Rectal Absorption

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Physicochemical, physiological and formulatory considerations in rectal absorption:

Physicochemical, physiological and formulatory considerations in rectal absorption

Presentation by Raghunadha sarma s.v.s M.Pharmacy Dept of pharmaceutical Technology Srinivasa Rao College of Pharmacy Visakhapatnam:

Presentation by Raghunadha sarma s.v.s M.Pharmacy Dept of pharmaceutical Technology Srinivasa Rao College of Pharmacy Visakhapatnam

INTRODUCTION:

INTRODUCTION What’s the need of Rectal Absorption? For any kind of ailment, the major route of drug administration is the oral route. The oral route is most commonly used and is most widely accepted among patients. But some cases need it otherwise.

INTRODUCTION:

INTRODUCTION The administration of drugs by routes other than the oral one has to be considered in several circumstances and for various reasons . Which arguably include: 1. THE PATIENT IS NOT ABLE TO MAKE USE OF THE ORAL ROUTE. 2.THE DRUG UNDER CONSIDERATION IS LESS SUITED FOR ORAL ADMINISTRATION.

INTRODUCTION:

INTRODUCTION 1. THE PATIENT IS NOT ABLE TO MAKE USE OF THE ORAL ROUTE. When, - the patient has a problem with their gastrointestinal tract , - is nauseous or - is postoperative (when they may be unconscious or not able to ingest a drug orally).

INTRODUCTION:

INTRODUCTION Furthermore, several categories of patients, i.e. the very young , the very old or the mentally disturbed , may more easily use the rectal than the oral route.

INTRODUCTION:

INTRODUCTION 2.THE DRUG UNDER CONSIDERATION IS LESS SUITED FOR ORAL ADMINISTRATION. This may be so in cases where, oral intake results in gastrointestinal side effects ; also, the drug may be insufficiently stable at the pH of the GI tract , or susceptible to enzymatic attack in the GI tract or during the first passage of the liver after absorption.

INTRODUCTION:

INTRODUCTION Also, drugs with an unacceptable taste can be administered rectally without this inconvenience to the patient. The formulation into suppositories of certain drugs that are candidates for abuse , has also been considered.

INTRODUCTION:

INTRODUCTION The rectal route also has several drawbacks . Slow and sometimes incomplete absorption . Considerable inter- and intrasubject variation . There are also problems with the large-scale production of suppositories. Problems with the achievement of a suitable shelf-life .

INTRODUCTION:

INTRODUCTION Rectal administration should certainly not be the route of first choice , but can be of great advantage to the patient in certain circumstances. The rectal route is used in many different therapies, intended either for local or for systemic effect.

INTRODUCTION:

INTRODUCTION Local effect is desired in the case of occurrence of haemorrhoids . Locally active drugs which are used include astringents, antiseptics, local anaesthetics , vasoconstrictors, anti-inflammatory compounds and soothing and protective agents. Also some laxatives fall into this category.

INTRODUCTION:

INTRODUCTION For the attainment of a systemic effect all orally given drugs can be used , bearing in mind the limitations discussed above. Antiasthmatic , antirheumatic and analgesic drugs are very much used for this purpose.

Anatomy and physiology of the rectum:

Anatomy and physiology of the rectum Anatomically the rectum is part of the colon, forming the last 150-200 mm of the GI Tract. The rectum can be subdivided into the anal canal and the ampulla , the latter forming approximately 80% of the organ.

Absorption of drugs from the rectum:

Absorption of drugs from the rectum

Anatomy and physiology of the rectum:

Anatomy and physiology of the rectum The rectum can be considered as a hollow organ with a relatively flat wall surface, without villi and with only three major folds , the rectal valves . The rectal wall is formed by an epithelium which is one cell layer thick .

Anatomy and physiology of the rectum:

Anatomy and physiology of the rectum The epithelium is composed of cylindrical cells and goblet cells which secrete mucus . The total volume of mucus is estimated as approximately 3 mL , spread over a total surface area of approximately 300 cm 2 .

Anatomy and physiology of the rectum:

Anatomy and physiology of the rectum The pH of the mucous layer is reported as approximately 7.5. Furthermore, there seems to be little buffer capacity.

Anatomy and physiology of the rectum:

Anatomy and physiology of the rectum Middle rectal vein tunica muscularis m. levator ani inferior rectal vein m. sphincter ani externus superior rectal vein Plexus venosus rectalis ( submucosus ) skin v. marginalis

Anatomy and physiology of the rectum:

Anatomy and physiology of the rectum As depicted in the diagram, the rectum has venous drainage comprised of, 3 veins, Muscular anal sphincter, Mucous layer.

