Compounding of Suppositories & Pessaries PDF

COMPOUNDING OF SUPPOSITORIES & PESSARIES ” Dr Mohd Hanif Zulfakar  The Rectum Rectum intestinum – straight intestine The last 150-200 mm of GI tract Part of the colon, hollow with flat wall surface Presence of 3 rectal valves Separated from the exterior...

COMPOUNDING OF SUPPOSITORIES & PESSARIES ” Dr Mohd Hanif Zulfakar  The Rectum Rectum intestinum – straight intestine The last 150-200 mm of GI tract Part of the colon, hollow with flat wall surface Presence of 3 rectal valves Separated from the exterior by the anus  Subdivision Anal canal (20%) Ampulla (80%) Rectal wall – single epithelial cell layer, cylindrical and goblet cells (mucus) Total surface area 300 cm2 , mucosal volume ~3 mL pH 7.5, minimal buffer capacity  Delivery of drugs to rectum provides both local and systemic effects 00 Absorption of drugs are entirely by passive diffusion Absence of esterase or peptidase enzymes  Advantages of rectal delivery depression attack For non-ambulatory and uncooperative patients, unable to deliver orally (vomiting, unconscious, elderly, infants) Beneficial for drugs with high incidence of GI side effects, pH sensitive, labile to enzymes or 1st pass effect Drugs with unacceptable taste Formulation of highly abused drugs i.e. for suicide into suppositories have been considered  Disadvantages of rectal delivery Strong traditional aversion Slow and incomplete absorption fund amount in rectum Unsuitable for very hydrophobic and low solubility drugs Inter- and intrasubject variability rate of absorption Proctitis may differ Problems associated with production and shelf life temperature sensitive  The Vagina Approximately 10 cm fibromuscular tube, 60cm2 area 3 distinct layers Adventitial layer Muscularis Mucosal Presence of rugae and microridges on epithelial surface increases surface area Vast network of blood vessels in vaginal wall – provides both systemic and local absorption of drugs  actaic very pH 3.5 – 4.5 – maintained by bioconverted (by vaginal microflora) lactic acid Vaginal fluids consists of secretions from multiple glands Presence of peptidase enzymes that degrades protein and amino acids with lower activity than GI Thickness of vaginal wall, amount of fluids, and pH is affected by age, cyclical changes, and pregnancy foreg 50old woman may have thinner vaginal wall  Advantages of Intravaginal Delivery Structural ability of vagina to retain dosage forms – prolonged release Minimal systemic side effects Increased bioavailability Avoidance of first pass effects and drug degradation by GI Theoretically reduced dose (vs GI) Quick onset of action Allows self medication can do it ourselves  Disadvantages of Intravaginal Delivery Gender specificity for woman only Traditional and cultural aversion – leads to incompliance Restricted selection of drugs Variable absorption – multifactorial Personal hygiene not thesedate vaginal discharge Some drugs are sensitive to vaginal pH exists amount Influenced by sexual intercourse  Rectal preparations Rectal preparations (BP definition): Intended for rectal use in order to obtain a systemic effect or local effect, or they may be intended for diagnostic purposes. The BP lists several types of rectal preparations: Suppositories Rectal capsules Rectal solutions and suspensions Powders and tablets for rectal solutions and suspensions Semi-solid rectal preparations (e.g. ointments) Enemas Rectal foams Rectal tampons  Vaginal preparations Can also be used for both local and systemic action Dosage forms include: Pessaries or vaginal suppositories Vaginal tablets Vaginal capsules Vaginal solutions Vaginal sprays Vaginal creams Vaginal ointments Vaginal foams  The suppository Usually about 32 mm (1.5 inches) long, cylindrical, 1 or both end tapered 0 Bullet or torpedo-shaped, with convenience of insertion a primary consideration easy to be inserted Variable weight  Local action : antihaemorrhoid, laxatives Systemic action : analgesia (oxymorphone HCl), nausea & vomiting (ondansetron, prochlorperazine, chlorpromazine) Drug content from 0.1% - 40% Composition and formulation technique of pessaries/vaginal suppositories essentially the same as rectal suppositories - Prepared mainly with glycerol-gelatin base. PEG may irritate. Fatty bases are less common  Release of drug from suppositories Suppository will either dissolve in rectal fluid, or melt on mucous layer Depending on the type of base used in formulation Dissolution is restricted by amount of rectal fluid – osmotic process absorps more water into suppository resulting in pain or unpleasant sensation Dissolved drugs will diffuse through mucosal layer Suspended drugs leave vehicle either via gravity or rectal motility before dissolution Formulation of suppositories 0 commonly