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Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of Pharmaceutics KLE University’s College of Pharmacy BELGAUm – 590010, Karnataka, India Cell.

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Presentation on theme: "Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of Pharmaceutics KLE University’s College of Pharmacy BELGAUm – 590010, Karnataka, India Cell."— Presentation transcript:

1 Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of Pharmaceutics KLE University’s College of Pharmacy BELGAUm – 590010, Karnataka, India Cell No: 00919742431000 E-mail: bknanjwade@yahoo.co.in 08/10/20101KLECOP, Nipani

2 CONTENTS Introduction of absorption. Introduction of absorption. Structure of the Cell Membrane. Structure of the Cell Membrane. Gastro intestinal absorption of drugs. Gastro intestinal absorption of drugs. Mechanism of Drug absorption. Mechanism of Drug absorption. Factors affecting drug absorption Factors affecting drug absorption Absorption of drugs from non-per oral routes Absorption of drugs from non-per oral routes Methods of determining absorption Methods of determining absorption References. References. 08/10/20102KLECOP, Nipani

3 Introduction of Absorption Definition : Definition : The process of movement of unchanged drug from the site of administration to systemic circulation.  There always exist a correlation between the plasma concentration of a drug & the therapeutic response & thus, absorption can also be defined as the process of movement of unchanged drug from the site of administration to the site of measurement. i.e., plasma. i.e., plasma. 08/10/20103KLECOP, Nipani

4 Minimum effective conc. Therapeutic success of a rapidly & completely absorbed drug. Therapeutic failure of a slowly absorbed drug. Subtherapeutic level Time Plasma Drug Conc.  Not only the magnitude of drug that comes into the systemic circulation but also the rate at which it is absorbed is important this is clear from the figure. 08/10/20104KLECOP, Nipani

5 08/10/20105KLECOP, Nipani

6 CELL MEMBRANE  Also called the plasma membrane, plasmalemma or phospholipid bilayer.  The plasma membrane is a flexible yet sturdy barrier that surrounds & contains the cytoplasm of a cell.  Cell membrane mainly consists of: 1. Lipid bilayer- 1. Lipid bilayer--phospholipid-Cholesterol-Glycolipids. 2. Proitens- -Integral membrane proteins -Lipid anchored proteins -Peripheral Proteins 08/10/20106KLECOP, Nipani

7 LIPID BILAYER 08/10/20107KLECOP, Nipani

8 LIPID BILAYER The basic structural framework of the plasma membrane is the lipid bilayer. The basic structural framework of the plasma membrane is the lipid bilayer. Consists primarily of a thin layer of amphipathic phospholipids which spontaneously arrange so that the hydrophobic “tail” regions are shielded from the surrounding polar fluid, causing the more hydrophilic “head” regions to associate with the cytosolic & extracellular faces of the resulting bilayer. Consists primarily of a thin layer of amphipathic phospholipids which spontaneously arrange so that the hydrophobic “tail” regions are shielded from the surrounding polar fluid, causing the more hydrophilic “head” regions to associate with the cytosolic & extracellular faces of the resulting bilayer. This forms a continuous, spherical lipid bilayer app. 7nm thick. This forms a continuous, spherical lipid bilayer app. 7nm thick. 08/10/20108KLECOP, Nipani

9 It consists of two back to back layers made up of three types: Phospholipid, Cholesterol, Glycolipids. It consists of two back to back layers made up of three types: Phospholipid, Cholesterol, Glycolipids. 1)Phospholipids :  Principal type of lipid in membrane about 75 %. Contains polar and non polar region.  Polar region is hydrophilic and non polar region is hydrophobic. Non polar head contain two fatty acid chain.  One chain is straight fatty acid chain.( Saturated ) Another tail have cis double bond and have kink in tail. ( Unsaturated ) 08/10/20109KLECOP, Nipani

10 CHOLESTEROL Amount in membrane is 20 %. Amount in membrane is 20 %. Insert in membrane with same orientation as phospholipids molecules. Insert in membrane with same orientation as phospholipids molecules. Polar head of cholesterol is aligned with polar head of phospholipids. Polar head of cholesterol is aligned with polar head of phospholipids.  FUNCTION: Immobilize first few hydrocarbons groups Immobilize first few hydrocarbons groups phospholipids molecules. phospholipids molecules. Prevents crystallization of hydrocarbons & Prevents crystallization of hydrocarbons & phase shift in membrane phase shift in membrane 08/10/201010KLECOP, Nipani

11 OH 08/10/201011KLECOP, Nipani

12 08/10/201012KLECOP, Nipani

13 GLYCOLIPIDS Another component of membrane lipids present about 5 %. Another component of membrane lipids present about 5 %. Carbohydrate groups form polar “head”. Carbohydrate groups form polar “head”. Fatty acids “tails” are non polar. Fatty acids “tails” are non polar. Present in membrane layer that faces the extracellular fluid. Present in membrane layer that faces the extracellular fluid. This is one reason due to which bilayer is asymmetric. This is one reason due to which bilayer is asymmetric. FUNCTIONS: FUNCTIONS: Protective Protective Insulator Insulator Site of receptor binding Site of receptor binding 08/10/201013KLECOP, Nipani

14 08/10/201014KLECOP, Nipani

15 COMPOSITION OF PROTEINS COMPOSITION OF PROTEINS PROTEINS INTEGRAL PROTEINS LIPID ANCHORED PROTEINS PERIPHERAL PROTEINS 08/10/201015KLECOP, Nipani

16 INTEGRAL PROTEINS Also known as “Transmembrane protein”. Also known as “Transmembrane protein”. Have hydrophilic and hydrophobic domain. Have hydrophilic and hydrophobic domain. Hydrophobic domain anchore within the cell membrane and hydrophilic domain interacts with external molecules. Hydrophobic domain anchore within the cell membrane and hydrophilic domain interacts with external molecules. Hydrophobic domain consists of one, multiple or combination of α – helices and ß – sheets protein mofits. Hydrophobic domain consists of one, multiple or combination of α – helices and ß – sheets protein mofits. Ex. – Ion Channels, Proton pump, GPCR. Ex. – Ion Channels, Proton pump, GPCR. 08/10/201016KLECOP, Nipani

17 LIPID ANCHORED PROTEIN Covalently bound to single or multiple lipid molecules. Covalently bound to single or multiple lipid molecules. Hydrophobically inert into cell membrane & anchor the protein. Hydrophobically inert into cell membrane & anchor the protein. The protein itself is not in contact with membrane. The protein itself is not in contact with membrane. Ex. – G Proteins. Ex. – G Proteins. 08/10/201017KLECOP, Nipani

18 PERIPHERAL PROTEINS Attached to integral membrane proteins OR associated with peripheral regions of lipid bilayer. Attached to integral membrane proteins OR associated with peripheral regions of lipid bilayer. Have only temporary interaction with biological membrane. Have only temporary interaction with biological membrane. Once reacted with molecule, dissociates to carry on its work in cytoplasm. Once reacted with molecule, dissociates to carry on its work in cytoplasm. Ex. – Some Enzyme, Some Hormone Ex. – Some Enzyme, Some Hormone 08/10/201018KLECOP, Nipani

19 GASTRO INTESTINAL ABSORPTION OF DRUGS GASTRO INTESTINAL ABSORPTION OF DRUGS 08/10/201019KLECOP, Nipani

20  Stomach :  The surface area for absorption of drugs is relatively small in the stomach due to the absence of macrovilli & microvilli.  Extent of drug absorption is affected by variation in the time it takes the stomach to empty, i.e., how long the dosage form is able to reside in stomach.  Drugs which are acid labile must not be in contact with the acidic environment of the stomach.  Stomach emptying applies more to the solid dosage forms because the drug has to dissolve in the GI fluid before it is available for absorption.  Since solubility & dissolution rate of most drugs is a function of pH, it follows that, a delivery system carrying a drug that is predominantly absorbed from the stomach, must stay in the stomach for an extended period of time in order to assure maximum dissolution & therefore to extent of absorption. 08/10/201020KLECOP, Nipani

21  Small Intestine :  The drugs which are predominantly absorbed through the small intestine, the transit time of a dosage form is the major determinant of extent of absorption.  Various studies to determine transit time:  Early studies using indirect methods placed the average normal transit time through the small intestine at about 7 hours.  These studies were based on the detection of hydrogen after an oral dose of lactulose. (Fermentation of lactulose by colon bacteria yields hydrogen in the breath). 08/10/201021KLECOP, Nipani

22  Newer studies suggest the transit time to be about 3 to 4 hours.  Use gamma scintigraphy.  Thus, if the transit time in small intestine for most healthy adults is between 3 to 4 hours, a drug may take about 4 to 8 hours to pass through the stomach & small intestine during fasting state.  During the fed state, the small intestine transit time may take about 8 to 12 hours. 08/10/201022KLECOP, Nipani Small Intestine :

23  Large intestine :  The major function of large intestine is to absorb water from ingestible food residues which are delivered to the large intestine in a fluid state, & eliminate them from the body as semi solid feces.  Only a few drugs are absorbed in this region. 08/10/201023KLECOP, Nipani

24 MECHANISM OF DRUG ABSORPTION 1)Passive diffusion 2)Pore transport 3)Carrier- mediated transport a) Facilitated diffusion a) Facilitated diffusion b) Active transport b) Active transport 4)Ionic or Electrochemical diffusion 5)Ion-pair transport 6)Endocytosis 08/10/201024KLECOP, Nipani

25 1)PASSIVE DIFFUSION Also known as non-ionic diffusion. Also known as non-ionic diffusion. It is defined as the difference in the drug concentration on either side of the membrane. It is defined as the difference in the drug concentration on either side of the membrane. Absorption of 90% of drugs. Absorption of 90% of drugs. The driving force for this process is the concentration or electrochemical gradient. The driving force for this process is the concentration or electrochemical gradient. 08/10/201025KLECOP, Nipani

