Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of Pharmaceutics KLE University’s...

Prof. Dr. Basavaraj K. Nanjwade Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. DM. Pharm., Ph. D

Department of PharmaceuticsDepartment of PharmaceuticsKLE University’s College of PharmacyKLE University’s College of PharmacyBELGAUm – 590010, Karnataka, IndiaBELGAUm – 590010, Karnataka, India

Cell No: 00919742431000Cell No: 00919742431000E-mail: [email protected]: [email protected]

08/10/201008/10/2010 11KLECOP, NipaniKLECOP, Nipani

CONTENTSCONTENTS 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 absorptionFactors affecting drug absorption Absorption of drugs from non-per oral routesAbsorption of drugs from non-per oral routes Methods of determining absorptionMethods of determining absorption References.References.


Introduction of AbsorptionIntroduction of Absorption Definition :Definition :

The process of movement of unchanged The process of movement of unchanged drug from the site of administration to systemic drug from the site of administration to systemic circulation.circulation.

There always exist a correlation between the plasma There always exist a correlation between the plasma concentration of a drug & the therapeutic response & concentration of a drug & the therapeutic response & thus, absorption can also be defined as the process of thus, absorption can also be defined as the process of movement of unchanged drug from the site of movement of unchanged drug from the site of administration to the site of measurement.administration to the site of measurement.

i.e., plasma.i.e., plasma.


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.


CELL MEMBRANECELL MEMBRANE Also called the plasma membrane, plasmalemma or Also called the plasma membrane, plasmalemma or

phospholipid bilayer.phospholipid bilayer. The plasma membrane is a flexible yet sturdy barrier that The plasma membrane is a flexible yet sturdy barrier that

surrounds & contains the cytoplasm of a cell.surrounds & contains the cytoplasm of a cell.

Cell membrane mainly consists of:Cell membrane mainly consists of: 1. Lipid bilayer-1. Lipid bilayer-

-phospholipid-phospholipid-Cholesterol-Cholesterol-Glycolipids.-Glycolipids.

2. Proitens-2. Proitens--Integral membrane proteins-Integral membrane proteins-Lipid anchored proteins-Lipid anchored proteins-Peripheral Proteins-Peripheral Proteins


LIPID BILAYERLIPID BILAYER


LIPID BILAYERLIPID BILAYER The basic structural framework of the plasma The basic structural framework of the plasma

membrane is the lipid bilayer.membrane is the lipid bilayer. Consists primarily of a thin layer of amphipathic Consists primarily of a thin layer of amphipathic

phospholipids which spontaneously arrange so that phospholipids which spontaneously arrange so that the hydrophobic “tail” regions are shielded from the the hydrophobic “tail” regions are shielded from the surrounding polar fluid, causing the more hydrophilic surrounding polar fluid, causing the more hydrophilic “head” regions to associate with the cytosolic & “head” regions to associate with the cytosolic & extracellular faces of the resulting bilayer.extracellular faces of the resulting bilayer.

This forms a continuous, spherical lipid bilayer app. This forms a continuous, spherical lipid bilayer app. 7nm thick.7nm thick.


It consists of two back to back layers made up of It consists of two back to back layers made up of three types: Phospholipid, Cholesterol, Glycolipids.three types: Phospholipid, Cholesterol, Glycolipids.

1)1) Phospholipids :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 )


CHOLESTEROLCHOLESTEROL

Amount in membrane is 20 %.Amount in membrane is 20 %. Insert in membrane with same orientation as Insert in membrane with same orientation as

phospholipids molecules.phospholipids molecules. Polar head of cholesterol is aligned with polar head of Polar head of cholesterol is aligned with polar head of

phospholipids.phospholipids.

FUNCTION: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 membranephase shift in membrane08/10/201008/10/2010 1010KLECOP, NipaniKLECOP, Nipani

OH


GLYCOLIPIDSGLYCOLIPIDS 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.

