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In the second half of 19 th century a scientific basis for rectal therapy was established.: Fig. HUMAN RECTUMPHISIOLOGY OF HUMAN RECTUM: : PHISIOLOGY OF HUMAN RECTUM: The human rectum is the terminal of GIT. It is 10 – 15 cm long slightly dilated part of the large intestine. In the resting position the rectum does not have any active motility. Normally the rectum is empty & contains 2-3 ml of inert mucus fluid. (pH 7-8), which is secreted by the goblet cells forming simple tubular glands in mucosal layer. This mucus has no enzymatic activity or buffering capacity. There are no villi or microvilli on the rectal mucosa & thus a very limited surface area (200 – 400 cm 2 ) is available for absorption. And this surface area is sufficient to absorb drug, Fig. PHISIOLOGY OF HUMAN RECTUM: Fig. PHISIOLOGY OF HUMAN RECTUMFATE OF DRUG IN RECTUM: : FATE OF DRUG IN RECTUM : Fate of drug absorbed from rectum is depends upon the position of it in the rectum. Both blood & lymphatic vessels are abundant in the sub mucosal region of rectal wall. Upper hemorrhoidal vein drains into the portal circulation, so the drug absorbed in the upper region will pass through the liver before entering the systemic circulation. While the lower & middle hamorrhoidal veins drain directly into the inferior venacava. So the drugs absorbed in the lower region of the rectum will directly enter into the systemic circulation.Advantages: : Advantages: The drug causing severe nausea & vomiting, the oral administration may cause emesis, so in such cases this route can be used. Irritation to stomach & small intestine associated with certain drug can be avoided. Hepatic first pass elimination of high clearance drug may be avoided, so prevention of drug from acidic & enzymatic degradation achieved. When oral intake is restricted, such as prior to x-ray studies or in patients having disease of upper GI tract or when patient is unable to swallow.: Useful in pediatric, geriatric & unconscious patients. Drug delivery can be stopped by removal of dosage form & drug absorption can be easily interrupted in cases of accidental overdose or suicide attempts. Drugs used traditionally are only given parentraly by making several combinations with absorption promoting additives. Disadvantages: Inconvenient for patients. The absorption of drugs is frequently irregular & difficult to predict.Factors affecting the absorption of drug from rectum: : Factors affecting the absorption of drug from rectum : 1) Physiological factors of drug- Colonic content- drug will have greater opportunity to get absorbed when the rectum is empty. For this purpose enema is given before rectal drug administration. Circulation route- if the drug is absorbed from lower hamorrhoidal veins it will directly take the drug to inferior venacava, so the absorption will be rapid and effective.@: @ pH and lack of buffering capacity of rectal fluids- the rectal fluid have pH7-8, hence no effective buffering capacity. So ionized or un-ionized form of the drugs will be having marked influence. 2) Physiochemical factors of drug- Lipid-water solubility – a lipophilic drug if given with fatty bases it will not escape from base easily. So absorption is altered. Particle size – the smaller the particle the greater will be the solubility. Nature of base- if the base interacts with the drug or if it irritates the mucus membrane it will decrease the absorption. Mainly in case of suppositories .: Different types of rectal dosage forms: In the rectal drug delivery system the following types of dosage forms are available. Rectal semisolids: 1) Creams 2) Gels 3) Ointments 4) Suppositories Rectal liquids : 1) Solutions 2) Suspensions Rectal aerosols@: @ Rectal semisolids : Rectal cream, gels and ointments- These preparations are used for topical application to the perianal area for insertion within the anal canal. They largely are used to treat local conditions of anorectal pruritis, inflammation and the pain and discomfort associated with hemorrhoids. The drugs includes astringents (eg. Zinc oxide), protectants and lubricants ( eg. Cocoa butter, lanolin), local anaestheics (eg. Pramoxine HCL), and antipruritis and anti inflammatory agents( eg. Hydrocortisone)@: @ The bases used in anorectal creams and ointments includes combinations of polyethylene glycol 300 & 3350 , emulsion cream bases using cetyl alcohol & cetyl esters wax , and white petroleum and mineral oil. The preservatives like methylparaben, propylparaben, benzlyacohol and butylated hydrocortisole (BHA) are also used. Several commercial rectal