26 Passive diffusion is best expressed by Fick’s first law of diffusion which states that the drug molecules diffuse from a region of higher concentration to one of lower concentration until equilibrium is attained & the rate of diffusion is directly proportional to the concentration gradient across the membrane. Passive diffusion is best expressed by Fick’s first law of diffusion which states that the drug molecules diffuse from a region of higher concentration to one of lower concentration until equilibrium is attained & the rate of diffusion is directly proportional to the concentration gradient across the membrane. = D A K m/w (C GIT – C) dt h dQ = D A K m/w (C GIT – C) dt h  Certain characteristic of passive diffusion can be generalized. a)Down hill transport 08/10/201026KLECOP, Nipani

27 b)Greater the surface area & lesser the thickness of the membrane, faster the diffusion. c)Equilibrium is attained when the concentration on either side of the membrane become equal. d)Greater the membrane/ water partition coefficient of drug, faster the absorption.  Passive diffusion process is energy independent but depends more or less on the square root of the molecular size of the drugs.  The mol. Wt. of the most drugs lie between 100 to 400 Daltons which can be effectively absorbed passively. 08/10/201027KLECOP, Nipani

28 2)Pore transport Also known as convective transport, bulk flow or filtration. Also known as convective transport, bulk flow or filtration. Important in the absorption of low mol. Wt. (less than 100). Low molecular size (smaller than the diameter of the pore) & generally water-soluble drugs through narrow, aqueous filled channels or pores in the membrane structure. Important in the absorption of low mol. Wt. (less than 100). Low molecular size (smaller than the diameter of the pore) & generally water-soluble drugs through narrow, aqueous filled channels or pores in the membrane structure. e.g. urea, water & sugars. e.g. urea, water & sugars.  The driving force for the passage of the drugs is the hydrostatic or the osmotic pressure difference across the membrane. 08/10/201028KLECOP, Nipani

29 The rate of absorption via pore transport depends on the number & size of the pores, & given as follows: The rate of absorption via pore transport depends on the number & size of the pores, & given as follows: dc = N. R 2. A. ∆C dt(η) (h) where, dc = rate of the absorption. dc = rate of the absorption.dt N = number of pores R = radius of pores ∆C = concentration gradient η = viscosity of fluid in the pores 08/10/201029KLECOP, Nipani

30 3)CARRIER MEDIATED TRANSPORT MECHANISM Involves a carrier (a component of the membrane) which binds reversibly with the solute molecules to be transported to yield the carrier solute complex which transverses across the membrane to the other side where it dissociates to yield the solute molecule Involves a carrier (a component of the membrane) which binds reversibly with the solute molecules to be transported to yield the carrier solute complex which transverses across the membrane to the other side where it dissociates to yield the solute molecule The carrier then returns to its original site to accept a fresh molecule of solute. The carrier then returns to its original site to accept a fresh molecule of solute. There are two types of carrier mediated transport system: There are two types of carrier mediated transport system: a) facilitated diffusion a) facilitated diffusion b) active transport b) active transport 08/10/201030KLECOP, Nipani

31 a) Facilitated diffusion This mechanism involves the driving force is concentration gradient. This mechanism involves the driving force is concentration gradient. In this system, no expenditure of energy is involved (down-hill transport), therefore the process is not inhibited by metabolic poisons that interfere with energy production. In this system, no expenditure of energy is involved (down-hill transport), therefore the process is not inhibited by metabolic poisons that interfere with energy production. 08/10/201031KLECOP, Nipani

32 Limited importance in the absorption of drugs. Limited importance in the absorption of drugs. e.g. Such a transport system include entry of glucose into RBCs & intestinal absorption of vitamins B 1 & B 2. e.g. Such a transport system include entry of glucose into RBCs & intestinal absorption of vitamins B 1 & B 2.  A classical example of passive facilitated diffusion is the gastro-intestinal absorption of vitamin B 12.  An intrinsic factor (IF), a glycoprotein produced by the gastric parietal cells, forms a complex with vitamin B 12 which is then transported across the intestinal membrane by a carrier system. 08/10/201032KLECOP, Nipani

33 b) Active transport More important process than facilitated diffusion. More important process than facilitated diffusion. The driving force is against the concentration gradient or uphill transport. The driving force is against the concentration gradient or uphill transport. Since the process is uphill, energy is required in the work done by the barrier. Since the process is uphill, energy is required in the work done by the barrier. As the process requires expenditure of energy, it can be inhibited by metabolic poisons that interfere with energy production. As the process requires expenditure of energy, it can be inhibited by metabolic poisons that interfere with energy production. 08/10/201033KLECOP, Nipani

34 If drugs (especially used in cancer) have structural similarities to such agents, they are absorbed actively. If drugs (especially used in cancer) have structural similarities to such agents, they are absorbed actively. A good example of competitive inhibition of drug absorption via active transport is the impaired absorption of levodopa when ingested with meals rich in proteins. A good example of competitive inhibition of drug absorption via active transport is the impaired absorption of levodopa when ingested with meals rich in proteins. The rate of absorption by active transport can be determined by applying the equation used for Michalies-menten kinetics: The rate of absorption by active transport can be determined by applying the equation used for Michalies-menten kinetics: dc = [C].(dc/dt) max dt Km + [C] dt Km + [C]Where, (dc/dt) max = maximal rate of drug absorption at high drug concentration. [C] = concentration of drug available for absorption Km = affinity constant of drug for the barrier. 08/10/201034KLECOP, Nipani

35 4)IONIC OR ELECTROCHEMICAL DIFFUSION This charge influences the permeation of drugs. This charge influences the permeation of drugs. Molecular forms of solutes are unaffected by the membrane charge & permeate faster than ionic forms. Molecular forms of solutes are unaffected by the membrane charge & permeate faster than ionic forms. The permeation of anions & cations is also influenced by pH. The permeation of anions & cations is also influenced by pH. Thus, at a given pH, the rate of permeation may be as follows: Thus, at a given pH, the rate of permeation may be as follows: Unionized molecule > anions > cations Unionized molecule > anions > cations 08/10/201035KLECOP, Nipani

36 The permeation of ionized drugs, particularly the cationic drugs, depend on the potential difference or electrical gradient as the driving force across the membrane. The permeation of ionized drugs, particularly the cationic drugs, depend on the potential difference or electrical gradient as the driving force across the membrane. Once inside the membrane, the cations are attached to negatively charged intracellular membrane, thus giving rise to an electrical gradient. Once inside the membrane, the cations are attached to negatively charged intracellular membrane, thus giving rise to an electrical gradient. If the same drug is moving from a higher to lower concentration, i.e., moving down the electrical gradient, the phenomenon is known as electrochemical diffusion. If the same drug is moving from a higher to lower concentration, i.e., moving down the electrical gradient, the phenomenon is known as electrochemical diffusion. 08/10/201036KLECOP, Nipani

37 5)ION PAIR TRANSPORT It is another mechanism is able to explain the absorption of such drugs which ionize at all pH condition. It is another mechanism is able to explain the absorption of such drugs which ionize at all pH condition. 08/10/201037KLECOP, Nipani

38 Transport of charged molecules due to the formation of a neutral complex with another charged molecule carrying an opposite charge. Transport of charged molecules due to the formation of a neutral complex with another charged molecule carrying an opposite charge. Drugs have low o/w partition coefficient values, yet these penetrate the membrane by forming reversible neutral complexes with endogenous ions. Drugs have low o/w partition coefficient values, yet these penetrate the membrane by forming reversible neutral complexes with endogenous ions. e.g. mucin of GIT. Such neutral complexes have both the required lipophilicity as well as aqueous solubility for passive diffusion. Such neutral complexes have both the required lipophilicity as well as aqueous solubility for passive diffusion. This phenomenon is known as ion-pair transport. This phenomenon is known as ion-pair transport. 08/10/201038KLECOP, Nipani

39 6)ENDOCYTOSIS It involves engulfing extracellular materials within a segment of the cell membrane to form a saccule or a vesicle (hence also called as corpuscular or vesicular transport) which is then pinched off intracellularly. It involves engulfing extracellular materials within a segment of the cell membrane to form a saccule or a vesicle (hence also called as corpuscular or vesicular transport) which is then pinched off intracellularly. 08/10/201039KLECOP, Nipani

40 In endocytosis, there are three process: In endocytosis, there are three process: A) Phagocytosis B) Pinocytosis C) Transcytosis 08/10/201040KLECOP, Nipani

41 A) Phagocytosis 08/10/201041KLECOP, Nipani

42 B) Pinocytosis This process is important in the absorption of oil soluble vitamins & in the uptake of nutrients. This process is important in the absorption of oil soluble vitamins & in the uptake of nutrients. 08/10/201042KLECOP, Nipani

43 C) Transcytosis It is a phenomenon in which endocytic vesicle is transferred from one extracellular compartment to another. It is a phenomenon in which endocytic vesicle is transferred from one extracellular compartment to another. 08/10/201043KLECOP, Nipani

44 Diagram Representing Absorption, Distribution, Metabolism and Excretion The ultimate goal is to have the drug reach the site of action in a concentration which produces a pharmacological effect. No matter how the drug is given (other than IV) it must pass through a number of biological membranes before it reaches the site of action. 08/10/201044KLECOP, Nipani

45 DIFFUSION THROUGH MEMBRANES Rate dependent on polarity and size. Polarity estimated using the partition coefficient. The greater the lipid solubility – the faster the rate of diffusion Smaller molecules (nm/A 0 ) penetrate more rapidly. Highly permeable to O 2, CO 2, NO and H 2 O. Large polar molecules – sugar, aa, phosphorylated intermediates – poor permeability These are essential for cell function – must be actively transported 08/10/201045KLECOP, Nipani

