British University Lecture Notes: Suppositories PDF

Pharmaceutics-iii Solid dosage forms Lecture 2 Suppositories Today you will learn the following: Factors affecting rectal drug absorption Types of bases Composition of suppositories Factors affecting rectal drug absorption Circulation route...

Pharmaceutics-iii Solid dosage forms Lecture 2 Suppositories Today you will learn the following: Factors affecting rectal drug absorption Types of bases Composition of suppositories Factors affecting rectal drug absorption Circulation route 1)Physiologic pH and Lack of Buffering Capacity of Factors the Rectal Fluids Colonic content Factors Lipid-water solubility 2) Physicochemical Particle size Factors Nature of the base 3 The rectum is a hollow organ with a relatively flat wall surface, without villi. The rectum is part of the colon, forming the last 15 – 20 cm of the GI tract. It contains only 2 – 3 ml of inert mucous fluid with pH of 7-8.  Circulation route ABSORPTION OF DRUGS FROM RECTUM INSERTION OF SUPPOSITORY IN RECTUM  ABSORPTION OF DRUGS FROM THE RECTUM Rectal Route: The rectum, which makes up the last part of the large intestine and ends at the anus, contains three types of hemorrhoidal veins: Superior hemorrhoidal vein Middle hemorrhoidal vein Inferior hemorrhoidal vein The inferior and middle hemorrhoidal veins transport substances absorbed in the rectum directly into the bloodstream via the iliac veins and the vena cava. the superior hemorrhoidal vein transports substances indirectly through the portal vein to the liver. Since the exact position of a suppository within the rectum is unpredictable, it is uncertain which pathway the active substance will take. However, it is accepted that about 50% to 70% of the active ingredients administered rectally follow the direct route, bypassing the liver and avoiding the first-pass metabolism. 7 Factors affecting rectal drug absorption 2- Colonic content for systemic effect: A- greater absorption is expected from empty rectum than that with fecal matter* B- other conditions may affect the rate and degree of drug absorption E.g. diarrhea 3- pH &lack of buffering capacity of the rectal fluid Rectal fluids have (pH = 7-8), almost neutral. So, drugs won`t be chemically changed by rectal fluids For systemic drug action For formulations using a cocoa butter base, it is generally preferable to incorporate the ionized (salt) form of the drug rather than the unionized (acid/base) form to optimize bioavailability. Although cocoa butter melts quickly at body temperature, it releases the drug slowly due to its immiscibility with body fluids. Degree of ionization: The barrier separating the colon lumen from the blood is preferentially permeable to the unionized forms of drugs, Therefore, enhancing drug absorption is often achieved by increasing the proportion of the un- ionized form as it can also pass easily through lipid membranes, irrespective of the type of base used. II- Physicochemical factors of the drug and base 1- Lipid water solubility: Drug solubility or its lipid-water partition coefficient controls the type of base and drug release fatty base (melt) : Lipophilic drug have a lower tendency to be released to aqueous fluid than hydrophilic drug 2- Particle size: The particle size of the drug will affect its absorption how? 3- Nature of the base: a) Base must be able to melt, soften, or dissolved to release drug yet solid at Room temperature B) A reaction between the base and the drug resulting in inhibition of drug release leading to impairment or prevention of absorption should be avoided C) This interaction may also affect the stability and bioavailability of the drug D) If the base is irritating to the rectum; it may fasten colonic response and bowel movement which may affect drug release and absorption FORMULATION OF SUPPOSITORIES A) Bases B) Antioxidants C) Emulsifying agents D) Hardening agents E) Preservatives F) Thickening agents G) Plasticizer 12  Suppository bases play an important role in maintaining their shape, solidity & also play an important role when inserted into the body cavity. Functions: 1- dilute the drug to nonirritating level 2- control the drug release rate 3- represents the drug in suitable and usable form IDEAL SUPPOSITORY BASE Stable on storage and Melts at body temperature or dissolves in body fluids. Non-toxic and non-irritant. Compatible with any medicament. Easily moulded and removed from the mould.  