PharmSci2 Lecture B - Suppositories.pdf

Suppositories 1  Learning Objectives At the end of this lecture and the associated tutorial and assignment you should know and understand the nature, design, properties, formulation and methods for compounding of suppositories, their clinical use, and their advanta...

Suppositories 1  Learning Objectives At the end of this lecture and the associated tutorial and assignment you should know and understand the nature, design, properties, formulation and methods for compounding of suppositories, their clinical use, and their advantages and disadvantages. 2  Outline 1. Introduction to Suppositories and Pessaries 2. Rectal Drug Delivery 3. Vaginal Drug Delivery 4. Formulation and Compounding of Rectal Suppositories 5. Formulation and Compounding of Vaginal Suppositories (“Pessaries”) 3  Drug Delivery via Rectum or Vagina Dosage Forms: ▪ Rectal solution enemas ▪ Vaginal douches ▪ Ointments ▪ Creams ▪ Gels ▪ Aerosol foams ▪ Vaginal tablets ▪ Rectal suppositories and vaginal pessaries * Note: The content of this lecture regarding vaginal drug delivery and suppositories may not be relevant to patients who have had a vagina surgically constructed or modified (e.g., as part of a sex change). 4 1. Introduction to Suppositories and Pessaries A suppository is a medicinal preparation in solid form suitable for insertion into the rectum or vagina (or rarely, the urethra). Vaginal suppositories are also called “pessaries.” Urethral suppositories are also called “bougies.” Suppositories may be used for local or systemic effect. Suppositories usually have a “waxy” hydrophobic or hydrophilic base that melts or softens at body temperature, or slowly dissolves in body fluids Shape, size and weight depends upon site of insertion and age and size of patient. It must be large enough to be retained in body cavity but not too large and cause undue distention 5  Suppositories: Characteristics Rectal (suppositories): Bullet-shaped Adult: 2-3 cm long, approx. 2 g, 2.2-2.4 mL Child: 1-1.5 cm long, approx. 1 g, 1.1-1.2 mL Vaginal (“pessaries”): Ovoid, globular, conical, bullet- or rod-shaped Approx. 5 g, 5 mL Urethral (“bougies”): Pencil-shaped Male: 10-15 cm long, 4 g Female: 6-7.5 cm long, 2g 6  Rectal Suppositories and Vaginal Pessaries Image from: https://upload.wikimedia.org/wikipedia/commons/thumb/c/ceSuppositories_three_ different_ sizes_ 2.jpg/1280pxSuppositories_three_different_sizes_2.jpg 7  Applications of suppositories and pessaries Local, topical treatment of rectum or vagina is required but cream/foam is unsuitable Systemic therapy required, but drug is unsuitable for oral, parenteral or other topical delivery Patient is unable to use oral medication Very young or very old Unconscious Too weak to swallow Have gastrointestinal issue (vomiting/nausea, irritation) Mentally disturbed 8  Applications of suppositories and pessaries Cathartic laxatives (e.g. bisacodyl and glycerol) Local anaesthetics (e.g. benzocaine) Analgesics (e.g. paracetamol, morphine) Anti-inflammatories Anti-emetics and anti-nausea drugs Sedatives/tranquilisers Antihaemorrhoidals Hormones Antibacterials Antifungals Contraceptives 9  Advantages of suppositories and pessaries Ease of both professional-administration and self- administration Possible to remove or flush out if necessary Very useful for young children and the elderly Rapid, targeted delivery when systemic delivery is unsuitable Limits systemic exposure to the drug Partial avoidance of first pass intestinal and hepatic metabolism allowing > 30% of dose to reach systemic circulation unchanged Can be used to deliver large doses 10  Advantages of suppositories and pessaries (cont’d) Can be used in unconscious and disabled patients Can be used in infants and young children