Suppositories & Rectal/Vaginal/Urethral Preparations PDF

10. Suppositories and other rectal, vaginal and urethral preparations Dr Medha Joshi Professor and Chair Pharmaceutical Sciences Suppositories › Solid dosage form of various weights and shapes intended for use in the rectum, vagina or urethra › Contain active ingredient and base › Melt, soften or...

10. Suppositories and other rectal, vaginal and urethral preparations Dr Medha Joshi Professor and Chair Pharmaceutical Sciences Suppositories › Solid dosage form of various weights and shapes intended for use in the rectum, vagina or urethra › Contain active ingredient and base › Melt, soften or dissolve in the body cavity – Distributes medication to the tissues of the region  local or regional action – In addition to local delivery, mucous membranes of rectum and vagina permit absorption of many soluble drugs  systemic action Suppositories › Historically – Consisted of pieces of cloth, plants, wood or other material – Used plain or soaked in medication solution Suppositories › Some drawbacks – Strong feelings of aversion to use in certain countries › US, UK in particular – Considerable inter- and intra-subject variation in absorption – Problems with large scale manufacturing › Including creation of products with sufficiently long shelf-life › Not generally considered route of first choice Suppositories › Why do we still use this dosage form?  Safe and effective alternative to oral route  Can give sustained systemic and/or local drug delivery  Therapy can be interrupted at any point by removing the system  Use of novel polymers provides ability for controlled release  According to reference texts, “non-messy, non-staining, convenient” Enema › Liquid preparation administered rectally › Retention enemas › Evacuation enemas: – Remove feces when: › Patient is constipated or impacted › Patient is preparing for lower GI exam Other related dosage forms › Inserted into rectum or vagina for local or systemic action › Examples: – Ointments – Creams – Aerosol foams – Vaginal films Suppositories (and other rectal and vaginal delivery systems) › Useful for administering drugs to: – Infants – Small children – Severely debilitated patients – Severely nauseated or vomiting patients – Those who cannot (or will not) take medication orally – Those for whom the parenteral route might be unsuitable Suppositories (and other rectal and vaginal delivery systems) › Advantages › Disadvantages – Works for drugs that degrade – Poor patient acceptance and in the GIT compliance – May be able to avoid first-pass – Messy metabolism › Suppositories can leak › More on this later – Slow absorption compared to – Can administer large dose of IV or oral administration drug – Upward migration from site of – Can control duration of action rectal administration can to some extent increase first-pass metabolism Practice Question › Which of the following is an advantage of rectal administration? – LO 1 › a. Administration is comfortable and convenient › b. Provides consistent systemic drug absorption › c. Generally avoids first pass metabolism › d. b&c › e. All of the above Various sizes and shapes › Rectal suppositories – Conical or cylindrical – Tapered or pointed on one end (bullet or torpedo shaped) › Size – Length: 1 to 5 inches – Weight: 1 to 4 g (normally 2 g) – For infants and children, about half the weight and size Image by Papakuro, 2010 https://ja.wikipedia.org/wiki/%E3%83%95%E3%82%A1%E3%82%A4%E3%83%AB:Suppositories.jpg Various sizes and shapes › Vaginal suppositories – AKA pessaries – Globular, ovi-form, or cone-shaped – When compounded, same mold is used as for rectal suppositories  Various sizes and shapes › Top: vaginal suppository › Middle: adult rectal › Bottom: children’s rectal Image by Alcibiades, 2007 https://commons.wikimedia.org/wiki/File:Suppositories_three_different_sizes.jpg Various sizes and shapes › Urethral suppositories – AKA bougies – Not commonly used – Slender, pencil-shaped › Typically 3-6 mm in diameter › Vary in length by gender – Female: 25-70 mm – Male: 50-125 mm – When compounded, use thin, long mold, or oral dosing syringe Various sizes and shapes Rectal Route Rectal Route › Oral route is preferred route for administration of drugs › Not practical or feasible if patient: – Has nausea or vomiting – Has altered levels of consciousness (such as convulsions) – Is uncooperative – Has restricted oral intake Rectal Route - Physiology › The rectum is the last 15-20 cm of the large intestine. The anal canal is the last 4 to 5 cm of the rectum › Rectal epithelium: – Highly vascularized – Similar to upper GIT epithelium but no villi › Lower rectum: – Inferior and middle hemorrhoidal (or rectal) veins drain directly into systemic circulation › Upper rectum: – Superior hemorrhoidal or rectal vein drains directly into portal circulation Rectal Route - Physiology › Drugs absorbed from the lower rectum do not undergo first pass hepatic metabolism because lower and middle rectal veins drain into general circulation › Drugs absorbed from the upper rectum are carried directly to the liver – because superior rectal vein drains into hepatic portal vein – Undergo first pass metabolism if placed too high – Patients should be counseled not to place the delivery system too high in the rectum unless specifically directed to do so by the physician Drug Absorption - Rectum › Main mechanism of drug absorption from rectum: passive diffusion › Absorption is mainly dependent on: – MW of drug – Lipid solubility – Degree of ionization Drug Absorption - Rectum › pH of the rectal fluids and rectal contents can influence a drug’s absorption › Rectal pH in adults: – Roughly 7.2 – Varies