Suppositories: Spring 2022 PDF

PHA 339 Alekha K. Dash, R.Ph., Ph.D. Ø Understand the composition, advantages and disadvantages of suppository dosage form. Ø Understand the skill necessary to compound a suppository dosage form. Ø Evaluate a good suppository dosage form. Ø Suppositories are solid dosage forms containing the medicin...

PHA 339 Alekha K. Dash, R.Ph., Ph.D. Ø Understand the composition, advantages and disadvantages of suppository dosage form. Ø Understand the skill necessary to compound a suppository dosage form. Ø Evaluate a good suppository dosage form. Ø Suppositories are solid dosage forms containing the medicinal agents intended for insertion into the rectum, vaginal cavity or the urethral tract. Ø After insertion they usually melt or undergo dissolution to release the drug for pharmacological effect. Ø Used for local or systemic action. Drug Release Rectal suppository: Ø Cylindrical with one or both end tapered. Ø Adult rectal sup: Two gram (Approx.) Ø Infant rectal sup: One gram (Approx.) Vaginal suppository: Ø Also known as Pessaries Ø Typically weighs 3-5 grams Ø Oviform or cone shaped Urethral suppository: Ø Also known as bougies Ø Pencil shaped 5 Ø The patient is unable to use the oral route (infection of GIT, nausea, vomiting, unconsciousness, post-operation and young, old and mentally disturbed patients) Ø The drug is less suited for oral route (causes GI side effects, insufficiently stable at pH of GIT, susceptible to enzymatic degradation, has first- pass effect, unacceptable taste) Slow and incomplete absorption Ø Inter and intra-subject variation Ø Development of local irritation and inflammation Ø Long preparation time Ø Problems with large scale production of suppositories and of achievement of a suitable shelf life Ø Demanding stringent storage conditions Ø Ø Rectal suppository are intended for treatment of constipation and hemorrhoids. Ø Suppositories are also administered for systemic action: üAnalgesics üAntispasmodics üSedatives & tranquilizers 8 Ø Physiological Volume Factors: Composition, Content, Ø Physicochemical Characteristics of Drug: Solubility of the drug, Particle size and concentration of the drug Ø Physiochemical properties of the base and other excipients: Melting point, Solubility, Chemical reactivity, Polymorphism Ø The human rectum is approximately 5-20 cm in the length Ø When empty of fecal material; it contains 2-3 ml of inert mucous fluid. Ø There is no villa or microvillus on rectal mucosa. Colonic Content: Ø Systemic effect (increased absorption): Evacuation or removal of fecal matters from rectum is needed. Ø An evacuation enema maybe administered before insertion of a suppository. Ø Diarrhea, colonic obstruction and tissue dehydration: influence the rate & degree of drug absorption from rectum. Circulation: Ø Drugs absorbed rectally: Partially bypass portal circulation. No metabolism in liver. Available for systemic effect. Ø Depending on the height at which absorption occurs at rectum, the drug passes into inferior, middle or superior hemorrhoid veins. Ø The inferior is nearest to the anus. Ø The upper hemorrhoid vein leads to portal circulation. Thus, it is advisable to keep suppository in the lower part of rectum. Ø 50% -70% of drug administered rectally, reported to go directly into general circulation. pH and lack of buffering capacity of the rectal fluid : Ø Rectal fluids are neutral (pH 7-8), have no effective buffer capacity. Ø The barrier separating colon lumen from the blood is preferentially permeable to the unionized forms of drugs. Ø Absorption of drug would be enhanced by change in pH of the rectal mucosa to one that increase the proportion of unionized drugs. Partition Coefficient: Ø The lipid water partition coefficient of a drug is important in selecting the suppository base and in anticipating drug release from that base. Ø Lipophilic drug distributed in a fatty suppository will be very difficult to partition with hydrophilic surrounding fluids. Ø Water-soluble salt are preferred in fatty base suppository. Ø Water-soluble base e.g: PEG, which dissolve in the rectal fluids, release both water-soluble and oil-soluble drugs. Degree of Ionization: Ø The barrier separating colon lumen from the blood is permeable to the unionized forms of drugs. Ø Absorption of drug can be enhanced by increase the proportion of unionized drugs Concentration of Drug: Ø The rate limiting step in drug absorption from suppository is the partitioning of the dissolved drug from the melted base and not the rate of solution of drug in the body fluid. Ø If the concentration of the drug in the intestinal lumen is above a particular amount, the rate of absorption will not change by increasing the concentration of drug. Other Factors affecting drug release from suppositories: Ø Drug diffusion from the surface to rectal fluid Ø Particle size Ø Presence of surface-active agents Nature of the Base: Ø Suppository base can soften or melt to release the drug from absorption Ø Excipients can affect drug absorption, change the physicochemical properties of the suppository base at body temperature, or can affect the