46 MOVEMENT OF SUBSTANCES ACROSS CELL MEMBRANES 08/10/201046KLECOP, Nipani

47 BIOLOGICAL FACTORS: BIOLOGICAL FACTORS: Penetration Of Drugs Through Gastro-intestinal Tract Penetration Of Drugs Through Gastro-intestinal Tract Penetration Of Drugs Through Blood Brain Barrier Penetration Of Drugs Through Blood Brain Barrier Penetration Of Drugs Through Placental Barrier Penetration Of Drugs Through Placental Barrier Penetration Of Drugs Through Across The Skin Penetration Of Drugs Through Across The Skin Penetration Of Drugs Through The Mucous Membrane Of The Nose, Throat, Trachea, Buccal Cavity, Lungs,Vaginal And Rectal Surfaces Penetration Of Drugs Through The Mucous Membrane Of The Nose, Throat, Trachea, Buccal Cavity, Lungs,Vaginal And Rectal Surfaces PHYSIOLOGICAL FACTORS: Gastrointestinal (Gi) Physiology Gastrointestinal (Gi) Physiology Influence Of Drug Pka And Gi Ph On Drug Absorbtion Influence Of Drug Pka And Gi Ph On Drug Absorbtion Git Blood Flow Git Blood Flow Gastric Emptying Gastric Emptying Disease States Disease States 08/10/201047KLECOP, Nipani

48 PENETRATION OF DRUGS THROUGH GASTRO-INTESTINAL TRACT The Git barrier that separates the lumen of the stomach and intestine from systemic circulation and is composed of lipids, proteins and polysaccharides. Git mucosa is a semi permeable membrane across which various nutrients like Carbohydrates, Amino acids, Vitamins and foreign substances are transported and absorbed into the blood by various mechanisms like: 1. Passive diffusion 2. Pore transport 3. Facilitated transport 4. Active transport 5. Pinocytosis 08/10/201048KLECOP, Nipani

49 1. PASSIVE DIFFUSION Major process for absorption of more than 90% of drugs Major process for absorption of more than 90% of drugs Diffusion follows Fick’s law: Diffusion follows Fick’s law: The drug molecules diffuse from a region of higher concentration to a region of lower concentration till equilibrium is attained. The drug molecules diffuse from a region of higher concentration to a region of lower concentration till equilibrium is attained. Rate of diffusion is directly proportional to the concentration gradient across the membrane. Rate of diffusion is directly proportional to the concentration gradient across the membrane. Factors affecting Passive diffusion: Factors affecting Passive diffusion: Diffusion coefficient of the drug Diffusion coefficient of the drug Related to lipid solubility and molecular wt. Related to lipid solubility and molecular wt. Thickness and surface area of the membrane Thickness and surface area of the membrane Size of the molecule Size of the molecule 08/10/201049KLECOP, Nipani

50 08/10/201050KLECOP, Nipani

51 2. PORE TRANSPORT It involves the passage of ions through Aq. Pores (4-40 A 0 ) It involves the passage of ions through Aq. Pores (4-40 A 0 ) Low molecular weight molecules (less than 100 Daltons) eg- urea, water, sugar are absorbed. Low molecular weight molecules (less than 100 Daltons) eg- urea, water, sugar are absorbed. Also imp. In renal excretion, removal of drug from CSF and entry Also imp. In renal excretion, removal of drug from CSF and entry of drugs into liver. of drugs into liver. 08/10/201051KLECOP, Nipani

52 3. FACILITATED DIFFUSION Carrier mediated transport (downhill transport) Carrier mediated transport (downhill transport) Faster than passive diffusion Faster than passive diffusion No energy expenditure is involved No energy expenditure is involved Not inhibited by metabolic poisons Not inhibited by metabolic poisons Important in transport of Polar molecules and charged ions that dissolve in water but they can not diffuse freely across cell membranes due to the hydrophobic nature of the phospholipids. Important in transport of Polar molecules and charged ions that dissolve in water but they can not diffuse freely across cell membranes due to the hydrophobic nature of the phospholipids. Eg. 1. entry of glucose into RBCs 2. intestinal absorption vitamin B1,B2 2. intestinal absorption vitamin B1,B2 3. transport of amino acids thru permeases 3. transport of amino acids thru permeases 08/10/201052KLECOP, Nipani

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54 4. ACTIVE TRANSPORT Carrier mediated transport (uphill transport) Carrier mediated transport (uphill transport) Energy is required in the work done by the carrier Energy is required in the work done by the carrier Inhibited by metabolic poisons Inhibited by metabolic poisons Endogenous substances that are transported actively include sodium, potassium, calcium, iron, glucose, amino acids and vitamins like niacin, pyridoxin. Endogenous substances that are transported actively include sodium, potassium, calcium, iron, glucose, amino acids and vitamins like niacin, pyridoxin. Drugs having structural similarity to such agents are absorbed actively Drugs having structural similarity to such agents are absorbed actively Eg. 1. Pyrimidine transport system – absorption of 5 FU and 5 BU and 5 BU 2. L-amino acid transport system – absorption of 2. L-amino acid transport system – absorption of methyldopa and levodopa methyldopa and levodopa 08/10/201054KLECOP, Nipani

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56 5. PINOCYTOSIS Pinocytosis ("cell-drinking") Uptake of fluid solute. Uptake of fluid solute. A form of endocytosis in which small particles are brought into the cell in the form of small vesicles which subsequently fuse with lysosomes to hydrolyze, or to break down, the particles. A form of endocytosis in which small particles are brought into the cell in the form of small vesicles which subsequently fuse with lysosomes to hydrolyze, or to break down, the particles. This process requires energy in the form of (ATP). This process requires energy in the form of (ATP). Polio vaccine and large protein molecules are absorbed by pinocytosis Polio vaccine and large protein molecules are absorbed by pinocytosis 08/10/201056KLECOP, Nipani

57 08/10/201057KLECOP, Nipani

58 PENETRATION OF DRUGS THROUGH BLOOD BRAIN BARRIER A stealth of endothelial cells lining the capillaries. A stealth of endothelial cells lining the capillaries. It has tight junctions and lack large intra cellular pores. It has tight junctions and lack large intra cellular pores. Further, neural tissue covers the capillaries. Further, neural tissue covers the capillaries. Together, they constitute the so called BLOOD BRAIN BARRIER Together, they constitute the so called BLOOD BRAIN BARRIER Astrocytes : Special cells / elements of supporting tissue found at the base of endothelial membrane. Astrocytes : Special cells / elements of supporting tissue found at the base of endothelial membrane. The blood-brain barrier (BBB) is a separation of circulating blood and cerebrospinal fluid (CSF) maintained by the choroid plexus in the central nervous system (CNS). The blood-brain barrier (BBB) is a separation of circulating blood and cerebrospinal fluid (CSF) maintained by the choroid plexus in the central nervous system (CNS). 08/10/201058KLECOP, Nipani

59 08/10/201059KLECOP, Nipani

60 Since BBB is a lipoidal barrier, It allows only the drugs having high o/w partition coefficient to diffuse passively where as moderately lipid soluble and partially ionised molecules penetrate at a slow rate. Endothelial cells restrict the diffusion of microscopic objects (e.g. bacteria ) and large or hydrophillic molecules into the CSF, while allowing the diffusion of small hydrophobic molecules (O 2, hormones, CO 2 ). Cells of the barrier actively transport metabolic products such as glucose across the barrier with specific proteins. Various approaches to promote crossing the BBB by drugs: Use of Permeation enhancers such as dimethyl sulfoxide (DMSO) Use of Permeation enhancers such as dimethyl sulfoxide (DMSO) Osmotic disruption of the BBB by infusing internal carotid artery Osmotic disruption of the BBB by infusing internal carotid artery with mannitol Use of Dihydropyridine redox system as drug carriers to the brain Use of Dihydropyridine redox system as drug carriers to the brain ( the lipid soluble dihydropyridine is linked as a carrier to the polar drug to form a prodrug that rapidly crosses the BBB ) 08/10/201060KLECOP, Nipani

61 PENETRATION OF DRUGS THROUGH PLACENTAL BARRIER Placenta is the membrane separating fetal blood from the maternal blood. Placenta is the membrane separating fetal blood from the maternal blood. It is made up of fetal trophoblast basement membrane and the endothelium. It is made up of fetal trophoblast basement membrane and the endothelium. Mean thickness (25 µ) in early pregnancy and reduces to (2 µ) at full term Mean thickness (25 µ) in early pregnancy and reduces to (2 µ) at full term Many drugs having mol. wt. < 1000 daltons and moderate to high lipid solubility e.g. ethanol, sulfonamides, barbiturates, steroids, anticonvulsants and some antibiotics cross the barrier by simple diffusion quite rapidly. Many drugs having mol. wt. < 1000 daltons and moderate to high lipid solubility e.g. ethanol, sulfonamides, barbiturates, steroids, anticonvulsants and some antibiotics cross the barrier by simple diffusion quite rapidly. Nutrients essential for fetal growth are transported by carrier mediated processes Nutrients essential for fetal growth are transported by carrier mediated processes 08/10/201061KLECOP, Nipani

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63 PENETRATION OF DRUGS THROUGH ACROSS THE SKIN Skin is composed of three primary layers: Skin is composed of three primary layers: the epidermis, which provides waterproofing and serves as a barrier to infection; the epidermis, which provides waterproofing and serves as a barrier to infection; the dermis, which serves as a location for the appendages of skin; and the dermis, which serves as a location for the appendages of skin; and the hypodermis (subcutaneous adipose layer). the hypodermis (subcutaneous adipose layer). The stratum corneum is the outermost layer of the epidermis and is composed mainly of dead keratinised cells (from lack of oxygen and nutrients). It has a thickness between 10 - 40 μm. The dermis is the layer of skin beneath the epidermis. It contains the hair follicles, sweat glands, sebaceous glands, apocrine glands, lymphatic vessels and blood vessels. Hypodermis - Its purpose is to attach the skin to underlying bone and muscle as well as supplying it with blood vessels and nerves. The main cell types are fibroblasts, macrophages and adipocytes (the hypodermis contains 50% of body fat). 08/10/201063KLECOP, Nipani

