Suppositories and pessaries

Pharmaceutics according to the syllabus of B. pharmacy TU

1. Suppositories and Pessaries Presented by Nabina 1

2. Definition 2

3. BP Definition : Suppository “Suppositories are solid, single-dose preparations. The shape, volume and consistency of suppositories are suitable for rectal administration .” 3

4. BP Definition: Pessaries “ Pessaries are single dose preparations. They have various shape usually ovoid with a volume and consistency suitable or insertion into vagina. They contain one or more active substances dispersed or dissolved in suitable basses that may be soluble or dispersible or melt at body temperature. Excipients such as diluents, adsorbents, surface active agents, lubricants, antimicrobial preservatives and colorizing material authorized by the competent authority may be added if necessary.” 4

5. pessaaries Common ingredients for inclusion in pessaries for local action include: antiseptics contraceptive agents l ocal anaesthetics various therapeutic agents to treat trichomonal , bacterial and monilial infections. 5

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8. Dosage form characteristics: a . Rectal suppositories for adults weigh 2 g and are torpedo shape . Children's suppositories weigh about 1 gm. b . Vaginal suppositories or Pessaries weigh about 3-5gm and are molded in globular or oviform shape or compressed on a tablet press into conical shape. c . Urethral suppositories called Bougies are pencil shape. Those intended for males weigh 4 g each and are 100-150 mm long. Those for females are 2 g each and 60-75 mm in length. 8

9. d . Nasal suppositories: Called nasal bougies or buginaria meant for introduction in to nasal cavity. They are prepared with glycerogelatin base. They weigh about 1 g and length 9-10 cm . e . Ear cones: Aurinaria and meant for introduction into ear. Rarely used. Theobroma oil is used as base . Prepared in urethral bougies mould and cut according to size . 9

10. Shape of suppositories 10

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12. Therapeutic Uses Suppository can be used for local or systemic effect. The action depends on nature of drug , concentration and rate of absorption Rectal suppository are intended for treatment of constipation and hemorrhoids. Suppositories are also administered for systemic action (analgesics, antispasmodics, sedatives & tranquilizers). 12

13. Location of suppository 13

14. Factor affecting drug absorption form rectal suppository: 1 ) Physiologic Factor: The human rectum is approximately 15-20 cm in the length, when empty of fecal material; it contains 2-3 ml of inert mucous fluid. In resting state, the rectum is non motile. There is no villa or microvillus on rectal mucosa. Physiological factors include : 14

15. A) Colonic Content: When systemic effect are desired from suppository greater absorption may be expected from a rectum that is void than that with fecal matter. An evacuation enema maybe administered before insertion of a suppository. Diarrhea, colonic obstruction and tissue dehydration influence the rate & degree of drug absorption from rectum. 15

16. B) Circulation : Drugs absorbed rectally partially by pass portal circulation, thereby enabling drug destroyed in liver to exert systemic effect. Depending on the height at which absorption occurs at rectum, the drug passes into inferior, middle or superior hemorrhoid veins. The inferior is nearest to the anus, the upper hemorrhoid vein —> portal circulation .thus it is advisable to keep suppositories in the lower part of rectum. 50% -70% of drug administered rectally, reported to go directly into general circulation. 16

17. C) pH and lack of buffering capacity of the rectal fluid Rectal fluids are neutral (pH 7-8), have no effective buffer capacity. The barrier separating colon lumen from the blood is preferentially permeable to the unionized forms of drugs, thus absorption of drug would be enhanced by change in pH of the rectal mucosa to one that increase the proportion of unionized drugs. 17

18. 2.Physiochemical characteristics of the drug : A)Lipid water solubility of a drug (partition coefficient The lipid water partition coefficient of a drug is important in selecting the suppository base and in anticipating drug release from that base lipophilic drug, in other word, distributed in a fatty suppository base has fewer tendencies to escape to the surrounding queues fluids. Thus water-soluble salt are preferred in fatty base suppository. water-soluble base : PEG, which dissolve in the rectal fluids, release both water-soluble and oil-soluble drugs. 18

19. B) Degree of ionization: The barrier separating colon lumen from the blood is preferentially permeable to the unionized forms of drugs, thus absorption of drug would be enhanced by increase the proportion of unionized drugs 19

