Suppositories Lecture Notes PDF

11/27/2024 1  11/27/2024 Types of suppositories: Urethral Vaginal Rectal suppository suppositories suppositories...

11/27/2024 1  11/27/2024 Types of suppositories: Urethral Vaginal Rectal suppository suppositories suppositories (Bougies) (pessaries) - conical or torpedo shape - Cylindrical or tube in globular (ball), oval - about 2 - 3 cm length shape (3-6 mm diameter) or cone-shaped Adults supp.  2 gm Males  4 gm. weigh about 4- 5 gm children supp. 1 gm 2  11/27/2024 Advantages of suppositories Drugs administered to the rectum or vagina are given for either : - local effect - systemic effect. A- Local effect: 1. Treatment of infection, pain, and inflammation (e.g. haemorrhoids, vaginal fungal infections) 2. Relieve constipation or to cleanse the bowel prior to surgery (supp. promote evacuation of the bowel by irritating the rectum, e.g. glycerin supp). 3. Local treatment of diseases of the colon, e.g. ulcerative colitis. Advantages of suppositories B- Systemic effect: 1. Babies or elderly who cannot swallow oral medication. 2. Post operative patients who cannot take oral medication. 3. People suffering from severe nausea or vomiting. 4. Drugs irritating to the stomach. 5. Drugs destroyed by the pH or enzymatic activity of the stomach or intestine. 6. Drugs destroyed by portal circulation (bypass first- pass metabolism). 3  11/27/2024 disadvantages of suppositories 1. Inconvenient  not preferred by patients. 2. Some suppositories , especially in children "leak" or are expelled 3. Rectal absorption of most drugs is slow, irregular and unpredictable. 4. Irritation for mucosa caused by some drugs or bases. 5. higher manufacturing and storage costs. Physiology of the rectum 15- 20 cm in length (terminal of the colon) 1.5 – 3 ml fluids pH 6.8 Hollow organ with flat wall surface 4  11/27/2024 Absorption of drugs from the rectum (for systemic action): Superior Hemorrhoidal vein into the portal vein (liver) First pass Middle effect Hemorrhoidal vein directly into the Inferior general Hemorrhoidal circulation vein 5  11/27/2024 After Rectal Insertion: 50-70% of Drug will be absorbed directly into blood Circulation bypassing first pass metabolism. Factors affecting rectal absorption Physiological factors Physicochemical factors 1- Site of insertion within the rectum 1- Partition coefficient 2- route of absorption and circulation 2- Particle Size 3- Quantity of fluid available 3- Nature of the base 4- Properties of rectal fluid 5- Contents of the rectum 6  11/27/2024 Physiological factors affecting rectal absorption 1- Site of insertion within the rectum 2- route of absorption and circulation 3- Quantity of fluid available 4- Properties of rectal fluid 5- Contents of the rectum 2- route of absorption and circulation Superior Hemorrhoidal vein into the portal Middle vein (liver) Hemorrhoidal vein First pass effect directly into the Inferior general Hemorrhoidal circulation vein 7  11/27/2024 If the drug absorbed through the inferior (lower) and middle H.V.  the drug is absorbed directly to systemic circulation throughout the body  avoid the liver first-pass metabolism. If the drug absorbed through The superior (upper) H.V.  The drug absorbed into the portal vein and carried with blood to the liver, where it is metabolized (first pass metabolism). 3- quantity of fluid available The quantity of fluid available for drug dissolution in the rectum is very small approximately 3 ml Drugs used rectally are preferred to have high aqueous solubility  so they dissolve and absorbed easily and spontaneously  dissolution of slightly soluble drugs causes very slow absorption process (dissolution of drug will be the slowest rate-limiting step) 8  11/27/2024 4- properties of rectal fluids The rectal fluid is: Neutral in pH (6.5 – 8) Has no buffer capacity  Any drug used should have good solubility in such conditions 5- contents of the rectum Empty rectum : the drug will be in good contact with the absorbing surface of the rectum  rapid absorption  rapid onset of action Full rectum : the drug will take longer time to dissolve and to be absorbed  slower absorption  delayed onset of action When systemic effects are required  greater absorption will be from empty rectum 9  11/27/2024 Physicochemical factors affecting the absorption 1- partition coefficient 2- Particle Size 3- Nature of the base 1- Partition Coefficient (Drug solubility in the base and aqueous rectal fluid) Drugs that are highly soluble in the base  (more soluble in the base than the surrounding rectal fluids)  the tendency to leave the base into the rectum will be small  so the release rate into the rectal fluid will be low  slow absorption and delayed effect. Drugs that are more soluble in the rectal fluids than the base  High tendency to leave the base into the rectum  so the release rate into the rectal fluid will be high.  fast absorption and rapid effect. 