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65 ROUTES OF PENETRATION ROUTES OF PENETRATION Through follicular region Through follicular region Through sweat ducts Through sweat ducts Through unbroken stratum corneum Through unbroken stratum corneum FACTORS IN SKIN PERMEATION 1. Thickness of the skin layer: ( Thickest on palms and soles & thinest on the face) 2. Skin condition: permeability of skin is affected by age, disease state or injury. 3. Skin temp.: permeability increases with increase in temp. 4. Hydration state APPROACHES TO ENHANCE SKIN PERMEATION 1. Innuction 2. Iontophoresis 3. Sonophoresis 4. Magnetophoresis 08/10/201065KLECOP, Nipani

66 Penetration Of Drugs Through The Mucous Membrane Of The Nose, Throat, Trachea, Buccal Cavity, Lungs,Vaginal And Rectal Surfaces The barrier for the drug absorption is the capillary endothelial membrane which is lipoidal and consists of pores. The barrier for the drug absorption is the capillary endothelial membrane which is lipoidal and consists of pores. Thus, lipid soluble drugs can easily penetrate by diffusion and smaller drug molecules can penetrate by pore transport. Thus, lipid soluble drugs can easily penetrate by diffusion and smaller drug molecules can penetrate by pore transport. 08/10/201066KLECOP, Nipani

67 pHMembraneBlood SupplySurface AreaTransit TimeBy-pass liver BUCCALapprox 6thinGood, fast absorption with low dose smallShort unless controlled yes ESOPHAGUS6Very thick, no absorption -smallshort- STOMACH1 – 3Normal Lipophilic,acidic and neutral drugs goodsmall30 - 40 minutes, reduced absorption no DUODENUM5 – 7Normal Mainly lipohilic and neutral drugs goodlargevery short (6" long) no SMALL INTESTINE 6 -7Normal All types of drugs goodvery large 10 - 14 ft, 80 cm 2 /cm about 3 hoursno LARGE INTESTINE 6.8 - 7-goodnot very large 4 - 5 ft long, up to 24 hrlower colon, rectum yes Gastrointestinal (GI) Physiology 08/10/201067KLECOP, Nipani

68 SMALL INTESTINE : SMALL INTESTINE : Major site for absorption of most drugs due to its large surface area (0.33 m 2 ). Major site for absorption of most drugs due to its large surface area (0.33 m 2 ). It is 7 meters in length and is approximately 2.5-3 cm in diameter. It is 7 meters in length and is approximately 2.5-3 cm in diameter. The Folds in small intestine called as folds of kerckring, result in 3 fold increase in surface area ( 1 m 2). The Folds in small intestine called as folds of kerckring, result in 3 fold increase in surface area ( 1 m 2). These folds possess finger like projections called Villi which increase the surface area 30 times ( 10 m 2). These folds possess finger like projections called Villi which increase the surface area 30 times ( 10 m 2). From the surface of villi protrude several microvilli which increase the surface area 600 times ( 200 m 2). From the surface of villi protrude several microvilli which increase the surface area 600 times ( 200 m 2). Blood flow is 6-10 times that of stomach. Blood flow is 6-10 times that of stomach. PH Range is 5–7.5, favourable for most drugs to remain unionised. PH Range is 5–7.5, favourable for most drugs to remain unionised. Peristaltic movement is slow, while transit time is long. Peristaltic movement is slow, while transit time is long. Permeability is high. Permeability is high. All these factors make intestine the best site for absorbtion of most drugs. 08/10/201068KLECOP, Nipani

69 INFLUENCE OF DRUG pKa AND GI PH ON DRUG ABSORBTION INFLUENCE OF DRUG pKa AND GI PH ON DRUG ABSORBTION DrugsSite of absorption Very weak acids (pKa > 8.0)Unionized at all ph values Absorbed along entire length of GIT Moderately weak acids (pKa 2.5 – 7.5)Unionized in gastric ph Ionized in intestinal ph Better absorbed from stomach Strong acids (pKa <2.5)Ionized at all ph values Poorly absorbed from git Very weak bases (pKa < 5)Unionized at all ph values Absorbed along entire length of GIT Moderately weak bases (pKa 5 – 11 )Ionized in gastric ph Unionized in intestinal ph Better absorbed from intestine Strong bases (pKa >11)Ionized at all ph values Poorly Absorbed from GIT 08/10/201069KLECOP, Nipani

70 GIT BLOOD FLOW GIT BLOOD FLOW It plays an imp. role in drug absorption by continuously maintaining the conc. Gradient across the epithelial membrane It plays an imp. role in drug absorption by continuously maintaining the conc. Gradient across the epithelial membrane Polar molecules that are slowly absorbed show no dependence on blood flow Polar molecules that are slowly absorbed show no dependence on blood flow The absorption of lipid soluble drugs and molecules that are small enough to easily penetrate through Aq. pores is rapid and highly dependent on rate of blood flow The absorption of lipid soluble drugs and molecules that are small enough to easily penetrate through Aq. pores is rapid and highly dependent on rate of blood flow 08/10/201070KLECOP, Nipani

71 GASTRIC EMPTYING The process by which food leaves the stomach and enters the duodenum. The process by which food leaves the stomach and enters the duodenum. It is a RDS in drug absorbtion. It is a RDS in drug absorbtion. Rapid Gastric Emptying Advisable when : Rapid Gastric Emptying Advisable when : Rapid onset of action is desired eg. Sedatives Rapid onset of action is desired eg. Sedatives Dissolution occurs in the intestine eg. Enteric coated tablets Dissolution occurs in the intestine eg. Enteric coated tablets Drugs not stable in gi fluids eg. penicillin G Drugs not stable in gi fluids eg. penicillin G Drug is best absorbed from small intestine eg. Vitamin B12 Drug is best absorbed from small intestine eg. Vitamin B12 Delay in Gastric Emptying recommended when Delay in Gastric Emptying recommended when Food promotes drug dissolution and absorbtion eg. Gresiofulvin Food promotes drug dissolution and absorbtion eg. Gresiofulvin Disintegration and dissolution is is promoted by gastric fluids Disintegration and dissolution is is promoted by gastric fluids 08/10/201071KLECOP, Nipani

72 Factors affecting Gastric Emptying Volume of Ingested Material As volume increases initially an increase then a decrease. Bulky material tends to empty more slowly than liquids Type of MealGastric emptying rate: carbohydrates > proteins > fats Temperature of FoodIncrease in temperature, increase in emptying rate Body PositionLying on the left side decreases emptying rate and right side promotes it Git PHRetarded at low stomach PH and promoted at higher alkaline PH Emotional stateAnxiety promotes where as depression retards it Disease states gastric ulcer, hypothyroidism retards it, while duodenal ulcer, hyperthyroidism promotes it. 08/10/201072KLECOP, Nipani

73 DISEASE STATES CHF decreases blood flow to the Git, alters GI PH, secretions and microbial flora. CHF decreases blood flow to the Git, alters GI PH, secretions and microbial flora. Cirrhosis influences bioavailability mainly of drugs that undergo considerable 1st pass metabolism eg. Propranolol Cirrhosis influences bioavailability mainly of drugs that undergo considerable 1st pass metabolism eg. Propranolol Git infections like cholera and food poisoning also result in malabsorbtion. Git infections like cholera and food poisoning also result in malabsorbtion. 08/10/201073KLECOP, Nipani

74 PHYSIO-CHEMICAL FACTORS  PHYSICAL FACTORS  PHYSIO-CHEMICAL FACTORS 08/10/201074KLECOP, Nipani

75 PHYSICAL FACTORS 1.PARTICLE SIZE  Smaller particle size, greater surface area then higher will be dissolution rate, because dissolution is thought to take place at the surface area of the solute( Drug).  This study is imp. for drugs that have low aqueous solubility. Absorption of such drugs can be increased by increasing particle size by Micronization.  ex. Griseofulvin, active intravenously but not effective when given orally. 08/10/201075KLECOP, Nipani

76  To poor soluble drug, disintegration agents and surface active agents may be added. ex. Bioavailability of Phenacetin is increased by tween 80.  Micronization also reduces the dose of some drugs ex. the dose of griseofulvin is reduced to one half while the dose of spironolactone is reduced to one twentieth. 08/10/201076KLECOP, Nipani 1.PARTICLE SIZE

77 Lesser particle size is always not helpful Ex. Micronization of Aspirin, phenobarbital, lesser effective surface area and hence lesser dissolution rate Reasons:  On their surface, hydrophobic drugs absorb air and reduce their wettability  Particle having size below 0.1 micron reaggregate to form large particle  Particle having certain micro size get electrical charge which preventing contact with wetting medium 08/10/201077KLECOP, Nipani

78 Finally drug size reduction and subsequent increase in surface area and dissolution rate is always not useful. Ex. of such drugs are Penicillin G & Erythromycin These Drugs are unstable and degrade quickly in solution. Sometime, reduction in particle size of nitrofurantoin and piroxicam increase gastric irritation These problem can be overcome by Microencapsulation. 08/10/201078KLECOP, Nipani

79 2. Crystal Form Substance can exist either in a crystalline or amorphous form. When substance exist in more than one crystalline form, the different form are called polymorphs and the phenomena as polymorphism. Two types of Polymorphism 1) Enantiotropic polymorph ex. Sulfur 2) Monotropic polymorph ex. Glyceryl Stearates Polymorphs have the same chemical structure but different physical properties such as solubility, density, hardness etc. ex. Chlormphenicol has a several crystal form, and when given orally as a suspension, the drug concentration in the body was found to be dependent on the percentage of β - polymorph in the suspension. The form is more soluble and better absorbed. 08/10/201079KLECOP, Nipani