20. C) Concentration of a drug in a base: The more drugs in a base, the more drug will be available for absorption. If the concentration of the drug in the intestinal lumen is above a particular amount, the rate of absorption is not change by further increase in concentration of drug. In general, the rate limiting step in drug absorption from suppository is the partitioning of the dissolved drug from the melted base and not the rate of solution of drug in the body fluid. 20

21. Scientists showed that: the rate, at which the drug diffuses to the surface of the suppository , Particle size , and presence of surface-active agents are factors that affect drug release from suppositories. 21

22. 3) Physiochemical Characteristics of the Base and Adjuvant: 1)Nature of the Base: Suppository base capable of melting, softening or dissolving to release the drug for absorption. If the base irritating the colon, it will promote colonic response, lead to increase bowl movement and decrease absorption. 22

23. 2) Presence of Adjuvant in Base : Adjuvant in a formula may affect drug absorption, change the rheological properties of the base at body temperature, or affected the dissolution of the drug. 23

24. Specifications for Suppository Bases : 1- Origin & Chemical Composition : A brief description of the composition of the base reveals the sours of the origin (natural or synthetic or modified natural products). Physical or chemical in- compatibilities with other constituents may be predicted if the exact formula composition is known including preservatives, antioxidants and emulsifiers. 24

25. 2- Melting Range : Suppository bases don't have a sharp melting point, their melting characteristics are expressed as ranges, indicating the temperature at which the fats start to melt and the temperature at which completely melted. Melting range is usually determination by " Wiley melting point", "Capillary melting point", Incipient melting (or thaw)point /Softening point. 25

26. 3. Solid-Fat Index (SFI): One can determine the solidification and melting ranges of fatty bases as well as the molding character, surface feel and hardness of the bases. A base with sharp drop in solids over a short temperature span proves brittle if molded too quickly. The solid content at room temperature could determine suppository hardness. Since skin temperature is about 32° C, one can predict that would be dry to touch from a solid content over 30% at that temperature. 26 .

27. 4- Solidification Point: This test allow to determine the time required for solidifying the base, when it is chilled in the mold. If the interval between the melting point and solidifying point is 10°C or more, time required for solidification may have to be shortened for a more efficient manufacturing procedure by refrigeration. 27

28. 5- Hydroxyl Value : It is the number of milligrams of KOH that would neutralize the acetic acid used to acetylate 1g of fat. It reflects the mono- and di-glyceride content of a fatty base. 6- Saponification Value: The number of milligrams of KOH required to neutralize the free fatty acids and saponify the ester contained in 1 g of a fat. From saponification value we can know the type of glyceride present (mono-, di- or tri-) and also amount present. 28

29. 7- Iodine Value: It is the number of grams of Iodine that reacts with l00 g of fat or other unsaturated material. The possibility of decomposition by moisture, acids, oxygen (which leads to rancidity of fats) increases with higher iodine value. 8- Water Number: It is the amount of water in grams that can be incorporated in l00g of fat. The "water number" can be increased by the addition of surface- active agents. 29

30. 9- Acid Value: It is the number of milligrams of KOH required neutralizing the free fatty acids in 1g substance (fat). Low acid value or absence of acid value is important for good suppository bases. 30

31. A) Bases B) Antioxidants C) Emulsifying agents D) Hardening agents E) Preservatives F) Thickening agents G) Plasticizer 31 FORMULATION OF SUPPOSITORIES

32. A) Properties of an Ideal Suppository Base: The ideal suppository base may be described as follows : Melts at rectal temperature 36°C, or dissolve in rectal fluid. Completely non toxic, and non irritating to sensitive and inflamed tissues. Compatible with a broad variety of drugs. No metastable forms. Shrinks sufficiently on cooling to be released form the mold without the need for mold lubricants. Non- sensitizing 32

33. Has a melting and emulsifying property. Water number is high (a high percentage of water can incorporated in it) It is stable on storage, dose not change odor, color, release pattern. Can be manufactured by molding either by hand, compression, machine . Acid value is below 0.2, saponification value ranges from 200 to 245, and Iodine value is less than 7. SFI(solid fat index) curve is sharp, in other word, the interval between melting point and solidification point is small 33

