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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.

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Presentation on theme: "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."— Presentation transcript:

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2 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 Emollients, astringents, antibacterial agents, steroids, and local anesthetics are dispensed in suppository anesthetics are dispensed in suppository for treating local conditions for treating local conditions Analgesics, antispasmodics, sed­atives, Analgesics, antispasmodics, sed­atives, tranquilizers, and antibacterial agents tranquilizers, and antibacterial agents are dispensed in suppository for systemic action are dispensed in suppository for systemic action

3 1.Rectal suppositories are tapered to resemble a torpedo shape. weigh about 2 g for adults and I g for Children. Types and shapes of suppositories 2.Vaginal suppositories molded in the globular or oviform shape, or compressed globular or oviform shape, or compressed on a tablet press into modified conical on a tablet press into modified conical shapes. weigh about 3 to 5 g. shapes. weigh about 3 to 5 g. 3.Urethral suppositories called bougies, are pencil shaped and pointed at one extremity. pencil shaped and pointed at one extremity. for males weigh about 4 g each and are for males weigh about 4 g each and are 100 to 150 mm long; 100 to 150 mm long; for females, they are 2 g each and usually for females, they are 2 g each and usually 60 to 75 mm in length. 60 to 75 mm in length.

4 Factors Affecting Drug Absorption from Rectal Suppositories Physiologic Factors Many drugs cannot be administered orally Why? Affected by the digestive juices Affected by the digestive juices Their therapeutic activity is modified by the liver Their therapeutic activity is modified by the liver enzymes after absorption from the small intestine. enzymes after absorption from the small intestine.

5 The lower hemorrhoidal veins surrounding the colon The lower hemorrhoidal veins surrounding the colon and rectum enter into the inferior vena cava and thus and rectum enter into the inferior vena cava and thus bypass the liver. bypass the liver. 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 upper hemorrhoidal vein does The upper hemorrhoidal vein does connect with the portal veins leading connect with the portal veins leading to the liver. to the liver. The lymphatic circulation helps also The lymphatic circulation helps also in absorbing a rectally administered in absorbing a rectally administered drug and in diverting the absorbed drug and in diverting the absorbed drug from the liver. drug from the liver.

6 2 The pH of the rectal mucosa has a rate-controlling role in drug absorption. 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 The colon has a pH of 6.8, with no buffer capacity, thus the dissolving drugs determine capacity, thus the dissolving drugs determine the pH in the ano-rectal area. the pH in the ano-rectal area.

7 Colonic lumen is permeable to the unionized forms of Colonic lumen is permeable to the unionized forms of drugs. Thus, weaker acids and bases are more readily drugs. Thus, weaker acids and bases are more readily absorbed than the stronger, highly ionized ones. Thus, absorbed than the stronger, highly ionized ones. Thus, the absorption of a drug would be enhanced by a change the absorption of a drug would be enhanced by a change in the pH of the rectal mucosa that would increase the in the pH of the rectal mucosa that would increase the proportion of unionized drug. proportion of unionized drug.

8 So absorption of acidic drugs can be increased when So absorption of acidic drugs can be increased when the pH of the surrounding fluids was lowered. the pH of the surrounding fluids was lowered. The absorption of salicylic acid rises from 12% at a pH The absorption of salicylic acid rises from 12% at a pH 7 to 42% at pH 4. In contrast, with a basic drug like 7 to 42% at pH 4. In contrast, with a basic drug like quinine, which becomes more ionized at the lower pH quinine, which becomes more ionized at the lower pH values, the absorption is decreased from 20% at pH 7 to 9% at pH 4.

9 The diffusivity is influenced by: The nature of the medicament, such as the presence of The nature of the medicament, such as the presence of surfactant or the water-lipoidal solubility of the drug surfactant or the water-lipoidal solubility of the drug The physiologic state of the colon (the amount and The physiologic state of the colon (the amount and chemical nature of the fluids and solids present). chemical nature of the fluids and solids present). The state of the anorectal membrane. This membranous The state of the anorectal membrane. This membranous wall is covered with a relatively continuous mucous wall is covered with a relatively continuous mucous blanket, which can act as a mechanical blanket, which can act as a mechanical barrier for the free passage of drug through barrier for the free passage of drug through the pore space where absorption occurs. the pore space where absorption occurs. 3 The diffusion of the drug to the site on the The diffusion of the drug to the site on the rectal mucosa at which absorption occurs. rectal mucosa at which absorption occurs.