80 One of the several form of polymorphic forms is more stable than other. Such a stable form having low energy state and high melting point and least aqueous solubility The remaining polymorphs are called as metastable forms which have high energy state, low melting point and high aqueous solubilities. About 40% of all organic compounds exhibit polymorphism. Some drug exists in amorphous form which have no internal crystal structure. Such drugs have high energy states than crystal form hence they have greater aqueous solubility than crystalline form. Ex. Novobiocin, cortisone acetate. 08/10/201080KLECOP, Nipani

81 3. Solvates And Hydrates Many drugs associate with solvent and forms solvates Solvent is water then it is called as hydrate eg. Anhydrous form of caffeine and theophylline dissolve more rapidly than hydrous form of these drugs. Solvate form of drugs with org. solvent may dissolve fast in water than non solvated form. eg. Fluorocortisone 4. Complexation This property can influence the effective drug concentration in gi fluids. Complexation of drug and gi fluids may alter the rate and extent of absorption eg. Intestinal Mucin form complex with Streptomycin and Dihydro Streptomycin. In some cases, Poor water soluble drugs can be administered as water soluble complexes. eg. Hydroquinone with Digoxin. 08/10/201081KLECOP, Nipani

82 5.Adsorption It is a physical and surface phenomena where the drug molecules are held on the surface of some inert substances by vanderwall’s forces. ex. Charcoal used as an antidote; When it is co-administered with promazine, then it reduces the rate and extent of absorption Cholestyramine reduces the absorption of warfarin. 6.Drug Stability And Hydrolysis In GIT Drugs undergoes various reactions due to wide spectrum of ph and enzymatic activity of GI fluid namely acid and enzymatic hydrolysis. eg. T½ of Penicillin G= 1 min. at pH 1 T½ of Penicillin G= 9 min. at pH2 So it means Penicillin G is stable at less acidic pH Erythromycin and its esters are unstable at gastric fluid (T½=Less than 2 min.) 08/10/201082KLECOP, Nipani

83  Certain salts also may have low solubility and dissolution rate. 7. Salts  Na or K salts of weak acid dissolves rapidly than free acid. ex. Na salts of Novobiocin shows improved bioavailability ex. Al salts of weak acid and pamoate salt of weak base 8. Presence Of Surfactant Use of wetting agent and Solubilizing agent improve the Dissolution rate & absorption of drugs. Ex. Tween 80 increase the rate & extent of absorption of Phenacetin. 9. Dissolution Disintegration is the formation of dispersed granules from an intact solid dosage form whereas the dissolution is the formation of solvated drug molecules from the drug 08/10/201083KLECOP, Nipani

84 SOLID DRUG DRUG AT ABSORPTION SITE DRUG IN SYSTEMIC CIRCULATION DISSOLUTION ABSORPTION 08/10/201084KLECOP, Nipani

85 NOYES AND WHITNEY’S EQUATION dc / dt = KS( C S - C ) Where, dc / dt = Rate constant, K = constant, S = surface area of the dissolving solid, Cs=solubility of the drug in the solvent, C=concentration of drug in the solvent at time t. Constant K=D / h Where, D is the diffusion coefficient of the dissolving material and h is the thickness of the diffusion layer Here, C will always negligible compared to Cs So, dc / dt=DSCs / h 08/10/201085KLECOP, Nipani

86 PHYSICOCHEMICAL FACTORS 1) pH PARTITION THEORY (Brodie) : It explain drug absorption from GIT and its distribution across biomembranes. Drug(>100 daltons) transported by passive diffusion depend upon:  dissociation constant, pKa of the drug  lipid solubility, K o/w  pH at absorption site. Most drugs are either weak acids or weak bases whose degree of ionization is depend upon pH of biological fluid. 08/10/201086KLECOP, Nipani

87 For a drug to be absorbed, it should be unionized and the unionized portion should be lipid soluble. The fraction of drug remaining unionized is a function of both Dissociation constant (pKa) and pH of solution. The pH partition theory is based on following assumption:  GIT acts as a lipoidal barrier to the transport of the drug  The rate of absorption of drug is directly proportional to its fraction of unionised drug  Higher the lipophilicity of the unionised degree, better the absorption. 08/10/201087KLECOP, Nipani

88 HENDERSON HASSELBATCH EQUATION For acid, pKa - pH = log[ Cu/Ci ] For base, pKa – pH = log[ Ci/Cu ] Eg. Weak acid aspirin (pKa=3.5) in stomach (pH=1) will have > 99%of unionized form so gets absorbed in stomach Weak base quinine (pKa=8.5) will have very negligible unionization in gastric pH so negligible absorption Several prodrugs have been developed which are lipid soluble to overcome poor oral absorption of their parent compounds. 08/10/201088KLECOP, Nipani

89 eg. Pivampicilin, the pivaloyloxy-methyl ester of ampicilin is More lipid soluble than ampicilin. Lipid solubility is provided to a drug by its partition coefficient between An organic solvent and water or an aq. Buffer (same pH of ab. Site) E.g. Barbital has a p.c. of 0.7 its absorption is 12% Phenobarbital ( p.c = 4.8 absorption=12%) Secobarbital (p.c =50.7 absorption=40%) 08/10/201089KLECOP, Nipani

90 2)DRUG SOLUBILITY The absorption of drug requires that molecule be in solution at absorption site. Dissolution, an important step, depends upon solubility of drug substance. pH solubility profile: pH environment of GIT varies from Acidic in stomach to slightly Alkaline in a small intestine. soluble 1)Basic drug 1) Acidic medium( stomach) 2)Acidic drug 2) basic medium( intestestine) 08/10/201090KLECOP, Nipani

91 Improvement of solubility:  Addition of acidic or basic excipient Ex: Solubility of Aspirin (weak acid) increased by addition of basic excipient.  For formulation of CRD, buffering agents may be added to slow or modify the release rate of a fast dissolving drug. 08/10/201091KLECOP, Nipani

92 PHARMACEUTICAL FACTORS MEANS Absorption rate depends on the dosage Form which is administred,ingredients used, procedures Used in formulation of dosage forms. The availability of the drug for absorption from the dosage forms is in order. Solutions > Suspensions > capsules > Compressed Tablets > Coated tablets. 08/10/201092KLECOP, Nipani

93 SOLUTIONS Shows maximum bioavailability and factors affecting Absorption from solution are as follows 1.Chemical stability of drug 2.Complexation: between drug and exipients of formulation to increase the solubility, stability. 3. Solubilization: incorporation of drug into micelles to increase the solubility of drugs. 4. Viscosity 5. Type of solution: Whether aqueous or oily solution. 08/10/201093KLECOP, Nipani

94 SUSPENSIONS: It comes next after solutions with respect to bioavailability Factors that affects absorption from suspensions are 1.Particle size and effective surface area of dispersed phase 2. Crystal form of drug: some drug can change their crystal structure. Eg. Sulfathiazole can change its polymorphic form, it can be overcome by addition by adding PVP. 3. Complexation: Formation of nonabsorbable complex between drug and other ingredients. Eg. Promazine forms a complex with attapulgite. 08/10/201094KLECOP, Nipani

95 4. Inclusion of surfactant Eg. The absorption of phenacitin from suspension is increased in presence of tween 80. 5. Viscosity of suspension Eg. Methyl cellulose reduces the rate and absorption of nitrofurantoin 6. Inclusion of colourants: Eg. Brilliant blue in phenobarbitone suspension. 08/10/201095KLECOP, Nipani

96 CAPSULES Two types of capsule 1.Hard gelatin capsule 2. Soft gelatin capsule 08/10/201096KLECOP, Nipani

97 HARD GELATIN CAPSULE The rate of absorption of drugs from capsule is function Of some factors. 1.Dissolution rate of gelatin shell. 2.The rate of penetration of GI fluids into encapsulated mass 3.The rate at which the mass disaggregates in the GI fluid 4. The rate of dissolution. 5. Effect of excipients; a).Diluents b).Lubricants c). Wetting characteristics of drug d).Packing density 08/10/201097KLECOP, Nipani

98 SOFT GELATIN CAPSULE SGS has a gelatin shell thicker than HGS,but shell is Plasticized by adding glycerin,sorbitol.SGS may used To contain non aqueous solution or liquid or semi solid. SGC have a better bioavailability than powder filled HGC And are equivalent to emulsions. Eg. Quinine derivative was better absorbed from SGC Containing drug base compared with HGC containing HCl salts. Grieseoflavin exhibited 88% absorption from soft gelatin Capsules compared to HGC(30%) 08/10/201098KLECOP, Nipani

99 TABLETS 1.Compressed tablets 2. Coated tablets 08/10/201099KLECOP, Nipani

100 Compressed tablets Bioavailability are more due to large reduction in surface area. Intact tablets a granules primary drug particles AB Drug in GI fluid Drug absorbed in body K1 K2 K3 K4 08/10/2010100KLECOP, Nipani

101 The rate constants decrease in the following order. K3>>K2>>K1 The overall dissolution rate and bioavailability of a poor Soluble drugs is influenced by 1.The physicochemical properties of liberated particles. 2. The nature and quantity of additives. 3. The compaction pressure and speed of compression. 4. The storage and age of tablet 08/10/2010101KLECOP, Nipani

102 1.Effect of diluents : Na Salicylates + starch = Faster dissolution Na salicylates + lactose=Poor dissolution. 2.Effect of Granulating agent: Phenobarbital + Gelatin solution=Faster dissolution Phenobarbital+PEG 6000= poor dissolution. 3.Effect of lubricants: Magnesium stearate will retard the dissolution of aspirin tablet Whereas SLS enhance the dissolution. 08/10/2010102KLECOP, Nipani

103 4.Effect of disintegrants: Starch tend to swell with wetting and break apart the dosage form. It is reported that 325mg of salicylic acid tablet were prepared by using different concentrations (5%,10%,20%) and max. dissolution was achieved With 20% starch. 5. Effect of colorants: 6.Effect of Compression force: 08/10/2010103KLECOP, Nipani

