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Suppositories. Suppositories. A suppository is a medicated or non medicated solid dosage form generally intended for use in the rectum, vagina and urethra.
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Suppositories • 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 • 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 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? • The lower hemorrhoidal veins surrounding the colon and rectum enter into the inferior vena cava and thus bypass the liver. 1 • 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.
The pH of the rectal mucosa has a rate-controlling role in drug absorption. 2 • 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.
The diffusion of the drug to the site on the rectal mucosa at which absorption occurs. 3 • 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 fluids- Absorption through the rectal mucosa drug absorption from the anorectal area • Release the drug from the suppository base. • Distribute by the surrounding fluids to sites of absorption • Dissolve in the fluids • Contact of the drug with the lumen walls, and to a large number of absorption sites.
Release 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 drug • is released as the vehicle melts, water-soluble oil-insoluble salts are preferred
For water-soluble bases from which the drug is • released as the vehicle dissolves, the water-soluble • type salt is the one of choice for quicker • drug absorption. • Ex. Ephedrine sulfate and quinine hydrochloride, • as well as sodium barbital and sodium salicylate, • are preferred than their bases and acids to increase • the absorption rate from suppositories.
The 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.
The 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.
The 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.
The presence of Surfactants in the formulation [surfactantcontaining vehicle] Surfactants increase drug absorption rate due to: • Surface tension lowering • The mucus-peptizing action • The 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.
Ex. 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.
2. 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 ammonium • compounds and sulfonic acid derivatives are poorly • absorbed. • Unionized substances that are lipid-insoluble are poorly • absorbed. • Thus, 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.
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.
Adjuvants • Changes in the rheological properties • of the base at body temperature • Drug release from hvdrogels of hydropolyethyl • methacrylate 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.
2. 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.
Specifications 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.
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 • 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, careful stability observations are recommended.
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: • Theαform • Obtained by suddenly cooling melted cocoa butter to 0°C. • It melts at 24°C • 2.Theβ’form • Crystallizes out of the liquefied cocoa butter with stirring • at 18 to 23°C. • Its melting between 28 and 31°C. • 3.Theβ’form • Changes slowly into the stableβform which melts • between 34 and 35°C. • This change is accompanied by a volume contraction. • 4.Theγform • 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 β 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: • If the mass is not completely melted, the remaining • crystals prevent the formation of the unstable form. • 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." • 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 of 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.
Hydrogenation • It is an inexpensive method • Hydrogenation of oil as corn oil to reduce the unsaturation • and so increase the percentage of solid triglycerides at • room temperature. • The triglycerides with lower melting points are removed by • solvent extraction or by pressing. • This type of fat products are referred to as "hard butter."
Interesterification • Interesterification of oils as coconut oil, palm kernel oil, • and/or palm oil (all chosen for their high content of lauric • acid moieties) are refined to remove free fatty acids, • deodorized to remove volatiles, hydrogenated as • described previously, and then interesterified. • This final step, catalyzed by sodium methoxide, more • equally distributes the fatty acid moieties among the • glycerin molecules, creating more common triglycerides, • and therefore a more narrow melting range.
Re-esterification First, 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.
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 formulaHOCH2 (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. This base has low-melting and require refrigeration. It is useful when rapid disintegration is desired. 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.