Absorption of drugs from the rectum:

Absorption of drugs from the rectum Blood supply, especially venous drainage , is important for the understanding of drug absorption. There are three separate veins, lower haemorrhoidal vein middle haemorrhoidal vein upper haemorrhoidal vein

Absorption of drugs from the rectum:

Absorption of drugs from the rectum The lower and middle haemorrhoidal veins drain directly into the general circulation . The upper one drains into the portal vein , which flows to the liver .

Absorption of drugs from the rectum:

Absorption of drugs from the rectum

Absorption of drugs from the rectum:

Absorption of drugs from the rectum This means that, drug molecules can enter the general circulation directly or by passing through the strongly metabolizing liver.

Absorption of drugs from the rectum:

Absorption of drugs from the rectum In the former case, all drug molecules will enter the general circulation intact. In the latter case, only a proportion of the drug molecules (if they are of the high clearance type) will enter the general circulation intact. Because they are metabolised by Liver .

Absorption of drugs from the rectum:

Absorption of drugs from the rectum Thus the bioavailability may be less than100%. Recent investigations have shown that avoiding the first passage through the liver is possible . But the extent of this effect cannot be generalized, because it will depend on the actual part of the rectum through which the drug is absorbed .

Absorption of drugs from the rectum:

Absorption of drugs from the rectum The insertion of a suppository into the rectum results in a chain of effects leading to the bioavailability of the drug. The melting and spreading of base and consequent sedimentation of the drug molecules . And later the wetting and eventual dissolution of the drug particles.

Absorption of drugs from the rectum:

Absorption of drugs from the rectum

Absorption of drugs from the rectum:

Absorption of drugs from the rectum Depending on the character of its vehicle (see later) a suppository will either dissolve in the rectal fluid or melt on the mucous layer . Because the volume of rectal fluid is so small , dissolution of the complete vehicle will be difficult and require extra water.

Absorption of drugs from the rectum:

Absorption of drugs from the rectum Owing to osmotic effects (of the dissolving vehicle) water is attracted , with the unpleasant consequence of a painful sensation for the patient.

Absorption of drugs from the rectum:

Absorption of drugs from the rectum Independent of the vehicle type, drugs that are dissolved in the suppository will diffuse out towards the rectal membranes . Suspended drugs will first have to leave the vehicle (if it is water immiscible) under the influence of either gravity or motility movements, and can then start dissolving in the rectal fluid .

Absorption of drugs from the rectum:

Absorption of drugs from the rectum The dissolved drug molecules will have to diffuse through the mucous layer and then into and through the epithelium forming the rectal wall.

Absorption of drugs from the rectum:

Absorption of drugs from the rectum The process of absorption will be a passive diffusion process, as it is throughout the whole GI tract for almost all drugs. Active transport processes, as shown in the upper regions of the GI tract, have not been shown to be present in the rectal area.

Factors Affecting Rectal Absorption:

Factors Affecting Rectal Absorption The factors affecting drug absorption include, Physiological Factors Physicochemical Factors Formulatory Factors .

Physiological Factors Affecting Rectal Absorption:

Physiological Factors Affecting Rectal Absorption The physiological Factors include 1. Quantity of fluid available 2. Properties of rectal mucus 3. Contents of the rectum 4. Motility of the rectal wall

Physiological Factors Affecting Rectal Absorption:

Physiological Factors Affecting Rectal Absorption 1. Quantity of fluid available The quantity of fluid available for drug dissolution is very small (approximately 3 mL , spread in a layer approximately 100 um thick over the organ).

Physiological Factors Affecting Rectal Absorption:

Physiological Factors Affecting Rectal Absorption Only under non-physiological circumstances is this volume enlarged , e.g. by osmotic attraction by water-soluble vehicles or by diarrhoea . Thus the dissolution of slightly soluble substances , for example phenytoin , can easily be the slowest step in the absorptive process.

Physiological Factors Affecting Rectal Absorption:

Physiological Factors Affecting Rectal Absorption 2. Properties of rectal mucus The properties of the rectal fluid, such as composition, viscosity and surface tension , are essentially unknown and have to be estimated from data available for other parts of the GI tract. The rectal fluid is neutral in pH (7 – 8).

Physiological Factors Affecting Rectal Absorption:

Physiological Factors Affecting Rectal Absorption 3. Contents of the rectum The rectum is usually empty , except temporarily when faecal matter arrives from higher parts of the colon. This material is either expelled or transported back into the colon, depending on the voluntary control exhibited on the anal sphincter.