FUNCTIONSFUNCTIONS:: ProtectiveProtective InsulatorInsulator Site of receptor bindingSite of receptor binding08/10/201008/10/2010 1313KLECOP, NipaniKLECOP, Nipani

COMPOSITION OF PROTEINSCOMPOSITION OF PROTEINS

PROTEINS

INTEGRALPROTEINS

LIPIDANCHOREDPROTEINS

PERIPHERALPROTEINS


INTEGRAL PROTEINSINTEGRAL 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 Hydrophobic domain anchore within the cell

membrane and hydrophilic domain interacts with membrane and hydrophilic domain interacts with external molecules.external molecules.

Hydrophobic domain consists of one, multiple or Hydrophobic domain consists of one, multiple or combination of combination of αα – – heliceshelices and ß – and ß – sheets protein sheets protein mofitsmofits. .

Ex. Ex. – – Ion Channels, Proton pump, GPCR.Ion Channels, Proton pump, GPCR.


LIPID ANCHORED PROTEINLIPID ANCHORED PROTEIN

Covalently bound to single or multiple lipid Covalently bound to single or multiple lipid molecules.molecules.

Hydrophobically inert into cell membrane & anchor Hydrophobically inert into cell membrane & anchor the protein.the protein.

The protein itself is not in contact with membrane.The protein itself is not in contact with membrane.

ExEx. – G Proteins.. – G Proteins.


PERIPHERAL PROTEINSPERIPHERAL PROTEINS

Attached to integral membrane proteins OR associated Attached to integral membrane proteins OR associated with peripheral regions of lipid bilayer.with peripheral regions of lipid bilayer.

Have only temporary interaction with biological Have only temporary interaction with biological membrane.membrane.

Once reacted with molecule, dissociates to carry on its Once reacted with molecule, dissociates to carry on its work in cytoplasm.work in cytoplasm.

Ex.Ex. – Some Enzyme, Some Hormone – Some Enzyme, Some Hormone


GASTRO INTESTINAL ABSORPTION OF DRUGSGASTRO INTESTINAL ABSORPTION OF DRUGS


Stomach :Stomach : The surface area for absorption of drugs is relatively small in The surface area for absorption of drugs is relatively small in

the stomach due to the absence of macrovilli & microvilli.the stomach due to the absence of macrovilli & microvilli. Extent of drug absorption is affected by variation in the time it 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 takes the stomach to empty, i.e., how long the dosage form is able to reside in stomach.able to reside in stomach.

Drugs which are acid labile must not be in contact with the Drugs which are acid labile must not be in contact with the acidic environment of the stomach.acidic environment of the stomach.

Stomach emptying applies more to the solid dosage forms Stomach emptying applies more to the solid dosage forms because the drug has to dissolve in the GI fluid before it is because the drug has to dissolve in the GI fluid before it is available for absorption.available for absorption.

Since solubility & dissolution rate of most drugs is a function Since solubility & dissolution rate of most drugs is a function of pH, it follows that, a delivery system carrying a drug that is of pH, it follows that, a delivery system carrying a drug that is predominantly absorbed from the stomach, must stay in the predominantly absorbed from the stomach, must stay in the stomach for an extended period of time in order to assure stomach for an extended period of time in order to assure maximum dissolution & therefore to extent of absorption. maximum dissolution & therefore to extent of absorption.


Small Intestine :Small Intestine :

The drugs which are predominantly absorbed through the small The drugs which are predominantly absorbed through the small intestine, the transit time of a dosage form is the major intestine, the transit time of a dosage form is the major determinant of extent of absorption.determinant of extent of absorption.

Various studies to determine transit time:Various studies to determine transit time:

Early studies using indirect methods placed the average normal Early studies using indirect methods placed the average normal transit time through the small intestine at about 7 hours.transit time through the small intestine at about 7 hours.

These studies were based on the detection of hydrogen after an These studies were based on the detection of hydrogen after an oral dose of lactulose. (Fermentation of lactulose by colon oral dose of lactulose. (Fermentation of lactulose by colon bacteria yields hydrogen in the breath).bacteria yields hydrogen in the breath).


Newer studies suggest the transit time to be about 3 to Newer studies suggest the transit time to be about 3 to 4 hours.4 hours.

Use gamma scintigraphy.Use gamma scintigraphy.

