2SuppositoriesA 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 localanesthetics are dispensed in suppositoryfor treating local conditionsAnalgesics, antispasmodics, sedatives,tranquilizers, and antibacterial agentsare dispensed in suppository for systemic action
3Types and shapes of suppositories Rectal suppositories are tapered to resemble a torpedo shape. weigh about 2 g for adults and I g for Children.2.Vaginal suppositories molded in theglobular or oviform shape, or compressedon a tablet press into modified conicalshapes. weigh about 3 to 5 g.3.Urethral suppositories called bougies, arepencil shaped and pointed at one extremity.for males weigh about 4 g each and are100 to 150 mm long;for females, they are 2 g each and usually60 to 75 mm in length.
4Factors Affecting Drug Absorption from Rectal SuppositoriesPhysiologic FactorsMany drugs cannot be administered orally Why?Affected by the digestive juicesTheir therapeutic activity is modified by the liverenzymes after absorption from the small intestine.
5More 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?The lower hemorrhoidal veins surrounding the colonand rectum enter into the inferior vena cava and thusbypass the liver.1The upper hemorrhoidal vein doesconnect with the portal veins leadingto the liver.The lymphatic circulation helps alsoin absorbing a rectally administereddrug and in diverting the absorbeddrug from the liver.
6The pH of the rectal mucosa has a rate-controlling role in drug absorption. 2The colon has a pH of ≈ 6.8, with no buffercapacity, thus the dissolving drugs determinethe pH in the ano-rectal area.
7Colonic lumen is permeable to the unionized forms of drugs. Thus, weaker acids and bases are more readilyabsorbed than the stronger, highly ionized ones. Thus,the absorption of a drug would be enhanced by a changein the pH of the rectal mucosa that would increase theproportion of unionized drug.
8So 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 pH7 to 42% at pH 4. In contrast, with a basic drug likequinine, which becomes more ionized at the lower pHvalues, the absorption is decreasedfrom 20% at pH 7 to 9% at pH 4.
93 The diffusion of the drug to the site on the rectal mucosa at which absorption occurs.3The diffusivity is influenced by:The nature of the medicament, such as the presence ofsurfactant or the water-lipoidal solubility of the drugThe physiologic state of the colon (the amount andchemical nature of the fluids and solids present).The state of the anorectal membrane. This membranouswall is covered with a relatively continuous mucousblanket, which can act as a mechanicalbarrier for the free passage of drug throughthe pore space where absorption occurs.
10Physicochemical Characteristics o f the Drug Drug in vehicle- Drug in colon fluids-Absorption through the rectal mucosadrug absorption from the anorectal areaRelease the drug from the suppository base.Distribute by the surrounding fluids to sites of absorptionDissolve in the fluidsContact of the drug with the lumen walls, and to a large number of absorption sites.
11Release the drug from the suppository base. The lipid/water partition coefficient.Solution of the drugs in solid water-soluble bases and oleaginous bases resulted in prolonged absorption times, because the drug is slowly eluted into the surrounding fluids.For fatty bases from which the drugis released as the vehicle melts, water-soluble oil-insoluble salts are preferred
12For water-soluble bases from which the drug is released as the vehicle dissolves, the water-solubletype salt is the one of choice for quickerdrug absorption.Ex. Ephedrine sulfate and quinine hydrochloride,as well as sodium barbital and sodium salicylate,are preferred than their bases and acids to increasethe absorption rate from suppositories.
13The rate-limiting step in drug absorption from suppositories is the partitioning of the dissolved drug from the melted base and not the rate of solution of the drug in the body fluids.The rate at which the drug diffuses to the surface of the suppository, the particle size of the suspended drug and the presence of surface active agents are factors that affect drug release from suppositories.Solution of the drugs in solid polyethylene glycol and oleaginous bases resulted in prolonged absorption times, because the drug is slowly eluted into the surrounding fluids.
14The particle size of the suspended drug The larger the particle size, the slower the rate of solution. Thus, the drug absorption rate is decreased with an increase in drug particle size.
15The concentration of the suspended drug Marked increases in drug concentration play no role in altering drug absorption rates but drug concentration is related to release rates from suppository bases.
16[surfactantcontaining vehicle] The presence of Surfactants in the formulation[surfactantcontaining vehicle]Surfactants increase drug absorption rate due to:Surface tension loweringThe mucus-peptizing actionThe rectal membrane is covered by a continuous mucous blanket, which may be washed away by colonic fluids that have reduced surface tension. The cleansing action caused by the surfactantcontaining vehicle may make additional pore spaces available for drug absorption, thus facilitating drug movement across the rectal membrane barrier.
