Semi solid dosage form the suppositories

Semi solid dosage form
All about suppositories

1. Suppositories

2. “Suppositories are semisolid dosage forms intended for insertion into body orifices where they melt, soften, or dissolve and exert localized or systemic effects .” The word suppositories derived from Latin word SUPPOSITORIUM that means “ TO PLACE UNDER”. 1.Definition

3. Suppositories are commonly employed rectally, vaginally and occasionally urethrally . Suppository generally have been employed for three reasons to: Promote defecation Introduce drugs into body Treat anorectal diseases 2. Body orifices for using

4. Rectal using Vaginal using Shape of suppositories

5. Therapeutic Uses

6. 3. Character of action Rectal suppositories are most frequently employed to relieve constipation or the pain, irritation, itching, and inflammation associated with hemorrhoids or other anorectal conditions. Vaginal suppositories or inserts are employed mainly as contraceptives, antiseptics in feminine hygiene , and as specific agents to combat an invading pathogen . Urethral suppositories may be used as antibacterial and as a local anesthetic preparative to urethral examination. 1)Local Action

7. (a) for the relief of nausea and vomiting and as a tranquilizer (b) for narcotic analgesia (c) for the relief of migraine syndrome (d) anti-inflammatory analgesic and antipyretic. 2)Systemic Action administered rectally in the form of suppositories for systemic effects include:

8. 3) Advantages over oral therapy ( rectal route for achieving systemic effects ) (a) drugs destroyed or inactivated by the pH or enzymatic activity of the stomach or intestines need not be exposed to these destructive environments; (b) drugs irritating to the stomach may be given without causing such irritation; (c) drugs destroyed by portal circulation may bypass the liver after rectal.

9. (d) The route is convenient for administration of drugs to adult or pediatric patients who may be unable or unwilling to swallow medication; (e) It is an effective route in the treatment of patients with vomiting episodes.

10. Examples of drugs: Following are the examples of drugs administered rectally in the form of suppository for their systemic effects. Prochlorperazine (for nausea and vomiting) Chlorpromazine (as a tranquillizer) Oxymorphine HCl (narcotic analgesic) Indomethacin (NSAID analgesic and anti-pyretic) Ergotamine tartarate (relief of migraine)

11. Base is an inert medium in which drug is incorporated to dissolve, suspend or emulsify for a particular period of time . Suppository bases play an important role in the release of the medicaments which they hold and therefore in the availability of the drug for absorption or systemic effects for localized action. Bases alone used as emollient or lubricating effects or as vehicles in the preparation of medicated suppositories . Suppository Bases:

12. It should be good in appearance. It should melt at body temperature (37°C). It should be non-toxic and non-irritating . It should be compatible with a broad variety of drugs . It should shrink (congealing) sufficiently on cooling to release from the mould . It should be non-sensitizing . It should have melting and emulsifying property . It should be stable on storage . It should be stable if heated above its melting point . It should keep its shape while handling. It should release the medicament easily. Characteristics of an Ideal Suppository Base (water and fatty base):

13. It should have good water number. It is the high percentage of water which can be incorported . The amount of water in grams which can be incorporated in 100g of fat is expresses by its value . The water no. can be increased by the addition of surface active agents or other emulsifiers. .

14. Additional Characteristics for Fatty Bases : If the base is fatty it has following requirements. 1. Acid value is below 0.2. It is also called as neutralization value. It is the mass of KOH (Potassium hydroxide) in mg that is required to neutralize one gram of chemical substance. 2. Saponification Value ranges from 200-245. It is the no. of mg of KOH required to neutralize the free acids and saponify the esters contained in 1gm of a fat. 3. Iodine Value is less than 1. It is the no. of gm of iodine that reacts with 100g of fat or other unsaturated material.

15. Suppository bases are classified into two main categories according to their physical characteristics and a third miscellaneous group. 1. Fatty or oleaginous bases a. Cocoa Butter ( Theobroma Oil) b. Hydrogenated Oil 2. The water soluble or water miscible bases a. Glycerogelatin Base b. Base of Polyethylene glycol 3. Miscellaneous bases a. Generally a combination of hydrophilic and hydrophobic susbstances Classification of Suppository Bases:

16. A. Cocoa Butter ( Theobroma Oil) Cocoa butter NF is defined as, ―the fat obtained from the roasted seeds of Theobroma cacao‖. FATTY OR OLEAGINOUS BASES