10  11/27/2024 2- particle size of the drug  For drugs present in suppository in un-dissolved state  the size of the drug particle will influence its rate of dissolution and so will affect its availability for absorption. The smaller the particle size  faster dissolution of the particle  greater & rapid absorption. 3- Nature of the base: -The base must melt, soften, or dissolve  Release its drug for absorption. So the rate of base melting, softening or dissolution will affect the rate of drug release  so will affect the rate of drug action. 11  11/27/2024 Also: If the base interacts with the drug inhibiting its release drug absorption will be impaired or even prevented.  if the base is irritating to the mucous membranes initiate a colonic response and a bowel movement  Evacuation of the bowel  Incomplete drug release and absorption. Suppository bases Ideal characteristics of suppository base: 1. Non-toxic and non-irritant. 2. Inert and Compatible with the drug used. 3. Melts or softens at body temperature or dissolves in body fluids. 4. Releases any medicament readily. 5. Easily molded and removed from the mould. 6. Stable to heating above the melting point. 7. Stable on storage. 8. Easy to handle. 12  11/27/2024 Types of suppository bases According to their physical characteristics (Nature) (2) hydrophilic (3) Water - (1) Fatty bases (water dispersible bases: (4) bases: miscible – Water- *Cocoa butter Emulsifying -Cocoa butter soluble): substitutes with base: - semi-synthetic - Glycerogelatin surfactants Witepsol fats -soap glycerin *Tween or span -PEG (Macrogol) 1- fatty bases (Oleaginous – hydrophobic bases) Those are fatty (Oleaginous – hydrophobic) bases that melt at body temperature: 1. Cocoa butter (Theobroma oil) 2. Cocoa butter substitutes (semi-synthetic hard fats) 13  11/27/2024 A- Cocoa butter (Theobroma oil) It is a yellowish-white solid and is a mixture of glyceryl esters of different unsaturated fatty acids (eg. stearic, palmitic, oleic acid). Advantages: a- Melting range of 30 – 36 °C (solid at room temperature but melts in the body). b- Readily melted on warming, rapid setting on cooling (easily manufactured). c- Miscible with many ingredients (inert – compatible). d- Non-irritating, non toxic. Disadvantages of cocoa butter as suppository base: 1- Polymorphism: When C.B. is melted and cooled  Solidifies in different crystalline forms (α, β, γ) depending on: - the temperature of melting - rate of cooling 14  11/27/2024  If melted at around 36° C and slowly cooled  stable β crystals with normal melting point (30-36 °C).  If quickly heated to higher temp. (over-heated) then cooled suddenly  unstable (α) crystals (melting at 20 °C) or (γ) crystals (melt at about 15 °C). Therefore, Cocoa butter must be slowly melted over a warm (non- boiling) water bath to avoid the formation of the unstable crystalline forms. 2- Adherence to the mould: Cocoa butter does not contract sufficiently on cooling to ease the suppositories removal from the mould this leads to Sticking of the supp. to the mould  this may be overcome by adequate soap lubrication. 3- Softening point (30-36 °C) too low for hot climates  Not suitable for tropical countries Should be refrigerated at all the manufacturing and storage steps 15  11/27/2024 4- Lowering of melting point by some drugs: Some medications (Phenol and chloral hydrate) are soluble in C.B. and have a tendency to lower the melting point of cocoa butter when added to the suppositories  melt at room temperature before introducing into the body  solidifying agents like beeswax (4%) may be incorporated to compensate this decrease in melting point. 5- Raising of melting point by some drugs: Some drugs such as lead acetate is soluble in C.B. and have a tendency to elevate the melting point of cocoa butter Does not melt at body temperature  No drug release Castor oil is added to the suppository base to compensate this increase in melting point. (Castor oil is added in an amount equal in weight to the weight of the drug.) 16  11/27/2024 6- Rancidity on storage: C.B. is mixture of glyceryl esters of different unsaturated fatty acids On storage  oxidation of unsaturated glycerides  rancidity 7- Poor water-absorbing ability: It is difficult to add aqueous drugs or drugs dissolved in water  this can be improved by adding emulsifying agents. 