Lecture 1 - Suppository (Part I) PDF

Lecture 1 SUPPOSITORIES (Part I) Dr. Amira Rashad Lecturer of pharmaceutics & Pharmaceutical Technology  Course contents Topic 1: Suppository (3 lectures) Topic 2: Powders and Granules (1 lectures) Topic 3: Tablets (3 lectures) Top...

Lecture 1 SUPPOSITORIES (Part I) Dr. Amira Rashad Lecturer of pharmaceutics & Pharmaceutical Technology  Course contents Topic 1: Suppository (3 lectures) Topic 2: Powders and Granules (1 lectures) Topic 3: Tablets (3 lectures) Topic 4: Capsules (2 lectures) Topic 5: Reaction kinetics (3 lectures) Weighting of Assessments Final Examination 50 % Oral Examination 10 % Practical Examination 25 % Quizzes, assignment 15 % Total 100 % Quizzes (1st Week 4th & 2nd in week 8th)  CLOs (Course Learning Outcomes) 1. Illustrate different types of suppositories, capsules, powdered dosage forms, granules and tablets and the excipients used in their preparation. 2. Show the importance of physicochemical properties of drugs during the design of different dosage forms  Suppositories Definition: Suppositories are single-dose preparation intended for insertion into body orifices e.g. rectum, vagina, urethra or less frequently into ear or nose where they melt or dissolve to release the drug to exert local or systemic action. They consist of the drug which is incorporated into an inert vehicle (base). The drug is incorporated into a fatty bases which melts at body temperature, or into hydrophilic bases which slowly dissolve in the mucous secretions.  Application of Suppositories 1- Desired in case of pain and itching, mostly due to occurrence of eg: Antiasthmatic, hemorrhoids. antirheumatic & analgesic 2- locally active drugs: astringents, drugs are very much used for antiseptics, local anesthetics, this purpose. vasoconstrictors, anti-inflammatory compounds and soothing & protective agents, also some laxatives.  Advantage of suppositories ❑ The suppository may be ideally used in: 1. Babies or old people who cannot swallow oral medication. 2. Post operative people who cannot be administered oral medication. 3. People suffering from severe nausea or vomiting. 4. Drugs that inactivated by the pH or enzymatic activity of the stomach or intestine. 5. Drugs that irritate to the stomach. 6. Drugs that destroyed by portal circulation.  Disadvantage of rectal suppositories 1. The problem of patient acceptability. 2. Suppositories are not suitable for patients suffering from diarrhea. 3. In some cases, the total amount of the drug must be given will be either irritating or in greater amount than reasonably can be placed into suppository. 4. The development of proctitis. 5. Problems with the large-scale production of suppositories and the achievement of a suitable shelf-life. 7. The slow and sometimes incomplete absorption, eg: a. Interruption of absorption by defecation, especially with irritant drugs. b. Surface area of rectum is far small for absorption compared to that of small intestine. c. Fluid content of rectum is much smaller than that of small intestine, may affect dissolution of some drugs. d. Microbial degradation may occur in rectum.  Type of suppositories according to route of administration ✓ The modern rectal suppository is a conical or torpedo shaped item which is about 2-3 centimeters in length. Suppositories for adults weigh 2 grams each and children suppositories weigh 1 gram each. ✓ Urethral suppositories for males weigh 4 grams each and for females they weigh 2 grams each. ✓ Vaginal suppositories also called pessaries, are usually globular (ball), oviform or cone-shaped and weigh about 3-5 grams. ✓ Nasal bougies: Thin pencil shaped with pointed ends 1- 2 g and 9 – 10 mm long. ✓ Ear cones: Also pencil shaped SHAPE OF SUPPOSITORIES  Anatomy and physiology of rectum ✓ The rectum is part of the colon, forming the last 15 – 20 cm of the GI tract. ✓ The rectumcan be considered as a hollow organ with a relatively flat wall surface, without villi. ✓ The total volume of mucus is estimated as approximately 3 ml, with pH of 7.5 spread over a total surface area of about 300 cm2. ✓ S.A of 300 cm2 that not assist dissolution of suppositories. ✓ No villi indicate lack of primary absorptive function, but passage of drug occur by passive diffusion. Absorption of drugs from the rectum  RECTAL BLOOD CIRCULATION - Main blood supply: ▪ Superior rectal artery - Blood return 3 blood veins: ▪ Superior (upper) hemorrhoidal vein ▪ Middle hemorrhoidal vein ▪ Inferior (lower) hemorrhoidal vein Superior hemorrhoidal vein Inferior mesenteric vein -> Hepatic portal vein -> Liver Middle and inferior hemorrhoidal vein Drug goes directly into systemic circulation No first pass metabolism by liver Drug avoids stomach and digestive enzymes ✓ Patient counseling -> don't place LOCATION OF SUPPOSITORY too high in rectum  Factors affecting drug absorption from rectal suppositories I. Physiological factors affecting absorption 1. Quantity of fluid available: The quantity of fluid available for drug dissolution is very small (approximately 3 ml). Thus the dissolution of slightly soluble substances is the slowest step in the absorption process. 