depending on rectal contents – Independent of sex, age (after puberty) and nutrition – Limited buffer capacity – Considerably lower than in children (9.6±0.9) Drug Absorption - Rectum – Factors other than drug / dosage form can play a role › Large inter- and intra-subject variability in absorption – Also affected by: › Diarrhea › Disease states Drug Release from a Suppository – Simplified version of absorption process: 1. Suppository dissolves or melts onto the mucous layer 2. Drug diffuses out toward the rectal membranes 3. Drug is absorbed by passive diffusion Drug Release from a Suppository › How does the drug actually dissolve? – Volume of rectal fluid is very small (~3 mL) – Dissolution will be incomplete and require extra water – Where does the water come from? › Water is drawn out of rectal tissues by osmotic effect › Uncomfortable for patients Drug Release from a Suppository › How does the drug actually dissolve? – What happens to the suspended drugs? › If water insoluble, will have to separate from suppository under influence of gravity or motility movements › Then can start dissolving in the rectal fluid › Dissolution of slightly water-soluble drugs can be slowest step in absorption process Drug Release from a Suppository › Rectal wall may exert pressure on a suppository by two distinct mechanisms: 1. Abdominal organs may simply press on to the rectum, especially when person is upright › May stimulate spreading of drug onto rectal wall and promote absorption 2. Motility of rectal wall muscles › May originate from the normally occurring colonic motor complexes › Associated with presence of food residues in the colon Drug Stability › No esterase or peptidase activity in rectum (unlike upper part of GIT) or vagina › Greater stability for peptide-like drugs – Need to be formulated with absorption enhancers such as surfactants › Polyoxyethylene lauryl alcohol ether is most powerful › However, this and may other surfactants are irritating › Further research in this area is needed Vaginal Route Vaginal route › In general, the product is self administered › Mostly to achieve local effect, systemic effect is not common but research is going on Vaginal physiology › Fibromuscular tube, about 6-10 cm long (adult), extending from cervix › Mucosa is highly vascularized – Similar to buccal membrane – Thickness varies with age and hormonal activity – Usually covered with a thin film of vaginal fluids › pH: – Neutral or slightly basic before menarche and after menopause – 3.5-4.5 between menarche and menopause – Varies with menstrual cycle – Affected by infections and presence of semen Factors influencing absorption and drug administration › Ketoconazole: a dibasic compound, used in treatment of candida infections – pKa = 6.54 – At acidic pH, it is protonated (ionized)  cannot cross cell membranes  “trapped” in the vagina – If vaginal fluid pH increases to neutral or slightly basic (as in postmenopausal women)  un-ionized  able to cross membranes of the vagina – Problems if systemic absorption occurs 1. Lower local concentration (problem when you are treating a local condition) 2. Undesired systemic side effects Vaginal administration › Advantages  Can be used for local or systemic administration  Absorption not affected by GI disturbances  Venous drainage is not into the hepatic portal vein, No first pass effect  Convenience of self-administration of a delivery system that potentially releases drug for weeks  Ease of self-administration  Painless application  Discreet use  Can effectively deliver lower dose of hormone by this route Vaginal administration › Disadvantages – Systemic absorption of drugs can be erratic and unpredictable because thickness of vaginal epithelium and pH varies with age, hormonal activity, and menstrual cycle › May not want systemic effects › Examples: ketoconazole example from previous slide, estradiol when prescribed for local effects – Leakage or slipping out may occur › Soiled clothing or undergarments – Some patients are reluctant to use vaginal delivery systems Vaginal administration › Dosage forms delivered by this route: – Solids › Tablets › Suppositories (other names pessary, ovule and insert) › Films › Inserts (rings) – Semisolids › Foams › Ointments › Creams › Gels – Solutions Vaginal Tablets › Stable and less messy than ointments or creams › Intended to disintegrate within the vagina, releasing their contents – Generally contain: › Lactose as filler › Disintegrating agent (such as starch) › Dispersing agent (such as polyvinylpyrrolidone) › Tablet lubricant (such as magnesium stearate) › Easy to manufacture › Easy to insert Vaginal Suppositories › Stable and less messy than ointments or creams › Intended to dissolve or melt within the vagina, releasing their contents › Not as easy to manufacture as tablets › Easy to compound › Easy to insert Vaginal Films › Paper thin translucent film – Dissolve quickly – Local action › Most contain spermicide › Some other drugs being investigated (antibacterial agents) – Inclusion of mucoadhesives would keep in place for longer Vaginal Rings › Flexible circular shaped polymeric delivery systems – Roughly 5.5 cm in diameter – Non-irritating material – Commonly made of ethylene acetate copolymers, silicone, or poly(dimethylsiloxane) Vaginal Rings Vaginal Rings – Not messy to use – Release a predetermined amount of drug per day for an extended period › Polymer is non-biodegradable › Reservoir system: – Drug is located in the center core – Release rate occurs via diffusion through the polymeric membrane coat – Release can be modified by changing the thickness of the coat or the diameter of the core Vaginal Rings Vaginal Semisolids › Generally used to