Thus, if the transit time in small intestine for most Thus, if the transit time in small intestine for most healthy adults is between 3 to 4 hours, a drug may healthy adults is between 3 to 4 hours, a drug may take about 4 to 8 hours to pass through the stomach & take about 4 to 8 hours to pass through the stomach & small intestine during fasting state.small intestine during fasting state.

During the fed state, the small intestine transit time During the fed state, the small intestine transit time may take about 8 to 12 hours.may take about 8 to 12 hours.


Small Intestine :

Large intestine :Large intestine :

The major function of large intestine is to absorb The major function of large intestine is to absorb water from ingestible food residues which are water from ingestible food residues which are delivered to the large intestine in a fluid state, & delivered to the large intestine in a fluid state, & eliminate them from the body as semi solid feces.eliminate them from the body as semi solid feces.

Only a few drugs are absorbed in this region.Only a few drugs are absorbed in this region.


MECHANISM OF DRUG MECHANISM OF DRUG ABSORPTIONABSORPTION

1)1) Passive diffusionPassive diffusion

2)2) Pore transportPore transport

3)3) Carrier- mediated transportCarrier- mediated transport

a) Facilitated diffusiona) Facilitated diffusion

b) Active transportb) Active transport

4)4) Ionic or Electrochemical diffusionIonic or Electrochemical diffusion

5)5) Ion-pair transportIon-pair transport

6)6) EndocytosisEndocytosis


1)1) PASSIVE DIFFUSIONPASSIVE DIFFUSION

Also known as non-ionic Also known as non-ionic diffusion.diffusion.

It is defined as the It is defined as the difference in the drug difference in the drug concentration on either side concentration on either side of the membrane.of the membrane.

Absorption of 90% of drugs.Absorption of 90% of drugs. The driving force for this The driving force for this

process is the concentration process is the concentration or electrochemical gradient.or electrochemical gradient.


Passive diffusion is best expressed by Fick’s first Passive diffusion is best expressed by Fick’s first law of diffusion which states that the drug law of diffusion which states that the drug molecules diffuse from a region of higher molecules diffuse from a region of higher concentration to one of lower concentration until concentration to one of lower concentration until equilibrium is attained & the rate of diffusion is equilibrium is attained & the rate of diffusion is directly proportional to the concentration gradient directly proportional to the concentration gradient across the membrane.across the membrane.

dQ == D A KD A Km/w m/w (C(CGITGIT – C) – C)

dt h dt h

Certain characteristic of passive diffusion can be Certain characteristic of passive diffusion can be generalized.generalized.

a)a) Down hill transportDown hill transport08/10/201008/10/2010 2626KLECOP, NipaniKLECOP, Nipani

b)b) Greater the surface area & lesser the thickness of the Greater the surface area & lesser the thickness of the membrane, faster the diffusion.membrane, faster the diffusion.

c)c) Equilibrium is attained when the concentration on Equilibrium is attained when the concentration on either side of the membrane become equal.either side of the membrane become equal.

d)d) Greater the membrane/ water partition coefficient of Greater the membrane/ water partition coefficient of drug, faster the absorption.drug, faster the absorption.

Passive diffusion process is energy independent but Passive diffusion process is energy independent but depends more or less on the square root of the depends more or less on the square root of the molecular size of the drugs.molecular size of the drugs.

The mol. Wt. of the most drugs lie between 100 to The mol. Wt. of the most drugs lie between 100 to 400 Daltons which can be effectively absorbed 400 Daltons which can be effectively absorbed passively.passively.


2)2) Pore transportPore transport Also known as convective transport, bulk flow or Also known as convective transport, bulk flow or

filtration.filtration. Important in the absorption of low mol. Wt. (less than Important in the absorption of low mol. Wt. (less than

100). Low molecular size (smaller than the diameter of the 100). Low molecular size (smaller than the diameter of the pore) & generally water-soluble drugs through narrow, pore) & generally water-soluble drugs through narrow, aqueous filled channels or pores in the membrane aqueous filled channels or pores in the membrane structure.structure.

e.g. urea, water & sugars.e.g. urea, water & sugars. The driving force for the passage of the drugs is the The driving force for the passage of the drugs is the

hydrostatic or the osmotic pressure difference across the hydrostatic or the osmotic pressure difference across the membrane.membrane.


