Suppositories and Inserts - CH4106 PDF

Section V Pharmaceutical inserts 11. Suppositories and inserts 1 http://pharmlabs.unc.edu In this section you will learn…. Applications, advantages and disadvantages Delivery to the rectum, vagina & urethra...

Section V Pharmaceutical inserts 11. Suppositories and inserts 1 http://pharmlabs.unc.edu In this section you will learn…. Applications, advantages and disadvantages Delivery to the rectum, vagina & urethra Types of suppository bases and their properties Manufacturing, packaging, storage and handling Vaginal inserts 2 Suppositories and Historical Use Solid dosage forms intended for insertion into body orifices where they melt, soften or dissolve and exert either local or systemic effects Drugs include astringents, antiseptic, anaesthetics, vasoconstrictors, anti-inflammatory, protective, soothing and laxatives Throughout history:  Egyptians, Greeks, Romans  Pieces of cloth, plants, wood or other material either plain or soaked in drug solution 3 Applications: Why Suppositories? Patient may not be able to use the oral route:  Very young, old or mentally disturbed  Patients with GI tract problems  Severely debilitated patients The drug is less suited for oral administration:  GI side effects  Drug stability: effect of pH or enzymes  Un acceptable drug taste/smell Parenteral route might be unsuitable 4 Advantages of Suppositories Self administration Avoidance of oral & parenteral routes and their problems Drug causes nausea or drug restrictions Patient suffering from sever vomiting Can be targeted delivery system:  Localized action: rectum, vagina & urethra  Get to site at a lower dose; reducing systemic toxicity 5 Disadvantages of Suppositories Mucosal irritation Slow, erratic and incomplete absorption Diarrhea & disease states affect absorption Installation may trigger defecation reaction High cost and problems with large scale manufacturing Stringent storage conditions: can melt at ambient temperatures, difficult to achieve suitable shelf-life Development of proctitis Not the route of choice! 6 Suppositories and Routes of Administrations Generally intended for:  Rectum  Vagina  Urethra Drug content varies from 0.1-40% 7 Factors Affecting Rectal Absorption The dosage of the drug given rectally may be greater than or less than the dose of the same drug given orally depending on:  Physicochemical factors Lipid-water solubility Particle size Nature of base/release  Physiologic factors Colonic content pH/buffer capacity Circulation route Part of rectum at which absorption is taking place 8 Physiology: Rectum Terminal 15-20 cm of large intestine Hollow with a relatively flat wall surface without villi Rectal wall is formed by an epithelium which is one cell layer thick – secretes mucous When empty contain 2-3 mL of inert mucous fluid. Surface area 300 cm2 Rectal fluids are neutral (pH 7.5) without buffering capacity  Mild environment where drug can change its pH 9 Villi Rectal Blood Circulation Main blood supply: superior rectal artery Blood return: by 3 blood veins -  Superior hemorrhoidal vein  Middle hemorrhoidal vein  Inferior hemorrhoidal vein 10 Rectal Blood Circulation Blood supply, especially venous drainage, is important for understanding drug absorption: Middle & inferior hemorrhoidal veins:  Blood flow: Iliac vein  inferior vena cava Drug goes directly into general circulation avoiding the liver Superior hemorrhoidal vein:  Blood flow: Inferior mesenteric  hepatic portal  Liver Drug pass thought the strongly metabolizing liver Keep drug in the lower part of the rectum! 11 Physiology: Vagina Fibromuscular tube about 7.5 cm long Vaginal fluids  Mixture of proteins and polysaccharides  Protective mucus originate in cervix  Low pH (4.5-6) Vaginal blood circulation:  Blood supply vaginal artery (branch of Iliac)  Blood return avoids the hepatic portal system 12 Physiology: Urethra The urethra is a short straight tube connecting the bladder to the outside Tube:  Males 20 cm  Females 4 cm Poorly perfused by blood 13 Types of Suppositories Rectal: normally cylindrical or conical  approx 2 g, about 1-1.5 inches long Vaginal: ovoid, globular, other shape  3 to 5 g Urethral: vary depending upon male/female  Male: 5 mm dia, 125 mm, 4 g  Female: 5 mm dia, 50 mm, 2 g Vaginal 14 Rectal Urethral Suppository Bases Ideal base has the following characteristics:  Cause no irritating or inflammation  Remains solid at r. t. but melts, dissolves, softens or disperses at 37oC  Chemically stable & inert: compatible with other drugs  Physically stable: manufacture & storage  Melting range: should be ideal for rapid solidification  Dose not affect the bioavailability of the drug  Suitable viscosity when melted: Doesn't leak from rectum or vagina 15 Classification of Suppository Bases Fatty or oleaginous:  Cocoa butter and its substitutes e.g., Wecobee Fattibase  Other fatty bases: e.g. Adeps solidus Water-soluble or water-miscible:  Glycerinated gelatin  Polyethylene glycol Miscellaneous:  Mixture of lipophilic and hydrophilic bases  Mixtures of fatty bases and emulsifying agents Non-base:  Tablets 16  