Pharmaceutical Biopharmaceutics PDF

Drug Product Performance Parameters: 1- Minimum effective concentration (MEC): The minimum concentration of drug needed at the receptors to produce the desired pharmacologic effect. 2- Minimum toxic concentration (MTC): The drug concentration needed to just produce a toxic effect. 3- Onset time:...

Drug Product Performance Parameters: 1- Minimum effective concentration (MEC): The minimum concentration of drug needed at the receptors to produce the desired pharmacologic effect. 2- Minimum toxic concentration (MTC): The drug concentration needed to just produce a toxic effect. 3- Onset time: The time required for the drug to reach the MEC. - Duration of action: The difference between the onset time and the time for the drug to decline back to the MEC Poor biopharmaceutical properties may result in: a. Poor and variable bioavailability b. Difficulties in toxicological evaluation c. Difficulties with bioequivalence of formulations d. Multiple daily dosing e. The requirement for a non-conventional delivery system f. Long and costly development times g. High cost of good. The therapeutic window is the drug concentrations which are above the minimum effective concentration and below the maximum safe concentration. II. Biopharmaceutics study of GIT drug absorption The factors that influence the rate and extent of absorption depend upon the route of administration. The intravenous route offers direct access to the systemic circulation and the total dose administered via this route is available in the plasma for distribution into other body tissues and the site(s) of action of the drug. Other routes will require an absorption step before the drug reaches the systemic circulation. Factors affecting this absorption will depend on; the physiology of the administration site(s) and the membrane barriers present at those site(s) that the drug needs to cross in order to reach the systemic circulation. The oral route of delivery is by far the most popular, with over 80% of medicines being given by mouth, mainly because it is natural and convenient for the patient and because it is relatively easy to manufacture oral dosage forms. Oral dosage forms do not need to be sterilized, are compact, and can be produced cheaply in large quantities by automated machines. The gastrointestinal tract is complex. In order to gain an insight into the numerous factors that can potentially influence the rate and extent of drug absorption into the systemic circulation, a schematic illustration of the steps involved in the release and absorption of a drug from a tablet dosage form. The slowest step in this series, which is the rate limiting step, controls the overall rate and extent of appearance of intact drug in the systemic circulation. The rate-limiting step will vary from drug to drug. For a drug which has a very poor aqueous solubility, the rate at which it dissolves in the gastrointestinal fluids is often the slowest step and tow the bioavailability of that drug is said to be dissolution rate limited. In contrast, for a drug that has a high aqueous solubility, its dissolution will be rapid and the rate at which the drug crosses the gastrointestinal membrane may be the rate-limiting step termed permeability limited. Other potential rate-limiting steps include: 1. The rate of drug release from the dosage form (this can be by design, in the case of controlled-release dosage forms), 2. The rate at which the stomach empties the drug into the small intestine, 3. The rate at which the drug is metabolized by enzymes in the intestinal mucosal cells during its passage through them into the mesenteric blood vessels, 4. The rate of metabolism of drug during its initial passage through the liver, often termed the ‘first-pass’ effect. The main functions of small intestine are: 1) Digestion: the process of enzymatic digestion, which began in the stomach, is completed in the small intestine 2) Absorption: the small intestine is the region where most nutrients and other materials are absorbed. Drugs that are metabolized by the liver are degraded before they reach the systemic circulation; this is termed hepatic presystemic clearance or first-pass metabolism. Physiological factors that effect on the drug absorption: A.Transit of pharmaceuticals in the gastrointestinal tract In general, most dosage forms, when taken in an upright position, transit through the oesophagus quickly, usually in less than 15 seconds. Transit through the oesophagus is TI dependent upon both the dosage form and posture. It depends on the following 1) Gastric emptying. It can be defined as the time a dosage form takes to traverse the stomach. It also called gastric residence time, gastric emptying time or gastric emptying rate. Gastric emptying of pharmaceuticals is highly variable and is dependent on the dosage form and the fed/fasted state of the stomach. Normal gastric residence times usually range between 5 minutes and 2 hours, although much longer time ( over 12 house) have been recorded, particularly for large single dosage units. Many factors influence gastric emptying, as well as the type of dosage form and the presence of food. These include a. Posture b. The composition of the food c. The effect of drugs d. Disease state. In general, food, particularly fatty foods, delays gastric emptying and hence the absorption of drugs. Therefore, a drug is likely to reach the small intestine most rapidly if it is administered with water to a patient whose stomach is empty. 