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Pharmaceutical Suppositories

  1. 1. Suppositories Mr. Pankaj Kusum Ramdas Khuspe M. Pharm (Pharmaceutics)
  2. 2. Syllabus  Introduction, definition, advantages and disadvantages, desirable features of suppositories, factors affecting rectal absorption.  Suppository bases specifications and desired‐ features, classification and selection of suppository bases, special bases.  Formulation and specific problems involved in formulating suppositories, large scale manufacture with equipments involved in each step, packaging.  Quality control tests, Examples of official formulations. 2
  3. 3. Definition  solid dosage forms  intended for insertion in to body cavities or orifices (Rectum, Vagina & Urethra)  where they melt or dissolved &  exert localized or systemic effect.”
  4. 4. Definition “Suppositories are solid dosage forms intended for insertion in to body cavities or orifices (Rectum, Vagina & Urethra) where they melt or dissolved & exert localized or systemic effect.”
  5. 5. Advantages o It avoid first pass effect. o Melt at body temperature. o It gives localized and systemic action. o It can be given to unconscious patient. o It is easy to use for pediatric and geriatric patients. o Useful to produce local effect. o Useful for rapid and direct effect in rectum. o Useful to promote evacuation of bowel o Convenient for those drug causes GIT irritation , vomiting etc. o Unit dosage form of the drug.
  6. 6. Disadvantages o Irritant drug cant administered o Embarrassment to patients o Need to store at low temp. o Cant easily prepared o Cost-expensive. o Defecation may interrupt the absorption process. o absorbing surface area of the rectum is much smaller than that of the small intestine. o fluid content of the rectum is much less than that of the small intestine; this may effect dissolution rate, etc. o Some drug may be degraded by the microbial flora present in the rectum. o Drug with narrow therapeutic margin,can not be interchange without the risk of toxicity.
  7. 7. Ideal Properties  Should be completely non-toxic & non-irritant.  Should be compatible with a broad variety of drugs.  Should be non-sensitizing.  Should have wetting & emulsifying properties.  Should be stable on the storage i.e. does not change color, odor or drug release pattern.  Should have acid value below 0.2.  Should have iodine value less than 7.  Should have “saponification value" ranges from 200 to 245.
  8. 8. Types of Suppositories 1. Rectal suppositories. 2. Vaginal suppositories. 3. Urethral suppositories. 4. Nasal suppositories. 5. Ear cones.
  9. 9. Factor affecting rectal (drug) absorption 1. Physiologic Factor a. Colonic Content b. Circulation c. pH and lack of buffering capacity of the rectal fluid 2. Physiochemical characteristics of the drug a. Lipid water solubility of a drug (partition coefficient) b. Degree of ionization c. Concentration of a drug in a base 3. Physiochemical Characteristics of the Base and Adjuvant a. Nature of the Base b. Presence of Adjuvant in Base
  10. 10. Factor affecting rectal (drug) absorption 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: 1. Colonic Content 2. Circulation 3. pH and lack of buffering capacity of the rectal fluid
  11. 11.  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. A) Colonic Content:
  12. 12. 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.
  13. 13. 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.
  14. 14. 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 fluids. - Thus water-soluble salt are preferred in fatty base suppository. water-soluble base e.g: PEG, which dissolve in the rectal fluids, release both water-soluble and oil-soluble drugs.
  15. 15. 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
  16. 16. 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. - 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.
  17. 17. 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.
  18. 18. 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.
  19. 19. Formulation consideration  Consider the following points 1. Medication intended for local or systemic use. 2. Site of application-rectal, vaginal and urethral. 3. Desired effect- quick, slow or prolonged.  First preliminary evaluation.  Stability at 4o C and at room temp.  Following parameter are studied:  Irritation  Drug availability. Etc.
  20. 20. Formulation of Suppositories 1. Drug 2. Additives a. Suppositories base b. Surfactants c. Preservatives d. Anti oxidants. e. Buffers f. Penetration enhancers g. Lubricants
  21. 21. Ideal Properties of Bases  It must retain the shape and size.  It should melt at body temperature.  It should be non-irritant.  It should shrink sufficiently to remove from mould.  It should not interfere in release or absorption of drug.  It should permit incorporation of drug.  It should be compatible with variety of drugs.  It should be physically stable on storage.  It should not be soften or harden on storage.
  22. 22. Suppository Bases 1. Oleaginous bases 1. Cocoa butter. 2. Emulsified cocoa butter. 3. Hydrogenated oils. 2. Hydrophilic bases 1. Glycero-gelatin base. 2. Soap-glycerin base. 3. Polyethylene glycol. 3. Emulsifying/Synthetic bases 1. Witepsol 2. Massa estarinum 3. Massuppol.
  23. 23. 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. 24. 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".
  25. 25. 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. 26. 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 amore efficient manufacturing procedure by refrigeration,  E.g.: If melting point 33° C and solidifying point 20° C then it will be liquid for 13° C, then the drug will sediment and the apex of the suppository will contain all the drug.