Soft gelatin capsules Cocoa Butter Base Obtained from the roasted seeds of Theobroma cacao Smells and tastes like chocolate Naturally occurring triglyceride (40 % unsaturated fatty acids, oleopalmitostearin, oleodistearin) Yellowish-white solid, m.p. 30-36oC Some drugs may depress m.p. (Liquefy) Stored in cool, dry, light protected Poor water absorptive properties Shows polymorphism (α, ß', ß, γ) 17 Cocoa Butter: Polymorphs α – form melting point 22oC γ – form melting point 18oC ß’ – form melting point 28 to 31oC ß – form melting point 34 to 35oC, most stable and desired form All forms can be converted to ß form:  Need ß seed crystals to get the required ß form  Heat enough to remove α, ß', but keep ß  Heat enough so that ß is still present and act as seed  May use seed crystals from stock 18 Cocoa Butter: Compounding Don't heat above 34.5 oC for long time Cocoa butter suppositories will release best if the molds:  Absolutely clean and dry and  The cocoa butter have not been overheated Disadvantages of cocoa butter: shows insufficient contraction at cooling, has low softening point, poor chemical stability and poor water adsorptive power, bad for high speed manufacture Cocoa butter replacements  Vegetable oils, wax, triglycerides of fatty acids, fatty alcohols C12-C18 19 Water-Soluble and Water-Miscible Bases May result in some irritation and dehydration as they take up water and dissolve Example 1: Glycerinated gelatin  Mixture of glycerin and gelatin in water  Example: USP 24 - mixture of glycerin (70 g) gelatin (20 g) and purified H2O (10 gm) Remember: glycerin is hygroscopic thus need to protect from H2O (bacterial growth) 20 Water-Soluble and Water-Miscible Bases – Cont. Example 2: Polyethylene glycol (PEG)  Polymers of varying molecular weights (MW)  Base properties change with MW: Liquid: 200-600 MW Wax-like solids: MW > 1000  Water soluble: dissolve in body fluids  Stable, must not store in polystyrene vials  Ratio of low to high MW PEGs can be altered to prepare a base: With a specific melting point Controlled release Do not leak 21 Compressed Tablets Not common for rectal suppositories  Low moisture environment Becoming more popular for vaginal use Advantages  Easier to manufacture  More stable (storage & chemical reaction) 22 Formulation: Specific Considerations Water Density Hygroscopicity Volume contraction Incompatibilities Dosage replacement Viscosity Weight/volume control Brittleness 23 Formulation Consideration Base selection: what base?  Composition  Melting behavior  Rheological properties Drug onset and action: quick, slow, prolonged effect Application and use: rectal, vaginal, urethral:  Systemic absorption Formulation is important as suppositories are prone to erratic absorption  Local absorption Not as critical. Most bases hold drug in contact 24 with target tissue Formulation Considerations: Drug Release Depending on the vehicle, the suppository will either dissolve in the rectal fluid or melt on the mucous layer Drugs need to diffuse out of the suppository through the mucous layer and then through the epithelium Drug Release  Suppositories with oleaginous bases Melt  spread  Suppositories with hydrophilic bases Dissolves in fluids  diffuses from fluids 25 Drug Release: Process Drug release process from suppository Melting and spreading Suppository Sedimentation Wetting Dissolution 26 Drug Release: Factors to Consider The release and onset of drug action is dependent upon:  The type of base  Solubility in water and the vehicle  Particle size  Amount of drug  Other additives 27 Drug Release: Factors to Consider – Cont. Relationship of drug release, the drug and the suppository base:  Oil soluble drug  oily base slow release, poor escaping tendency  Water soluble drug  oily base rapid release  Oil soluble drug  water miscible base moderate release rate  Water soluble drug  water miscible base rapid release...based on diffusion...all water soluble Water soluble drugs in fatty base preferred 28 Drug Release: Factors to Consider – Cont. Particle size: Small particles show better dissolution, less irritation and better sedimentation rate  Suggested size 50-100µm Amount of drug  As the number of particles increase, chance of agglomerate formation increase. This is affected by the particle size and the additives present  Density/dose replacement calculations are required if more than 100mg drug is used in 2g suppository Other additives: surfactants, viscosity additives  May cause depression in the m.p.  Deglomeration to prevent cake formation 29 Preparation of Suppositories Hand rolling and shaping  Only use cocoa butter  No equipment and no heat needed Cold compression  Suitable for bases formulated under pressure Molding from a melt (Fusion)  Heat  Equipment: need molds, etc.  