seen  rectum for Suppository bases Must be capable of melting, softening or dissolving to release drugs at body temperature “Melts in your rectum, not in your hands”!facially for bases fatty Inert – no interaction with drug Physically and chemically stable Good drug release profile Non-irritant – avoid evacuation rectum  Remain solid at room temperature, small melting range to give rapid solidification during preparation Exhibit enough volume contraction during solidification to permit removal from mould Appropriate viscosity  1. Fatty or oleaginous bases Most frequently used Cocoa butter (classic), hydrogenated fatty acids of vegetable oils e.g PKO, cottonseed oil, fat-based compounds containing compounds of glycerin with HMW fatty acids In practice, a mixture of bases are used to achieve desired hardness and temperature profiles Less common in vaginal suppositories/pessaries  careful not to overheat Theobroma oil a. Cocoa butter Imines o Fat obtained from roasted seed of Theobroma cacao Yellowish-white solid (room temp.) with faint chocolate odour A trigylceride of oleoplamitostearin and olea distearin Melting range 30-36°C need neat to prepare Usually added with solidifying agents such as cetyl esters T.net wax, beeswax  Disadvantages: Exhibits marked polymorphism – α (metastable, lower melting point) and β crystalsmust be slowly and evenly melted 240C Insufficient contraction at cooling, low softening point, chemically instable, poor water absorption may have difficulty to remove it from mould  b. Other fatty bases Commercial bases, synthetic/semi-synthetic Produced by hydrogenation of selected vegetable oils Adeps solidus Fattibase (TG from palm, PK and coconut oils with self-emulsifying Is glyceryl monostearate & polyoxyl stearate Weecobee bases (TG derived from coconut oil) Witepsol bases (TG of saturated Fas C12-C18 with varied portions of corresponding partial glycerides)  Have many advantages of cocoa butter but fewer disadvantages. However, there are a few potential problems: very needto solidify quickly The viscosity of the melted fats is lower – greater risk of drug particle sedimenting  non-uniform distribution which can give localized irritancy. This problem is partly compensated for in that these bases set very quickly. These bases become brittle if cooled too rapidly – should not be refrigerated during preparation. it will bebrittle Most manufacturers produce a series of grades of synthetic fatty bases, each with different hardness and melting point ranges. These can be used to compensate for melting point reduction by soluble drugs.  2. Water-soluble & water-miscible bases Main members : glycerinated gelatin (GG) and macrogols e.g. polyethylene glycols (PEG) macroyols polyethylene glycols GG : dissolving granular gelatin (20%) in glycerin (70%) and adding medication solution (10%) exclusively for laxative and vaginal suppositories slower to soften and mix with physiological fluidsprovides slower release have tendency to absorb moisture – hygroscopic, dehydrating effect and irritate tissues  Much more difficult to prepare and handle than other bases and the solution time depends on the content and quality of the gelatin and also the age of the supp. Because of the water content, microbial contamination is more likely than with the fatty bases. Preservatives may be added to the product but can lead to problems of incompatibilities.  PEG/Macrogols Polymers of ethylene oxide and water prepared to various chain lengths, MW and physical states Range of weights : 300, 400, 600, 1000, 1500, 1540, 3350, 4000, 6000 and 8000 300, 400, 600 clear colourless liquids, > 1000 wax-like white solids  PEG melting range MW Temp. (°C) 300 -15-(-18) 400 4-8 600 20-25 1000 37-40 1450 43-46 3350 54-58 4600 57-61 6000 56-63 8000 60-63  Various combination of these PEGs may be combined by fusion PEG suppositories do not melt at body temperature; they dissolve slowly in bodily fluids PEG suppositories that do not contain at least 20% water should be moistened before use May irritate if used in vaginal suppositories  3. Miscellaneous bases Chemical or physical mixtures of oleaginous and water- soluble/miscible materials Preformed emulsions (w/o), or capable of dispersing in aqueous liquids e.g polyoxyl 40 stearate  Displacement value (DV) of suppository bases Def: No. of parts by weight of the active ingredient that displaces one part by weight of the suppository base Arises from the difference in density of drugs used – same volume suppositories may have different weight E.g. displacement value of 3 (theobroma oil) means 3g drug will displace 1g base (theobroma oil) Weight of base required in final formulation must be substracted with amount displaced by all drugs contained within Preparation by moulding Melting the base Medication incorporation Pouring into moulds cooling Removal of formed suppositories  Moulds made from stainless steel, aluminium, brass or plastic Moulds are lubricated with mineral oil (e.g. liquid paraffin) to facilitate removal, especially with cocoa butter/theobroma or GG bases Moulds need to be calibrated – weight and volume It’s common to prepare extra suppositories (typically 2) to account for loses during preparation Metal moulds Plastic moulds  Size of suppositories Two nominal sizes of supps (1 g and 2 g) Important: daunts The nominal size refers to the weight of the supp base that would be required to fill a supp mould. It does not refer to the actual weight of the finished product.  