The rate of absorption via pore transport depends on the The rate of absorption via pore transport depends on the number & size of the pores, & given as follows:number & size of the pores, & given as follows:

dcdc == N. RN. R22. A . . A . ∆C∆Cdtdt ((ηη) (h)) (h)

where, where, dcdc = rate of the absorption. = rate of the absorption.

dtdtN = number of poresN = number of poresR = radius of poresR = radius of pores∆∆C = concentration gradientC = concentration gradientηη = viscosity of fluid in the pores = viscosity of fluid in the pores


3)3) CARRIER MEDIATED CARRIER MEDIATED TRANSPORT MECHANISMTRANSPORT MECHANISM

Involves a carrier (a component of the membrane) Involves a carrier (a component of the membrane) which binds reversibly with the solute molecules to be which binds reversibly with the solute molecules to be transported to yield the carrier solute complex which transported to yield the carrier solute complex which transverses across the membrane to the other side transverses across the membrane to the other side where it dissociates to yield the solute moleculewhere it dissociates to yield the solute molecule

The carrier then returns to its original site to accept a The carrier then returns to its original site to accept a fresh molecule of solute.fresh molecule of solute.

There are two types of carrier mediated transport There are two types of carrier mediated transport system:system:

a) facilitated diffusiona) facilitated diffusion b) active transportb) active transport


a)a) Facilitated diffusionFacilitated diffusion

This mechanism involves This mechanism involves the driving force is the driving force is concentration gradient.concentration gradient.

In this system, no In this system, no expenditure of energy is expenditure of energy is involved (down-hill involved (down-hill transport), therefore the transport), therefore the process is not inhibited by process is not inhibited by metabolic poisons that metabolic poisons that interfere with energy interfere with energy production.production.


Limited importance in the absorption of drugs.Limited importance in the absorption of drugs.

e.g. Such a transport system include entry of glucose e.g. Such a transport system include entry of glucose into RBCs & intestinal absorption of vitamins Binto RBCs & intestinal absorption of vitamins B11 & & BB22..

A classical example of passive facilitated diffusion is A classical example of passive facilitated diffusion is the gastro-intestinal absorption of vitamin Bthe gastro-intestinal absorption of vitamin B1212..

An intrinsic factor (IF), a glycoprotein produced by An intrinsic factor (IF), a glycoprotein produced by the gastric parietal cells, forms a complex with the gastric parietal cells, forms a complex with vitamin Bvitamin B12 12 which is then transported across the which is then transported across the intestinal membrane by a carrier system.intestinal membrane by a carrier system.


b) Active transportb) Active transport More important process than More important process than

facilitated diffusion.facilitated diffusion. The driving force is against The driving force is against

the concentration gradient or the concentration gradient or uphill transport.uphill transport.

Since the process is uphill, Since the process is uphill, energy is required in the energy is required in the work done by the barrier.work done by the barrier.

As the process requires As the process requires expenditure of energy, it can expenditure of energy, it can be inhibited by metabolic be inhibited by metabolic poisons that interfere with poisons that interfere with energy production. energy production.


If drugs (especially used in cancer) have structural similarities If drugs (especially used in cancer) have structural similarities to such agents, they are absorbed actively.to such agents, they are absorbed actively.

A good example of competitive inhibition of drug absorption A good example of competitive inhibition of drug absorption via active transport is the impaired absorption of levodopa via active transport is the impaired absorption of levodopa when ingested with meals rich in proteins.when ingested with meals rich in proteins.

The rate of absorption by active transport can be determined The rate of absorption by active transport can be determined by applying the equation used for Michalies-menten kinetics:by applying the equation used for Michalies-menten kinetics:

dcdc == [C].(dc/dt)[C].(dc/dt)maxmax

dt Km + [C]dt Km + [C]Where,Where,

(dc/dt)(dc/dt)max max = maximal rate of drug absorption at high drug = maximal rate of drug absorption at high drug concentration. concentration.

