrigeration to produce a more efficient manufacturing procedure. 6. Saponification Value. Is the number of milligrams of potassium hydroxide required to neutralize the free acids and saponify the esters contained in 1 g of a fat is an indication of the type (mono-, di-, or tri-) glyceride, as well as the amount of glyceride present. 7. Iodine Value. Is the number of grams of iodine that reacts with 100 g of fat or other unsaturated material. The possibility of decomposition by moisture, acids, and oxygen (which leads to rancidity in fats) increases with high iodine values. 8. Water Number. Is the amount of water, in grams, that can be incorporated in 100 g of fat. The "water number" can be increased by the addition of surface active agents, monoglycerides, and other emulsifiers. 9. Acid Value. Is the number of milligrams of potassium hydroxide required to neutralize the free acid in 1 g of substance. Low "acid values" or complete absence of acid are important for good suppository bases. Free acids complicate formulation work, because they react with other ingredients and can also cause irritation when in contact with mucous membranes. Types of Suppository Bases The Ideal Suppository Base for long shelf-life 1. Having reached equilibrium crystallinity. The majority of components melt at rectal temperature 36°C Bases with higher melting ranges may be employed for: eutectic mixtures, addition of oils, balsams, and suppositories intended for use in tropical climates. 2. Completely nontoxic and nonirritating to sensitive and inflamed tissues. 3. Compatible with a broad variety of drugs. 4. Has no metastable forms. 5. Shrinks sufficiently on cooling to release itself from the mold without the need for mold lubricants. 6. Has wetting and emulsifying properties. 7. High water number. i.e. a high percentage of water can be incorporated in it. 8. Stable on storage. i.e. does not change color, odor, or drug release pattern. 9. Can be manufactured by molding by either hand, machine, compression, or extrusion. If the base is fatty, it has the following additional requirements: 10. Acid value below 3 11. Saponification value ranges from 200 to 245 12. Iodine value less than 7 13. The interval between "melting point (34oC)" and "solidification (32oC) point" is small 14. Low melting ranges (30- 34oC) for incorporating drugs that increases the melting range of the base. Ex. Silver nitrate or lead acetate High melting ranges (37-41°C) for incorporating drugs that lower melting points of the base. Ex. Camphor, chloral hydrate, menthol, phenol, thymol, and several types of volatile oils or for formulating suppositories for use in tropical climates. Oleogenous Suppository Bases Cocoa Butter (Theobroma Oil) Cocoa butter is a yellowishwhite, solid, brittle fat. Smells and tastes like chocolate. Its melting point lies between 30°C and 35°C. Its iodine value is between 34 and 38. Its acid value is no higher than 4. ADVANTAGES of CACAO BUTTER as SUPPOSITORY BASE The most widely used suppository base It satisfies many of the requirements for an ideal base Safe, non reactive and melts at body temperature. DISADVANTAGES of CACAO BUTTER as SUPPOSITORY BASE Cocoa butter does not contain emulsifiers and therefore does not take up large quantities of water (maximum 20 to 30 g of water to 100 g of cocoa butter). The addition of emulsifiers such as Tween 60 (5 to 10%) increases the water absorption considerably. Emulsifiers also help to keep insoluble substances suspended in the fat. Suspension stability is further obtained by the addition of materials (aluminum monostearate, silica) that give melted fats thixotropic properties. There is always the possibility that the suppositories containing these additives will harden on storage. Therefore, prolonged, observations are recommended. careful stability Low contractility during solidification causes the suppositories to adhere to molds and necessitates the use of mold release agents or lubricants. Drugs as volatile oils, creosote, phenol, and chloral hydrate lower the melting point of cocoa butter. To correct this condition, wax and spermaceti are commonly used. Cacao butter exhibits different polymorphisms each has different melting points Cocoa butter is primarily a triglyceride. A phenomenon due to the high proportion of unsaturated triglycerides is that it exhibits polymorphism (the property of existing in different crystalline forms). Each of the different forms of cocoa butter has different melting points, and different drug release rates. When cocoa butter is heated above its melting temperature (36°C) and chilled to its solidification point (below 15°C), immediately after returning to room temperature this cocoa butter has a melting point of about 24°C, approximately 12° below its original state. Cocoa butter is thought to be capable of existing