8- Expensive B- Cocoa butter substitutes (semi-synthetic solid fats) Vegetable oil + Hydrogenation: Unsaturated glyceride  Saturated fats (hard fats) e.g. Suppocire, Witepsol. Advantages: 1- no polymorphism  unaffected by overheating or cooling rate. 2-lower content of unsaturated fatty acids  good resistance to oxidation  avoid rancidity 17  11/27/2024 3- They contract significantly on cooling  No mould lubricant is necessary 4- The difference between melting and setting points is small  they set quickly  the risk of sedimentation of suspended ingredients is low. 5- They are marketed in a series of grades with different melting point ranges, which can be chosen to suit particular products and climatic condition. 6-They contain a proportion of w/o emulsifying agents, and therefore, their water-absorbing capacities are good. Disadvantages: 1- More expensive 2- Brittle if cooled rapidly  avoid refrigeration during preparation. 3- On prolonged storage  synthetic fats are subject to crystallization (can be reduced by storage in a cold place) 4- If the melted fats are less viscous than theobroma oil  greater risk of drug particles to sediment during preparation  lack of uniform drug distribution which might cause localized irritation. 18  11/27/2024 Types of suppository bases (2) hydrophilic bases (3) Water - (1) Fatty (water-miscible or dispersible bases: (4) bases: water-soluble): Cocoa butter Emulsifying -Cocoa butter substitutes base: - Glycerogelatin - synthetic fats + tween or span Witepsol - PEG (Macrogol) -soap glycerin 2) hydrophilic bases (water-miscible – Water-soluble) Those are water soluble bases  they dissolve rather than melt in the rectal fluids. e.g. 1- Glycero-gelatin 2- PEG (Macrogol) 3- soap glycerin 19  11/27/2024 2) hydrophilic bases (water- miscible – Water-soluble) 1- Glycero - gelatin bases: Ideal glycerogelatin suppository should be : - Clear -Non- sticky -Non- gritty -No air bubbles The most common Glycerol Suppositories Base: BP USP Glycerin 70 % 70 % Gelatin 14 % 20 % Water Q.S. to 100 100 Those are water soluble bases  they dissolve rather than melt in the rectal fluids. Drug release depends on the base dissolving rather than melting. 20  11/27/2024 Disadvantages: 1- Laxative effect: during dissolving in the mucous secretions of the rectum  osmosis occurs  glycerin absorbs water from surrounding tissues  laxative effect. 2- Rectal irritation: Due to hygroscopic nature dehydrating effects on the rectal or vaginal mucosa with the small amount of liquid present in them leading to irritation. 3-Hygroscopic: So, they should be packaged in tight containers. Disadvantages: 4-Unpredictable dissolution time  unpredictable drug effect. 5- Risk for Microbial contamination. 6- Long preparation time. 7- Lubrication of the mould is essential. 21  11/27/2024 2) hydrophilic bases 2- Macrogol (Polyethylene glycol, PEG) bases: Polyethylene glycol (PEG) = polyethylene oxide (PEO) = polyoxyethylene (POE) Ethylene glycol Polymerization or Ethylene oxide PEGs are polymers of ethylene oxide  (prepared by polymerization of ethylene oxide to various chain lengths, molecular weights, and physical states.) Depending on their molecular weights  PEG are liquids or low-melting solids: PEGs having average molecular weights of: - 300, 400, and 600  clear, colorless liquids - 800 -1000  semisolids. - Greater than 1000  wax-like, white solids with the hardness that increases with increasing the molecular weight.  PEGs can be blended together  produce suppository bases with varying:  Melting points  Physical characteristics.  Dissolution rates 22  11/27/2024 Those are water soluble bases  they dissolve rather than melt in the rectal fluids. Therefore, although their melting point is often around 50° C BUT Drug release depends on the base dissolving rather than melting. Advantages: 1- No laxative effect. 2- Less microbial contamination. 3- The base contract on cooling and no lubricant is necessary. 4- Melting point above body temperature (50° C): - Cool storage is not so critical. - Suitable for hot climates 5- The base might be formulated to dissolve in the body and disperse the medication slowly  sustained effect. 23  11/27/2024 6- Produce high-viscosity solutions  no leakage from moulds.  no drug sedimentation during formulation 7- Good solvent properties. Disadvantages: a- Lower bioavailability of some drugs  The good solvent properties may result in retention of the drug in the liquefied base with consequent reduction in therapeutic effect. b- Incompatibilities with several drugs and packaging materials (penicillin and plastic). c- Brittleness: if cooled too quickly and also on storage. 