dissolution of the drug. Ø Compatibility between drug, base and excipients is required. Ø Melts at rectal temperature 37.50 C Ø Nontoxic and nonirritating to sensitive and inflamed tissues Ø Convenient to handle by the patient and does not break or melt Ø Does not leak from the rectum Ø Stable on storage, does not change color, odor, and drug release pattern. Ø Physically stable and compatible with variety of drugs Ø No meta-stable forms. Ø Dissolve or disintegrate in the presence of mucous secretions or melt at body temperature to allow for the release of the medication. A. Oleaginous 1. Cocoa butter (Theobroma oil) 2. Cocoa butter substitutes B. Water soluble 1. Glycerinated gelatin 2. Polyethylene glycol mixtures C. Water dispersible (derived from Oleaginous and Water soluble bases) 1. Polyethylene glycol derivatives 2. Cocoa butter substituted with surfactants 1- Theobroma oil (Cocoa butter) Ø It is a yellowish-white solid with an odor of chocolate and is a mixture of glyceryl esters of different unsaturated fatty acids. Ø Cocoa butter is the most widely used suppository base used for rectal use. Ø This is the base of choice when no suppository base is specified. It satisfies many of the requirements for an ideal base. Advantages: ü A melting range of 30 - 36°C (solid at room temperature but melts in the body). ü Readily melted on warming, rapid setting on cooling. ü Miscible with many ingredients. ü Non-irritating. Disadvantages: Polymorphism: Ø When melted and cooled it solidifies in different crystalline forms, depending on the temperature of melting, rate of cooling and the size of the mass. Ø If melted at not more than 36°C and slowly cooled it forms stable beta crystals with normal melting point. Ø If over-heated then cooled it produce unstable gamma crystals which melt at about 15°C or alpha crystals melting at 20°C. ü Cocoa butter must be slowly melted over a warm water bath to avoid the formation of the unstable crystalline form. Disadvantages: Others: Ø Adherence to the mold Ø Softening point too low for hot climates. Ø Melting point reduced by soluble ingredients: Phenol and chloral hydrate have a tendency to lower the melting point of cocoa butter ü solidifying agents like beeswax (4%) may be incorporated to compensate for the softening effect of the added substance. Ø Poor water-absorbing ability: üImproved by the addition of emulsifying agents. These type of bases do not melt at body temp., but dissolve in the secretions of the body cavity in which they are inserted. Glycerinated-gelatin: Ø The commonest is Glycerol Suppositories Base B.P., which has 14% w/w gelatin, and 70% w/w glycerol & water Q.S. to 100%. Ø Ø The glycerol-gelatin base U.S.P. consisted of 20% w/w gelatin, and 70% w/w glycerol & water Q.S. to 100%. Ø Hygroscopic Polyethylene Glycols: Ø Polyethylene glycols are polymers of ethylene oxide and water, prepared to various chain lengths, molecular weights, and physical states. Ø The numerical designations refer to the average molecular weights of each of the polymers. Ø Polyethylene glycols (PEGs) having average molecular weights of 300, 400, and 600 are clear, colorless liquids, while those with molecular weights of 600-1000 are semisolids. Ø Those having average molecular weights of greater than 1000 are waxlike, white solids with the hardness increasing with an increase in the molecular weight. Polyethylene Glycols: Ø The melting point is often around 50°C. Ø Drug release depends on the base dissolving rather than melting. Ø PEG with various MW: blended together to produce suppository bases with varying: ◦ melting points, ◦ dissolution rates ◦ physical characteristics Ø Origin and Chemical composition: Natural, synthetic or modified. Physical or chemical incompatibilities with other constituents can be predicted Ø Melting range: Broad melting range, initiation and end point of melting. Ø Solidification value: Time required for base solidification when it is cooled. ØIodine Value: This value express the number of grams of iodine that react with 100 gm of fat or other unsaturated material. § The possibility of decomposition by moisture, acids, and oxygen (leads to rancidity in fats) increases with high iodine values. Ø Acid Value: The number of milligrams of potassium hydroxide required to neutralize the free acid in 1 gm of substance is expressed by this value. 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. Ø Water Number: The amount of water in grams, which can be incorporated in 100 gm of fat is expressed by this value. § The water number can be increased by addition of surface active agents. Four methods are generally used: (1) (2) (3) (4) Hand molding Compression molding Pour molding Automatic molding This is the oldest and simplest method of making suppositories. Ø the drug and the base (cocoa butter) mixture is triturated thoroughly in a mortar Ø the plastic mass formed is rolled into a cylinder on a ointment slab with the help of a steel-blade spatula. Ø divided into equal segments with a sharp blade depending on the number of suppositories to be prepared Øused when only a few suppositories are to be prepared