2) Small intestinal transit There are two main types of intestinal movement a. Propulsive b. Mixing. The propulsive movements primarily determine the intestinal transit rate and hence the residence time of the drug or dosage forms in the small intestine. As this is the main site of absorption in the gastrointestinal tract for most drugs, the small intestinal transit time is an important factor with respect to drug bioavailability. Small intestinal residence time is particularly important for: 1. Dosage forms that release their drug slowly (e.g. Controlled-, sustained- or prolonged-release systems) as they pass along the length of the GIT. 2. Enteric-coated dosage forms which release drug only when they reach the small intestine 3. Drugs that dissolve slowly in intestinal fluids 4. Drugs that are absorbed by intestinal carrier mediated transport systems 5. Drugs that are not absorbed well in the colon. Small intestinal transit is normally considered to be between 3 to 4 hours although both faster and slower transit has been measured. 6. In contrast to the stomach, the small intestine does not discriminate between solids and liquids, and hence between dosage forms, or between the fed and the fasted state. 3) Colonic transit The colonic transit of pharmaceuticals is prolonged and variable, and depends on the type of dosage form, diet, eating pattern, defecation pattern and frequency and disease state. Contractile activity in the colon can be divided into two main types: 1. Propulsive contractions or mass movements that are associated with the aboral (away from the mouth) movement of contents 2. Segmental or haustrat contractions that serve to mix the luminal contents and result in only small aboral movements. Colonic transit is characterized by short bursts of activity followed by long periods of stasis. Colonic transit can vary from anything between 2 and 48 hours. In most individuals, total transit times (i.e. mouth to anus) are between 12 and 36 hours however they can range from several hours to several days. B. Barriers to drug absorption some of the barriers to absorption that a drug may encounter once it is released from its dosage form and has dissolved into the gastrointestinal fluids. The requirement of the drugs to be absorbed from barrier includes: 1. Needs to remain in solution, 2. Not become bound to food or other material within the gastrointestinal tract 3. Not precipitate. 4. It needs to be chemically stable in order to withstand the PH of the gastrointestinal tract 5. It must be resistant to enzymatic degradation in the lumen After passing through the cellular barrier, the drug encounters the liver and all its metabolizing enzymes before it reaches the systemic circulation. Factors related with barrier of drug absorption include: A. Environment within the lumen The environment within the lumen of the gastrointestinal tract has a major effect on the rate and extent of drug absorption. It includes: (1) Gastrointestinal pH The pH of fluids varies considerably along the length of the gastrointestinal tract. The gastrointestinal pH may influence the absorption of drugs in a variety of ways. If the drug is a weak electrolyte, pH may influence the drug’s chemical stability in the lumen, its rate and extent of dissolution or its absorption characteristics. Chemical degradation due to pH-dependent hydrolysis can occur in the gastrointestinal tract. The result of this instability is incomplete bioavailability, as only a fraction of the administered dose reaches the systemic circulation in the form of intact drug. (2) Luminal enzymes Drugs that resemble nutrients, such as nucleotides and fatty acids, may also be susceptible to enzymatic degradation. The lipases may also affect the release of drugs from fat/oil-containing dosage forms. Drugs that are esters can also be susceptible to hydrolysis in the lumen. (3) Influence of food in the gastrointestinal tract The presence of food in the gastrointestinal tract can influence the rate and extent of absorption, either directly or indirectly via a range of mechanisms by: Complexation of drugs with components in the diet. Alteration of pH. Alteration of gastric emptying. Stimulation of gastrointestinal secretions.  Competition between food components and drugs for specialized absorption mechanisms. Increased viscosity of gastrointestinal contents. Food-induced changes in presystemic metabolism. Food-induced changes in blood flow, Drug-food interactions are often classified into five categories: those that cause reduced, delayed, increased or accelerated absorption, and those on which food has no effect. (4) Disease state and physiological disorders, Local diseases can cause alterations in gastric pH that can affect the stability, dissolution and/or absorption of the drug. Gastric surgery can cause drugs to exhibit differences in bioavailability from that in normal individuals. B. Mucus and the unstirred water layer, Before drugs can permeate across the epithelial surface the mucous layer and unstirred water layer need to be crossed. The mucus layer, whose thickness and turnover rates can vary along the length of the gastrointestinal tract, can hinder drug diffusion. Some drugs are capable of complexing with mucus, thereby reducing their availability for absorption. C. Gastrointestinal membrane The gastrointestinal membrane has a bilayer structure, There are two main mechanisms of drug transport across the gastrointestinal epithelium: transcellular (i.e. across the cells) and paracellular (i.e. between the cells). The transcellular pathway is further divided into simple passive