17Ex. in the case of sodium iodide, absorption is accelerated in the presence of surfactants and be proportional to the relative surface tension lowering of the vehicle.N.B. In the case of phenol-type drugs, absorption rate is decreased in the presence of surfactant, due to the formation of a drug-surfactant complex.
182. Absorption from the lumen walls The anorectal and colonic mucosae are selectively permeable to the uncharged drug molecule. Thus, lipid-soluble undissociated drug is the most readily absorbed form.Completely ionized drugs like quaternary ammoniumcompounds and sulfonic acid derivatives are poorlyabsorbed.Unionized substances that are lipid-insoluble are poorlyThus, drug absorption can be increased by the use of buffer solutions or salts that convert the pH of the anorectal area to a value that increases the concentration of unionized drug.
19Physicochemical 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 rangesSince fatty bases may harden for several months after molding, this rise in melting range certainly would affect absorptionFor Polyethylene Glycol BasesThe absorption rate increases along with hydroxyl values.The absorption rate is faster as the molecular mass of the polyethylene glycols (PEGs) used increased.
20Adjuvants Changes in the rheological properties of the base at body temperatureDrug release from hvdrogels of hydropolyethylmethacrylate decreased as increasing percentages of the cross-linking agent ethylene glycol dimethacrylate.Addition of hydrophobic colloidal silicon oxide to fat base Suppositories dramatically changes the rheologic behavior of the mass.
212. Affecting the dissolution of the drug in the media of the dosage form. In emulsion type bases. the amount of water-soluble drug released increased with the water content of the base, and that the rate of drug released could be prolonged by the addition of an aqueous polymer.Salicylates improve the rectal absorption of water-soluble antibiotics in lipophilic bases.
22Specifications for suppository bases Origin and Chemical Composition.A brief description of the composition of the base reveals the source of origin (i.e., 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.
232. Melting Range.Since fatty suppository bases are complex mixtures of triglycerides and therefore do not have sharp melting points, their meltingcharacteristics are expressed as a range indicating the temperature at which the fat starts to melt and the temperature at which it is completely melted.
243. 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.
254. 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.
265. 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.
276. 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.
287. 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.
298. Water Number. 9. Acid Value. 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.
30Types of Suppository Bases The Ideal Suppository Base for long shelf-lifeHaving reached equilibrium crystallinity.The majority of components melt at rectaltemperature 36°CBases with higher melting ranges may be employed for:eutectic mixtures, addition of oils, balsams, andsuppositories intended for use in tropical climates.
312. 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 itselffrom the mold without the need for moldlubricants.
326. 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.
33If the base is fatty, it has the following additional requirements: 10. Acid value below 311. Saponification value ranges from 200 to 24512. Iodine value less than 713. The interval between "melting point (34oC)" and"solidification (32oC) point" is small
3414. Low melting ranges (30- 34oC) for incorporating drugs that increases the melting range of the base.Ex. Silver nitrate or lead acetateHigh melting ranges (37-41°C) for incorporating drugsthat lower melting points of the base.Ex. Camphor, chloral hydrate, menthol, phenol, thymol,and several types of volatile oils or for formulatingsuppositories for use in tropical climates.
35Oleogenous 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.
36 The most widely used suppository base ADVANTAGES of CACAO BUTTER as SUPPOSITORY BASEThe most widely used suppository baseIt satisfies many of the requirements for an ideal baseSafe, non reactive and melts atbody temperature.
37 DISADVANTAGES of CACAO BUTTER as SUPPOSITORY BASE Cocoa butter does not contain emulsifiers andtherefore does not take up large quantities ofwater (maximum 20 to 30 g of water to 100 gof 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, careful stability observations are recommended.
38Low 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.
39 Cacao butter exhibits different polymorphisms each has different melting pointsCocoa 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.
40Cocoa butter is thought to be capable of existing in four crystalline states: The α formObtained by suddenly cooling melted cocoa butter to 0°C.It melts at 24°C2. The β’ formCrystallizes out of the liquefied cocoa butter with stirringat 18 to 23°C.Its melting between 28 and 31°C.3. The β’ formChanges slowly into the stable β form which meltsbetween 34 and 35°C.This change is accompanied by a volume contraction.4. The γ formMelting at 18°CObtained by pouring a cool (20°C) cocoa butter, before itsolidifies, into a container which is cooled at deepfreezetemperature.