creams and ointments and gels - ANUSOL ointment - GLAXOSMITHKLINE ( starch) TRONOLANE cream - ROSS ( pramoxine HCL) ANALPRAM -HC cream DIASTAT Gel - AcuDial ( Diazepam )Fig. Rectal creams and ointments : Fig. Rectal creams and ointments@: @ APPLICATION - Before applying rectal ointments and cream the perianal skin and the affected area should be cleaned and dried. Special types of applicators are used for applications of creams & several market preparations are available with perforated applicator tips and inserters. Fig. rectal cream and ointment applicator@: @ Fig. rectal gel inserter Different graded applicators are available in market for application of rectal creams. Packaging: rectal ointments creams and gels are packed with special perforated plastic tips for products to be administered in to the anus.Rectal suppositories: : Rectal suppositories: Solid suppositories are the most common dosage form used for rectal drug administration and represent greater than 98% of all rectal dosage forms. Typically, these are torpedo-shaped dosage forms composed of fatty bases (low-melting) or water-soluble bases (dissolving) which vary in weight from 1 g (children) to 2.5 g (adult). Lipophilic drugs are usually incorporated into water-soluble bases while hydrophilic drugs are formulated into the fatty base suppositories.@: @ For suppositories made from fatty bases, melting should occur rapidly near body temperature (37°C). Ideally the resultant melt would readily flow to provide thin, broad coverage of the rectal tissue, thereby minimizing lag time effects due to slow release of the drug from the suppository base. Water-soluble suppositories should likewise readily dissolve at 37°C to facilitate drug release and subsequent absorption.Table 1 : Suppository bases : Table 1 : Suppository bases Vehicle Melting range (°C) Solidification point (°C) Fatty bases Witepsol 32-44 27-38 Cocoa butter 30-35 24 Hard butters 36-45 32-40 Estarinum 29-50 26-40 Suppocire 35-45 30-37 Agrasup A;H 35-40 — Water soluble Myrj 51 39-42 39 PEGa 38-49 38-42 Tween 61 35-49 —@: @ Several commercial suppository products: DULCOLAX - CIBA ( bisacodyl ) CANASA - AXAN SCANDIPHARM ( mesalamine ) NUMORPHAN - ENDO ( oxymorphane ) ANUSOL HC - WARNER_LAMBERT ( hydrocortisone ) PANADOL Fig. DIFFERENT TYPES OF SUPPOSITORIES Acetaminophen/ PCM Eucalyptol Insertion of suppositories : There are different types of suppository inserters are available in market. A typical suppository inserter is shown in the figure. Fig. SUPPOSITORY INSERTER : Insertion of suppositories : There are different types of suppository inserters are available in market. A typical suppository inserter is shown in the figure. Fig. SUPPOSITORY INSERTER Glycero-Gelatin Laxative@: @ PACKAGING: Packaging is done after lubrication with proper lubricant in aluminum foil or in other suitable material. And with indication [ STORE IN A COOL PLACE ] The use of gels, foams or ointments for rectal administration can afford advantages over liquid formulations because retention of the dosage form in the rectal cavity reduces patient compliance problems. Drug release with semisolid dosage forms is usually limited to local indications such as hemorrhoids and lower bowel inflammation (proctitis). Drug release and subsequent pharmacologic action is usually faster with semisolid formulations than with solid suppositories since a lag time is not required for melting or dissolution.@: @ Rectal liquids: Rectal suspensions, emulsions & solutions Solutions, suspensions, or retention enemas represent rectal dosage forms with very limited application, largely due to inconvenience of use and poor patient compliance. In many cases, these formulations are utilized to administer contrast media and imaging agents for lower GI roentgenography. Although drug absorption from solutions has been shown to exceed that from solid suppositories in some cases so this particular administration route is only infrequently employed. This dosage forms are mainly used as enemas Retention enema : For systemic or local effect this is used. The drugs like hydrocortisone (local effect) or aminophylline (systemic effect) etc are used in this dosage form. Evacuation enema: For cleansing of bowel this enemas are used. The agents are sodium phosphate and sodium biphosphate, glycerin and doccusate potassium and light mineral oil.Applicators or inserts for rectal liquids: Applicators or inserts for rectal liquids There are several types of applicators available as follow- Bubble insert, squeeze insert. Fig. Rectal liquid inserts Fig .Rectal solution of ASACOL@: @ RECTAL AEROSOLS: Rectal aerosols or foams- Rectal aerosol foam products are also accompanied by applicators to facilitate administration. The applicator is attached to the container and filled with a measured dose of product. Metered dose aerosols are available. The inserter is inserted in to the anus and the plunger is pushed to deliver the drug product.