in four crystalline states: 1.The α form Obtained by suddenly cooling melted cocoa butter to 0°C. It melts at 24°C 2. The β form Crystallizes out of the liquefied cocoa butter with stirring at 18 to 23°C. Its melting between 28 and 31°C. 3. The β’ form Changes slowly into the stable β form which melts between 34 and 35°C. This change is accompanied by a volume contraction. γ 4. The form Melting at 18°C Obtained by pouring a cool (20°C) cocoa butter, before it solidifies, into a container which is cooled at deepfreeze temperature. The formation of various forms of cocoa butter depends on: The degree of heating The cooling process The conditions during this process. At temperatures below 36°C, negligible amounts of the unstable forms are obtained But prolonged heat above that critical temperature causes the formation of the unstable crystals with resulting lowered melting points. Thus, prolonged heating in the process of melting the fats must be avoided The reconversion to the stable 3 form takes one to four days, depending on the storage temperature, the higher the temperature, the faster the change. The formation of the unstable forms can be avoided by: 1. If the mass is not completely melted, the remaining crystals prevent the formation of the unstable form. 2. Small amounts of stable crystals added to the melted cocoa butter accelerate the change from the unstable to the stable form; this process is called “Seeding." 3. The solidified melt is tempered at temperatures between 28 and 32oC for hours or days, causing a comparatively quick Change from the unstable to the stable form. Cocoa Butter Substitutes Cocoa butter substitutes maintain the desirable properties of cocoa butter and eliminate the undesirable ones. Treatment o f Vegetable Oils to Produce Suppository Bases Synthetic or natural oils as vegetable oils as coconut or palm kernel oil are modified by: Esterification, hydrogenation and fractionation at different melting ranges to obtain the desired product. Hydrophilic Suppository Bases Glycerin Suppositories Glycerinated gelatin suppositories do not melt at body temperature but dissolve in the secretions of the body cavity in which they are inserted (vaginal or rectal). Solution time is regulated by the proportion of gelatin/glycerin/water used, the nature of the gelatin used, and the chemical reaction of the drug with gelatin. Glycerinated gelatin suppositories support mold or bacterial growth, thus, they are stored in a cool place and often contain agents that inhibit microbial growth. Because glycerin is hygroscopic, these suppositories are packaged in materials that protect them from environmental moisture. The Polyethylene Glycols (Carbowax and Polyglycols) Long-chain polymers of ethylene oxide have the general formula HOCH2 (CH2OCH2)X CH2OH When their average molecular weight ranges from 200 to 600 they exist as liquids, and as wax-like solids when their molecular weights are above 1000. Their water solubility, hygroscopicity, and vapor pressure decrease with increasing average molecular weights. The wide range of melting points and solubilities makes possible to formulate suppositories with various degrees of heat stability and different dissolution rates. Several combinations of polyethylene glycols have been prepared for suppository bases having different physical characteristics. Base 1 Polyethylene glycol 1000 Polyethylene glycol 4000 96 % 4 % This base has low-melting and require refrigeration. It is useful when rapid disintegration is desired. Base 2 Polyethylene glycol 1000 Polyethylene glycol 4000 75 % 25 % More heat stable than Base 1 and stored at higher temperatures. It is useful when a slow release of active ingredients is desired. ADVANTAGES of POLYETHYLENE GLYCOL as SUPPOSITORY BASE Polyethylene glycol suppositories do not require a mold lubricant and are easier to prepare than cocoa butter suppositories. They are physiologically inert, do not hydrolyze or deteriorate and do not support mold growth. DISADVANTAGES of POLYETHYLENE GLYCOL as SUPPOSITORY BASE Most patients do feel discomfort from the use of these suppositories, because this type of Bases cause irritation "sting“ to mucous membranes when water drawn from the mucosa. This irritation may be eliminated by dipping in water before insertion or by addition of 10% water to facilitate solution of the suppository after insertion. Water-Dispersible Bases These are nonionic surface active materials, related chemically to the polyethylene glycols. The surfactants most commonly used in suppository formulations are the polyoxyethylene sorbitan fatty acid esters (Tween), the polyoxyethylene stearates (Myrj) and the sorbitan fatty acid esters (Span and Arlacel). These surface active agents may be used alone, blended, or used in combination with other suppository vehicle materials to yield