17. Chemically it is triglyceride t hat is combination of glycerin with one or more fatty acids. It is yellowish white solid, brittle fat which smells and taste like chocolate. Its melting point is between 300°C to 350°C . Its iodine value is ranges from 34 to 38 . Its acid value is not higher than 4. Because cocoa butter is easily melt and rancidify it must be stored at cool and dry place and must be protected from sunlight. It is an ideally suppository base melt just below body temperature and yet maintains its solidity at usual room temperature. The Particular Characteristics of Cocoa Butter:

18. Cocoa butter exhibits marked polymorphism (the property of a substance which exists in different crystalline forms). This phenomenon attributes to the high proportion of the unsaturated triglycerides. Each of the different forms of cocoa butter has different melting points as well as different drug release rates (Melting point increases hence release of drug decreases).

19. Cocoa butter exhibits in four states. i . α-form: The α-form melts at 24°C and it is obtained by suddenly cooling the melted cocoa butter to 0°C. ii. β-form: It crystallizes out from the liquefied cocoa butter with stirring at 18-23C°. Its melting point ranges from 28°C to 31°C. iii. β’-form: β’-form changes slowly into the stable form which melts between 34 to 35°C and this change is accompanied by a volume contraction. iv. γ-form: It melts at 18°C and it is obtained by pouring a cool cocoa butter before it solidifies into a container which is cooled at deep freeze temperature. Different Crystalline Forms of Cocoa Butter

20. The formation of unstable crystalline forms can be avoided by different methods : 1. If the mass is not completely melted , the remaining crystals prevent the formation of unstable forms. 2. The small amount of stable crystals is added to the melted cocoa butter which accelerate s the change from unstable to stable form . This process is called as seeding. 3. As a general rule, the minimum use of heating in the process to melt the fat is recommended. Prolong heating must be avoided as much as possible e.g. cocoa butter must be slowly and evenly melted preferably over water bath of the warm water to avoid the formation of unstable crystalline forms. Methods to Prevent the Unstable Crystalline Forms:

21. Some drugs e.g . volatile oils, camphor, menthol, phenol or chloral hydrate, lower the melting point of cocoa butter to considerable extent. In such case, the solidifying agents e.g. cetylester was about 20% or beeswax about 4% may be melted with cocoa butter to compensate for the softening effect of the added substances. The addition of hardening agent must not be so excessive that: It prevents the melting of the base after the suppositories have been inserted into the body. Problems Associated with Volatile Drugs and the Cocoa Butter:

22. Topical Treatment of Vegetable Oils to produce Suppository Bases: The fat type suppository bases are produce from a variety of material either synthetic or natural in origin e.g. vegetable oils including: Coconut Oil Cotton Seed Oil Palmitic Oil B. Hydrogenated Oil (Cocoa Butter Substitutes)

23. The main members of this group are: o Glycerogelatin Bases o Polyethylene glycol A. Glycerogelatin Bases Glycerogelatin bases may be prepared by dissolving gelatin 20%, glycerin (70%), and adding solution or suspension of medicament (10%). WATER SOLUBLE / MISCIBLE BASES:

24. 1. Glycerogelatin base is not frequently used in preparation of vaginal suppositories where prolong localized action of medicinal agent is usually desired. 2. It is slower to soften and mix with physiological fluids. It provides a more prolonged release. 3. They have a tendency to absorb the moisture due to hygroscopic nature of glycerin. 4. Therefore they must be protected from atmospheric moisture in order to maintain their shape and consistency. 5. Due to hygroscopicity of the glycerin , these suppositories may have a dehydrated effect and be irritating to tissue upon insertion. Glycerogelatin Base in Vaginal Suppositories:

25. 1. The urethral suppositories may be prepared from the Glycerogelatin base. 2. For urethral suppositories the gelatin constitutes about 60% of the weight of formula, glycerin about 20% and the medicated aqueous portion 20%. 3. Urethral suppositories of glycerogelatin are more easily inserted then suppositories with cocoa butter base Glycerogelatin Base in Urethral Suppositories:

26. Polyethylene glycol is polymers of ethylene oxide and water prepare to various chain length, molecular weights and physical states. These are available in a number of molecular weight ranges. The more commonly used polyethylene glycol bases are PEG 200, 400, 600, 800, 1500, 1540, 3350, 4000, 6000 and 8000. These numerical designations refer to the average molecular weight of the polymers. PEG having average molecular weight of 200, 400 and 600 are clear colorless liquids and those which have average molecular weight of greater than 1000 are wax-like solids with hardness increasing with an increase in molecular weight. B. Polyethylene Glycol Bases ( Carbowax )

27. Various combinations of these PEG may be combined by fusion, using two or more of various type s to achieve a suppository base of desired consistency and characteristics. PEG suppositories don’t melt at body temperature and dissolve slowly in body fluids. It is possible to prepare suppositories from PEG mixture having melting point higher than that of body temperature.