[C] = concentration of drug available for absorption[C] = concentration of drug available for absorption

Km = affinity constant of drug for the barrier.Km = affinity constant of drug for the barrier.08/10/201008/10/2010 3434KLECOP, NipaniKLECOP, Nipani

4)4) IONIC OR ELECTROCHEMICAL IONIC OR ELECTROCHEMICAL DIFFUSIONDIFFUSION

This charge influences the permeation of drugs.This charge influences the permeation of drugs. Molecular forms of solutes are unaffected by the Molecular forms of solutes are unaffected by the

membrane charge & permeate faster than ionic forms.membrane charge & permeate faster than ionic forms. The permeation of anions & cations is also influenced The permeation of anions & cations is also influenced

by pH.by pH. Thus, at a given pH, the rate of permeation may be as Thus, at a given pH, the rate of permeation may be as

follows:follows:

Unionized molecule > anions > cationsUnionized molecule > anions > cations


The permeation of ionized drugs, particularly the The permeation of ionized drugs, particularly the cationic drugs, depend on the potential difference or cationic drugs, depend on the potential difference or electrical gradient as the driving force across the electrical gradient as the driving force across the membrane.membrane.

Once inside the membrane, the cations are attached to Once inside the membrane, the cations are attached to negatively charged intracellular membrane, thus negatively charged intracellular membrane, thus giving rise to an electrical gradient.giving rise to an electrical gradient.

If the same drug is moving from a higher to lower If the same drug is moving from a higher to lower concentration, i.e., moving down the electrical concentration, i.e., moving down the electrical gradient , the phenomenon is known as gradient , the phenomenon is known as electrochemical diffusionelectrochemical diffusion..


5)5) ION PAIR TRANSPORTION PAIR TRANSPORT

It is another It is another mechanism is mechanism is able to explain able to explain the absorption of the absorption of such drugs such drugs which ionize at which ionize at all pH condition.all pH condition.


Transport of charged molecules due to the formation Transport of charged molecules due to the formation of a neutral complex with another charged molecule of a neutral complex with another charged molecule carrying an opposite charge.carrying an opposite charge.

Drugs have low o/w partition coefficient values, yet Drugs have low o/w partition coefficient values, yet these penetrate the membrane by forming reversible these penetrate the membrane by forming reversible neutral complexes with endogenous ions.neutral complexes with endogenous ions.

e.g. mucin of GIT.e.g. mucin of GIT. Such neutral complexes have both the required Such neutral complexes have both the required

lipophilicity as well as aqueous solubility for passive lipophilicity as well as aqueous solubility for passive diffusion.diffusion.

This phenomenon is known as ion-pair transport.This phenomenon is known as ion-pair transport.


6)6) ENDOCYTOSISENDOCYTOSIS

It involves engulfing It involves engulfing extracellular materials extracellular materials within a segment of within a segment of the cell membrane to the cell membrane to form a saccule or a form a saccule or a vesicle (hence also vesicle (hence also called as corpuscular called as corpuscular or vesicular transport) or vesicular transport) which is then pinched which is then pinched off intracellularly.off intracellularly.


In endocytosis, there are three process:In endocytosis, there are three process:

A) PhagocytosisA) Phagocytosis

B) PinocytosisB) Pinocytosis

C) TranscytosisC) Transcytosis


A) PhagocytosisA) Phagocytosis


B) PinocytosisB) Pinocytosis

This process is This process is important in the important in the absorption of oil absorption of oil soluble vitamins & in soluble vitamins & in the uptake of the uptake of nutrients.nutrients.


C) TranscytosisC) Transcytosis

It is a phenomenon in which endocytic vesicle It is a phenomenon in which endocytic vesicle is transferred from one extracellular is transferred from one extracellular compartment to another.compartment to another.


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.


DIFFUSION THROUGH MEMBRANESDIFFUSION THROUGH MEMBRANES

Rate dependent on polarity and size.Rate dependent on polarity and size.

Polarity estimated using the partition coefficient.Polarity estimated using the partition coefficient.

The greater the lipid solubility – the faster the rate of diffusionThe greater the lipid solubility – the faster the rate of diffusion

Smaller molecules (nm/ASmaller molecules (nm/A00) penetrate more rapidly.) penetrate more rapidly.