41The formation of various forms of cocoa butter depends on: The degree of heatingThe cooling processThe conditions during this process.At temperatures below 36°C, negligible amounts of theunstable forms are obtainedBut prolonged heat above that critical temperature causesthe formation of the unstable crystals with resultinglowered melting points. Thus, prolonged heating in theprocess of melting the fats must be avoidedThe reconversion to the stable β form takes one to fourdays, depending on the storage temperature, the higher thetemperature, the faster the change.
42The formation of the unstable forms can be avoided by: If the mass is not completely melted, the remainingcrystals prevent the formation of the unstable form.Small amounts of stable crystals added to the meltedcocoa butter accelerate the change from the unstable tothe stable form; this process is called “Seeding."The solidified melt is tempered at temperatures between28 and 32oC for hours or days, causing a comparativelyquick Change from the unstable to the stable form.
43Cocoa Butter Substitutes Cocoa butter substitutes maintain the desirable properties of cocoa butter and eliminate the undesirable ones.Treatment of Vegetable Oils to Produce Suppository BasesSynthetic 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.
44Hydrogenation It is an inexpensive method Hydrogenation of oil as corn oil to reduce the unsaturationand so increase the percentage of solid triglycerides atroom temperature.The triglycerides with lower melting points are removed bysolvent extraction or by pressing.This type of fat products are referred to as "hard butter."
45InteresterificationInteresterification of oils as coconut oil, palm kernel oil,and/or palm oil (all chosen for their high content of lauricacid moieties) are refined to remove free fatty acids,deodorized to remove volatiles, hydrogenated asdescribed previously, and then interesterified.This final step, catalyzed by sodium methoxide, moreequally distributes the fatty acid moieties among theglycerin molecules, creating more common triglycerides,and therefore a more narrow melting range.
46Re-esterificationFirst, the oil is split into fatty acids and glycerin by treatment with high-pressure steam.The glycerin is removed from the mixture, and the remaining free fatty acids consist of C6-C18 chain length compounds are (caproic, caprylic, capric, lauric, myristic, palmitic, oleic, and stearic acids).Caproic, caprylic, and capric acids are removed by fractional vacuum distillation, because they are readily rancidified and may cause irritation of mucous membranes.The remaining fatty acids, consisting mainly of lauric acid, are hydrogenated to harden the mixture and lower its iodine value.
47Hydrophilic Suppository Bases Glycerin SuppositoriesGlycerinated 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.
48The Polyethylene Glycols (Carbowax and Polyglycols) Long-chain polymers of ethylene oxide have the general formula HOCH2 (CH2OCH2)X CH2OHWhen their average molecular weight ranges from 200 to600 they exist as liquids, and as wax-like solids whentheir molecular weights are above 1000.Their water solubility, hygroscopicity, and vapor pressuredecrease with increasing average molecular weights.The wide range of melting points and solubilities makespossible to formulate suppositories with various degreesof heat stability and different dissolution rates.
49Several combinations of polyethylene glycols have been prepared for suppository bases having different physical characteristics.Base 1Polyethylene glycol %Polyethylene glycol %This base has low-melting and require refrigeration.It is useful when rapid disintegration is desired.Base 2Polyethylene glycol %Polyethylene glycol %More heat stable than Base 1 and stored at higher temperatures.It is useful when a slow release of active ingredients is desired.
50ADVANTAGES of POLYETHYLENE GLYCOL as SUPPOSITORY BASEPolyethylene 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.
51DISADVANTAGES of POLYETHYLENE GLYCOL as SUPPOSITORY BASEMost patients do not 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.
52The polyethylene glycol suppositories cannot be prepared by hand rolling but prepared by both molding and cold compression methods.Special precautions are necessary in preparing a molded suppository with the polyethylene glycol bases.The mold must be dry because the base is soluble in water.The suppository will be fissured owing to thecrystallization and contraction of the polymer. Suchsuppositories may be easily fractured in packaging orhandling. To solve this problem the melted mass must beallowed to cool to the congealing point before pouring.
53Water-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.
54ADVANTAGES of WATER-DISPERIBLE BASES as SUPPOSITORY BASE Can be used for formulating both water-soluble and oil-soluble drugs.Can be stored and handed at elevated temperaturesHave broad drug compatibility.Nonsupport of microbial growth, nontoxic and not causesensitivity.