  27. 27. 5- Hydroxyl Value: "It is the number of milligrams.of KOH (Potassium hydroxide) 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 (Potassium hydroxide) 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. 28. 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. 9- Acid Value:  It is the number of milligrams of KOH (Potassium hydroxide) required neutralizing the free fatty acids in I g substance (fat).  Low acid value or absence of acid value is important for good suppository bases.
  29. 29. Oleaginous bases
  30. 30. Cocoa Butter Source • Cocoa butter is fat obtained from the roasted seed of Theobroma cocoa. Properties • At room temperature it is a yellowish, white solid having a faint, agreeable chocolate like odour. • Chemically, it is a triglyceride (combination of glycerin and one or different fatty acids) primarily of oleopalmitostearin and oleodistearine. • It melts at 30 - 350 C,
  31. 31. Cocoa Butter Advantages  Melting just below the body temperature.  Maintaining its solidity at usual room temperatures.  Readily liquefy on heating and solidify on cooling. Disadvantages  Exhibits marked polymorphism.  Rancidity.  Stick to mould.  Leakage from body cavity.  Costly.  Immiscibility with body fluid.  Chloral hydrate or lactic acid liquefy it.
  32. 32. Hydrophilic bases
  33. 33. Hydrophilic bases  It is a mixture of glycerin and water which is made stiff by the addition of gelatin.  Properties:  It is colourless, transparent, translucent in nature.  It is soft to touch.  It melts at 30 - 350 C.  Type of gelatin bases: to avoid incompatibility.  Type A or Pharmagel A: acidic in nature and used for acidic drugs.  Type B or Pharmagel B: alkaline in nature and used for basic drugs.  Used for vaginal suppositories.
  34. 34. Glycero- Gelatin Base  Advantages:  It melt at body temperature.  It mix with body fluid.  Not rancid.  It can be used to prepare suppositories using boric acid, chloral hydrate bromides, iodides, iodoform opium etc.  Disadvantages:  Difficult to prepare and handle.  Chance of bacterial growth.  Hygroscopic in nature. (become hard on drying and soft in cont with moisture)  Laxative in action.  Incompatible with tannic acid, gallic acid, ferric chloride etc.
  35. 35. Polyethylene Glycols/ Macrogols:  Water-miscible bases are composed of PEGs possessing a molecular weight greater than 1000 g/mol.  The melting point of these higher grades of PEGs increases as the molecular weight increases, e.g. the melting points of PEG 1000 and PEG 8000 are 370 –400 C and 600 – 630 C, respectively.  Typically the melting point of PEG suppository bases is 420 C; this is generally achieved and controlled using the appropriate mixtures of grade of this polymer.  The higher melting point of these systems obviates the need for storage under cold conditions.  In addition to controlling the melting point, different molecular weights of this polymer may also be blended to control the mechanical properties of PEG based suppositories.  In this scenario, the lower-molecular-weight PEGs, e.g. PEG 400, will act to reduce the brittle behaviour of these suppository bases.  PEG is known to enhance the solubility of therapeutic agents and therefore this interaction between the drug and polymer may affect the subsequent release of the drug from the liquefied base.  Secondly, the solubility of the drug in the solid base may change as functions of both storage conditions and time and this may result in crystal growth within the suppository.
  36. 36. Polyethylene Glycols/ Macrogols:  These are commonly known as carbowax.  These are available in solid, liquid or semi-solid state depending on molecular weight.  Advantages: 1. They are chemically stable. 2. Inert, Non-irritant. 3. Do not allow bacterial growth. 4. Physical properties changes according to molecular weight. 5. Provide prolonged action. 6. Do not stick to mould. 7. Suppositories are clean and smooth in appearance.
  37. 37. Polyethylene Glycols:  Disadvantages:  Hygroscopic in nature.  Incompatibility with some drugs tannins phenol etc.  Good solvent properties.  Supersaturation takes place.
  38. 38. Emulsifying bases
  39. 39. Advantage of Emulsifying bases  They solidify rapidly.  They are non-irritant.  The lubrication of mould is not required.  Overheating does not affect the physical properties of the base.  They can absorb fairly large amount of water or aqueous liquids.  The white, odourless, clean and attractive suppositories are produced.  They are less liable to get rancid.
  40. 40. Disadvantage of Emulsifying bases  They should not be cooled rapidly in a refrigerator because they become brittle.  They are not very viscous on melting, so the medicaments incorporated with the base settle down rapidly.
  41. 41. Emulsifying bases Witepsol:  They consist of triglycerides of saturated vegetable fatty acid with varying percentage of partial esters.  A small amount of beeswax is added for use in hot climate.  It should not be cooled rapidly as it become brittle and fracture.  Lubrication is required.
  42. 42. Massa Estarinum  It is a mixture of mono, di and triglycerides of saturated fatty acids having the formula C11H23COOH to C17H35COOH.  This is also known as adeps solidus.  It is a white, brittle, almost odourless and tasteless solid.  It has a m.p. 33.5 to 35.50 C.  They are available in various grades but grade B is commonly used in dispensing.