28. 1. It permits the slow release of medicament from base. 2. Convenient storage of these suppositories without need of refrigerator and without danger of softening in warm weather. 3. They’re chemically stable. 4. Inert, and non-irritating 5. It doesn’t allow bacterial growth . 6. P hysical properties changes according to molecular weight . 7. It provides prolonged action. 8. It doesn’t stick to mold . 9. Suppositories are clean and smooth in appearance. Advantages:

29. Disadvantages: 1. If PEG suppository doesn’t contain atleast 20% of water they can cause irritation to mucous membrane after insertion. In such case they are dipped in water just prior to use. This procedure prevents the moisture which is being drawn from tissue after insertion and produces the ― stinging‖ sensation.

30. 1 . In the miscellaneous group of bases are included those which are mixtures of the oleaginous and water soluble or water miscible materials. 2. These materials may be physical or chemical mixtures. 3. Some materials are preformed emulsions generally w/o type or they may be dispersing in aqueous fluids . 4. One of these substances is polyoxyl 40 sterate . MISCELLANEOUS BASES:

31. Characteristics of Polyoxyl 40 Sterate : a. It is a surface active agent that is employed in a no. of commercial suppositories bases. b. This substance is waxy white solid that is water soluble . c. Its melting point is 39 – 40C. d. Mixtures of many fatty bases including cocoa butter with emulsifying agen t capable of forming w/o emulsions . e. These bases have ability to hold water or aqueous solutions and sometimes refer to as hydrophilic suppositories bases.

32. Suppositories are prepared by three methods: A. Molding from a melt (fusion) B. Compression (Cold Compression) C. Hand Rolling and Shaping Preparation of Suppositories

33. Preparation of Suppositories by molding (fusion):

34. Bases Used: Cocoa butter Glycerinated gelatin Polyethylene glycol 1. Suppository Molds: Molds in common use today are made from stainless steel, aluminum, brass, or plastic. They’re reusable and disposable . Commercially available molds available for preparation of rectal, vaginal, and urethral s uppositories can produce individual or large numbers of suppositories of various shapes and sizes . 2. Lubrication of the Mold: Mold is a hollow container used to give shape to molten or hot liquid material when it cools and hardens. Depending on the formulation, suppository molds may require lubrication before the melt is poured to facilitate clean and easy removal of the molded suppositories. .

35. Lubrication is seldom necessary when the base is cocoa butter or polyethylene glycol . Lubrication is usually necessary with glycerinated gelatin . A thin coating of mineral oil applied with the finger to the molding surfaces usually suffices. Lubrication before the melt is poured to facilitate clean and easy removal of the molded suppositories. .

36. Preparing and Pouring the Melt: Using the least possible heat over a water bath , the weighed suppository base material is melted on porcelain casserole. Medicinal substances are incorporated into a portion of the melted base by mixing on a glass or porcelain tile with a spatula. After incorporation, this material is stirred into the remaining base, which has been allowed to cool almost to its congealing point . - Any volatile materials or heat-labile substances should be incorporated at this point with thorough stirring. The melt is poured carefully and continuously into each cavity of the mold, which has been previously equilibrated to room temperature.

37. Allowing the melt to cool and Congeal into Suppositories: The mold is usually placed in the refrigerator , after hardening ; the mold is removed from the refrigerator and allowed to come to room temperature. Then the sections of the mold are separated , and the suppositories are dislodged , with pressure being exerted principally on their ends and only if needed on the tips. Removing the formed suppositories from the mold: Generally, little or no pressure is required , and the suppositories simply fall out of the mold when it is opened . Advantages: It is a simple method. It gives suppositories that are more elegant than hand mould suppositories. Sedimentation of solids in base is prevented. It is suitable for heat labile medicaments . .

38. Preparation by Compression(Cold Compression)

39. Advantages: This technique is time saving . It gives suppositories that are more elegant than hand mould suppositories. Suitable for heat labile medicinal substances. No mold preparation No heating is required. Disadvantages: The disadvantage to compression is that the special suppository machine is required and there is some limitation as to the shapes of suppositories that can be made. Manipulation requires considerable skills . Appearance is not elegant. It is not commonly done.