10 Physicochemical Characteristics o f the Drug absorption drug absorption from the anorectal area Drug in vehicle- Drug in colon fluids- Absorption through the rectal mucosa 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.

11 1.Release the drug from the suppository base. The lipid/water partition coefficient. 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. 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. o For fatty bases from which the drug is released as the vehicle melts, water-soluble oil- insoluble salts are preferred is released as the vehicle melts, water-soluble oil- insoluble salts are preferred

12 o For water-soluble bases from which the drug is released as the vehicle dissolves, the water-soluble released as the vehicle dissolves, the water-soluble type salt is the one of choice for quicker type salt is the one of choice for quicker drug absorption. drug absorption. Ex. Ephedrine sulfate and quinine hydrochloride, as well as sodium barbital and sodium salicylate, as well as sodium barbital and sodium salicylate, are preferred than their bases and acids to increase are preferred than their bases and acids to increase the absorption rate from suppositories. the absorption rate from suppositories.

13 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-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. 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. 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.

14 The particle size of the suspended drug 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 larger the particle size, the slower the rate of solution. Thus, the drug absorption rate is decreased with an increase in drug particle size.

15 The concentration of the suspended drug 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. 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 The presence of Surfactants in the formulation The presence of Surfactants in the formulation [surfactant­containing vehicle] [surfactant­containing vehicle] Surfactants increase drug absorption rate due to: Surfactants increase drug absorption rate due to: 1.Surface tension lowering 2.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 surfactant ­ containing vehicle may make additional pore spaces available for drug absorption, thus facilitating drug movement across the rectal membrane barrier. 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 surfactant ­ containing vehicle may make additional pore spaces available for drug absorption, thus facilitating drug movement across the rectal membrane barrier.

17 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.

18 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 Completely ionized drugs like quaternary ammonium compounds and sulfonic acid derivatives are poorly compounds and sulfonic acid derivatives are poorly absorbed. absorbed. Unionized substances that are lipid-insoluble are poorly Unionized substances that are lipid-insoluble are poorly absorbed. 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.

19 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 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 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 increases along with hydroxyl values. The absorption rate is faster as the molecular mass of the polyethylene glycols (PEGs) used increased.

20 1.Changes in the rheological properties of the base at body temperature of the base at body temperature Drug release from hvdrogels of hydropolyethyl Drug release from hvdrogels of hydropolyethyl methacrylate decreased as increasing percentages of the cross-linking agent ethylene glycol dimethacrylate. 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. Addition of hydrophobic colloidal silicon oxide to fat base Suppositories dramatically changes the rheologic behavior of the mass. Adjuvants

21 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.

22 1. 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. Specifications for suppository bases

23 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. 2. Melting Range. Since fatty suppository bases are complex mixtures of triglycerides and therefore do not have sharp melting points, their melting

24 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.

25 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.

26 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.

27 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.

28 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.

29 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.

30 Types of Suppository Bases The Ideal Suppository Base for long shelf-life 1. Having reached equilibrium crystallinity. The majority of components melt at rectal The majority of components melt at rectal temperature 36°C temperature 36°C Bases with higher melting ranges may be employed for: Bases with higher melting ranges may be employed for: eutectic mixtures, addition of oils, balsams, and eutectic mixtures, addition of oils, balsams, and suppositories intended for use in tropical climates. suppositories intended for use in tropical climates.

31 2. Completely nontoxic and nonirritating to sensitive and inflamed tissues. 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 from the mold without the need for mold lubricants. lubricants.

32 6. Has wetting and emulsifying properties. 7. High water number. i.e. a high percentage of water can be incorporated in it. 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. i.e. does not change color, odor, or drug release pattern. 9. Can be manufactured by molding by either hand, machine, compression, or extrusion. machine, compression, or extrusion.