104 COATED TABLETS: There are three types of coating Sugar coating Film coating Enteric coating SUGAR COATING: Sugar,Shellac,fatty glycerides, bees wax, silicone resin Sub coating agent: Talc,acacia,starch. FILM COATING: Polymers, dispersible cellulose derivatives like HPMC CMC. ENTERIC COATING: Shellac, cellulose acetate phthalate etc. 08/10/2010104KLECOP, Nipani

105 Factors affecting the drug release are 1.Thickness of coating e.g.. Quinine shows decrease in rate of absorption if coated with cellulose acetate phthalate. 2.The amount of dusting powder: 3.Effect of ageing: e.g. The shellac coated tablets of Para amino salicylic acid when given after two years plasma concentration of 6-7mg/100ml. However the tablets stored for 3½ years showed plasma concentration of only 2mg/100ml which is the sub therapeutic effect. 08/10/2010105KLECOP, Nipani

106 SUBLINGUAL / BUCCAL ROUTE SUBLINGUAL ROUTE: the dosage form is placed beneath the tongue. SUBLINGUAL ROUTE: the dosage form is placed beneath the tongue. BUCCAL ROUTE: Dosage form is placed between the cheek and teeth or In the cheek pouch. BUCCAL ROUTE: Dosage form is placed between the cheek and teeth or In the cheek pouch. Drugs administered by this route are supposed to produce systemic drug effects, and consequently, they must have good absorption from oral mucosa. Drugs administered by this route are supposed to produce systemic drug effects, and consequently, they must have good absorption from oral mucosa. Oral mucosal regions are highly vascularised therefore rapid onset of action is observed. Oral mucosal regions are highly vascularised therefore rapid onset of action is observed. For Eg, anti-anginal drug Nitroglycerin. For Eg, anti-anginal drug Nitroglycerin. 08/10/2010106KLECOP, Nipani SUBLINGUAL / BUCCAL ROUTE

107 SUBLINGUAL / BUCCAL ROUTE SUBLINGUAL / BUCCAL ROUTE Blood perfuses oral regions drains directly into the general circulation. Blood perfuses oral regions drains directly into the general circulation. Barrier to drug absorption from these routes is epithelium of oral mucosa. Barrier to drug absorption from these routes is epithelium of oral mucosa. Passive diffusion is the major mechanism of absorption of most drugs. Passive diffusion is the major mechanism of absorption of most drugs. In general, sublingual tablets are designed to dissolve slowly to minimize possibility of swallowing the dose. In general, sublingual tablets are designed to dissolve slowly to minimize possibility of swallowing the dose. Exception include: Nitroglycerin, Isosorbide dinitrate tablets which dissolves within minutes in buccal cavity to provide prompt treatment of acute anginal episodes. Exception include: Nitroglycerin, Isosorbide dinitrate tablets which dissolves within minutes in buccal cavity to provide prompt treatment of acute anginal episodes. 08/10/2010107KLECOP, Nipani

108 08/10/2010108KLECOP, Nipani

109 08/10/2010109KLECOP, Nipani

110 Factors to be considered: Lipophilicity of drug: The lipid solubility should be high for absorption. 1. Salivary secretion: drug should be soluble in buccal fluid. 2. pH of saliva: pH of saliva is usually 6. 3. Storage compartment: some drugs have storage compartment in buccal mucosa. Eg, Buprenorphine 4. Thickness of oral epithelium : Sublingual absorption is faster than buccal, because former region is thinner than that of buccal mucosa. absorption is faster than buccal, because former region is thinner than that of buccal mucosa. 08/10/2010110KLECOP, Nipani

111 FACTORS LIMITTING DRUG ADMINISTRATION: 1. Limited mucosal surface area. 2. Taste of medicament and discomfort. EXAMPLES: Nitroglycerin, Isosorbide dinitrate, Progesterone, Oxytocin, Fenosterol, Morphine. EXAMPLES: Nitroglycerin, Isosorbide dinitrate, Progesterone, Oxytocin, Fenosterol, Morphine. 08/10/2010111KLECOP, Nipani

112 RECTAL ADMINISTRATION: Absorption across the rectal mucosa occurs by passive diffusion. Absorption across the rectal mucosa occurs by passive diffusion. This route of administration is useful in children, old people and unconscious patients. This route of administration is useful in children, old people and unconscious patients. Eg., drugs that administered are: aspirin, acetaminophen, theophylline, indomethacin, promethazine & certain barbiturates. Eg., drugs that administered are: aspirin, acetaminophen, theophylline, indomethacin, promethazine & certain barbiturates. 08/10/2010112KLECOP, Nipani

113 PARENTERAL ROUTES:. 08/10/2010113KLECOP, Nipani

114 INTRAVENOUS ROUTE: Absorption phase is bypassed (100% bioavailability) 1.Precise, accurate and almost immediate onset of action, 2. Large quantities can be given, fairly pain free 3. Greater risk of adverse effects a. High concentration attained rapidly b. Risk of embolism 08/10/2010114KLECOP, Nipani INTRAVENOUS ROUTE:

115 This route is used when a rapid clinical response is required like treatment of epileptic seizures, acute asthmatic and cardiac arrhythmias. This route is used when a rapid clinical response is required like treatment of epileptic seizures, acute asthmatic and cardiac arrhythmias. There may also be a danger of precipitation of drug in the vein if the inj. is too rapidly. This could result in thrombophlebitis. There may also be a danger of precipitation of drug in the vein if the inj. is too rapidly. This could result in thrombophlebitis. This mode of administration is required with drugs having short half lives and narrow therapeutic index. This mode of administration is required with drugs having short half lives and narrow therapeutic index. Bioavailability is not considered by this route. Bioavailability is not considered by this route. Mainly antibiotics are administered by this route. Mainly antibiotics are administered by this route. 08/10/2010115KLECOP, Nipani

116 Intra arterial injection In this route the drugs are injected directly into the artery. In this route the drugs are injected directly into the artery. It is mainly used for cancer chemotherapy. It is mainly used for cancer chemotherapy. It increased drug delivery to the area supplied by the infused artery and decreased drug delivery to systemic circulation. It increased drug delivery to the area supplied by the infused artery and decreased drug delivery to systemic circulation. 08/10/2010116KLECOP, Nipani

117 INTRA MUSCULAR INJECTION Absorption of drug from muscles is rapid and absorption rate is perfusion rate limited. Absorption of drug from muscles is rapid and absorption rate is perfusion rate limited. Polypeptides of less than approx 5000 gram per mole primarily pass through capillary pathway Polypeptides of less than approx 5000 gram per mole primarily pass through capillary pathway Greater than about 20000 g/mol are less able to traverse capillary wall, they primarily enter blood via lymphatic pathway. Greater than about 20000 g/mol are less able to traverse capillary wall, they primarily enter blood via lymphatic pathway. 08/10/2010117KLECOP, Nipani

118 Factors determining rate of drug absorption: 1. Vascularity to the inj. Site: Blood flow rates to intramuscular tissues are: Arm (deltoid) > thigh (vastus lateralis) > buttocks (gluteus maximus). 2. Lipid solubility and ionisation of drug. 3. Molecular size of drug. 4. Volume of inj. And drug concentration. 5. pH & viscosity of inj. vehicle. 08/10/2010118KLECOP, Nipani

119 SUBCUTANOUS ROUTE: 1. Slow and constant absorption 2. Absorption is limited by blood flow, affected if circulatory problems exist. 3. The blood supply to this is poorer than that of muscular tissue. 4. Concurrent administration of vasoconstrictor will slow absorption, e.g. Epinephrine. 5. The absorption is hastened by massage, application of heat to increase blood flow and inclusion of enzyme Hyaluronidase in drug solution. eg. Insulin. 08/10/2010119KLECOP, Nipani

120 08/10/2010120KLECOP, Nipani

121 TOPICAL ADMINISTRATION : MUCOSAL MEMBRANES(eye drops, antiseptic, sunscreen, nasal, etc.) SKIN a. Dermal - rubbing in of oil or ointment (local action) b. Transdermal - absorption of drug through skin (systemic action) i. stable blood levels ii. no first pass metabolism iii. drug must be potent. 08/10/2010121KLECOP, Nipani

122 Skin consist of three layers : Epidermis Epidermis Dermis Dermis Subcutaneous fat tissue Subcutaneous fat tissue The main route for the penetration of the drugs is generally through epidermal layer The main route for the penetration of the drugs is generally through epidermal layer Stratum corneum is the rate limiting barrier in passive percutaneous absorption of drug. Stratum corneum is the rate limiting barrier in passive percutaneous absorption of drug. 08/10/2010122KLECOP, Nipani

123 The stratum corneum is the outermost layer of the epidermis and is composed mainly of dead keratinized cells (from lack of oxygen and nutrients). It has a thickness between 10 - 40 μm. The dermis is the layer of skin beneath the epidermis. It contains the hair follicles, sweat glands, sebaceous glands, apocrine glands, lymphatic vessels and blood vessels. Hypodermis - Its purpose is to attach the skin to underlying bone and muscle as well as supplying it with blood vessels and nerves. The main cell types are fibroblasts, macrophages and adiposities (the hypodermis contains 50% of body fat). 08/10/2010123KLECOP, Nipani

124 08/10/2010124KLECOP, Nipani

125 OCULAR ADMINISTRATION Eye is the most easily accessible site for topical administration of a medication. Topical application of drug to eyes meant for : Mydriasis, miosis, anaesthesia, treatment of infection, glaucoma etc. Opthalmic solution are administered into cul-de-sac. Barrier to intra occular penetration is cornea. It possess both hydrophilic and lipophilic characterstics. pH of lacrimal fluid is 7.4. pH of lacrimal fluid influences absorption of weak electrolyte like Pilocarpine. 08/10/2010125KLECOP, Nipani