a wide range of melting points and consistencies. ADVANTAGES of WATER-DISPERIBLE BASES as SUPPOSITORY BASE Can be used for formulating both water-soluble and oilsoluble drugs. Can be stored and handed at elevated temperatures Have broad drug compatibility. Nonsupport of microbial growth, nontoxic and not cause sensitivity. DISADVANTAGES of WATER-DISPERIBLE BASES as SUPPOSITORY BASE Caution must be taken in the use of surfactants with drugs due to the increase in the rate of drug absorption. These surface active agents can show interaction with drugs and a consequent decrease in therapeutic effects. Compressed Tablet Suppositories Rectal suppositories usually are not compressed as tablets, because the amount of liquid in the rectal cavity is insufficient for tablet disintegration. Effervescent tablets aid disintegration, as carbon dioxide releasing laxative suppositories. This compressed rectal suppository is coated with water-soluble polyethylene glycol to aid in insertion into the rectum. The compressed tablet for vaginal use weighing about 3 g with almond shape to ease insertion. The moisture level of the vagina is sufficient for disintegration and dissolution. A typical vaginal tablet contains active ingredients, with boric and/or phosphoric acid for adjusting the acidity of the vagina to pH 5. Vaginal suppositories are usually used for systemic or topical therapy, as in the treatment of vaginitis, or as a spermatocide. Soft gelatin capsules filled with liquid or solid drugs used for vaginal use. The suppositories are non-melting, but dissolve in body fluids. Formulation of Suppositories Hygroscopicity Glycerinated gelatin suppositories are hygroscopic, they lose moisture by evaporation in dry climates and absorb moisture under conditions of high humidity. Polyethylene glycol bases are hygroscopic, the rate of moisture change in polyethylene glycol bases depends on humidity, temperature and on the chain length of the molecule. As the molecular hygroscopicity decreases. weight increases, the Water in Suppositories Use of water as a solvent for incorporating substances in suppository bases should be avoided for the following reasons. 1. Water accelerates the oxidation of fats. 2. If the water evaporates, the dissolved substances would crystallize out. 3. Reactions between ingredients are more likely to occur in the presence of water. 4. Bacterial or fungal growth necessitates the addition of bacteriostatic agents as parabens. Viscosity The viscosity of the melted suppository mass is important in the manufacture of the suppository and to its behavior in the rectum after melting. Melted cocoa butter and some of its substitutes have low viscosities, whereas the glycerinated gelatin and polyethylene glycol type base have viscosities considerably higher than cocoa butter. In the manufacture of suppositories made with lowviscosity bases, extra care must be exercised to avoid the sedimentation of suspended particles. Poor technique can lead to nonuniform suppositories, particularly in the distribution of active ingredients. To prevent segregation of particles suspended in molten bases, the well-mixed mass should be handled at the lowest temperature necessary to maintain fluidity, constantly stirred without entrapping air, and quickly solidified in the mold. The following approaches may be taken to overcome the problems caused by use of low viscosity bases. 1. Use a base with a more narrow melting range that is closer to body temperature. 2.The inclusion of approximately 2% aluminum monostearate not only increases the viscosity of the fat base considerably, but also aids in maintaining a homogeneous suspension of insoluble materials. Cetyl, stearyl, or myristyl alcohols or stearic acid are added to improve the consistency of suppositories. Brittleness Suppositories made from cocoa butter are elastic and do not fracture. Synthetic fatty bases with a high degree of hydrogenation are more brittle. Fracturing of the suppository made with such bases is induced by rapid chilling (shock cooling) of the melted bases in an extremely cold mold. Brittle suppositories have problems in manufacturing, handling and wrapping. To overcome this difficulty, the temperature differential between melted base and mold should be as small as possible. Addition of a small amount of Tween 80, Tween 85, fatty acid monoglycerides, castor oil, glycerin, or propylene glycol increases its plasticity and renders it less brittle. Density To calculate the amount of drug per suppository, the density of the base must be known. The volume of the mold cavity is fixed, and therefore, the weight of the individual suppository depends on the density of the mass. Knowledge of the suppository weight can be obtained from a given mold and density of the chosen base; the active ingredients can then be added to the bulk