33 If the base is fatty, it has the following additional requirements: If the base is fatty, it has the following additional requirements: 10. Acid value below Saponification value ranges from 200 to Iodine value less than The interval between "melting point (34 o C)" and "solidification (32 o C) point" is small "solidification (32 o C) point" is small

34 14. Low melting ranges ( o C) for incorporating drugs 14. Low melting ranges ( o C) for incorporating drugs that increases the melting range of the base. that increases the melting range of the base. Ex. Silver nitrate or lead acetate 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.

35 Cocoa Butter (Theobroma Oil) Cocoa butter is a yellowish­white, solid, brittle fat. Cocoa butter is a yellowish­white, solid, brittle fat. Smells and tastes like chocolate. Smells and tastes like chocolate. Its melting point lies between 30°C and 35°C. Its melting point lies between 30°C and 35°C. Its iodine value is between 34 and 38. Its iodine value is between 34 and 38. Its acid value is no higher than 4. Its acid value is no higher than 4. Oleogenous Suppository Bases

36 ADVANTAGES of CACAO BUTTER as SUPPOSITORY BASE ADVANTAGES of CACAO BUTTER as SUPPOSITORY BASE The most widely used suppository base It satisfies many of the requirements for an ideal base It satisfies many of the requirements for an ideal base Safe, non reactive and melts at Safe, non reactive and melts at body temperature. body temperature.

37 Cocoa butter does not contain emulsifiers and 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. DISADVANTAGES of CACAO BUTTER as SUPPOSITORY BASE

38 Drugs as volatile oils, creosote, phenol, and chloral hydrate lower the melting point of cocoa butter. 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. Low contractility during solidification causes the suppositories to adhere to molds and necessitates the use of mold release agents or lubricants. Low contractility during solidification causes the suppositories to adhere to molds and necessitates the use of mold release agents or lubricants.

39 Cacao butter exhibits different polymorphisms each Cacao butter exhibits different polymorphisms each has different melting points has different melting points 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 primarily a triglyceride. 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).

40 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. Obtained by suddenly cooling melted cocoa butter to 0°C. It melts at 24°C It melts at 24°C 2. The β form Crystallizes out of the liquefied cocoa butter with stirring Crystallizes out of the liquefied cocoa butter with stirring at 18 to 23°C. at 18 to 23°C. Its melting between 28 and 31°C. Its melting between 28 and 31°C. 3. The β form Changes slowly into the stable β form which melts Changes slowly into the stable β form which melts between 34 and 35°C. between 34 and 35°C. This change is accompanied by a volume contraction. This change is accompanied by a volume contraction. 4. The γ form Melting at 18°C Melting at 18°C Obtained by pouring a cool (20°C) cocoa butter, before it Obtained by pouring a cool (20°C) cocoa butter, before it solidifies, into a container which is cooled at deep­freeze solidifies, into a container which is cooled at deep­freeze temperature. temperature.

41 The formation of various forms of cocoa butter depends on: The degree of heating The degree of heating The cooling process The cooling process The conditions during this process. The conditions during this process. At temperatures below 36°C, negligible amounts of the At temperatures below 36°C, negligible amounts of the unstable forms are obtained unstable forms are obtained But prolonged heat above that critical temperature causes But prolonged heat above that critical temperature causes the formation of the unstable crystals with resulting the formation of the unstable crystals with resulting lowered melting points. Thus, prolonged heating in the lowered melting points. Thus, prolonged heating in the process of melting the fats must be avoided process of melting the fats must be avoided The reconversion to the stable β form takes one to four The reconversion to the stable β form takes one to four days, depending on the storage temperature, the higher the days, depending on the storage temperature, the higher the temperature, the faster the change. temperature, the faster the change.

42 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. 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 cocoa butter accelerate the change from the unstable to the stable form; this process is called Seeding." the stable form; this process is called Seeding." 3. The solidified melt is tempered at temperatures between 28 and 32 o C for hours or days, causing a comparatively 28 and 32 o C for hours or days, causing a comparatively quick Change from the unstable to the stable form. quick Change from the unstable to the stable form.

43 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.