126 OCULAR ADMINISTRATION High pH of formulation: decrease tear flow and Low pH of formulation: increases tear flow. Human eye can hold around 10 microlitre of fluid. So small volume in concentrated form increases effectiveness. Viscosity empartners increases bioavailability eg, oily solutions, ointment etc. Systemic entry of drug occur by lacrimal duct which drains lacrimal fluid into nasal cavity. 08/10/2010126KLECOP, Nipani

127 Composition of eye Water - 98% Solid -1.8% Organic element – Protein - 0.67%, sugar - 0.65%, Nacl - 0.66% Other mineral element sodium, potassium and ammonia - 0.79% 08/10/2010127KLECOP, Nipani

128 08/10/2010128KLECOP, Nipani

129 Characteristics required to optimize ocular drug delivery system Good corneal penetration. Prolong contact time with corneal tissue. Simplicity of instillation for the patient. Non irritative and comfortable form (viscous solution should not provoke lachrymal secretion and reflex blinking) Appropriate rheological properties concentrations of the viscous system. 08/10/2010129KLECOP, Nipani

130 Advantages Increase ocular residence….. Improving bioavailability Prolonged drug release….. better efficacy Less visual & systemic side effects Increased shelf life Exclusion of preservatives Reduction of systemic side effects Reduction of the number of administration Better patient compliance Accurate dose in the eye…. a better therapy 08/10/2010130KLECOP, Nipani

131 FACTOR INFLUENCING PERCUTANEOUS ABSORPTION 1. Drug release from dosage form 2. Drug concentration in the formulation 3. Drug oil water partition coefficient. 4. Drug affinity to the skin tissue 5. Surface area 6. Site of application 7. Hydration of skin 8. Nature of vehicle used 08/10/2010131KLECOP, Nipani

132 FACTOR INFLUENCING PERCUTANEOUS ABSORPTION 9. Rubbing 10. Contact period 11. Permeation enhancers 08/10/2010132KLECOP, Nipani

133 INHALATIONAL ROUTE: 1.Gaseous and volatile agents and aerosols. 2.Rapid onset of action due to rapid access to circulation a.Large surface area b.Thin membranes separates alveoli from circulation c.High blood flow Particles larger than 20 micron and the particles impact in the mouth and throat. Smaller than 0.5 micron and they aren't retained. 08/10/2010133KLECOP, Nipani

134 INTRA NASAL ADMINISTRATION INTRA NASAL ADMINISTRATION Drugs generally administered by intra nasal route for treatment of local condition such as perennial rhinitis, allergic rhinitis and nasal decongestion etc. Drugs generally administered by intra nasal route for treatment of local condition such as perennial rhinitis, allergic rhinitis and nasal decongestion etc. Absorption of lipophilic drugs through nasal mucosa by passive diffusion and absorption of polar drugs by pore transport. Absorption of lipophilic drugs through nasal mucosa by passive diffusion and absorption of polar drugs by pore transport. Rate of absorption of lipophilic drugs depend on their molecular weight. Rate of absorption of lipophilic drugs depend on their molecular weight. Drugs with molecular weight less than 400 daltons exhibit higher rate of absorption. Drugs with molecular weight less than 400 daltons exhibit higher rate of absorption. 08/10/2010134KLECOP, Nipani

135 cont… cont… Drugs with molecular weight 1000 daltons show moderate rate of absorption. Drugs with molecular weight 1000 daltons show moderate rate of absorption. Presently nasal route is becoming popular for systemic delivery of peptide and proteins, this is because of high permeability of nasal mucosa with vasculature. Presently nasal route is becoming popular for systemic delivery of peptide and proteins, this is because of high permeability of nasal mucosa with vasculature. 08/10/2010135KLECOP, Nipani

136 08/10/2010136KLECOP, Nipani

137 Advantages Rapid drug absorption via highly-vascularized mucosa Rapid onset of action Ease of administration, non-invasive Avoidance of the gastrointestinal tract and first-pass metabolism Improved bioavailability Lower dose/reduced side effects Improved convenience and compliance Self-administration. 08/10/2010137KLECOP, Nipani

138 Disadvantages Nasal cavity provides smaller absorption surface area when compared to GIT. Relatively inconvenient to patients when compared to oral delivery since there is possibility of nasal irritation. The histological toxicity of absorption enhancers used in the nasal drug delivery system is not yet clearly established. 08/10/2010138KLECOP, Nipani

139 Enhancement in absorption Following approaches used for absorption enhancement :-   Use of absorption enhancers   Increase in residence time.   Administration of drug in the form of microspheres.   Use of physiological modifying agents 08/10/2010139KLECOP, Nipani

140 Enhancement in absorption   Use of absorption enhancers:- Absorption enhancers work by increasing the rate at which the drug pass through the nasal mucosa. Various enhancers used are surfactants, bile salts, chelaters, fatty acid salts, phospholipids, cyclodextrins, glycols etc. 08/10/2010140KLECOP, Nipani

141 Various mechanisms involved in absorption enhancements are:- Increased drug solubility Decreased mucosal viscosity Decrease enzymatic degradation Increased Paracellular transport Increased transcellular transport 08/10/2010141KLECOP, Nipani

142 Various mechanisms involved in absorption enhancements are:-   Increase in residence time:- By increasing the residence time the increase in the higher local drug concentration in the mucous lining of the nasal mucosa is obtained. Various mucoadhesive polymers like methylcellulose, carboxy methyl cellulose or polyarcylic acid are used for increasing the residence time. 08/10/2010142KLECOP, Nipani

143 Various mechanisms involved in absorption enhancements are:-   Use of physiological modifying agents:- These agents are vasoactive agents and exert their action by increasing the nasal blood flow. The example of such agents are histamine, leukotrienene D4, prostaglandin E1 and β-adrenergic agents like isoprenaline and terbutaline. 08/10/2010143KLECOP, Nipani

144 Applications of nasal drug delivery A. A. Nasal delivery of organic based pharmaceuticals :- Various organic based pharmaceuticals have been investigated for nasal delivery which includes drug with extensive presystemic metabolism. E.g. Progesterone, Estradiol, Nitroglycerin, Propranolol, etc. 08/10/2010144KLECOP, Nipani

145 Applications of nasal drug delivery B. B. Nasal delivery of peptide based drugs :- Nasal delivery of peptides and proteins is depend on –   The structure and size of the molecule.   Nasal residence time   Formulation variables (pH, viscosity) E.g. calcitonin, secretin, albumins, insulin, glucagon, etc. 08/10/2010145KLECOP, Nipani

146 PULMONARY ADMINISTRATION PULMONARY ADMINISTRATION The drugs may be administered for local action of bronchioles or their systemic effects through absorption of lungs. The drugs may be administered for local action of bronchioles or their systemic effects through absorption of lungs. Inhalation sprays and aerosols are used to deliver the drugs to the lungs. Inhalation sprays and aerosols are used to deliver the drugs to the lungs. Larger surface area of alveoli, high permeability of alveolar epithelium for drug penetration, and a rich vasculature are responsible for rapid absorption of drugs by this route Larger surface area of alveoli, high permeability of alveolar epithelium for drug penetration, and a rich vasculature are responsible for rapid absorption of drugs by this route 08/10/2010146KLECOP, Nipani

147 PULMONARY ADMINISTRATION PULMONARY ADMINISTRATION In general particles greater than 10mm are retained in the throat and upper airways whereas fine particles reach the pulmonary epithelium In general particles greater than 10mm are retained in the throat and upper airways whereas fine particles reach the pulmonary epithelium Drugs generally administered by this route are bronchodilators (e.g.. Salbutamol, isoproterenol), antiallergic (e.g.. Cromolym sodium), and antiinflammatory (e.g.. Betamethasone, dexamethasone). Drugs generally administered by this route are bronchodilators (e.g.. Salbutamol, isoproterenol), antiallergic (e.g.. Cromolym sodium), and antiinflammatory (e.g.. Betamethasone, dexamethasone). 08/10/2010147KLECOP, Nipani

148 08/10/2010148KLECOP, Nipani

149 Advantages Smaller doses can be administered locally. Reduce the potential incidence of adverse systemic effect. It used when a drug is poorly absorbed orally, e.g. Na cromoglicate. It is used when drug is rapidly metabolized orally, e.g. isoprenaline 08/10/2010149KLECOP, Nipani

150 IN-VITRO METHODS  Everted small intestine sac method.  Everted sac modification.  Circulation technique.  Everted intestinal ring or slice technique. 08/10/2010150KLECOP, Nipani

151 Why in-vitro studies Because of economical & ethical limitations of in-vivo studies. Because of economical & ethical limitations of in-vivo studies. Simple & provide valuable information. Simple & provide valuable information. To assess the major factors involved in absorption. To assess the major factors involved in absorption. Predict the rate & extent of drug absorption. Predict the rate & extent of drug absorption. Procedures are of great value during screening of new drug candidates. Procedures are of great value during screening of new drug candidates. Carried out outside the body. Carried out outside the body. Used to assess permeability of drug using animal tissues. Used to assess permeability of drug using animal tissues. 08/10/2010151KLECOP, Nipani

152  Everted small intestine sac technique Isolation of rat intestine Inverting the intestine Filling the sac with drug free buffer solution Immersion of sac in Erlenmeyer flask containing drug buffer solution Contd… 08/10/2010152KLECOP, Nipani

153 Flask & its contents oxygenated & agitated at 37 o C for specific period of time After incubation, the serosal content is assayed for drug content 08/10/2010153KLECOP, Nipani

154 Figure( reverted sac technique) Serosal side Mucosal side (intestinal segment before eversion) Buffer solution Ligature Mucosal side Serosal side (after eversion) 08/10/2010154KLECOP, Nipani