2. PH of the rectal fluid: The rectal fluid is neutral in pH (7– 8), so drug is not changed chemically in rectum. 3. Contents of the rectum: - When systemic effects are desired, greater absorption may be expected from an empty rectum as the drug will be in good contact with the absorbing surface of the rectum. - Fecal matter ↓ contact of drug with absorbing surface → ↓ absorption. 4. Circulation route: - The lower hemorrhoidal veins surrounding the colon receive the absorbed drug and initiate its circulation throughout the body, bypassing the liver. while upper rectal vein drain to portal circulation. so, suppositories not inserted deeply to decrease the portion of the drug lost in liver. II. Physico-chemical factors of the drug and suppository base affecting absorption 1- Drug solubility in vehicle (lipid/water solubility): ▪ The rate at which a drug is released from a suppository and absorbed by the rectal mucous membrane is extremely related to its solubility in the vehicle or, in other words, to the partition coefficient of the drug between the vehicle and the rectal liquids. ▪ When the drugs are highly soluble in the vehicle the tendency to leave the vehicle will be small and so the release rate into the rectal fluid will be low, So drug must be opposite in nature to the base to partitio n out easily (released from the base) Solubility of drug Base of choice Recommended base Water soluble (Hydrophilic) Oily base Cocoa Butter Lipid soluble (Lipophilic = Aqueous base Glycerinated gelatin or Hydrophobic) PEG  2- Particle Size of drug: - For drugs present in a suppository in the undissolved state, the size of the drug particle will influence its rate of dissolution and its availability for absorption. - The smaller the particle size the more readily the dissolution of the particles the greater chance for rapid absorption. 3- Degree of Ionization of the Drug (Pka of drug): - The barrier separating colon lumen from the blood is preferentially permeable to the unionized (un-dissociated) forms of drugs, thus absorption of drug would be enhanced by increase the proportion of unionized drugs. - As pH of rectum is 7‐ 8 , so only weak acid (pKa > 4.5) and weak bases (pKa < 8.5) will be completely absorbed from rectum but strong acids (pKa < 3) and strong bases (pKa > 10) will not be completely absorbed 4- Surface Activity of base: ▪  SA of base ➔  w e t t i n g of drug →↑ ra t e o f a b s o r p t i o n ▪ If it is low, SAA (surface active agent) is added to enhance the wetting of the drug. 5- Nature of the base: - The base must be capable of melting, softening, or dissolving to release its drug components for absorption. - If the base interacts with the drug, it will inhibit its release, a n d drug absorption will be impaired or even prevented. - Also, if the base is irritating to the mucous membranes of the rectum, it may initiate a colonic response and a bowel movement and, then incomplete drug release and absorption.  Specifications of suppository bases 1- Origin and chemical composition ▪ Origin: natural, synthetic or modified natural product ▪ Chemical composition: must be well defined, to determine if there is there any physical or chemical incompatibilities of the base with preservatives, antioxidants or emulsifiers. 2- Melting range ▪ The temperatures at which base starts to melt and temperature at which it is completely melted are ranges because bases have no sharp melting point. 3- Solidification point ▪ Predict t i m e required for solidification of base when it is chilled in mould, if difference between melting range and solidification point > 10 oC, refrigeration is needed to decrease ti m e of cooling 4- Saponification value ▪ Definition; No. of mgs of KOH required to saponify esters present in 1 gm of fat. It measures the average molecular weight or chain length of all the fatty acids present (mono-‐,di-‐or tri-‐ glycerides). 5- Acid value ▪ Definition: No. of mgs of KOH required to neutralize free acids in 1 gm fat. less acid value is better because free acids may react with other ingredients or cause irritation of rectum. 6- Iodine number ▪ Definition: No. of gms of I2 that react with 100 gm of fat or other unsaturated materials. ▪ ↑ I2 No.→↑ degree of unsaturation of fat→↑ liability of fat to rancid by oxidation. 7- Water number ▪ Definition: amount of water in gms that can be incorporated in 100 gms of fat. ▪ Water number can be ↑ by addition of SAA or other emulsifiers.  The ideal characters of Suppository base 1. Melts at body temperature or dissolves in body fluids. 2. Solidify quickly after melting 3. Non-toxic and non-irritant. 