44 It is an inexpensive method It is an inexpensive method Hydrogenation of oil as corn oil to reduce the unsaturation Hydrogenation of oil as corn oil to reduce the unsaturation and so increase the percentage of solid triglycerides at and so increase the percentage of solid triglycerides at room temperature. room temperature. The triglycerides with lower melting points are removed by The triglycerides with lower melting points are removed by solvent extraction or by pressing. solvent extraction or by pressing. This type of fat products are referred to as "hard butter." This type of fat products are referred to as "hard butter." Hydrogenation

45 Interesterification of oils as coconut oil, palm kernel oil, Interesterification of oils as coconut oil, palm kernel oil, and/or palm oil (all chosen for their high content of lauric and/or palm oil (all chosen for their high content of lauric acid moieties) are refined to remove free fatty acids, acid moieties) are refined to remove free fatty acids, deodorized to remove volatiles, hydrogenated as deodorized to remove volatiles, hydrogenated as described previously, and then interesterified. described previously, and then interesterified. This final step, catalyzed by sodium methoxide, more This final step, catalyzed by sodium methoxide, more equally distributes the fatty acid moieties among the equally distributes the fatty acid moieties among the glycerin molecules, creating more common triglycerides, glycerin molecules, creating more common triglycerides, and therefore a more narrow melting range. and therefore a more narrow melting range. Interesterification

46 First, the oil is split into fatty acids and glycerin by treatment with high-pressure steam. 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 C 6 -C 18 chain length compounds are (caproic, caprylic, capric, lauric, myristic, palmitic, oleic, and stearic acids). The glycerin is removed from the mixture, and the remaining free fatty acids consist of C 6 -C 18 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. 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. The remaining fatty acids, consisting mainly of lauric acid, are hydrogenated to harden the mixture and lower its iodine value. Re-esterification

47 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). 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. 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. 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. Because glycerin is hygroscopic, these suppositories are packaged in materials that protect them from environmental moisture.

48 The Polyethylene Glycols (Carbowax and Polyglycols) (Carbowax and Polyglycols) Long-chain polymers of ethylene oxide have the general formula HOCH 2 (CH 2 OCH 2 ) X CH 2 OH When their average molecular weight ranges from 200 to When their average molecular weight ranges from 200 to 600 they exist as liquids, and as wax-like solids when 600 they exist as liquids, and as wax-like solids when their molecular weights are above their molecular weights are above Their water solubility, hygroscopicity, and vapor pressure Their water solubility, hygroscopicity, and vapor pressure decrease with increasing average molecular weights. decrease with increasing average molecular weights. The wide range of melting points and solubilities makes The wide range of melting points and solubilities makes possible to formulate suppositories with various degrees possible to formulate suppositories with various degrees of heat stability and different dissolution rates. of heat stability and different dissolution rates.

49 Several combinations of polyethylene glycols have been prepared for suppository bases having different physical characteristics. Base 1 Polyethylene glycol % Polyethylene glycol % Base 2 Polyethylene glycol % Polyethylene glycol % 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.

50 Polyethylene glycol suppositories do not require a mold lubricant and are easier to prepare than cocoa butter suppositories. 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. They are physiologically inert, do not hydrolyze or deteriorate and do not support mold growth. ADVANTAGES of POLYETHYLENE GLYCOL as SUPPOSITORY BASE

51 Most 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. Most 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. DISADVANTAGES of POLYETHYLENE GLYCOL as SUPPOSITORY BASE as SUPPOSITORY BASE

52 The polyethylene glycol suppositories cannot be prepared by hand rolling butprepared by both molding and cold compression methods. The 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. 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 mold must be dry because the base is soluble in water. The suppository will be fissured owing to the The suppository will be fissured owing to the crystallization and contraction of the polymer. Such crystallization and contraction of the polymer. Such suppositories may be easily fractured in packaging or suppositories may be easily fractured in packaging or handling. To solve this problem the melted mass must be handling. To solve this problem the melted mass must be allowed to cool to the congealing point before pouring. allowed to cool to the congealing point before pouring.

53 Water-Dispersible Bases 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. These are nonionic surface active materials, related chemically to the polyethylene glycols.