155 Advantages Prolongs the viability & integrity of the preparation after removal from the animal. Prolongs the viability & integrity of the preparation after removal from the animal. Convenience & accuracy with respect to drug analysis. Convenience & accuracy with respect to drug analysis. The epithelial cells of the mucosal surface are exposed directly to the oxygenated mucosal fluid. The epithelial cells of the mucosal surface are exposed directly to the oxygenated mucosal fluid.  Difficulty in obtaining more than one sample per intestinal segment 08/10/2010155KLECOP, Nipani

156  Everted sac modification Crane & Wilson modification. Crane & Wilson modification. Essential features of simple sac methods are retained. Essential features of simple sac methods are retained. Modification- the intestine is tied to a cannula. Modification- the intestine is tied to a cannula. 08/10/2010156KLECOP, Nipani

157 cannula Plain buffer Buffer solution with drug Water maintained at 37 o C (FIG: EVERTED SAC MODIFICATION) aerator 08/10/2010157KLECOP, Nipani

158 Procedure Animal fasted for 20-24hrs Water is allowed ad libitum Animal killed with blow on head or anesthetized with ether or chloroform Entire small intestine is everted Contd …. 08/10/2010158KLECOP, Nipani

159 Distal ends tied & proximal end is attached to cannula Segments of 5-15cm length are cut from specific region of the intestine Segments suspended in 40-100ml of drug mucosal solution. About 1ml/5cm length of drug free buffer is then placed in serosal compartment Mucosal solution aerated 08/10/2010159KLECOP, Nipani

160 How to determine the rate of drug transfer The entire volume of serosal solution is removed from the sac at each time interval with the help of syringe & it is replaced with fresh buffer solution. The entire volume of serosal solution is removed from the sac at each time interval with the help of syringe & it is replaced with fresh buffer solution. The amount of drug that permeates the intestinal mucosa is plotted against time to describe the absorption profile of the drug at any specific pH. The amount of drug that permeates the intestinal mucosa is plotted against time to describe the absorption profile of the drug at any specific pH. 08/10/2010160KLECOP, Nipani

161 Advantages  A number of different solutions may be tested with a single segment of the intestine unlike in the sac technique.  Simple & reproducible.  It distinguishes between active & passive absorption.  It determines the region of the small intestine where absorption is optimal, particularly in the case of active transport.  Also used to study the effect of pH, surface active agents, complexation & enzymatic reaction. 08/10/2010161KLECOP, Nipani

162 Disadvantages  The intestinal preparation is removed from the animal as well as from its blood supply. Under these conditions, the permeability characteristics of the membrane are significantly altered.  The rate of transport of drug as determined from the everted sac technique, may be slower than in the intact animal. 08/10/2010162KLECOP, Nipani

163  Circulation technique Small intestine may or may not be everted. Small intestine may or may not be everted. In this method either entire small intestine of small lab animal or a segment is isolated. In this method either entire small intestine of small lab animal or a segment is isolated. Oxygenated buffer containing the drug is circulated through the lumen. Oxygenated buffer containing the drug is circulated through the lumen. Drug free buffer is also circulated on the serosal side of the intestinal membrane & oxygenated. Drug free buffer is also circulated on the serosal side of the intestinal membrane & oxygenated. Absorption rate from the lumen to the outer solution are determined by sampling both the fluid circulating through the lumen. Absorption rate from the lumen to the outer solution are determined by sampling both the fluid circulating through the lumen. 08/10/2010163KLECOP, Nipani

164 Advantages  This is applicable to kinetic studies of the factors affecting drug absorption.  Both surface are oxygenated.  Eversion is not necessary. 08/10/2010164KLECOP, Nipani

165  Everted intestinal ring or slice technique The entire small intestine(everted) is isolated from fasted expt animal Intestine cut wit scalpel or scissors into ring like slices, 0.1-0.5cm length Intestine washed with buffer & dried by blotting with filter paper Dried rings transferred to stoppered flask containing buffer with drug at 37 o C Contd… 08/10/2010165KLECOP, Nipani

166 Contents are continuously agitated & aerated. At selected time intervals, the tissues slices are assayed for drug content 08/10/2010166KLECOP, Nipani

167 Advantages Simple & reproducible. Simple & reproducible. Kinetic studies can be performed. Kinetic studies can be performed.  Process of cutting the intestine into rings may expose highly permeable areas of cut or damage tissue to medium.  MAJOR DISADVANTAGE OF IN-VITRO METHODS is that the are based on approximation & oversimplification of the actual in-vivo conditions. 08/10/2010167KLECOP, Nipani

168 In-situ methods  Absorption from small intestine.  Perfusion technique.  Intestinal loop technique.  Absorption from the stomach. 08/10/2010168KLECOP, Nipani

169 Why in-situ studies. In this method the animals blood supply remains intact & thus the results of rate of absorption determined may be more realistic than those from in-vitro techniques. In this method the animals blood supply remains intact & thus the results of rate of absorption determined may be more realistic than those from in-vitro techniques. Alternative means to in-vivo models in evaluating the relative contribution of GI absorption to oral bioavailability. Alternative means to in-vivo models in evaluating the relative contribution of GI absorption to oral bioavailability. Act as bridge between in-vitro & in-vivo methods. Act as bridge between in-vitro & in-vivo methods. Mimic the in-vivo physiological process with significant reduction in cost & time. Mimic the in-vivo physiological process with significant reduction in cost & time. 08/10/2010169KLECOP, Nipani

170  ABSORPTION FROM SMALL INTESTINE Adult male rats fasted for about 16-24hrs. Animal anesthetized, a midline abdominal incision is made. isolation & cannulation of Small intestine Contd… 08/10/2010170KLECOP, Nipani

171 Replacement of intestine. Incision closed & duodenal cannula is attached to an infusion pump Intestine cleared off particulate matter using drug free buffer (1.5ml/30min) Drug buffer solution is perfused (1.5ml/30min) Contd… 08/10/2010171KLECOP, Nipani

172 Samples at 10min interval collected from ileal cannula Samples assayed for drug content Relative rate of absorption calculated Relative rate of absorption = difference in the drug concentration entering & leaving the intestine 08/10/2010172KLECOP, Nipani

173 Figure 08/10/2010173KLECOP, Nipani

174 Here, single or multiple intestinal loops are used for studying absorption Adult male rat fasted & water with held for 1-2hrs before expt. Under anesthesia an abdominal incision is made & small intestine exposed. Placement of proximal ligature & distal ligature. Introduction of drug solution. Contd.. 08/10/2010174KLECOP, Nipani

175 Replacement of intestinal loop. After a predetermined period of time, animal is sacrificed. Intestinal loop is rapidly excised & homogenized. The amount of drug unabsorbed is determined. 08/10/2010175KLECOP, Nipani

176 Advantages Simple & reproducible. Simple & reproducible.  Only 1 sample can be obtained from the experimental animal. For preparing multiple loops, the procedure is identical to single loop preparation with a distance of approximately one half inch left between successive loops. 08/10/2010176KLECOP, Nipani

177  Absorption from the stomach Fasted adult male rats anesthetized, stomach exposed & cardiac end ligated. Introduction of cannula (pylorus). Lumen washed several times with saline & subsequently with 0.1N HCl containing 0.15M NaCl Drug solution of known concentration is introduced into the stomach Contd…. 08/10/2010177KLECOP, Nipani

178 After 1hr, the drug solution is removed from the gastric pouch & assayed for drug content. % of drug absorbed in 1hr may be calculated. The gastric pouch may also be homogenized & analyzed for drug. In-situ techniques equate absorption with loss of drug from the GI lumen & if a drug is significantly accumulated or metabolized in gut wall, one will get an overestimate of the amount of drug absorbed 08/10/2010178KLECOP, Nipani

179 In-vivo methods Direct method. Direct method. Indirect method. Indirect method. 08/10/2010179KLECOP, Nipani

180 Why in-vivo studies  Only method to assess the importance of many factors like-  Gastric emptying.  Intestinal motility.  Effect of drug on GIT.  The influence of dosage form variables on drug absorption can also be studied. 08/10/2010180KLECOP, Nipani

181  Direct method The drug level in blood or urine is determined as a function of time. The drug level in blood or urine is determined as a function of time. Absorption studies on experimental animals & clinical trials. Absorption studies on experimental animals & clinical trials. Selection of experimental animals- pigs, dogs, rabbits, rat. Selection of experimental animals- pigs, dogs, rabbits, rat. 08/10/2010181KLECOP, Nipani

182 Procedure A blank urine or blood sample is taken for the test animal before the experiment. Administration of test dosage form. Blood or urine sampling. Assay for drug content & determination of rate & extent of drug absorption. 08/10/2010182KLECOP, Nipani

183  Indirect method Adopted when the measurement of drug concentration in blood or urine is difficult or not possible. Adopted when the measurement of drug concentration in blood or urine is difficult or not possible. Pharmacological response is taken as the index of drug absorption. Pharmacological response is taken as the index of drug absorption. LD 50 appears to be dependent on the rate of absorption of drug & hence on the rate of dissolution. LD 50 appears to be dependent on the rate of absorption of drug & hence on the rate of dissolution. A plot of log dose vs. duration of response time is plotted. A plot of log dose vs. duration of response time is plotted. 08/10/2010183KLECOP, Nipani

184 Log dose Duration of response time Fk a /2.303 x y Where, F= bioavailability. K a = the absorption rate constant. d= threshold dose d 08/10/2010184KLECOP, Nipani

185 REFERENCES 1.Biopharmaceutics & pharmacokinetics by D.M.Brahmankar & Sunil B. Jaiswal. 2.Biopharmaceutics & pharmacokinetics by P.L.Madan. 3.Biopharmaceutics & pharmacokinetics by G.R.Chatwal. 4.Human anatomy & physiology by Tortora. 5.www.google.com. 08/10/2010185KLECOP, Nipani

186 Thank you Cell No: 00919742431000 E-mail: bknanjwade@yahoo.co.in 08/10/2010186KLECOP, Nipani


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