55DISADVANTAGES of WATER-DISPERIBLE BASES as SUPPOSITORY BASE Caution must be taken in the use of surfactants with drugsdue to the increase in the rate of drug absorption.These surface active agents can show interaction withdrugs and a consequent decrease in therapeutic effects.
56Compressed 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 coatedwith water-soluble polyethylene glycol to aidin insertion into the rectum.
57The suppositories are non-melting, but dissolve in body fluids. 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.
58Unusual Types of Suppositories Layered suppository has an outer shell with 37 to 38°C melting point and a core with 34 to 35°C melting point. This is prepared by dipping the suppository in the coating solution until the desired coating thickness is obtained. Each layer contains different drugs or used to prevent coalescing of adjacent suppositories during storage.
59The layering also may be multilayering in the horizontal plane The layering also may be multilayering in the horizontal plane. This is prepared by partially filling the mold, allowing the mass to congeal, and pouring additional layers. Multilayered suppositories used for separating incompatible drugs in different layers and providing different melting characteristics for controlling the rate of drug absorption.
60Problems in Formulating Suppositories Formulation of SuppositoriesProblems in Formulating SuppositoriesHygroscopicityGlycerinated 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 weight increases, the hygroscopicity decreases.
61Water 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 substanceswould crystallize out.3. Reactions between ingredients are more likely to occurin the presence of water.4. Bacterial or fungal growth necessitates the addition ofbacteriostatic agents as parabens.
62Incompatibilities Polyethylene glycol are incompatible with silver salts,tannic acid, aminopyrine, quinine, ichthammol, aspirin,benzocaine, iodochlorhydroxyquin, and sulfonamides.Many chemicals have a tendency to crystallize out ofpolyethylene glycol, e.g. sodium barbital, salicylic acid,and camphor.Higher concentrations of salicylic acid soften polyethyleneglycol to an ointment-like consistency, and aspirincomplexes with it.Penicillin G, although stable in cocoa butter and otherfatty bases, decomposes in polyethylene glycol bases.Fatty bases with significant hydroxyl values may reactwith acidic ingredients.
63ViscosityThe 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.
64In the manufacture of suppositories made with low-viscosity 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.
65The 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 iscloser 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.
66Brittleness Suppositories made from cocoa butter are elastic and do not fracture.Synthetic fatty bases with a high degree of hydrogenationare more brittle. Fracturing of the suppository made withsuch bases is induced by rapid chilling (shock cooling) ofthe 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.
67Density 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.
68If volume contraction occurs in the mold during cooling, additional compensationmust 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.
69Volume 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.
702. Contraction hole formation at the open end of the mold 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.
71Lubricants or Mold Release Agents Cocoa butter adheres to suppositorymolds 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 of suppositories from damaged molds was improved by coating the cavities with polytetrafluoroethylene (Teflon).
72Dosage Replacement Factor The amount of base that is replaced by active ingredients in the suppository formulation can be calculated.The replacement factor, f, is derived from the following equation:where: E = weight of pure base suppositoriesG = weight of suppositories with X% active ingredientf = 100 (E - G) + 1(G)(X)
73Weight and Volume Control The amount of active ingredient in each suppository depends on:Its concentration in the mass;The volume of the mold cavity;The specific gravity of the base;The volume variation between molds, good machining ofthe molds should keep the volume of each cavity within2% of a desired value;Weight variations between suppositories due to theinconsistencies in the manufacturing process,e.g., incomplete closing of molds, uneven scrapings.Regardless of the reason for the variation in weight, itshould be within ±5%.
74The German and Russian Pharmacopeias state individual weight variations of rectal suppositories at ±5% of the average weight.The Pharmacopeia Nordica allows ± 10% of the average weight for 90% of the suppositories, but these deviations must not exceed ±20%.
75Rancidity 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 weightsaturated and unsaturated aldehydes, ketones and acids, which have strong, unpleasant odors.
76The 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.
77Examples 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 (BHA) and butylhydroxytoluene (BHT).
78An 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?
79Preliminary suppository bases to be studied are first evaluated by measuring drug availability from thesuppository in water at 36 to 37°C.Availability and cost of the suppository basesStability of both active ingredients and base at 4°C androom temperature.Ease of molding and release in the manufacturingequipment.Toxicity (irritancy) and drug availability are measured inanimals before the medication is ready for humanclinical trials.