base in such an amount that the exact quantity of drug is present in each molded suppository. If volume contraction occurs in the mold during cooling, additional compensation must be made to obtain the proper suppository weight. Thus, density alone cannot be the sole criterion for calculating suppository weight per fixed volume mold. When volume contraction occurs, the suppository weight is determined empirically by small batch runs. Volume Contraction This phenomenon occurs in many melted suppository bases after cooling in the mold. The results are manifested in the following two ways. 1. Good mold release. This is caused by the mass pulling away from the sides of the mold. This contraction facilitates the removal of the suppositories from the mold, eliminating the need for mold release agents. 2. Contraction hole formation at the open end of the mold. This undesirable feature results in lowered suppository weight and imperfect appearance of the suppository. The contraction can be eliminated by pouring a mass slightly above its congealing temperature into a mold warmed to about the same temperature. In volume production using standard molds, where adequate control of temperature may not be feasible, the mold is overfilled so that the excess mass containing the contraction hole can be scraped off. Lubricants or Mold Release Agents Cocoa butter adheres to suppository molds because of its low volume contraction. These suppositories are difficult to remove from the molds, and various mold lubricants or release agents must be used to overcome this difficulty. Mineral oil, an aqueous solution of sodium lauryl sulfate, various silicones, alcohol, and tincture of green soap are examples of agents employed for this purpose. They are applied by wiping, brushing, or spraying. The release improved of suppositories by coating fluoroethylene (Teflon). from the damaged cavities with molds was polytetra- Rancidity and Antioxidants Confusion may take place between the acidity of fats with rancidity. The presence of free fatty acids is no indication of rancidity or that such a product may become rancid. Rancidity results from the autoxidation and decomposition of unsaturated fats into low and medium molecular weight saturated and unsaturated aldehydes, ketones and acids, which have strong, unpleasant odors. The lower the content of unsaturated fatty acid constituents in a suppository base, the greater is its resistance to rancidity. Since this reaction begins with the formation of hydroperoxides, the measure of autoxidation is the peroxide value (active oxygen) which is a measure of the iodine liberated from an acidified solution of potassium iodide by "peroxide oxygen" of the fats. Examples of effective antioxidants: Phenols: such as m- or p-diphenols; α-naphthol; Quinones: such as hydroquinone or β-naphthoquinone; Tocopherols: particularly the α and β forms; Gossypol present in cottonseed oil; Sesamol present in sesame oil; Propyl gallate and gallic acid; Tannins and tannic acid; Ascorbic acid and its esters; Butylhydroxyanisole (BHT). (BHA) and butylhydroxytoluene An Approach in Formulating Suppositories The important considerations of the formulator are: Is the medication intended for local or systemic use? Is the site of application rectal, vaginal or urethral? Is the desired effect to be quick or slow and prolonged? Preliminary suppository bases to be studied are first evaluated by measuring drug availability from the suppository in water at 36 to 37°C. Availability and cost of the suppository bases Stability of both active ingredients and base at 4°C and room temperature. Ease of molding and release in the manufacturing equipment. Toxicity (irritancy) and drug availability are measured in animals before the medication is ready for human clinical trials. Manufacture of Suppositories Three methods are used in preparing suppositories: Molding by hand Compression molding Pour molding Compression Molding A more uniform and pharmaceutically elegant suppository can be made by compressing the cold mass into a desired shape. A handturned wheel pushes a piston against the suppository mass contained in a cylinder, so that the mass is extruded into molds (usually three). Pour Molding The most commonly used method for producing suppositories on both a small and a large scale. First, the base material is melted, preferably on a water or steam bath to avoid local overheating Then the active ingredients are either emulsified or suspended in it. Finally, the mass is poured into cooled metal molds, which are usually chrome or nickel-plated. Packaging of Molded Suppositories Suppositories must be packaged so that each suppository is overwrapped, or they must be placed in a container in that they do not touch each other. Suppositories usually are foiled in tin, aluminum, paper and plastic strips.