24  11/27/2024 2) hydrophilic bases e.g. Glycero-gelatin - PEG (Macrogol) -soap glycerin 3- Soap glycerin: stearic acid + sodium carbonate in glycerin solution  sodium stearate = stearin soap.  used as suppository base. Advantages: 1- It makes harder suppositories than glycerogelatin suppositories. 2- It allows the incorporation of large quantity of glycerin  up to 90- 95% of the mass. 3- Soap assists the laxative action of glycerin, whereas gelatin does not. 25  11/27/2024 Disadvantages: Very Hygroscopic  1- local tissue irritation. 2- require special packing & protected from the atmosphere. Problems in formulation and storage of suppositories: 1- Water in suppositories: Water should be avoided in preparation of suppositories and for dissolving drugs in suppositories for the following reasons: 1. Presence of water may accelerate the oxidation of fats 2. support bacterial and fungal growth. 3. increase degradation rate of many drugs. 4. enhance reaction between drug and other components in suppositories. 5. If the suppositories are manufactured at a high temperature, the water evaporates, the drugs crystallize out. 26  11/27/2024 2- Hygroscopicity :  suppositories containing Glycerin and PEG are hygroscopic substances.  Glycerogelatin suppositories lose moisture in dry climates and absorb moisture in humid conditions  The hygroscopicity of PEG bases depends on the chain length of the molecule  As the molecular weight of these ethylene oxide polymers increases (↑)  the hygroscopicity decreases (↓) 3. Viscosity If the viscosity of suppositories is low, it may be necessary to add suspending agent such as silica gel to keep the drug uniformly dispersed during manufacturing until solidification. 27  11/27/2024 4. Brittleness:  Brittle suppositories can be difficult to handle, wrap and use as they are very easily broken.  Cacao butter suppositories generally are not brittle unless there is a high percentage of solid present  when the percent of solid exceeds 30% brittleness can result  This can be solved by addition of small quantity (2%) of tween 80, caster oil , glycerin or PEG will make the suppositories less brittle. 1- Appearance. 2- weight uniformity test 3- drug content uniformity 4-Liquefaction Time or Softening Time Test 5- Breaking Test (Hardness) 6- Dissolution test 7- stability test 28  11/27/2024 1- Appearance: All the suppositories should be: - Uniform in size and shape. - have elegant appearance - No cracks and pits or air bubbles due to entrapment of air in the molten mass. 2- weight uniformity: 1- Weigh each of the 20 2- Weigh all the suppositories suppositories alone S1, together = W. S2, S3,…S20. 4- compare the average 3- Calculate the weight to the individual average weight weights. = W/20 Limits for acceptance: a. No suppository differs from the average weight by more than 10%. b. Not more than 2 suppositories differ from the average weight by more than 5% 29  11/27/2024 3- Drug content uniformity: 20 suppositories are assayed for their drug content. All the suppositories should NOT deviate from 90 -110% of the labeled drug content. 4- Liquefaction Time (Softening Time Test - melting range): Determines the time taken by an entire suppository to melt when it is immersed in a constant temperature bath at 37° C. The suppository is the time for the entire completely immersed in suppository to melt or the constant temperature disperse in the surrounding water bath (37° C) water is measured. 30  11/27/2024 5- Breaking Test (Hardness): The breaking test is designed as a method for measuring the fragility or brittleness of suppository. 1-The suppository is placed in the instrument. 2- Add 600 g  leave it for one min using stop watch  If not broken, add 200 g every one min. until the suppository is broken. The hardness of the suppository is calculated by adding the weights together. The more weights the suppository withstand the harder it is. 6- Dissolution test: a. The dissolution test is carried out using the USP dissolution apparatus II (basket method) 31  11/27/2024 7- Stability Testing:  Cocoa butter suppositories “bloom” on storage  they form a white powdery deposit on the surface  This can be avoided by storing the suppositories at uniform cool temperatures and by wrapping them in foils.  Fat based suppositories harden on storage  there is an increase in MP due to slow crystallization to the more stable polymorphic forms of the base.  An odor may arise from suppositories with vegetable extracts due to fungal contamination.  Suppositories with some dyes may discolor due to oxidation of the dyes. 32