Suppository Suppository bases bases Hydrophilic Miscellaneous Oily base bases base 1-Cacao butter Theobroma oil 1-Glycerinated gelatin Generally 2-Emulsified combinations of Theobroma oil 2-PEG Macrogols lipophilic and 3-Synthetic hard fat hydrophilic Hydrogenated oils 3-Soap glycerin substances 3-a-Witepsol 3-b-Wecobee ❑ It is the most widely used suppository base. It satisfies many requirements for an ideal suppository base. ❑ Cocoa butter is fat obtained from the roasted seed of Theobroma cocoa. ❑ At room temperature it is a yellowish-white solid having a faint, agreeable chocolate-like odour. ❑ Chemically, it is a triglyceride of saturated and unsaturated fatty acid, primarily stearic, palmitic, oleic, and linoleic. ❑ It melts at 30 - 350C  Advantages ◦ Melting at the body temperature. ◦ Maintaining its solidity at usual room temperatures. ◦ Readily liquefy on heating and solidify on cooling. Disadvantages: a- Polymorphism b. Adherence to the mould* c. Softening point too low for hot climates* d. Melting point reduced by soluble ingredients: Phenol and chloral hydrate tend to lower the melting point of cocoa butter.- So, solidifying agents like beeswax (4%) may be incorporated to compensate for the softening effect of the added substance. e. Rancidity on storage* f. Poor water-absorbing ability: Improved by the addition of emulsifying agents. g.Leakage from the body h. Expensive  Polymorphism ( the property of existing in different crystalline forms). due to high proportion of unsaturated triglycerides. - Cocoa butter exists in different crystalline forms ( Ɣ, α , β`, β) When melted and cooled it solidifies in different crystalline forms, depending on the temperature of melting, rate of cooling, and the size of the mass. - If melted at not more than 36°C and slowly cooled it forms stable beta crystals with normal melting point. - If overheated then cooled it produces unstable gamma crystals which melt at about 18 °C or alpha crystals melting at 22°C. Cocoa butter must be slowly melted over a warm water bath to avoid the formation of an unstable crystalline form. 17 How to overcome the polymorphism of cocoa butter? 1- Not the whole amount is melted so the remaining solid crystals prevent the formation of unstable form 2- Seeding: small amount of stable crystals is added to the melted base; this will accelerate the change from unstable to stable form 3- Melt then solidify the base; this solidified base is then stored between 28-32 ͦ C for h or days. This will cause a change from unstable to stable form 18 ⦁ Emulsified theobroma oil may be used as a base when large quantities of aqueous solutions are to be incorporated. ⦁ 5% glyceryl monostearate, 10% lanette wax, 2-3% cetyl alcohol & 4% bees wax is recommended for emulsified theobroma oil.  Synthetic hard fat Hydrogenated oils To overcome the disadvantages of theobroma oil synthetic substitutes were searched. ⦁ Obtained from hydrogenation and heat treatment to vegetable oils ⦁ Hydrogenation saturates unsaturated glycerides II- The Wecobee bases (triglycerides derived from coconut oil) III- Witepsol bases (triglycerides of saturated fatty acids) Hydrogenated oils ⦁ Advantages ▪ Overheating does not affect the solidifying point. ▪ They are resistant to oxidation. ▪ Lubrication of the mould is not required. Disadvantages ▪ On rapid cooling they become brittle. ▪ When melted they have lower viscosity than Theobroma oil & result in greater sedimentation of the drug. 21  Glycero-gelatin base. Soap-glycerin base. Polyethylene glycol. It is a mixture of glycerin and water which is made into stiff jelly by the addition of gelatin. Properties: It is colorless, transparent, translucent in nature. It is soft to touch. ⦁ Advantages: ◦ It dissolves slowly in body fluids providing slow and continuous release of the drug. ◦ Do not rancid. ◦ It can be used to prepare all types of suppositories ⦁ Disadvantages: a. laxative effect: osmosis occurs during the