Highly permeable to OHighly permeable to O22, CO, CO22, NO and H, NO and H22O .O .

Large polar molecules – sugar, aa, phosphorylated intermediates – Large polar molecules – sugar, aa, phosphorylated intermediates –

poor permeabilitypoor permeability

These are essential for cell function – must be actively These are essential for cell function – must be actively

transportedtransported


MOVEMENT OF SUBSTANCES ACROSSMOVEMENT OF SUBSTANCES ACROSS CELL MEMBRANES CELL MEMBRANES


BIOLOGICAL FACTORS:BIOLOGICAL FACTORS: Penetration Of Drugs Through Gastro-intestinal TractPenetration Of Drugs Through Gastro-intestinal Tract Penetration Of Drugs Through Blood Brain BarrierPenetration Of Drugs Through Blood Brain Barrier Penetration Of Drugs Through Placental BarrierPenetration Of Drugs Through Placental Barrier Penetration Of Drugs Through Across The SkinPenetration Of Drugs Through Across The Skin Penetration Of Drugs Through The Mucous Membrane Of The Penetration Of Drugs Through The Mucous Membrane Of The

Nose, Throat, Trachea, Buccal Cavity, Lungs ,Vaginal And Rectal Nose, Throat, Trachea, Buccal Cavity, Lungs ,Vaginal And Rectal SurfacesSurfaces

PHYSIOLOGICAL FACTORS:PHYSIOLOGICAL FACTORS: Gastrointestinal (Gi) PhysiologyGastrointestinal (Gi) Physiology Influence Of Drug Pka And Gi Ph On Drug AbsorbtionInfluence Of Drug Pka And Gi Ph On Drug Absorbtion Git Blood FlowGit Blood Flow Gastric EmptyingGastric Emptying Disease StatesDisease States08/10/201008/10/2010 4747KLECOP, NipaniKLECOP, Nipani

PENETRATION OF DRUGS THROUGH PENETRATION OF DRUGS THROUGH GASTRO-INTESTINAL TRACTGASTRO-INTESTINAL TRACT

The Git barrier that separates the lumen of the stomach and intestine from The Git barrier that separates the lumen of the stomach and intestine from systemic circulation and is composed of lipids, proteins and polysaccharides.systemic circulation and is composed of lipids, proteins and polysaccharides.

Git mucosa is a semi permeable membrane across which various nutrients Git mucosa is a semi permeable membrane across which various nutrients like Carbohydrates, Amino acids, Vitamins and foreign substances are like Carbohydrates, Amino acids, Vitamins and foreign substances are transported and absorbed into the blood by various mechanisms like:transported and absorbed into the blood by various mechanisms like:

1. Passive diffusion1. Passive diffusion

2. Pore transport2. Pore transport

3. Facilitated transport3. Facilitated transport

4. Active transport 4. Active transport

5. Pinocytosis5. Pinocytosis


1. PASSIVE DIFFUSION1. PASSIVE DIFFUSION Major process for absorption of more than 90% of drugsMajor 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 The drug molecules diffuse from a region of higher concentration to a region of lower concentration till concentration to a region of lower concentration till equilibrium is attained. equilibrium is attained.

Rate of diffusion is directly proportional to the Rate of diffusion is directly proportional to the concentration gradient across the membrane. concentration gradient across the membrane.

Factors affecting Passive diffusion:Factors affecting Passive diffusion: Diffusion coefficient of the drugDiffusion coefficient of the drug

Related to lipid solubility and molecular wt. Related to lipid solubility and molecular wt. Thickness and surface area of the membraneThickness and surface area of the membrane Size of the moleculeSize of the molecule


2. PORE TRANSPORT2. PORE TRANSPORT

It involves the passage of ions through Aq. Pores (4-40 AIt involves the passage of ions through Aq. Pores (4-40 A00)) Low molecular weight molecules (less than 100 Daltons) Low molecular weight molecules (less than 100 Daltons)

eg- urea, water, sugar are absorbed.eg- urea, water, sugar are absorbed. Also imp. In renal excretion, removal of drug from CSF Also imp. In renal excretion, removal of drug from CSF

and entryand entry of drugs into liver.of drugs into liver.