use glass slab The supp base is melted and the drug incorporated into the base whilst it is molten. The molten mixture is allowed to cool and thicken slightly and is then poured (slight excess) into the supp mould and allowed to solidify, normally about 15 mins. EE The surface of the mould is trimmedmatigner to remove excess material. and Judging the time at which to pour the supps is the most difficult part in their manufacture.  very liquid Pouring too early will allow insoluble material to sediment to the Of bottom of the mould and will look unsightly. Pouring too late will result in the mixture congealing during the pouring action and therefore holes and bubbles may be seen in the final product The manufacturing process is very slightly different when solids or liquid are added. wait for a while not too early I too late  Addition of solid, insoluble drugs use glass slab The solid, insoluble drug should be reduced in size (triturated) to ensure that the final product is not gritty. The drug is then incorporated into a small portion of the molten base on an ointment tile (in the same way ointments are made) The drug-base mixture is the added back to the remainder of the molten base and mixed well. Finally, the supps are poured to the moulds. This additional step of incorporating the drug on a tile ensures complete distribution of the drug in the base and reduces sedimentation after pouring. Just add to the base Yes find  Addition of solid, soluble drugs easier as the drugs dissolve in the base In this case, the drug is added to the molten base and stirred well to ensure complete dissolution. The supps are then poured to the moulds  Addition of liquid drugs add drugs when the base is in molten stage In this case, the drug is added to the molten base and stirred well to ensure complete dispersion. When adding plant extracts (e.g. Strammonium Tincture BP), allow the molten base to cool slightly (but not set) before adding the extract. Stir well. They will eventually mix in.  Shelf life Provided they are well packaged and the storage temperature is low, supps and pessaries are relatively stable preps. Unless other information is available, an expiry date of 4 weeks is appropriate  Labelling Adequate information should appear on the label so that the patient knows how to use the product. In addition, the following info should appear: ‘Store in a cool place’ ‘For rectal use only’ or ‘For vaginal use only’ ‘Do not swallow’ can be put on the label BUT, do not use ‘For external use only’ – the preparation is being inserted into the body cavity and this instruction is therefore incorrect.  Packaging Nowadays, suppositories are prepared in disposable, sealable plastic suppository moulds (instead of the traditional metal moulds), with each mould containing 6 supps. Once the supp has been prepared, the full mould is sealed and then placed in a cardboard box for ease of carrying.  Example alert with the unit Rx value g displacement Resorcinol 75 mg (DV 1.5,each 1.5 g displaces 1 g base) Zinc oxide 150 mg (DV5.0, each 5 g displaces 1 g base) Bismuth subgallate 200 mg (DV 3.0,each 3 g displaces 1 g base) Cocoa butter/theobroma oil 2g mould Mitte 8. prepare 10 based on the mould  Calculate amount of ingredients for 8+2 suppositories = 10 Resorcinol 75 mg x 10 = 750 mg @ 0.75g Zinc oxide 150 mg x 10 = 1500 mg @ 1.5g Bi subgallate 200 mg x 10 = 2000 mg @ 2g Total drug amount = 0.75+1.5+2 = 4.25 g Remember the DVs!! eviriiniiiuiiiii.ino Resorcinol : 0.75/1.5 = 0.5 g base displaced ZnO : 1.5/5 = 0.3 g base displaced O Bi subgallate =a2/3 = 0.67 g base displaced Total base displaced = 0.5+0.3+0.67 = 1.47 g FIT  Amount of base required = (size [weight] of mould x no. of supp.)- total base displaced = (2 g x 10)- 1.47 g 20 -1.47 = 18.53 g coco butter/theobroma needed Each suppository will weigh : (total weight of drug + total weight of base) no. of supp. (18.53+4.25) g / 10 convert into g 2.28 g weigh for each suppository  Packaging Individual packs, either PVC or aluminium foil Important to protect against moisture and oxygen