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cocoa butter based suppository formulation

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cocoa butter based suppository formulation

  1. 1. Suppository Formulation andSuppository Formulation and ManufactureManufacture Jim McElroy
  2. 2. What Is A Suppository?What Is A Suppository? A suppository is a medicated solid dosage form used in the rectum, vagina and urethra. Suppositories often contain vehicles that melt or soften at body temperature. Vaginal suppositories, called pessaries, can be made as compressed tablets. Urethra suppositories are called bougies.
  3. 3. Shapes and Weights ofShapes and Weights of SuppositoriesSuppositories Rectal suppositories weigh about 2 grams for adults and 1 gram for children. They are bullet shaped. Vaginal suppositories weigh about 3 to 5 grams and are oval or globular shaped. Urethral suppositories for males weigh about 4 grams & are 100-150 mm long. Female urethral suppositories weigh about 2 grams and are 60- 75mm in length. They are pencil shaped and pointed on one end.
  4. 4. Typical SuppositoriesTypical Suppositories
  5. 5. Types of Suppository BasesTypes of Suppository Bases  Oleaginous (i.e. triglycerides) Lipid based suppositories are typically used for hemorrhoidal preparations but can be used for vaginal and urethral dosing.  Glycerinated Gelatin Used particularly for vaginal suppositories. They are a translucent gelatinous solid that tend to disperse slowly in mucous secretions to provide prolonged release of active ingredients.  Polyethylene Glycol (PEG) polymers PEG based suppositories offer rapid delivery of the API with minimal manufacturing issues.  Surfactants Surfactant based suppositories offer rapid delivery but cannot be used for an extended period of time because of irritation.  Tablets Used particularly for vaginal suppositories.
  6. 6. TriglyceridesTriglycerides A triglyceride is a lipid with a glycerin backbone with three fatty acid groups A molecule of glycerin can be pictured as a capital E. It becomes a glyceride when one of the “forks” becomes attached to a fatty acid. If all the forks contain fatty acid groups, the result is a triglyceride. Cocoa butter (theobroma oil) and most suppository bases intended for hemorrhoid therapy are triglycerides.
  7. 7. Crystallization and Melting RangesCrystallization and Melting Ranges of Cocoa Butterof Cocoa Butter Cocoa butter is a polymorphic substance. There are four to six forms of crystals in cocoa butter. Different researchers have used different nomenclatures over the years. Different researchers disagree over the number of crystal forms.
  8. 8. Crystal Melting Ranges of Cocoa ButterCrystal Melting Ranges of Cocoa Butter VAECK (1960) DUCK (1964) WILLIE & LOVEGREN (1966) LOVEGREN ET. AL (1976) DAVIS & DIMICK (1986) Form Temperature Form Temperature Form Temperature Form Temperature Form Temperature γ 17 γ 18 I 17.3 VI 13.0 I 13.1/17.6 ά 21-24 ά 23.5 II 23.3 V 20.0 II 17.7/19.9 III 25.5 IV 23.0 III 22.4/24.5 β' 28 β'’ 28.0 IV 27.3 III 25.0 IV 26.4/27.9 β' 33.0 V 33.8 II 30.0 V 30.7/34.4 β 34-35 β 34.4 VI 36.3 I 33.5 VI 33.8/34.1
  9. 9. Tempering Cocoa ButterTempering Cocoa Butter Tempering is a process that puts desired crystal structure in cocoa butter. Tempering improves product stability. Poor tempering results in a poor product with marginal overall aesthetics.
  10. 10. The Tempering ProcessThe Tempering Process  Melt the cocoa butter completely at 50-52ºC (eliminates crystal memory)  Cool the cocoa butter with mixing to 25ºC. (mitigates the formation of Form I, II and III crystals).  Continue to mix at this temperature product until the viscosity is at a maximum (maximum crystal growth of Form IV, V and VI).  Heat the product to 33-35ºC with continued mixing (Form V predominates).  Form into suppositories
  11. 11. Synthetic Fatty BasesSynthetic Fatty Bases Most if not all triglycerides (including synthetic triglycerides) go through a phase transition. Typically, it is the form V to VI. Some manufacturers insist that Span 65 be used to stabilize the formulation. Regardless, post hardening of the suppository is an issue and must be addressed during formulation.
  12. 12. Fat BloomFat Bloom Fat bloom is recognized as a grayish white film on the surface. Fat bloom is occurs because fat migrates to the surface through micro-fissures and crystallizes as “bloom.” Fat bloom is an aesthetic issue and does not have an impact on product quality.
  13. 13. Causes of Fat BloomCauses of Fat Bloom Poor tempering Bloom can form if cocoa butter is mixed with incompatible fats High moisture
  14. 14. Surfactant Use Inhibits Fat BloomSurfactant Use Inhibits Fat Bloom The mechanism is as follows: The IV to V transition is facilitated because this transition occurs in the liquid phase only. The V to VI transition is hindered because there is less solid fraction in the butter and this transition occurs only in the solid phase.
  15. 15. Surfactant RatiosSurfactant Ratios Span 60 + Tween 60 (75:25) Span 65 + Tween 65 (50:50) Span 60 + Tween 65 (75:25) Span 65 + Tween 60 (50:50) Span 65 + Tween 65 (50:50) Span 65 + Tween 65 (75:25) Span 65 (100) All surfactants to be used at 1 to 10%
  16. 16. Surfactants as BioavailabilitySurfactants as Bioavailability EnhancersEnhancers Cleansing action caused by the surfactant- containing vehicle may make additional pore spaces available for drug absorption. Drug movement across the rectal membrane is facilitated.
  17. 17. DrawbacksDrawbacks of Surfactant Use in Suppositoriesof Surfactant Use in Suppositories Absorption is decreased for phenol type drugs, likely due to drug surfactant complex Surfactants can disrupt mucosal membrane and produce a marked histological change to the mucosa after prolonged administration.
  18. 18. Insoluble APIsInsoluble APIs It is difficult to suspend insoluble APIs while forming suppositories. Content uniformity is a challenge. Some commonly used APIs (i.e. phenylephrine HCl) are present at 0.15%. Possible formulation strategies include solubilizing the API and spraying it onto starch (or other carrier)
  19. 19. Soluble APIsSoluble APIs Water soluble, oil insoluble salts are preferred in fat based suppositories. If the drug has a lipid-water coefficient favoring fat solubility, the drug will be released slowly if at all.
  20. 20. Water Soluble BasesWater Soluble Bases Ideally, water soluble bases should be used whenever possible. Typical water soluble bases are glycerinated gelatin and PEG
  21. 21. Suppository TabletsSuppository Tablets Typically used for vaginal dosing Ingredients include API, lactose and /or dextrose, boric and/or phosphoric acid to adjust acidity of the vagina to pH 5. Vaginal tablet suppositories are used for topical therapy.
  22. 22. Drug Absorption From OralDrug Absorption From Oral AdministrationAdministration Drug is absorbed from the small intestine and is carried to by the hepatic portal vein to the liver. Therapeutic activity may be modified by the liver. Systemic effectiveness may be affected because the liver chemically modifies many drugs after absorption.
  23. 23. Drug Absorption From RectalDrug Absorption From Rectal SuppositoriesSuppositories Drug absorption by the hemorrhoidal veins surrounding the colon and rectum enter into the inferior vena cava and by-pass the liver. The upper hemorrhoidal vein does connect with portal veins leading to the liver. The rate limiting step is the diffusion of the drug to the site of the drug to the site of the rectal mucosa at which absorption occurs.
  24. 24. ConclusionsConclusions Suppository formulations using cocoa butter (or synthetics) requires detailed knowledge of the raw materials used to manufacture suppositories. Suppository formulation using water soluble bases are the ideal and are preferred. Drug absorption is dependent on many factors such as pH , drug solubility and suppository vehicle.