3. FACILITATED DIFFUSION3. 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 poisonsNot inhibited by metabolic poisons

Important in transport of Polar molecules and charged Important in transport of Polar molecules and charged ions that dissolve in water but they can not diffuse freely ions that dissolve in water but they can not diffuse freely across cell membranes due to the hydrophobic nature of across cell membranes due to the hydrophobic nature of the phospholipids.the phospholipids.

Eg. 1. entry of glucose into RBCs Eg. 1. entry of glucose into RBCs 2. intestinal absorption vitamin B1 ,B22. intestinal absorption vitamin B1 ,B2

3. transport of amino acids thru permeases3. transport of amino acids thru permeases


4. ACTIVE TRANSPORT4. 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 poisonsInhibited by metabolic poisons

Endogenous substances that are transported actively Endogenous substances that are transported actively include sodium, potassium, calcium, iron, glucose, amino include sodium, potassium, calcium, iron, glucose, amino acids and vitamins like niacin, pyridoxin.acids and vitamins like niacin, pyridoxin.

Drugs having structural similarity to such agents are Drugs having structural similarity to such agents are absorbed actively absorbed actively Eg. 1. Pyrimidine transport system – absorption of 5 FU 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 levodopamethyldopa and levodopa08/10/201008/10/2010 5454KLECOP, NipaniKLECOP, Nipani

5. PINOCYTOSIS 5. PINOCYTOSIS Pinocytosis ("cell-drinking") Pinocytosis ("cell-drinking")

Uptake of fluid solute.Uptake of fluid solute.

A form of endocytosis in which small particles are brought into A form of endocytosis in which small particles are brought into the cell in the form of small vesicles which subsequently fuse the cell in the form of small vesicles which subsequently fuse with lysosomes to hydrolyze, or to break down, the particles. 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 Polio vaccine and large protein molecules are absorbed by pinocytosispinocytosis


PENETRATION OF DRUGS THROUGH PENETRATION OF DRUGS THROUGH BLOOD BRAIN BARRIERBLOOD 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 Together , they constitute the so called BLOOD BRAIN BARRIER BARRIER

Astrocytes : Special cells / elements of supporting tissue found at Astrocytes : Special cells / elements of supporting tissue found at the base of endothelial membrane.the base of endothelial membrane.

The blood-brain barrier (BBB) is a separation of circulating The blood-brain barrier (BBB) is a separation of circulating blood and cerebrospinal fluid (CSF) maintained by the choroid blood and cerebrospinal fluid (CSF) maintained by the choroid plexus in the central nervous system (CNS). plexus in the central nervous system (CNS).


Since BBB is a lipoidal barrier, Since BBB is a lipoidal barrier, It allows only the drugs having high o/w partition coefficient It allows only the drugs having high o/w partition coefficient

to diffuse to diffuse passively where as moderately lipid soluble and passively where as moderately lipid soluble and partially ionised molecules penetrate at a slow rate.partially ionised molecules penetrate at a slow rate.

Endothelial cells restrict the diffusion of microscopic objects (e.g. Endothelial cells restrict the diffusion of microscopic objects (e.g. bacteria ) and large or hydrophillic molecules into the CSF, while bacteria ) and large or hydrophillic molecules into the CSF, while

allowing the diffusion of small hydrophobic molecules (Oallowing the diffusion of small hydrophobic molecules (O22, hormones, , hormones,

COCO22). Cells of the barrier actively transport metabolic products such as ). Cells of the barrier actively transport metabolic products such as

glucose across the barrier with specific proteins. glucose across the barrier with specific proteins. Various approaches to promote crossing the BBB by drugs:Various approaches to promote crossing the BBB by drugs:

• Use of Use of Permeation enhancersPermeation enhancers such as dimethyl sulfoxide (DMSO)such as dimethyl sulfoxide (DMSO)• Osmotic disruption of the BBBOsmotic disruption of the BBB by infusing internal carotid artery by infusing internal carotid artery

with mannitolwith mannitol• Use of Use of Dihydropyridine redox systemDihydropyridine redox system as drug carriers to the brainas drug carriers to the brain

( the lipid soluble dihydropyridine is linked as a carrier to the polar ( the lipid soluble dihydropyridine is linked as a carrier to the polar

drug to form a prodrug that rapidly crosses the BBB )drug to form a prodrug that rapidly crosses the BBB )


PENETRATION OF DRUGS THROUGHPENETRATION OF DRUGS THROUGH PLACENTAL BARRIER PLACENTAL BARRIER

Placenta is the membrane separating fetal blood from the Placenta is the membrane separating fetal blood from the maternal blood.maternal blood.