Special calculations 30 Hand Rolling and Shaping Not used much anymore: simplest & oldest method Procedure:  Weigh ingredients  Grate cocoa butter  Adding active ingredient  Mixing thoroughly utilizing (a mortar/pestle or a pill tile/spatula)  Shape into a long cylinder (diameter)  Cut into the desired length, rounding the tips  Packaging and labeling Use plastic gloves 31 Cold Compression The base and medication mixture is forced into special molds using suppository making machines  Especially used for ingredients that are heat labile Procedure:  Mix base and other ingredients thoroughly. Use mortar and pestle or mechanical mixtures  Pressure is applied to the mold  Special machines are required  Example: mixture of 6% hexanetriol-1, 2,6 with PG 1450 and 12% polyethylene oxide polymer 4000 32 Molding From A melt Most commonly used Procedure  Base material gently heated to melt  Active ingredients and excipients are added with mixing  The melt is poured into molds  Allow the melt to cool and congeal into suppositories  The suppositories are trimmed, packaged and labeled Suitable bases: Cocoa butter, glycerinated gelatin, polyethylene glycol 33 Molding From A melt – Cont. You must consider:  Suppository molds: plastic, stainless steel, aluminum, brass …  Lubrication of mold Use lubricant for mold release e.g.: glycerinated gelatin and mineral oils  Amount of base required  Calibration of mold  Preparation & pouring of melt Melt over water bath with least possible heat Stir during pouring into chilled mold 34 Molding From a Melt: Calibration of Mold Prepare the molds, clean and dry cavities Melt sufficient suppository base to fill 6-12 molds Pour in the mold, cool and trim Remove the suppositories and weigh Divide the total weight by the number of blank suppositories prepared to obtain the average weight of each suppository for this particular base Use this weight as the calibrated value for that specific mold using that specific lot of suppository base Put in beaker & melt to get volume Calculate weight and volume of each cell Different bases will have different ρ's 35 Suppositories Molding: Hints Calibrate the mold before calculating the total batch Prepare 10% overage more to allow for loss The mold should be clean and dry Melt temperature critical for plastic molds Determine whether or not lubricants should be used Do not refrigerate or freeze suppositories or suppository molds prior to pouring Slightly overfill each cavity in a suppository mold to allow for contraction upon cooling Once pouring is initiated, do not stop 36 Calculations For Suppositories If the active drug < 100 mg, then the volume it occupy is insignificant and need not be considered (based on a 2 g suppository weight) If a suppository mold used is less than 2 g, the active drug volume may need to be considered The density factors of various bases and drugs need to be known to determine the proper weights of the ingredients to be used If the density factor of a base is not known, it is simply calculated as the ratio of the blank weight of the base and cocoa butter See page 325 37 Calculations For Suppositories – Cont. Three methods to calculate the quantity of base that the active medication will occupy and quantity of ingredients required:  Dosage replacement factor  Density factor-Paddock method  Occupied volume method Must understand the calculations from Ansel: pages 325-327 (Physical pharmacy capsule 12.1) 38 Quality Control Testing Melting range test Liquefaction time test Breaking test Softening/liquefaction temperature test 39 Packaging, Storage and Labeling Suppositories are individually wrapped or dispensed in a disposable mold in which they are prepared Poor packaging leads to deformed, stained, broken or chipped suppositories Should be protected form heat and may store in a refrigerator, they generally should not be frozen Glycerin and polyethylene glycol-based suppositories should be protected from moisture, they are hygroscopic Directions for use: Unwrap, moisten and insert... or Unwrap and insert... 40 Example Prescriptions: Hydrocortisone Acetate Suppositories Product: Hydrocortisone Acetate 25 mg and 30 Suppositories Synonyms: Cortisol Acetate Suppositories Chemical family: Steroid/anti-inflammatory Ingredients:  Hydrocortisone Acetate : 1.4 %  Hydrogenated Vegetable Oil : 98.6 % Melting point: 32-35oC Water solubility: Insoluble Appearance and odor: White to creamy white; odorless 41 Case Study: Effects of interacting variables on the release properties of chloroquine and aminophylline suppositories: By K.J. Jaiyeoba Purpose: The individual and interaction effects of formulation variables on the release of suppositories were investigated using a 2 factorial experimental design. The variables studied were nature of base (B), type of drug (D), and presence of surfactant (S). Method: Suppositories were formulated with theobroma oil and Witepsol H15 as bases. Chloroquine and aminophylline, both water-soluble drugs, were incorporated as active constituents at ‘low’ and ‘high’ levels respectively while Tween 80 was incorporated as surfactant in some of the formulations. Disintegration time and time taken for 50% of the drug to dissolve were used as assessment parameters. Conclusion: The results suggest that in formulating water- soluble drugs such as chloroquine and aminophylline as suppositories in a hydrophobic base, the presence 42of a surfactant is the most influential variable