34. Properties of an ideal suppository base 34

35. Type of Suppository Bases : A- Fatty Bases B- Hydrophilic Suppository Bases C-Water dispersible Bases 35

36. A. Fatty Bases: Cocoa Butter ( T heobroma oil) It is the most widely used suppository base. It satisfies many requirement for ideal suppository base. Bland. Non reactive. Melt at body temperature. Cocoa Butter is a triglyceride, yellowish white, solid, brittle fat, smells and taste like chocolate. Its melting point between 30-35° C, its’ iodine value is “between” 34-38 . Its acid value is no higher than 4, because cocoa butter can melt and become rancid. So it must be stored in cool dry place protected from light. 36

37. Advantages Melting range 30-36 c,easily melts in the body Readily melted on warming,rapid settling on cooling. Miscible with many other ingredients. Non-irritating. 37

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39. Polymorphism ( the property of existing in different crystalline forms). Polymorphism in cocoa butter is observed due to high proportion of unsaturated triglycerides. The formation of various forms of cocoa butter depends on the degree of heating, on the cooling process and on the conditions during this process. Each form of cocoa butter has different melting point and drug release rates. 39

40. Cocoa butter exits in four crystalline state 40

41. Cocoa butter <= 36°C > 36°C Stable ß crystals with normal melting point Unstable γ crystals melt about 15°C Slow Cooling Rapid Cooling Heated Unstable α crystals melts about 20°C Unstable forms return to stable form after several days & may not set at room temp. Or if set by cooling may remelt in warm conditions 41

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44. Synthetic fats 44

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48. B. Hydrophilic Suppository Bases : 1-Glycerine Suppositories(USP): Glycerine 91 g Sod. Stearate 4g Purified water 5g To make approximately l00g 2- Glycerated gelatin suppositories(USP) : Drug & purified water 10g Gelatin 20g Glycerin 70g - 48

49. Glycero -gelatin 49

50. PREPARATION OF GLYCERO-GELATINE BASES GLYCEROL WATER GELATINE GLYCERO-GELATINE BASES 50

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52. Macrogols (PEG) 52

53. Advantages of macrogols 53

54. Advantages of macrogols 54

55. Disadvantages of macrogols 55

56. Disadvantages of macrogols 56

57. 3.WATER - DISPERSIBLE BASE: Several non-ionic surface active materials, closely related chemically to PEG as suppository bases. The bases can be used for formulation both water-soluble and oil-soluble drugs (e.g.; Tween & Span). These surface active agents may be used alone, blended or used in combination with other suppository vehicle. Another type of water dispersible suppository vehicle is based on the use of water soluble cellulose derivatives (e.g. methylcellulose & Sod.CMC ) 57

58. Advantages of Water Dispersible Bases: 1. Stable on storage at elevated temperature. 2 . Compatible with many drugs. 3 . Non support of microbial growth, non toxic and non sensitive. 58

59. 59 (B) ANTI OXIDANTS It protect the drugs and bases from getting degraded due to oxidation. These are commonly used in all types of suppositories. EXAMPLES- Ethyl or propyl gallate Ascorbic acid Butylated hydroxy anisole (BHA) Butylated hydroxy toluene (BHT) Hydroquinone Tocopherol

60. 60 (C) EMULSIFYING AGENTS These increase the water absorbing capacity of fatty bases. EXAMPLES Poly sorbates (TWEEN 61) Wool alcohol Wool fats

61. 61 (D) HARDENING AGENTS These are involved in those formulation where the melting point of the bases is decrease by the drugs. These are the agents which are used to bring the melting point to normal. EXAMPLES Beeswax Macrogols at high molecular weight.

62. 62 (E) PRESERVATIVES These are the agents which are used in prevent the growth of microbial in suppository which contains water soluble bases. EXAMPLES Chorocresol Methyl paraben Propyl paraben

63. 63 (F) THICKENING AGENTS These are the agents which are used to increases the viscosity of molten bases and prevent sedimentation of suspended in solid bases. EXAMPLES Aluminium monostearate Colloidal silica Magnisium stearate Steary alcohol

64. 64 (G) PLASTICIZERS These are the agent which are used to improved flexibility of suppositories. It is also used to make the less brittles to suppositories. EXAMPLES Castor oils Glycerine Glycol Tween 80 Tween 85

65. Method Of Manufacture Of Suppositories: 1- Hand Molding: It is the oldest and simplest method, by rolling the suppository into the desired shape. The mass is then rolled into a cylindrical rod of desire length and diameter. 65 STEPS INVOLVED IN HAND MOLDING The drugs and other additives are made into a fine powder . It is incorporated into the suppository base by kneading with it or by trituration in a mortar. Then these masses are rolled into the shape of a cylindrical rod on the rolling tile in presence of lubricants to prevent the adherence of masses. Then cut the rods and made one end to pointed.