Physiological Factors Affecting Rectal Absorption:

Physiological Factors Affecting Rectal Absorption 4. Motility of the rectal wall The rectal wall may exert a pressure on a suppository present in the lumen by two distinct mechanisms. First, the abdominal organs may simply press on to the rectum , especially when the body is upright. This may stimulate spreading and thus promote absorption.

Physiological Factors Affecting Rectal Absorption:

Physiological Factors Affecting Rectal Absorption The second source of pressure is the motility of the muscles of the rectal wall, which may originate from the normally occurring colonic motor complexes. These are waves of contractions running over the wall of the colon in a caudal direction and are associated with the presence of food residues in the colon.

Physicochemical Factors Affecting Rectal Absorption:

Physicochemical Factors Affecting Rectal Absorption Physicochemical Factors include Drug Solubility Surface properties Particle size Amount of drug

Physicochemical Factors Affecting Rectal Absorption:

Physicochemical Factors Affecting Rectal Absorption 1. Drug Solubility The drug solubility in the vehicle is of particular interest from the biopharmaceutical point of view, as it directly determines the type of product, i.e. solution or suspension suppository. The drug solubility in the rectal fluid determines the maximum attainable concentration and thus the driving force for absorption.

Physicochemical Factors Affecting Rectal Absorption:

Physicochemical Factors Affecting Rectal Absorption Drug Solubility When a drug has a high vehicle to water partition coefficient it is likely to be in solution to an appreciable extent (or completely) in the vehicle. This means that the tendency to leave the vehicle will be small and so the release rate into the rectal fluid will be low. This is obviously unfavourable for rapid absorption.

Physicochemical Factors Affecting Rectal Absorption:

Physicochemical Factors Affecting Rectal Absorption Drug Solubility On the other hand, a certain lipid solubility is required for penetration through the rectal membranes. The optimal balance between these two requirements is usually found using the rules listed as followed.

Physicochemical Factors Affecting Rectal Absorption:

Physicochemical Factors Affecting Rectal Absorption

Physicochemical Factors Affecting Rectal Absorption:

Physicochemical Factors Affecting Rectal Absorption Drug Solubility This table assumes that the release from the dosage form is considered as the rate-limiting step. Thus the tendency to remain in the base should be lowered as much as possible (rules 1 and 2).

Physicochemical Factors Affecting Rectal Absorption:

Physicochemical Factors Affecting Rectal Absorption Drug Solubility When the solubility in fat and water are both low no definite rule can be given. It may well be that the dissolution rate will become the controlling step, and thus it seems advisable to use micronized drug particles.

Physicochemical Factors Affecting Rectal Absorption:

Physicochemical Factors Affecting Rectal Absorption Surface Properties The surface properties of drug particles are also important, as these particles will be transferred from one phase to another . This happens first when the drug is brought into contact with the vehicle and air has to be displaced from its surface.

Physicochemical Factors Affecting Rectal Absorption:

Physicochemical Factors Affecting Rectal Absorption Surface Properties When this is not achieved particles may form agglomerates. This adversely affects final content uniformity by creating an increased tendency to separate.

Physicochemical Factors Affecting Rectal Absorption:

Physicochemical Factors Affecting Rectal Absorption Surface Properties If wetting by the vehicle has taken place displacement by rectal fluid will be required to let the drug go into solution, which is the prerequisite for absorption. This is the underlying reason why people have tried the addition of surfactants to their formulation.

Physicochemical Factors Affecting Rectal Absorption:

Physicochemical Factors Affecting Rectal Absorption Particle Size The particle size of the drug is an important parameter, both technologically and biopharmaceutically . To prevent undue sedimentation during or after preparation the particle size should be limited .

Physicochemical Factors Affecting Rectal Absorption:

Physicochemical Factors Affecting Rectal Absorption Particle Size It is, of course, assumed that no agglomeration is taking place. The smaller the particles the less the possible mechanical irritation to the patient (esp . < 50 µ m ) and the higher the dissolution rate, and therefore drugs with a low water solubility will be dispensed in small, preferably micronized, particles.

Physicochemical Factors Affecting Rectal Absorption:

Physicochemical Factors Affecting Rectal Absorption Particle Size One should, however , be aware of the increased tendency of these particles to agglomerate as a result of strongly increased van der Waals forces in this case. Also, an unnecessary size reduction operation should be avoided if possible.