diffusion, carrier mediated transport (active transport and facilitated diffusion) and endocytosis. - Passive diffusion This is the preferred route of transport for relatively small lipophilic molecules and thus many drugs. In this process, drug molecules pass across the lipoidal membrane via passive diffusion from a region of high concentration in the lumen to a region of lower concentration in the blood. - Carrier-mediated transport As already stated, the majority of drugs are absorbed across cells (i.e. transcellularly) via passive diffusion. However, certain compounds and many nutrients are absorbed transcellularly by a carrier-mediated transport mechanism of which there are two main types: Active transport and facilitated diffusion Facilitated transport - Active transport In contrast to passive diffusion, active transport involves it is the active participation by the apical cell membrane of the columnar absorption cells. A carrier or membrane transporter is responsible for binding a drug and transporting it across the membrane Active transport is a process whereby materials can be transported against a concentration gradient across a cell membrane, i.e. transport can occur from a region of lower concentration to one of higher concentration. Therefore, active transport is an energy consuming process. Active transport mechanisms: 1. Must have a carrier molecule 2. Must have a source of energy 3. Can be inhibited by metabolic inhibitors such as dinitrophenol 4. Show temperature dependence 5. Can be competitively inhibited by substrate analogues.Active transport also plays an important role in the intestinal, renal and biliary excretion of many drugs. - Facilitated diffusion or transport This carrier-mediated process differs from active transport in that it cannot transport a substance against a concentration gradient of that substance. Therefore, facilitated diffusion does not require an energy input but does require a concentration gradient for its driving force like passive diffusion - Endocytosis It is the process by which the plasma membrane of the cell invaginates and the invaginations become pinched off, forming small intracellular membrane-bound vesicles that enclose a volume of material. Thus, material can be transported into the cell. After invagination, the material is often transferred to other vesicles or lysosomes and digested. - Pinocytosis Fluid-phase endocytosis or pinocytosis is the engulfment of small droplets of extracellular fluid by membrane vesicles. The cell will internalize material regardless of its metabolic importance to that cell. The efficiency of this process is low. The fat-soluble vitamins A, D, E and K are absorbed via pinocytosis. - Receptor-mediated endocytosis Many cells within the body have receptors on their cell surfaces that are capable of binding with suitable ligands to form ligand-receptor complexes. These complexes cluster on the cell surface and then invaginate and break off from the membrane to form coated vesicles. The binding process between the ligand and the receptor on the cell surface is thought to trigger conformational change in the a membrane to allow this process to occur. - Phagocytosis It can be defined as the engulfment by the cell membrane of particles larger than 500 nm. This process is important for the absorption of polio and other vaccines from the gastrointestinal tract. - Transcytosis It is the process by which the material internalized by the membrane domain is transported through the cell and domain is transported secreted on the opposite side. - Paracellular pathway The paracellular pathway differs from all the other absorption pathways as it is the transport of materials in the aqueous pores between the cells rather than across them. The cells are joined together via closely fitting tight. junctions on their apical side. It is important for the transport of ions such as calcium and for the transport of sugars, amino acids and peptides at concentrations above the capacity of their carriers. - Efflux of drugs from the intestine Efflux proteins or transporters that expel specific drugs back into the lumen of the gastrointestinal tract after they have been absorbed can play a key role on the bioavailability of drugs. One of the key counter-transport proteins is P-glycoprotein. P-glycoprotein is expressed at high levels on the apical surface of columnar cells (brush border membrane) in the jejunum. D.Presystemic metabolism An oral dose of drug could be completely absorbed but incompletely available to the systemic circulation because microvillus of first-pass or presystemic metabolism by the gut wall and/or liver. - Physicochemical factors influencing bioavailability (1) Dissolution and solubility Solid drugs need to dissolve before they can be absorbed. The dissolution of drugs can be described by the Noyes-Whitney equation dm/dt = DA(Cs - C)/h ,n Where dm/dt is the rate of dissolution of the drug particles, D is the diffusion coefficient of the drug in solution in the gastrointestinal fluids, A is the effective surface area of the drug particles in contact with the gastrointestinal fluids, h is the thickness of the diffusion layer around each drug particle, Cs is the saturation solubility of the drug in solution in the diffusion layer, C is the concentration of the drug i in the gastrointestinal fluids. - Drug factors affecting dissolution rate Drug factors that can influence the dissolution rate include 1. The particle size 2. The wettability mildum 3. The solubility 4. The form of the drug (whether a salt or a free form)