provide local action in the vagina – Delivery of: › Spermicides › Antibacterial drugs › Hormones › Drugs used for cervical ripening – Usually delivered with plastic applicator – Results in high local concentration of drug › Only maintained for short amount of time › More viscous products remain in place longer › Contact time with epithelial surface is increased if drug is formulated into bioadhesive or mucoadhesive gels Vaginal Semisolids › Messy to use › Can be uncomfortable to patient – Tend to leak instead of remaining in place › Vaginal foams: – Similar advantages / disadvantages as other semisolids – Contain propellants that help deliver the drug – Because of the pressure exerted by the propellant, the formulation that is released into the applicator fills the available space Dosage form design consideration for vaginal products › Product pH – Some products are formulated to match vaginal pH – pH is important factor for drug solubility and stability › Microbial presence – Products should be free of microorganisms, yeast and molds › Product attributes after administration – Retention › The product should be retained long enough for the drug to distribute adequately – Liquefaction › The product should disintegrate, dissolve or melt within a reasonable time – Distribution › The product should spread well throughout the vaginal cavity e.g. tablets spread least, foam and liquids spread the best – Leakages › The product should not leak too quickly or excessively. Mucoadhesive may help here. Practice Question › Which of the following dosage forms (select all that apply) can be administered vaginally A. Tablets B. Capsules C. Syrups D. Rings E. Films Formulation of Suppositories Formulation Characteristics › Formulation plays a very significant role in influencing drug absorption › Absorption of drug administered as an aqueous or alcoholic solution: – May occur very rapidly – Example: diazepam rectal solution › Absorption of a drug from a suppository: – Generally slower – Dependent on: › The nature of the suppository base › Presence of other additives › Physicochemical properties of the drug Formulation Characteristics › Formulated into different shapes and sizes – Generally weigh 1-4 g – Drug ranges from 0.1% - almost 40% – Also include: › Vehicle into which the drug is incorporated (the base) › Sometimes additional additives Suppository Bases Suppository bases › Play an important role in the release of medication › Should: – Be solid at room temperature – Melt or soften at body temperature, or dissolve in body fluids – Be stable on storage – Be non-irritating to mucous membranes – Be chemically and physiologically inert – Have melting range small enough to give rapid solidification after preparation › Prevents sedimentation of suspended, esp. high density, particles › Should not: – Bind to or interfere with the release and absorption of drug Suppository bases › Classes of base: – Fatty bases – Water-soluble bases › Choosing a base: – Requires much practical experience – Can only be partly guided by scientific data – General guidelines have been established Desired release rate Fatty base Water-soluble base Oil soluble drug Slow release rate* Moderate release rate Water soluble drug Rapid release rate Moderate release rate * Inclusion of surfactants / emulsifying agents can improve bioavailability in these cases Fatty or oleaginous bases In general › Have soothing, emollient action › Most used today are semi- or fully synthetic › Preferred for rectal suppositories – Less irritating to rectal tissues than other base types › Less commonly used for vaginal and urethral suppositories – No sphincter muscles to prevent leakage from these orifices – Oily material less desirable in these cases › Release drug after melting in the rectum In general › Drug must partition out of the base and dissolve – Sufficient aqueous media at site of action is necessary for this step to occur – Absorption can only occur after drug is in solution Cocoa butter (theobroma oil) › Mixture of liquid triglycerides entrapped in a network of crystalline, solid triglycerides › Soothing, emollient action › Melts quickly at body temperature – Softens at 30ºC and melts at 34ºC – Must store in refrigerator – Exhibits marked polymorphism  β form is most stable – Precaution: do NOT heat above 34ºC Cocoa butter (theobroma oil) › Fat-soluble drugs get trapped within the oil instead of mixing with the aqueous body fluids › Water-soluble drugs tend to be released quickly › May leak from the body orifice as it is immiscible with body fluids › Some drugs lower the melting point – Chloral hydrate, phenol – Add hardening agents like cetyl esters wax or white wax Cocoa butter (theobroma oil) › Not used much now due to disadvantages: – Polymorphism – Insufficient contraction on cooling to easily remove from mold (particularly in an industrial setting) – Low softening point – Chemical instability – Poor water-absorptive power – Price › Still occasionally used in a compounding setting Semi-synthetic fatty bases › Sometimes referred to as adeps solidus – Hard fat consisting of a mixture of: › Triglycerides › Diglycerides › Monoglycerides – Obtained either by natural fatty acid esterification with glycerol or by natural fats transesterification – Each type of hard fat is characterized by its: › Melting point › Hydroxyl value › Saponification value – Contain no additives  Semi-synthetic fatty bases › Comparison to cocoa butter – Semi-synthetic: most acids are saturated – Cocoa butter: contains considerable unsaturated oleic acid › Almost solely responsible for unique properties Melting Acid Hydroxyl Iodine Range Number Number Number (AN)* (HN)* (IN)* Cocoa 31-34ºC