in a cocoa butter base. Ø Method involves compression using suppository making machines. On a small scale, a mortar and pestle may be used (preheated mortar facilitate softening of the base). Ø The suppository base and the other ingredients are combined by thorough mixing. Ø The friction of the process causes the base to soften into a paste-like consistency. Ø The method requires that the capacity of the molds first be determined by compressing a small amount of the base into the dies and weighing the finished suppositories. Most commonly used method for the preparation of suppositories. Ø the material is melted on a steam bath Ø active ingredients are added to the molted mass Ø finally, the mass is poured into cooled metal/disposable molds ØPouring, cooling and removal from the mold can be performed by rotary automatic molding machines. ØThe output of a typical rotary machine is from 3,500 to 6,000 suppositories per hour. Ø Polyethylene glycol suppositories stored at usual room temperature without the requirement of refrigeration. Ø Both cocoa butter and glycerinated gelatin suppositories stored preferably in a refrigerator. Ø Plastic or Metal Molds Ø Disposable plastic molds are now available with some additional advantages over the conventional metal molds. üCostly molds and wrapping materials are not required. üMold shapes can be changed with less expense. üThe costly and time consuming wrapping process with aging and precooling is eliminated 1. Melting range test 2. Liquefaction time test for rectal suppositories: Time required for suppositories to liquefy under pressures similar to those found in rectum in presence of water at 37 C. 3. Breaking test 4. Disintegration and In-vitro release test 5. Stability testing Presence of water in the suppositories: Use of water as a solvent for drug should be avoided ?? üWater accelerates oxidation of fats. üIf water evaporates, the dissolved substance crystallizes out. üReaction between ingredients (in suppository) are more likely to occur in the presence of water. üThe incorporation of water can lead to bacteria or fungi growth on storage and can necessitates the addition of bacteriostatic agents (as parabens) Hygroscopicity: üGlycerinated gelatin suppositories have moisture loss by evaporation in dry climates and absorbs moisture under conditions of high humidity. üPEG bases are also hygroscopic. Rancidity and Antioxidant: üRancidity results from the autoxidation and subsequent decomposition of unsaturated fats into low & medium molecular weight saturated & unsaturated aldehydes , ketones and acids , which have strong unpleasant odor. üExample of effective antioxidant are phenols such as " hydroquinone or B-naphtholquinone. Lubricant or mold adherance: ü Cocoa butter adhere to suppository molds ü Various mold lubricants or release agents must be used to overcome this difficulty (mineral oil , aqueous solution of sodium lauryl sulfate , alcohol , silicones , soap). ü The release of suppository can be improved by coating the cavities with polytetrofluoroethylene (Teflone). Volume contraction: Occurs in many melted suppository base after cooling the mold, result in: ü Contraction hole formation at the open end of the mold. ü The contraction can be eliminated by pouring a mass slightly above its congealing temperature into a mold warmed at about the same temperature or the mold is overfilled so that the excess mass containing the contraction hole can be scraped off. Low Viscosity: Ø Can result in the sedimentation of suspended particles. Ø The viscosity of the melted suppository base is important in the manufacture of the suppository and to its behavior in the rectum after melting. Ø Melted cocoa butter have low viscosity than glycerinated gelatin and PEG type base To overcome the problems caused by use of low viscosity bases: Ø Use base with a more narrow melting range that is closer to body temperature. Ø Cetyl , stearyl or myristyl alcohols or stearic acid are added to improve the consistency of suppositories Incompatibilities: Ø PEG bases are incompatible with silver salt, tannic acid, aminopyrine , quinine , icthammol, asprine , benzocaine & sulphonamides. Ø Many chemicals have a tendency to crystallize out of PEG, e.g.: sodium sarbital, salicylic acid & camphor. Ø Higher concentration of salicylic acid softens PEG to an ointment-like consistency, d- Aspirin complexes with PEG. Ø Penicillin G , although stable in cocoa butter and other fatty bases was found to decompose in PEG bases. Ø Fatty bases with significant hydroxyl values may react with acidic ingredients. Ø Progesterone vaginal suppositories, F < 10%, Poor absorption and high 1st pass metabolism, Lessen the possibility of miscarriage, luteal phase defect, In vitro fertilization (IVF) -> uterine lining development Ø Miconazole Vaginal Suppositories, Fungus resides on mucosal membranes, i.e., outside the body, need high dose Ø Pharmaceutics: Basic Principles and Application to Pharmacy Practice by Dr Dash § Chapter 11- Semi solid dosage forms ØAnsel’s Pharmaceutical Dosage Forms and Drug Delivery Systems; § Chapter 12- Suppositories and Inserts