Avoidance of problems with oral administration, e.g. Taste or smell (esp. for children) Degradation of drug in stomach acid Nausea and vomiting Pre-surgical need to keep stomach empty 11  Disadvantages of suppositories and pessaries Absorption is slow vs. oral or IV Percentage absorption is variable and unpredictable Not suitable for narrow therapeutic range drugs Rectal suppository migrating upwards in rectum leading to first pass metabolism and erratic absorption Potential mucosal irritation Potential triggering of defecation and loss of product from rectum Diarrhoea and GI disease reducing absorption 12  Disadvantages of suppositories and pessaries (cont’d) Menstruation affecting vaginal absorption Leakage of melted product Aesthetics, patient embarrassment and reluctance May be difficult for arthritics to self-administer Cost of production (esp. if compounded specially) 13 2. Rectal Drug Delivery Image from: https://thumbs.dreamstime.com/z/insertion-suppository-24862463.jpg 14  How to insert a rectal suppository 1. Wash hands. 2. Put on rubber or vinyl gloves 3. Remove the suppository from its wrapping. 4. Moisten suppository if necessary. 5. Lie on left side with right knee pulled up towards chest. 6. Gently push the suppository (pointed end first) in just past the anal sphincter. 7. Lower the legs, roll over onto the stomach and remain still for a few minutes. 8. Resist the urge to expel the suppository or defecate. 9. Lie still and press the buttocks together to allow the suppository to melt or begin to dissolve in the rectum. 10. Remove and dispose of gloves. 11. Wash hands. 15 How to insert a rectal suppository Image from: https://img.memecdn.com/You-have-to-take-off-pants-completely_o_23930.jpg 16  Why lie on the left side?  Lying on left side Right Left  Standing Front view Image from https://www.cancer.gov/images/cdr/live/CDR739733.jpg Lying on right side 17 Insertion of a rectal suppository: Alternative standing method Image from: https://pharmlabs.unc.edu/labs/suppository/images/rectal_supp1.jpg 18  Anatomy of the rectum Image from: https://image.slidesharecdn.com/rectumanalcanaldr-170213132616/95/rectum-anal-canal-22-638.jpg?cb=1486992777 19  Physiology of the Rectum Terminal 15-20 cm of the large intestine Rectal mucosal fluids (1-3 ml) pH 6.8-7.5, almost neutral with no buffering capacity Small surface area (ca 300 cm2) Main blood supply via superior rectal artery Blood return via superior, middle and inferior haemorrhoidal veins Anorectal dynamics may change with age, trauma and disease/disorder (e.g. haemorrhoids, rectal prolapse) 20  Rectal blood circulation Portal vein Superior rectal vein drains into hepatic portal vein → “first pass hepatic metabolism” of drug Middle and inferior rectal veins connect directly into general systemic circulation → little “first pass hepatic metabolism” of drug Image from: http://ueu.co/wp-content/uploads/2014/09/loadBinaryCAUX3Q4T.jpg 21 Rectal suppository placement Too high OK Image from: https://thumbor.kenhub.com 22  Rectal drug absorption (Hydrophobic base suppository) melted suppository Drug very thin mucus layer Passive diffusion epithelial cells blood vessels Systemic circulation 23  Rectal drug absorption (Hydrophilic base suppository) mucous suppository dissolved suppository + mucus Drug Passive diffusion epithelial cells blood vessels Systemic circulation 24  Factors affecting rectal absorption Type of base Type of drug Solubility in vehicle (surfactant may be needed) Concentration Particle size ( 42°C, does not require refrigeration Will not support fungal growth Hygroscopic: absorbs water from mucosal membranes and may cause stinging, so wet with water before use Image from: https://previews.123rf.com/images/molekuul/molekuul1310/molekuul131000053/23255144-polyethylene-glycol-10-000-peg- polyethylene-oxide-peo-molecule-chemical-structure---linear-fragment--Stock-Photo.jpg 37  Hydrophilic Base: Glycogelatin Glycerin + Gelatin + Water (e.g. 70:20:10) Not used as much as cocoa butter and PEG bases Not as good as cocoa butter for many rectal suppositories but good for laxative suppositories Used for vaginal suppositories (e.g. local antimicrobials) Will support mould/bacterial growth, and may need to contain preservative Hygroscopic Absorbs water from mucosal membranes and may cause irritation/stinging, and may cause defecation Wet with water before use 38 Drug release rates from different bases Drug solubility Oily base Water-miscible base Oil >> Water Slow Moderate Water >> Oil Rapid Slow - Fast 39  Suppository Moulds Images from: https://upload.wikimedia.org/wikipedia/commons/thumb/a/a4/Suppository_ casting_mould_2.jpg/800px-Suppository_casting_mould_2.jpg https://www.totalpharmacysupply.com/media/catalog/product/cache/1/ image/9df78eab33525d08d6e5fb8d27136e95/7902.jpg https://cdn-a.william- reed.com/var/wrbm_gb_food_pharma/storage/images/7/2/7/1/1671727-5- eng-GB/ProbioTech-wants-probiotic-suppository-to-be-counted-as- 40 supplement.jpg 41  Suppositories compounded by UC Pharmacy students 2019 White = PEG blanks Yellow = cocoa butter blanks Green/blue = CuSO4 in cocoa butter 42  Examples of Suppositories Morphine sulphate slow-release analgesic suppository: Morphine sulphate 50 mg (active) Alginic acid 25% (slow-release agent) Cocoa butter base qs (base) Antiemetic suppository: Haloperidol 5 mg (active) Diphenhydramine hydrochloride 25 mg (active) Lorazepam 2 mg (active) Silicon dioxide 30 mg (suspending aid) Polyethylene glycol base qs (base) 43 Example of Complex Suppositories Compound Bismuth Subgallate Suppository BP (Use: deodorising flatulence) Ingredient: Amount: Bismuth subgallate 200 mg Resorcinol 60 mg Zinc oxide 120 mg Castor oil 60 mg Hard fat base qs 44  Formulating suppositories Suppositories have a fixed volume determined by the volume of the mould. Therefore, when formulating suppositories with >5% w/w drug we need to allow for the volume of base “displaced” by the drug and reduce the quantity of the base in the mixture accordingly (cf. powder filled capsules). Drug Suppository Base Base 45  Example Suppository mould = 4 mL Density of base = 1.25 g/mL Blank weighs 4 mL x 1.25 g/mL = 5.0 g Suppositories with 1.0 g drug weigh 5.5 g “blank” 5.0 g Drug 1.0 g Base = 5.5 -1.0 = 4.5 g (Drug + base = 5.5 g) “Displacement Value” (DV) Base 0.5 g = Drug (1.0 g) / Base displaced (0.5 g) = 2.0 (i.e., 2.0 g of drug displaces 1.0 g of base) 46  Formulating suppositories Drugs have a “displacement value” (DV) or “density factor” The “displacement value” (DV) (also called “density factor”) is the number of grams of the active ingredient that will displace 1 gram of base DV = Density of drug / density of cocoa butter DV’s listed in reference books usually refer to displacement of cocoa butter base which has density = 0.9 g/mL Examples of DVs: Substance: DV: Boric acid 1.5 Codeine phosphate 1.1 Hydrocortisone 1.5 Morphine HCl 1.6 Paracetamol 1.5 Phenobarbital 1.2 Zinc oxide 4.0 47  Displacement Values relative to PEG bases PEG bases have density = 1.09 g/mL (about 1.20 times the density of cocoa butter). Therefore, to calculate the DV of a drug relative to PEG a base, we divide its DV relative to cocoa butter by 1.2, For example: Displacement Value (DV) vs. Cocoa butter vs. PEG Boric acid 1.5 1.2 Codeine phosphate 1.1 0.9 Hydrocortisone 1.5 1.2 Morphine HCl 1.6 1.3 Paracetamol 1.5 1.2 Phenobarbital 1.2 1.0 Zinc oxide 4.0 3.3 48  Formulating Suppositories Drug Base Suppository Base Base displaced = weight of drug ÷ DV of drug If we know (1) the weight of base per blank (= volume x density) (2) the weight of drug per suppository, and (3) the DV of the drug we can easily calculate the amount of base the drug would displace and therefore the base remaining in the suppository. 