40. This is the oldest and simplest method for the suppository preparation. It is a method of choice when only a few suppositories are to be prepared in a cocoa butter base. A plastic like mass is prepared by ― triturating‖ grated cocoa butter and active ingredients in a mortar. The mass is formed into a ball in the palm of hands, the rolled into a uniform cylinder with a large spatula or small flat board on a pill tile. The cylinder is then cut into appropriate number of pieces which are rolled on Hand Rolling Method

41. Suppositories are classified into following types: 1. Rectal suppositories 2. Vaginal suppositories or Pesseries 3. Urethral suppositories or Bougies 4. Nasal suppositories or Bouginaria 5. Ear suppositories CLASSIFICATION OF SUPPOSITORIES:

42. 1. These are conical or cylindrical in shape. 2. These have flat base and tapered at the other end for easy insertion into rectum. 3. Its length is usually 32 mm and has a bullet shape e.g. Bisacodyl suppositories, USP (10mg). 4. USP-NF states that adult rectal suppository should weight about 2 gram , when cocoa butter is employed as the suppository base. 5. Rectal suppositories are used by infants or children are about half the weight and size of the adult suppository and assume more pencil like shape. 6. Rectal suppositories are used for local, systemic or mechanical effect. a. Local effect e.g. in hemorrhoids infection b. Systemic effect e.g. infection away from rectum c. Mechanical effect e.g. in evacuation of bowel in constipation Rectal Suppositories:

43. Some Official Rectal Suppositories Drug Use Action Aspirin Suppository Analgesic and Anti-pyretic Systemic Biscodyl Suppository ( Dulcolax ) Laxative Local Glycerine Suppository Laxative Local

44. The size of these suppositories is larger than rectal suppositories . 2. Officially, their weight is about 5g (3-6g). 3. They are globular, oval, and rod and cone shaped. 4. They are used for local actions. 5. When these suppositories are in tablet or capsule form they are called as tablet inserts . 6. For their manufacture usually polyethylene glycol is used . 7. Parabens (e.g. Methyl parabens / propyl parabens ) are used as preservative of these suppositories . 8. For their use pH of vagina should be 4.5. 9. These suppositories are buffered to pH 4.5 . Vaginal Suppositories or Pessaries :

45. These are long, thin and pencil shaped . 2. These are rounded from both sides . 3. Their diameter is 5mm. 4. Their length for male is 25 mm and for female is 50 mm. 5. Their weight for female is 2g and for male is 4g. 6. These are rarely prescribed. 7. For their formulation base is composed of glyceryl monosterate and polyoxyethylene . 8. E.g. Furacin Urethral Inserts (Anti-septic) Urethral Suppositories ( Bougies ):

46. These are pencil shaped similar to urethral suppositories. 2. These are shorter in length i.e. about 32 mm. 3. Base for their formulation is usually glycerogelatin base. Nasal Suppositories ( Bouginaria ):

47. 1. These are pencil shaped similar to urethral suppositories . 2. These are shorter in length i.e. about 32 mm . 3. Base for their formulation is usually cocoa butter . 4. E.g. Paracetamolo  Paracetamolo 120 mg  Composition: 1 suppository contains paracetamol 0.120g.  Excipient : Semi-synthetic glyceride  Pharmaceutical Form: Suppository  Therapeutic Indication : Analgesic and Anti-pyretic  Product: For Export Only  Packaging : Box of 6 suppositories Oral Suppositories:

48. The displacement value of a medicament is the no. of parts by weight of a medicament that will displace one part of suppository base (normally Theobroma oil ). Displacement values for various medicaments are given in B.P.C. ( British Pharmaceutical Codex ). It is the amount of drug that will displace one part of base . Displacement Values

49. Mathematically, Where , d = Amount of drug in suppositories a – c = Amount of base e.g. Theobroma oil i.e. displaced by gram of medicine D.V. of a medicament is required when calculating the weight of suppository base required preparing a medicated suppository .

50. Suppositories are often packaged in partitioned boxes that hold the suppositories upright . Glycerine and glycerinated derivatives are often packed in screw-capped glass containers. Many other suppositories are wrapped individually in tin, aluminum foil, paper, plastic or PVC-polyethylene. Poorly packed suppositories may give rise to staining, breakage or deformation by melting. Strip packaging is common place. All suppositories particularly Theobroma oil suppositories and glycerogelatin suppositories should be refrigerated Packaging and Storage