80Suppositories for Systemic Effect The drug should be homogeneously dispersiblein base used it, but releasable at the desired rate to the aqueous body fluids surrounding the suppository.Therefore, the solubility of the active ingredient in water or other solvents should be known.If the drug favors water, a fatty base with low water number may be preferred.On the other hand, if the drug is highly fat-soluble, a water-type base, with the addition of a surfactant to enhance solubility may be the preferred choice.
81To enhance the homogeneity of drug in the desired base, either a suitable solvent is used or the drug is finely ground before incorporation.A drug that is soluble in a minimal quantity of water, or in another liquid miscible with the base, can be dissolved and the solution added to the molten base.If the drug is to be incorporated directly into the base, it should be finely ground so that 100% can be passed through a 100-mesh USP screen.Fragility, brittleness tests must be performed.
82The theoretically desirable suppository formulations are molded in the laboratory and stored at room temperature (25 ± 3°C) for at least 48 hours before in vitro testing for release rate.In-vitro release rates as a quality control procedure and the suppository formulation chosen yields the in vitro release rate pattern that is to be used as the desired standard.Chemical and physical stability, consistency of in vitro drug release patterns within theoretically desired ranges, and animal toxicity are some characteristics studied before suppository formulas are chosen for human clinical trials.
83The suppositories are stored at room temperature (25 ± 3°C) and at 4°C for prolonged stability tests. They are tested at regular intervals (1- ,3-, and 6-month and 1- and 2-year periods) for changes in appearance, melting and softening range, drug stability, base stability, and in vitro drug release pattern.In vivo clinical findings in man are the last criteria for choosing a desired formulation. The clinical findings may be based on blood levels of the drug and/or desired clinical effects in man.
84Suppositories for Local Effect Drugs intended for local action are generally non-absorbable, e.g., drugs for hemorrhoids, local anesthetics, and antiseptics.The bases used for these drugs are virtually non-absorbable, slow in melting, and slow in drug release, as contrasted with suppository bases intended for systemic drugs.Local effects are generally delivered withina half hour and last at least 4 hours.
85The desired base should release an adequate amount of drug within a half hour, and completely melt with release of all drug between 4 and 6 hours. A suppository that does not melt within the 6-hour test period would probably not completely release its drug, cause discomfort to the patient and be expelled by the patient before it is fully utilized.Tests in animals must show no irritancy if the suppository is to be used in man.
86Manufacture of Suppositories Three methods are used in preparing suppositories:Molding by handCompression moldingPour molding
87Hand MoldingThe simplest and oldest method of preparing a suppository is by hand, i.e. by rolling the wellblended suppository base containing the active ingredients into a cylindrical rod of desired length and diameter, or into vaginal balls of the intended weight.Starch or talc powder on the rolling surfaceand hands prevent the mass from adhering.The rod is cut into portions, and one end is pointed.This method is practical and economical for the manufacture of small numbers of suppositories.
88Compression Molding A more uniform and pharmaceutically elegant suppository can be made by compressing the coldmass into a desired shape.A handturned wheel pushes a piston against thesuppository mass contained in a cylinder, so that themass is extruded into molds (usually three).
89Advantages over hand molding method: It avoids the possibilities of sedimentation of the insoluble solids in the suppository baseDisadvantages:Too slow for large-scale production.Molding fat type base suppositories is air entrapment.This makes close weight control impossible and alsofavors the possible oxidation of both the base andactive ingredients.
90Pour 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 orsteam bath to avoid local overheatingThen the active ingredients are either emulsified orsuspended in it.Finally, the mass is poured into cooled metal molds, whichare usually chrome or nickel-plated.
93Packaging 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.
94Poorly wrapped and packaged suppositories can cause: Staining, breakage, or deformation by melting caused by adhesion.Suppositories in direct contact with one another are spoiled by fusion resulting from changes in temperature. Partially melted suppositories stain the outer package unless they are overwrapped or are packaged with some other barrier that prevents contact with the outer container.
95In-Package Molding Suppositories It is a method for molding suppositories directly in their wrapping material either plastic or aluminum foil.The tops of the molds are left open for the entrance of filling nozzles. After the mass has been injected, the tops are sealed.The strips are then passed in an upright position through a cooling station.
96 The advantages of in-package molding: High production rates.No bulk handling or storage of unwrapped suppositories.Disposable molds have the additional advantage of being suited for suppositories intended for tropical climates. If the mass should melt at the high storage temperatures, the mold still retains its proper shape, so that upon cooling it can be dispensed without deformation.The disadvantages of in-package molding:Dependence on the shape of the formed mold