49  Example of formulation of suppositories Formulate rectal suppository as follows: Suppository mould volume = 2.67 mL Use cocoa butter base with density = 0.90 g/mL Suppositories to contain 600 mg (0.6 g) Drug X with DV = 1.2 For 1 “blank” suppository without drug: base required 2.67 mL x 0.90 g/mL = 2.4 g For 1 suppository with drug: 0.60 g drug displaces base with weight = drug weight divided by DV = 0.6 ÷ 1.2 = 0.5 g of base Therefore, base required is weight of blank minus weight of displaced base = 2.4 g – 0.5 g = 1.9 g base Therefore: 1 suppository = 0.6 g Drug X + 1.9 g Base = 2.5 g (total weight) 50  Preparing cocoa butter suppositories 1. If necessary, prepare “blank” suppositories and determine weight and volume of specified base per mould cell. 2. Calculate quantities of active ingredient and base (allowing for volume of active if > 5%) needed to deliver prescribed drug dose per suppository. [Allow 2 suppositories “overage” to compensate for losses during preparation.] 3. Determine and measure out ingredients for required number of suppositories. [Allow a small overage (excess) to compensate for losses during production.] 51 Preparing cocoa butter suppositories (cont’d) 4. Gently melt required quantity of base. Do not overheat. 5. Incorporate other ingredients and mix well. [For large quantities of powder, it is helpful to moisten powder with a few drops of mineral oil before blending with melted base] 6. Lubricate mould, if required. 7. Pour stirred melt into mould quickly in one movement. Allow a slight overfill (to be trimmed off later) 8. Allow slow cooling and congealing (rapid cooling produces low melting point polymorphs of cocoa butter). 52 Preparing cocoa butter suppositories (cont’d) 9. Trim excess if required before suppositories have completely hardened. 10. Carefully remove suppositories from mould. Minimise handling with hands and fingers to prevent melting. 11. Wrap and put in container. 12. Label. 13. Dispense. 53 5. Formulation and Compounding of Vaginal Pessaries 54  Examples of Vaginal Pessaries Hormone replacement pessary: Progesterone 200 mg (active) Silicon dioxide (silica gel) 35 mg (suspending aid) Polyethylene glycol base qs (base) Antibiotic for vaginal vaginosis: Metronidazole 500 mg (active) Glycerinated gelatin base qs (base) 55  Example of formulation of vaginal pessaries Formulate pessaries as follows: Pessary mould volume = 4.0 mL Use glycerinated gelatin (glycogelatin) base with density = 1.20 g/mL Suppositories to contain 500 mg (0.50 g) metronidazole with DV = 1.7 For 1 “blank” pessary without drug: base required 4.0 mL x 1.20 g/mL = 4.80 g For 1 suppository with drug: 0.50 g drug displaces base with weight = drug weight divided by DV = 0.50 g ÷ 1.7 = 0.29 g of base Therefore, base required is weight of blank minus weight of displaced base = 4.80 g – 0.29 g = 4.51 g base Therefore: 1 pessary = 0.50 g Drug + 4.51 g Base 56  Packaging of Suppositories and Pessaries Image from: https://i.ytimg.com/vi/1oWfQM_wIMg/maxresdefault.jpg 57  Summary Suppositories and pessaries are solid dosage forms designed to deliver drugs to the rectum or vagina. Some suppositories are designed to deliver drugs locally and others are designed to deliver drugs systemically. Suppositories are useful where the patient cannot actively take medicines by mouth. Drug is contained in a hydrophilic or lipophilic base that melts or dissolves allowing the drug to diffuse into the tissues Rate of delivery depends upon physicochemical properties of the drug and the base Correct application is essential 58