66. DRUG+ADDITIVES FINE POWDER MIXED IN BASES APPLY LUBRICANTS ON ROLLING TILE ABOVE MASSES ARE ROOLED IN CYLINDRICAL SHAPE CUT THE RODS PACKED STORED 66

67. 2- COMPRESSION MOLDING: Elegant suppository can be made compression the cold-grated mass into the desired shape . simple and more elegant appearance than hand molding. Avoids the possibility of sedimentation of the insoluble solids in the suppository base. ADVANTAGE- It is suitable for thermolabile drugs because in this method no heat is required. Rate of production is more. DISADVANTAGE- The main disadvantage is air entrapment occurs during production so oxidation takes place in suppository. 67

68. PROCEDURE DRUG+ADDITIVES FINE POWDER MIXED WITH BASES LUBRICANTS APPLY IN MOLDS PLACED THE MASSES IN CYLINDER APPLY PRESSURE RELEASE SUPPOSITORY COOLED PACKED STORED 68

69. 3- Pour Molding (Heat molding) Most commonly used method for production of suppository on both small & large scale. First, the base is melted on water bath, and then the drugs are either emulsified or suspended in it. Then, the mass is pour into cooled metal molds, which are usually chrome or nickel plated. 69

70. MELTING THE BASES DRUGS FINE POWDER TRITURATE WITH WARM WATER LIQUIDS MIXED ½ PARTS OF LIQUIDS MIXING PROPER ADD REMAINS LIQUIDS 70

71. CONT…… APPLY THE LUBRICANTS IN MOLD OVERFILLING OF MASSESIN MOLDS REMOVE THE EXTRA MASSES COOLING (10-15MIN) OPEN MOLDS PACKED STORED 71

72. 4 - Automatic Molding Machine: All the operations in pour molding are done by automatic machines. Using this machine, up to about 10,000 suppositories per hour can be produced. By this the rate of production of suppositories is more higher than hand molding. In this ,there are no chance of air entrapment and contamination of suppositories. In this ,if any mass deposited in mold is not removed during cleaning, so produce overweight suppositories with mold marks 72

73. There are two types of machines used they are following--- Rotary Machine- The rate of production of suppositories are about 3500-6000/hr. This machine consists of a turn table in which metal molds are fitted. This table rotates sequentially, the mold gets filled with drug , additives, bases and cooled and ejects the suppositories. Before mass filled in mold ,the lubricant are apply in mold wall. The excess mass is removed by the scraping unit. The cooling system results the solidification of suppositories. After the cooling the mold is moves towards ejection station , it consists of a stainless steel rod which push out the suppositories from molds. Then completed the ejection process , the empty molds are again moves towards the filling unit for further processes. 73

74. DRUG+ADDITIVES FINE POWDER MELT BASES + POWER HOPPER LUBRICATED THE MOLDS FILL ABOVE MIXTURE IN MOLD COOLING SYSTEM EJECTION SYSTEM PACKED STORED 74

75. (b) LINEAR MACHINE It is similar to rotary machine. Except the rate of production is more higher than rotary machine about 10000/hr. All steps involved is similar to rotary machine. There is no chance of air entrapment and contamination of suppositories as similar to rotary machine. The rate of production is higher than rotary machine. 75

76. Preparation of suppositories - Moulds 76

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78. SPECIFIC PROBLEMS IN FORMULATING SUPPOSITORIES : 1- Water in suppositories: Use of water as a solvent should be avoided: Reasons: Water accelerates oxidation of fats. If water evaporates, the dissolved substance crystallizes out. Unless H2O is present at level than that requires for dissolving the drug, the water has little value in facilitating drug absorption. Absorption from water containing suppository enhance only if an oil in water emulsion exist with more than 50% of the water in the external phase . 78

79. Reaction between ingredients (in suppository) are more likely to occur in the presence of water. The incorporation of water or other substances that might be contaminate with bacteria or fungi necessitates the addition of bacteriostatic agents (as parabens) 79