Editor's Notes

  • From Lachman , “The word suppositories is derived from the Latin word suppositorium and was first used to designate this medicinal form about the seventeenth century.”
  • Tween 61, Myrj 51, etc.
    Not enough colonic fluid to dissolve a tablet.
    Since the water miscible suppositories dissolve in body fluids and need not be formulated to melt at body temperature, they can be formulated with much higher melting points and thus may be safely stored at room temperature.
  • If one fatty acid is attached it is a monoglyceride. If two fatty acid molecules are attached it is a diglyceride. If three are attached it is a triglyceride. Most naturally occurring lipids are triglycerides.
  • If the crystal structure is not properly managed while manufacturing cocoa butter the resulting product will not harden in a reasonable amount of time or there may be post-hardening issues or considerable fat bloom.
  • Gamma only forms at temperatures under 17 C
    Alpha forms only from gamma is present at temperatures up to 24 C
    Beta prime forms at temperatures above 24 C. It also forms from alpha crystals. If product does not go below 24 C only beta can form.
    Eventually everything goes to beta
  • Poor tempering results in poor product
    Microscopic cracks can occur
    Moisture transfer in or out of the suppository
    Micro-fissures allow crystal migration (fat bloom)
    Creates a dull surface.
    Use examples of fat bloom and poor temper.
  • All steps of the tempering process are critical.
  • Milk fat also inhibits bloom.
  • The IV to V transition occurs in the liquid phase only. Since the liquid phase is increased by the addition of the surfactant, this allows the transition to occur readily.
    The V to VI transition is hindered because there is less solid fraction due to the surfactant.
    Use of a surfactant causes the resulting suppository to become softer. This is because the liquid fraction is increased.
    That is why milk chocolate is softer than dark chocolate.
  • Examples are: Aspirin, Oxymorphone HCl.
  • Most OTC suppositories manufactured in the US are for hemorrhoidal preparations. For this application, a fatty base is an integral part of the therapy.
  • The liver chemically modifies many drugs after absorption.
  • More than half of rectally administered drugs are absorbed directly into the general circulation. The lymphatic circulation helps in absorbing the drug and diverts it from the liver.
  • From 1…and the API and its uptake by the circulatory system.
    From 2…pH is a major factor.