Physicochemical Factors Affecting Rectal Absorption:

Physicochemical Factors Affecting Rectal Absorption Particle Size There are good indications that size reduction is not a good decision for all drugs. It has been shown, especially for readily water-soluble drugs, that large particles give blood levels that are higher than or at least equivalent to small particles.

Physicochemical Factors Affecting Rectal Absorption:

Physicochemical Factors Affecting Rectal Absorption Particle Size This would lead to the suggestion to use particles in the size range 50-100 µm. The lower limit of 50 µ m to increase transport through the molten vehicle and the upper limit of 100 µm is a safe protection against undue sedimentation during preparation.

Physicochemical Factors Affecting Rectal Absorption:

Physicochemical Factors Affecting Rectal Absorption Particle Size It should also be borne in mind that the spreading suppository mass should drag the suspended particles along to maximize the absorption surface. For heavy compounds it has become clear that this is a problem.

Physicochemical Factors Affecting Rectal Absorption:

Physicochemical Factors Affecting Rectal Absorption Amount of drug A complicating factor is the amount of drug present in a suppository. If the number of particles increases, this would also increase the rate of agglomerates formation . This will depend very much on particle size and the presence of additives.

Physicochemical Factors Affecting Rectal Absorption:

Physicochemical Factors Affecting Rectal Absorption Amount of drug Another consequence of the presence of suspended particles is the increased viscosity of the molten base . Also in this case we have to rely largely on empirical data, rather than on theory .

Formulation Factors Affecting Rectal Absorption:

Formulation Factors Affecting Rectal Absorption The formulation factors involved in the rectal absorption are, Composition Melting behaviour Rheological properties

Formulation Factors Affecting Rectal Absorption:

Formulation Factors Affecting Rectal Absorption Composition A good suppository base should further be chemically and physically stable during storage as a bulk product , and after preparation into a suppository. It should have no incompatibility with drug molecules and should permit an optimal release of the drug it contains .

Formulation Factors Affecting Rectal Absorption:

Formulation Factors Affecting Rectal Absorption Melting behaviour A suppository should either melt after insertion in the body or dissolve in (and mix with) the available volume of rectal fluid. For fatty bases this means a melting range lower than approximately 37°C ( one must be aware of the fact that the body temperature might be as low as 36°C at night ).

Formulation Factors Affecting Rectal Absorption:

Formulation Factors Affecting Rectal Absorption Melting behaviour The melting range should be small enough to give rapid solidification after preparation, thereby preventing the separation of suspended, especially high-density, drug particles and agglomeration. When the solidification rate is high this may result in fissures, especially when rapid cooling is applied.

Formulation Factors Affecting Rectal Absorption:

Formulation Factors Affecting Rectal Absorption Melting behaviour On the other hand, the melting range should be large enough to permit easy preparation , which on an industrial scale may take a considerable length of time.

Formulation Factors Affecting Rectal Absorption:

Formulation Factors Affecting Rectal Absorption Rheological Properties During solidification a suppository should exhibit enough volume contraction to permit removal from the mould or plastic former. The viscosity of the molten base plays an important role both from a technological and from a biopharmaceutical point of view.

Formulation Factors Affecting Rectal Absorption:

Formulation Factors Affecting Rectal Absorption Rheological Properties During preparation the viscosity determines the flow into the moulds , but also the separation of drug particles. During and after melting in the rectal cavity the suppository mass is forced to spread over the absorbing surface, the rate of which may be determined partly by its viscosity.

Formulation Factors Affecting Rectal Absorption:

Formulation Factors Affecting Rectal Absorption Rheological Properties Drug particles that have to be transported through the base to the interface with the rectal fluid, and have to pass this interface to be released. Hence viscosity is a determining factor in their journey.

CONCLUSION:

CONCLUSION Over the years man has been suffering from different kinds of ailments. It is necessary not only to develop new drugs but also to optimize the different routes of administration so as to increase the effectiveness and minimize the adverse effects. Of all the routes of administration the oral route is most widely used and has better acceptance among the patients.

CONCLUSION:

CONCLUSION Where in the cases the oral route has its own drawbacks, the alternative routes of administration gain their importance. In this way rectal route is important particularly in case of the very young and very elderly patients.

ACKNOWLEDGEMENT:

A CKNOWLEDGEMENT Special Thanks to Prof .Dr. M.B.Venkatapathi Raju Sir,Principal,SRCP . Prof : G.Sudhakar sir , Vice principal,SRCP . Prof .Dr. R. Santosh Kumar sir , H.O.D,SRCP. My Teachers and other faculty members and non teaching staff,SRCP . Finally to Srinivasa Rao College of Pharmacy Management

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