@: @ Several marketed rectal aerosols are like PROCTOFOAM HC ( Schwarz ), CORTIFOAM ( Alaven )etc. AREA OF INTREST : AREA OF INTREST CONTROLLED RELEASE VIA RECTAL ROUTE- Controlled-release formulations are designed to release the active agent in a sustained and controlled fashion. They have been the subject of considerable research but have yet to make a significant impact. Hydrogels have been shown in human clinical studies to provide an acceptable polymeric system for rate-controlled delivery of antipyrine and theophylline. Since the total acceptable size of a rectal formulation significantly exceeds the size possible for oral formulations, rectal administration for the purposes of controlled-release offers a significant advantage. A major limiting factor is, however, the need to incorporate controlling agents designed to regulate drug release which would significantly increase the total size of the dosage form.@: @ Since adult rectal dosage forms are acceptable up to 2.5 g, the total drug load which can be formulated in a rectal controlled-release formulation can be 2-3 times that possible in an oral formulation. For some therapeutic agents, this higher drug load can offer an advantage which is not achievable via the oral route. Development and marketing of rectal controlled-release formulations will, however, still be disadvantaged because of the perceived reluctance of patients to employ this route and problems of poor patient compliance. Only a limited number of therapeutic agents are currently marketed as rectal dosage forms. @ @REASEARCH ARTICLE:: REASEARCH ARTICLE: Rectal infusion of the model drug antipyrine with an osmotic delivery system L. G. J. De Leede 1 , A. G. De Boer 1 , D. D. Breimer 2 Article first published online: 13 JAN 2006 DOI: 10.1002/bdd.2510020205REASEARCH ARTICLE (cont.) :osmotically-powered rectal drug delivery system: REASEARCH ARTICLE (cont.) : o smotically-powered rectal drug delivery system An osmotically-powered rectal drug delivery system, was used for the rectal infusion of the model drug antipyrine. The system, which is slightly larger than a normal suppository, has a nominal pumping rate of 43 μl h − 1 over at least 30 h. Observations: Four healthy volunteers kept two such systems in their rectum for a sum total of 98 h. Saliva and plasma concentrations were determined at regular intervals and in all cases a very constant steady-state saliva and plasma concentration was reached and maintained. Defecation and reinsertion of the drug delivery system did not cause any irregularities in the concentration profile. The system was very well tolerated by the volunteers.Table 2 Rectal dosage forms marketed in the United States for systemic indications : Table 2 Rectal dosage forms marketed in the United States for systemic indications Therapeutic category and drug Drug load, solid (mg) Antihistamine Promethazine 12.5-50 Antimigraine Ergotamine 2 NSAID Aspirin 60-1200 Indomethacin 50 Analgesic Hydromorphone 3 Morphine 5-30 Opium 30-60 Oxymorphone 5 Acetaminophen 120-650@: @ Insomnia Pentobarbital 30-200 Chloral hydrate 325-650 Promethazine 12.5-50 Tranquilizer Chlorpromazine 25-100 Prochlorperazine 2.5-25 Bronchodilator Aminophylline 105 Antiemetic Thiethylperazine 10 Trimethobenzamide 100-200 Hyperkalemia Polystyrene sulfonate 1250b Portal-systemic encephalopathy Lactulose Variablec@: @ CONCLUSION In certain areas of the world, particularly some European countries and Japan, rectal dosage forms are somewhat more accepted by the patient population and, hence, development of rectal dosage forms has surpassed that in other countries. According to a survey in 1970, approximately 7.5% of all prescriptions in France were formulations intended for rectal administration. Even though a few countries may find rectal dosage forms more acceptable, these still represent a small area of the world-wide market share which can be assigned to rectal drug therapy.@: @ REFFRENCE: Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems, by Howard c. Ansel , Loyd v. Allen, Jr. Nicholas G. Popovich. 8 th edition Rectal drug delivery , Wikipedia. Encyclopedia of pharmaceutical technology ,3 rd edition By J. Howard Rytting Images from Google images.@: @ Thank you You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.