4. Compatible with great variety of drugs. 5. Releases any medicament readily. 6. Easily moulded and removed from the mould. 7. Shrink on cooling to release itself from mould thus require no lubrication of mould. 8. Has high water number. 9. Stable on storage, show no change in colour, odour and drug release pattern. 10. Be chemically stable even when molten. 11. Fatty base should have the following: a) Acid value < 0.2, b) Saponification value: 200 – 245 c) I2 value < 7 d) Interval between melting point and solidification point is small  Classification of suppository bases Hydrophilic bases Fatty (Oleaginous) bases 1- Water soluble (miscible) bases 1.Cocoa butter (theobroma oil) 2- Water dispersible bases 2.Emulsified theobroma oil 3- Emulsifying base 3.Synthetic fats  FATTY BASES ❑ Designed to melt at body temperature Cocoa Butter (Theobroma Oil) 1- It is the most widely used suppository base. And it is used in the prescriptions when no base is specified. Properties 2- It is naturally occurring triglyceride with oleopalmitostearin and oleodistearin glyceride chain and contains 40% of the unsaturated fatty acid. 3- It is yellowish white, solid, brittle fat, which smells and tastes like chocolate. 4- Its melting point lies between 30-35oC (86-95oF) its iodine value is between 34-38 and its acid value is not higher than 4. 5- It satisfies the requirements for an ideal base – inert, non- reactive, and melts at body temp.  Disadvantages Cocoa butter does not contract sufficiently on cooling to loosen 1- Adherence to the mould the suppositories in the mould, sticking may be overcome by adequate lubrication. 2- Softening To raise the softening point, white bees wax may be added point is too low to theobroma oil suppositories intended for use in tropical for hot climates and subtropical countries. 3- Melting Phenol and chloral hydrate have a tendency to lower the point reduced melting point of cocoa butter. by soluble So, solidifying agents like beeswax (4%) may be incorporated ingredients to compensate for the softening effect of the added substance 4- Rancidity Due to the oxidation of unsaturated glycerides on storage 5- Poor water- Improved by the addition of emulsifying agent absorbing ability 6- Leakage from Sometimes the melted base escapes from the rectum or the body vagina, so, it is rarely used as a pessary base 7- Expensive Relatively high cost  8- POLYMORPHISM 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, the cooling process and on the conditions during this process. Each form of cocoa butter has different melting point and drug release rates. Cocoa Butter exits in four crystalline state: ❖ α form: melts at 24oC, obtained by suddenly cooling of melted cocoa butter to 0oC. ❖ ß form: Stable form, melts between 34 and 35oC. ❖ ß` form: Changes slowly into the stable ß form. Its melting point lies between 28 and 31oC, obtained by stirring liquefied cocoa butter at 18 to 23oC ❖ γ form: melts at 18oC, obtained by pouring liquefied cocoa butter, before it solidifies, into a container which is cooled at deep freeze temp.  Slow 36°C Rapid Cooling Unstable γ crystals melt about 18°C How to reduce polymorphism? 1. 2/3 base is melted and 1/3 remain Unstable α solid to prevent formation of crystals melts unstable polymorphs. about 24°C 2. Seeding: add stable β form to melted cocoa butter to a c c e l e rat e c h a n ge of Unstable forms return to stable u n s t a b l e t o s t a b l e fo r m. form after several days 3. Storage at room temperature for 5–6 days t i l l u n s ta b l e convert to stable forms.  Synthetic fats ✓ To overcome the disadvantages of theobroma oil, synthetic substitutes were developed. ✓ Obtained from hydrogenation and heat treatment of vegetable oils such as palm kernel and arachis oil. ✓ Hydrogenation saturates unsaturated glycerides and heat treatment splits some of the triglycerides into fatty acid and partial esters (mono and di glycerides). Advantages Disadvantages 1- High softening point are advantageous1- They should not be cooled in a for tropical and sub tropical areas. refrigerator or ice because they become 2- They usually contain a proportion of brittle if cooled quickly. Additives such as partial glycerides e.g. glyceryl polysorbate 80 correct this fault. monostearate, are w/o emulsifying 2- They are (less viscous) than theobroma agents , so their emulsifying and water oil when melted and so, the sedimentation absorbing capacities are good. is greater. Thickeners such as magnesium 3- No mould lubricant is needed because stearate, bentonite, 2% Aluminum they contract significantly on cooling. monostearate reduce this problem. 4- They produce suppositories that are 3- The release and absorption of drugs white and almost odourless and have in the body may differ for theobroma oil attractive, and polished appearance. and synthetic bases.