80. 2- Hygroscopicity: Glycerinated gelatin suppositories lost moisture by evaporation in dry climates and absorbed moisture under conditions of high humidity PEG bases are also hygroscopic. 80

81. 3- Incompatibilities: a- PEG bases are incompatible with silver salt, tannic acid, aminopyrine , quinine , icthammol , asprine , benzoc.aine & sulphonamides . b- Many chemicals have a tendency to crystallize out of PEG, e.g.: sodium sarbital , salicylic acid & camphor. c- Higher concentration of salicylic acid softens PEG to an ointment-like consistency, d- Aspirin complexes with PEG. e- Penicillin G , although stable in cocoa butter and other fatty bases , was found to decompose in PEG bases . f- Fatty bases with significant hydroxyl values may react with acidic ingredients. 81

82. 4- Viscosity: The viscosity of the melted suppository base is important in the manufacture of the suppository and to its behavior in the rectum after melting. Melted cocoa butter have low viscosity than glycerinated gelatin and PEG type base in low viscosity bases, extra care must be exercised to avoid sedimentation of suspended particles. 82

83. To overcome the problems caused by use of low viscosity bases: a- Use base with a more narrow melting rang that is closer to body temperature. b- The inclusion of approximately 2% aluminum monostearate not only increase the viscosity of the fat base but to maintain homogenous suspension of insoluble material. c- Cetyl , stearyl or myristyl alcohols or stearic acid are added to improve the consistency of suppositories . 83

84. 5- Brittleness : Suppositories made from cocoa butter are elastic and don't fracture readily. Synthetic fat base with high degree of hydrogenation and high stearate content and a higher solids content at room temperature are usually more brittle. To overcome : 1) the temperature difference between the melted base & the mold should be minimal. 2) Addition of small amount of Tween 80, castor oil, glycerin imparts plasticity to a fat 84

85. 85 6- Volume contraction: Occurs in many melted suppository base after cooling the mold, result in : Good mold release (contraction facilitate the removal of the suppository from the mold , eliminating the need for mold release agents). Contraction hole formation at the open end of the mold, this will lowered suppository . The contraction can be eliminated by pouring a mass slightly above its congealing temperature into a mold warmed at about the same temperature or the mold is overfilled so that the excess mass containing the contraction hole can be scraped off.

86. Lubricant or mold releasing agent: Cocoa butter adhere to suppository molds because of its low volume contraction. A various mold lubricants or release agents must be used to overcome this difficulty (mineral oil , aqueous solution of sodium lauryl sulfate , alcohol , silicones , soap). The release of suppository from damaged mold was improved by coating the cavities with polytetrofluoroethylene ( Teflone ). 86

87. LUBRICANTS FOR USE WITH SUPPOSITORY BASES: 87

88. 7- Rancidity and Antioxidant: Rancidity results from the autoxidation and subsequent decomposition of unsaturated fats into low & medium molecular weight saturated & unsaturated aldehydes , ketones and acids , which have strong unpleasant odor. Example of effective antioxidant are phenols such as " hydroquinone or B- naphtholquinone . 88

89. DOSAGE REPLACEMENT FACTOR The amount of base that is replaced by active ingredient in suppository formulation can be calculated. The replacement factor (f) is derived from the following equation: F=100(E-G)+1 Where: E= weight of pure suppository base. G= weigh of suppositories with x% active ingredient. 89

90. WEIGHT AND VOLUME CONTROLE: The amount of active ingredient in each suppository depends on: 1 . Its concentration in the mass. 2. The volume of the mold cavity. 3. The specific gravity of the base. 4. The volume variation between molds (within 2% of the desired value). 5. Weight variations between suppositories due to inconsistencies in the manufacturing process. e.g. incomplete closing of molds, uneven scrapings (variations in weight should be within ± 5%) 90

91. Evaluation of Suppository Melting range test Softening time test Breaking test Disintegration / dissolution test 91

92. 1) MELTING RANGE TEST: Also called the macromelting range test & is a measure of time which takes for entire suppositories to melt when immersed in a constant temperature 37◦C water bath. Micromelting range test is the melting range measured in capillary tubes for fat base only. The suppository melting point apparatus consist of graduated tube like glass chamber. The sample to be tested is placed in spiral shaped glass test basket inside test chamber i.e. surrounded by water jacket heated by circulation thermostat. Time for the entire suppository to melt or disperse in the surrounding water is measured. 92