  43. 43. Massuppol  It consists of glyceryl esters mainly of lauric acid to which small amount of glyceryl monostearate has been added to improve its water absorbing capacity.
  44. 44. Method of preparation Hand rolling. Machine moulding. Fusion method. Cold compression.
  45. 45. Hand rolling  It is the oldest and simplest method of suppository preparation and may be used when only a few suppositories are to be prepared in a cocoa butter base.  It has the advantage of avoiding the necessity of heating the cocoa butter.  A plastic-like mass is prepared by triturating grated cocoa butter and active ingredients in a mortar.
  46. 46. Hand rolling  The mass is formed into a ball in the palm of the hands, then rolled into a uniform cylinder with a large spatula or small flat board on a pill tile.  The cylinder is then cut into the appropriate number of pieces which are rolled on one end to produce a conical shape.  Effective hand rolling requires considerable practice and skill. The suppository "pipe" or cylinder tends to crack or hollow in the center, especially when the mass is insufficiently kneaded and softened.
  47. 47. Suppository moulds
  49. 49. Fusion Method 1. Melting the suppository base 2. Dispersing or dissolving the drug in the melted base. 3. The mixture is removed from the heat and poured into a suppository mold. 4. Allowing the melt to congeal 5. Removing the formed suppositories from the mold.  The fusion method can be used with all types of suppositories and must be used with most of them.
  50. 50. Fusion Method
  51. 51. Fusion Method  Small scale molds are capable of producing 6 or 12 suppositories in a single operation.  Industrial molds produce hundreds of suppositories from a single molding.
  52. 52. Compression moulding  Compression molding is a method of preparing suppositories from a mixed mass of grated suppository base and medicaments which is forced into a special compression mold using suppository making machines.  The suppository base and the other ingredients are combined by thorough mixing.  The friction of the process causing the base to soften into a past-like consistency.
  53. 53. Compression moulding  On a small scale, a mortar and pestle may be used (preheated mortar facilitate softening of the base).  On large scale, mechanically operated kneading mixers and a warmed mixing vessel may be applied.  In the compression machine, the suppository mass is placed into a cylinder which is then closed.  Pressure is applied from one end to release the mass from the other end into the suppository mold or die.
  54. 54. Compression moulding  When the die is filled with the mass, a movable end plate at the back of the die is removed and when additional pressure is applied to the mass in the cylinder, the formed suppositories are ejected.  The end plate is returned, and the process is repeated until all of the suppository mass has been used.
  55. 55. Compression moulding  The method requires that the capacity of the molds first be determined by compressing a small amount of the base into the dies and weighing the finished suppositories.  When active ingredients are added, it is necessary to omit a portion of the suppository base, based on the density factors of the active ingredients.
  56. 56. Packaging and storage  Suppositories are usually packed in tin or aluminum, paper or plastic.  Poorly packed suppositories may give rise to staining, breakage or deformation by melting.  Both cocoa butter and glycerinated gelatin suppositories stored preferably in a refrigerator.  Polyethylene glycol suppositories stored at usual room temperature without the requirement of refrigeration.
  57. 57. 59 Quality Control of Suppository 1) Surface appearance and shape:  To evaluate: absence of fissuring – absence of migration of active ingredient, absence of pitting, absence of fat blooming (dullness of surface)
  58. 58. 60 2) MELTING RANGE TEST:  Macro-melting range: measures the time it takes for the entire suppository to melt when immersed in a constant temperature (370C) water bath.  Micro-melting range: is the melting range measured in capillary tubes for the fat base only.  The apparatus used for measuring the melting range of the entire suppository is a USP tablet disintegration apparatus.  The suppository is completely immersed in the constant temperature water bath, and the time for the entire suppository to melt or dispense in the surrounding water is measured.  The in-vitro drug release pattern is measured by using the same melting range apparatus.
  59. 59. 61 3) LIQUIFACTION OR SOFTENING TIME TESTS OF RECTAL SUPPOSITORIES:  The "softening test" measures the liquefaction time of rectal suppositories are an apparatus that simulate in-vitro conditions (at 37oC).
  60. 60. 62
  61. 61. 63 4) 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 37C 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.
  62. 62. 64
  63. 63. 65 5) Mechanical strength: It is a force necessary to break a supp. And indicate whether supp is brittle or elastic. ( not less than 1.8-2 Kg) by Erweka method 6) Melting & solidification Solidification can be determine by using evacuated flask into which the melt is placed, the temp of cooling is noted to determine the solidification point.
  64. 64. 66 7) DISSOLUTION TESTING:  The patterned is measured by using the same melting range apparatus.  If the volume of water surrounding the suppository is known, then by measuring aliquots of the water for drug content at various intervals within the melting period.  A (time versus drug release) curve could be established and can be plotted.
  65. 65. 67 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.
  66. 66. Thank you…