54 Can be used for formulating both water-soluble and oil- Can be used for formulating both water-soluble and oil- soluble drugs. soluble drugs. Can be stored and handed at elevated temperatures Can be stored and handed at elevated temperatures Have broad drug compatibility. Have broad drug compatibility. Nonsupport of microbial growth, nontoxic and not cause Nonsupport of microbial growth, nontoxic and not cause sensitivity. sensitivity. ADVANTAGES of WATER-DISPERIBLE BASES as SUPPOSITORY BASE

55 Caution must be taken in the use of surfactants with drugs Caution must be taken in the use of surfactants with drugs due to the increase in the rate of drug absorption. due to the increase in the rate of drug absorption. These surface active agents can show interaction with These surface active agents can show interaction with drugs and a consequent decrease in therapeutic effects. drugs and a consequent decrease in therapeutic effects. DISADVANTAGES of WATER-DISPERIBLE BASES as SUPPOSITORY BASE

56 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. 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.

57 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. Soft gelatin capsules filled with liquid or solid drugs used for vaginal use. The suppositories are non-melting, but dissolve in body fluids.

58 Unusual 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.

59 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. 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.

60 Glycerinated gelatin suppositories are hygroscopic, they lose moisture by evaporation in dry climates and absorb moisture under conditions of high humidity. 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 weight increases, the hygroscopicity decreases. 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. Hygroscopicity Formulation of Suppositories

61 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. would crystallize out. 3. Reactions between ingredients are more likely to occur in the presence of water. in the presence of water. 4. Bacterial or fungal growth necessitates the addition of bacteriostatic agents as parabens. bacteriostatic agents as parabens. Water in Suppositories

62 Polyethylene glycol are incompatible with Polyethylene glycol are incompatible with silver salts, silver salts, tannic acid, aminopyrine, quinine, ichthammol, aspirin, tannic acid, aminopyrine, quinine, ichthammol, aspirin, benzocaine, iodochlorhydroxyquin, and sulfonamides. benzocaine, iodochlorhydroxyquin, and sulfonamides. Many chemicals have a tendency to crystallize out of Many chemicals have a tendency to crystallize out of polyethylene glycol, e.g. sodium barbital, salicylic acid, polyethylene glycol, e.g. sodium barbital, salicylic acid, and camphor. and camphor. Higher concentrations of salicylic acid soften polyethylene Higher concentrations of salicylic acid soften polyethylene glycol to an ointment-like consistency, and aspirin glycol to an ointment-like consistency, and aspirin complexes with it. complexes with it. Penicillin G, although stable in cocoa butter and other Penicillin G, although stable in cocoa butter and other fatty bases, decomposes in polyethylene glycol bases. fatty bases, decomposes in polyethylene glycol bases. Fatty bases with significant hydroxyl values may react Fatty bases with significant hydroxyl values may react with acidic ingredients. with acidic ingredients. Incompatibilities

63 The viscosity of the melted suppository mass is important in the manufacture of the suppository and to its behavior in the rectum after melting. 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. 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. Viscosity

64 In 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. In 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. 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.

65 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. 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.

66 Suppositories made from cocoa butter are elastic and do Suppositories made from cocoa butter are elastic and do not fracture. not fracture. Synthetic fatty bases with a high degree of hydrogenation Synthetic fatty bases with a high degree of hydrogenation are more brittle. Fracturing of the suppository made with are more brittle. Fracturing of the suppository made with such bases is induced by rapid chilling (shock cooling) of such bases is induced by rapid chilling (shock cooling) of the melted bases in an extremely cold mold. the melted bases in an extremely cold mold. Brittle suppositories have problems in manufacturing, Brittle suppositories have problems in manufacturing, handling and wrapping. 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. Brittleness

67 To calculate the amount of drug per suppository, 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. 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. Density

68 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.

69 This phenomenon occurs in many melted suppository bases after cooling in the mold. 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. Volume Contraction

70 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.