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94. 2. Softening time test Softening time test apparatus consists of a U- tube partially submersed in a water bath. A constriction on one side holds suppository in place in the tube. A glass rod is placed on top of suppository & time to pass through constriction is recorded as softening time i.e carried out at various temp. 35.5-37◦C. A water bath both cooling & heating elements should be used to assure control within 0. 1◦C. The penetration tester(PM 30) has been designed to carry out reproducible measurements of softening time of suppository at predetermined temp. Construction of tester makes visual observation of melting characteristics extremely simple & unit comprises 3 test station. 94

95. 3) BREAKING TEST: It is designed as a method for measuring the fragility or brittleness of suppositories. The apparatus consists of double-wall chamber in which the test suppository is placed. Water at 37◦C is pumped through the double walls of the chamber, and the suppository, contained in the drug inner chamber, supports a disk to which a rod is attached. The outer end of the rod consists of another disc to which weights are applied. 95

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97. 4) DISINTEGRATION DISSOLUTION TESTING: In an effort to control the variation in mass/medium interface, various means have been employed including wire mesh basket or membrane to separate sample chamber from reservoir. Sample sealed in dialysis tubing or natural membranes have also been studied. Flow cell apparatus have been used holding the sample in place with cotton, wire, screening & most recently with glass beads. The basic suppositories disintegration tester complies with the latest specifications. 97

98. PACKAGING OF SUPPOSITORY Suppository must be placed in a container in such a manner that they do not touch each other. Staining, breakage or deformation by melting caused by adhesion can result from poorly wrapped packaged suppository. Suppository is foiled in tin or Al paper and plastic. Over wrapping is done by hand or machine. Many suppositories are not individually, wrapped. In such cases, they are placed into cardboard boxes or plastic containers that have been molded to provide compartment for 6 or 12 suppositories. 98

99. IN- PACKAGE MOLDING: A significant advance in suppository manufacturing was the development of automated method for molding suppository, directly in their wrapping materials. This is currently accomplished with either plastic or Al-foil. *ADVANTAGE OF INPACKAGE MOLDING: 1. high production rate. 2. no generation of scraping. 3. no bulk handling. 4. maintenance of strict temperature control 99

100. STORAGE Suppository should be protected from heat, preferably stored in the refrigerator Glycerinated gelatin suppositories should be protected from heat, moisture, and dry air by packaging in well-sealed containers and storing in a cool place. 100

101. Displacement value : The number of parts by weight of drug that displaces one part of base. Calculation of DV: Wt. of 6 CB suppository, W CB Wt. of 6 medicated(40%) suppository, W MS Wt. of drug in suppository, W D = W MS x 40/100 Wt. of CB in suppository, W B = W MS – W D Wt. of CB displaced by drug, W DCB = W CB – W B Displacement value, DV = W D /W DCB 101

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103. Q) Prepare six suppositories each containing 250 mg bismuth subgallate . Quantities are calculated for an excess of two suppositories. Therefore calculate for eight suppositories. DV of bismuth subgallate = 2.7 A l g mould will be used with mould calibration = 0.94. To calculate the amount of base required, a simple equation is used: Amount of base = (N x y) – (N x D/ DV) N=8 y = 0.94 D = 250 mg = 0.25 g DV = 2.7 Amount of base required = (8 x 0.94) –((8x0.25)/2.7) = 7.52-0.741 = 6.779 9 = 6.78 g 103

104. Calculations for more than one drug: Calculate the quantities required to make 15 suppositories each containing 150 mg hamamelis dry extract and 560 mg of zinc oxide. A 2g mould , with mould calibration of 2.04, will be used. Calculate for 17 suppositories (2 excess). DV of hamamelis dry extract = 1 .5, DV of zinc oxide = 4.7. Weight of hamamelis dry extract = 17 x 0.15 = 2.55 g. Weight of zinc oxide = 17 x 0.56 = 9.52 g. Weight of base = 17 x 2.04- (2.55/1.5 + 9.52/4.7) = 34.68- (1.7 + 2.03) = 30.95 g. 104

105. THANKS 105