dissolving in the mucous secretions of the rectum, producing a laxative effect. b.Can cause rectal irritation due to the small amount of liquid present. c. Unpredictable solution time. d.Hygroscopic: So, they should be packaged in tight containers and also have dehydrating effects on the rectal and vaginal mucosa leading to irritation. e.Microbial contamination likely. f- Long preparation time. g- Lubrication of the mould is essential. ❑Factors affecting dissolution time of glycerinated gelatin 1- Proportion of gelatin, glycerin and water used 2- Nature of gelatin (type A, type B) 3- Chemical reaction of the drug with gelatin How to increase the consistency of gelatin base? 1- increasing Gelatin content from 20% to 30% 2- Replacing a portion of the water or glycerin with mucilage of acacia  They are long-chain polymers of ethylene oxide with general formula HOCH2(CH2OCH2)8CH2OH These are commonly known as carbowaxes & polyglycols. These are available in solid, liquid, or semi-solid state depending on molecular weight. Those polymers having a molecular weight between 200 and 1000 are liquids & those having a molecular weight higher than 1000 are wax-like solids. ⦁ They are chemically stable. ⦁ Inert, Non-irritant, no laxative effect ⦁ Less bacterial growth. ⦁ Physical properties changes according to molecular weight. ⦁ Provide prolonged action. ⦁ Do not stick to mould.  Disadvantages of macrogols 1. They are hygroscopic so careful storage is required. Irritancy can be reduced by incorporating about 20% of water in the mass or by instructing the patient to dip the preparation in water just before insertion. This type of base is suitable for systemically active drugs. 2. They are incompatible with bismuth salts, tannins and phenol. They lower the activity of some antibacterial agents and dissolve certain plastics necessitating care in choosing containers. 29  Soap glycerin combines the properties of glycerin with various soap components, such as sodium stearate or other fatty acid salts, Soap Component (e.g., Sodium Stearate or Sodium Palmitate): Acts as a solidifying agent to form a stable suppository structure. Soap components are salts of fatty acids that combine with glycerin to produce a base that is firm at room temperature yet dissolves or softens in the presence of moisture. The soap acts as an emulsifier, enhancing the distribution of active ingredients. Due to the hygroscopic nature of glycerin and the stimulating effect of soap, these bases are widely used for rectal laxative suppositories, such as glycerin suppositories for constipation. Disadvantages: Hygroscopic, so need : 1- wrapped in waxed paper or foil 2- protected from atmosphere by storing in well-closed container 30  FORMULATION OF SUPPOSITORIES A) Bases B) Antioxidants C) Emulsifying agents D) Hardening agents E) Preservatives F) Thickening agents G) Plasticizer 31  ANTI OXIDANTS It protect the drugs and bases from getting degraded due to oxidation. These are commonly used in all types of suppositories. EXAMPLES- Ethyl or propyl gallate Ascorbic acid Butylated hydroxy anisole (BHA) Butylated hydroxy toluene (BHT) Hydroquinone Tocopherol  EMULSIFYING AGENTS These increase the water absorbing capacity of fatty bases. EXAMPLES Poly sorbates (TWEEN ) Wool alcohol Wool fats  HARDENING AGENTS These are involved in those formulation where the melting point of the bases is decreased by the drugs. These are the agents which are used to bring the melting point to normal. EXAMPLES Beeswax Macrogols at high molecular weight.  PRESERVATIVES These are the agents that are used in preventing the growth of microbial in suppositories that contains water-soluble bases. EXAMPLES Chorocresol Methyl paraben Propyl paraben  THICKENINGAGENTS These are the agents which are used to increase the viscosity of molten bases and prevent sedimentation of suspended in solid bases. EXAMPLES Aluminium monostearate Colloidal silica Magnisium stearate Steary alcohol PLASTICIZERS These are the agent which are used to improve flexibility of suppositories. It is also used to produce less brittles suppositories. EXAMPLES ❑Castor oils ❑Glycerine ❑Glycol ❑Tween 80 ❑Tween 85 Infrastructure Deterioration Models 38