71 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 of suppositories from damaged molds was improved by coating the cavities with polytetra­ fluoroethylene (Teflon). Lubricants or Mold Release Agents

72 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 suppositories G = weight of suppositories with X% active ingredient Dosage Replacement Factor f = 100 (E - G) + 1 (G)(X) (G)(X)

73 The amount of active ingredient in each suppository depends on: Its concentration in the mass; Its concentration in the mass; The volume of the mold cavity; The volume of the mold cavity; The specific gravity of the base; The specific gravity of the base; The volume variation between molds, good machining of The volume variation between molds, good machining of the molds should keep the volume of each cavity within the molds should keep the volume of each cavity within 2% of a desired value; 2% of a desired value; Weight variations between suppositories due to the Weight variations between suppositories due to the inconsistencies in the manufacturing process, inconsistencies in the manufacturing process, e.g., incomplete closing of molds, uneven scrapings. e.g., incomplete closing of molds, uneven scrapings. Regardless of the reason for the variation in weight, it Regardless of the reason for the variation in weight, it should be within ±5%. should be within ±5%. Weight and Volume Control

74 The 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%.

75 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. Rancidity and Antioxidants

76 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.

77 Examples of effective antioxidants: Phenols: such as m- or p-diphenols; α -naphthol; Phenols: such as m- or p-diphenols; α -naphthol; Quinones: such as hydroquinone or β-naphthoquinone; Quinones: such as hydroquinone or β-naphthoquinone; Tocopherols: particularly the α and β forms; 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).

78 An Approach in Formulating Suppositories The important considerations of the formulator are: Is the medication intended for local or systemic use? Is the medication intended for local or systemic use? Is the site of application rectal, vaginal or urethral? Is the site of application rectal, vaginal or urethral? Is the desired effect to be quick or slow and prolonged? Is the desired effect to be quick or slow and prolonged?

79 Preliminary suppository bases to be studied are first Preliminary suppository bases to be studied are first evaluated by measuring drug availability from the evaluated by measuring drug availability from the suppository in water at 36 to 37°C. suppository in water at 36 to 37°C. Availability and cost of the suppository bases Availability and cost of the suppository bases Stability of both active ingredients and base at 4°C and Stability of both active ingredients and base at 4°C and room temperature. room temperature. Ease of molding and release in the manufacturing Ease of molding and release in the manufacturing equipment. equipment. Toxicity (irritancy) and drug availability are measured in Toxicity (irritancy) and drug availability are measured in animals before the medication is ready for human animals before the medication is ready for human clinical trials. clinical trials.

80 Suppositories for Systemic Effect The drug should be homogeneously dispersible The drug should be homogeneously dispersible in 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. 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. 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.

81 To enhance the homogeneity of drug in the desired base, either a suitable solvent is used or the drug is finely ground before incorporation. To 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. 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. 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. Fragility, brittleness tests must be performed.

82 The 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. The 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. 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. 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.

83 The 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. The 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. 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.

84 Suppositories for Local Effect Drugs intended for local action are generally non- absorbable, e.g., drugs for hemorrhoids, local anesthetics, and antiseptics. 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. 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 within Local effects are generally delivered within a half hour and last at least 4 hours. a half hour and last at least 4 hours.

85 The 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. The 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. Tests in animals must show no irritancy if the suppository is to be used in man.

86 Manufacture of Suppositories Three methods are used in preparing suppositories: Molding by hand Compression molding Pour molding

87 Hand Molding The 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 surface and 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.

88 Compression Molding A more uniform and pharmaceutically elegant A more uniform and pharmaceutically elegant suppository can be made by compressing the cold suppository can be made by compressing the cold mass into a desired shape. mass into a desired shape. A hand­turned wheel pushes a piston against the A hand­turned wheel pushes a piston against the suppository mass contained in a cylinder, so that the suppository mass contained in a cylinder, so that the mass is extruded into molds (usually three). mass is extruded into molds (usually three).

89 Advantages over hand molding method: It avoids the possibilities of sedimentation of the insoluble solids in the suppository base Disadvantages: Too slow for large-scale production. Too slow for large-scale production. Molding fat type base suppositories is air entrapment. Molding fat type base suppositories is air entrapment. This makes close weight control impossible and also This makes close weight control impossible and also favors the possible oxidation of both the base and favors the possible oxidation of both the base and active ingredients. active ingredients.

90 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.

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93 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. aluminum, paper and plastic strips.

94 Poorly 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.

95 In-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 Dependence on the shape of the formed mold


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