It is made up of fetal trophoblast basement membrane It is made up of fetal trophoblast basement membrane and the endothelium.and the endothelium.

Mean thickness (25 µ) in early pregnancy and reduces to (2 Mean thickness (25 µ) in early pregnancy and reduces to (2 µ) at full termµ) at full term

Many drugs having mol. wt. < 1000 daltons and moderate Many drugs having mol. wt. < 1000 daltons and moderate to high lipid solubility e.g. ethanol, sulfonamides , to high lipid solubility e.g. ethanol, sulfonamides , barbiturates, steroids , anticonvulsants and some barbiturates, steroids , anticonvulsants and some antibiotics cross the barrier by simple diffusion quite antibiotics cross the barrier by simple diffusion quite rapidly .rapidly .

Nutrients essential for fetal growth are transported by Nutrients essential for fetal growth are transported by carrier mediated processes carrier mediated processes


PENETRATION OF DRUGS THROUGH ACROSS PENETRATION OF DRUGS THROUGH ACROSS THE SKINTHE SKIN

Skin is composed of three primary layers:Skin is composed of three primary layers: the the epidermisepidermis , which provides waterproofing and serves as a barrier to infection; , which provides waterproofing and serves as a barrier to infection; the the dermisdermis , which serves as a location for the appendages of skin; and , which serves as a location for the appendages of skin; and the the hypodermis (subcutaneous adipose layer)hypodermis (subcutaneous adipose layer). .

The The stratum corneum stratum corneum is the outermost layer of the epidermis and is composed is the outermost layer of the epidermis and is composed mainly of dead keratinised cells (from lack of oxygen and nutrients). It has a mainly of dead keratinised cells (from lack of oxygen and nutrients). It has a thickness between 10 - 40 μm.thickness between 10 - 40 μm.

The The dermis dermis is the layer of skin beneath the epidermis. It contains the hair follicles, is the layer of skin beneath the epidermis. It contains the hair follicles, sweat glands, sebaceous glands, apocrine glands, lymphatic vessels and blood sweat glands, sebaceous glands, apocrine glands, lymphatic vessels and blood vessels. vessels.

Hypodermis Hypodermis - Its purpose is to attach the skin to underlying bone and muscle as - 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 well as supplying it with blood vessels and nerves. The main cell types are fibroblasts, macrophages and adipocytes (the hypodermis contains 50% of body fibroblasts, macrophages and adipocytes (the hypodermis contains 50% of body fat).fat).


ROUTES OF PENETRATIONROUTES OF PENETRATION Through follicular region Through follicular region Through sweat ductsThrough sweat ducts Through unbroken stratum corneumThrough unbroken stratum corneum

FACTORS IN SKIN PERMEATIONFACTORS IN SKIN PERMEATION1.1. Thickness of the skin layer: Thickness of the skin layer:

((Thickest on palms and soles & thinest on the face)Thickest on palms and soles & thinest on the face)

2.2. Skin condition: permeability of skin is affected by age, disease state or Skin condition: permeability of skin is affected by age, disease state or injury.injury.

3.3. Skin temp.: permeability increases with increase in temp.Skin temp.: permeability increases with increase in temp.

4.4. Hydration stateHydration state

APPROACHES TO ENHANCE SKIN PERMEATIONAPPROACHES TO ENHANCE SKIN PERMEATION1.1. InnuctionInnuction

2.2. Iontophoresis Iontophoresis

3.3. SonophoresisSonophoresis

4.4. Magnetophoresis Magnetophoresis 08/10/201008/10/2010 6565KLECOP, NipaniKLECOP, Nipani

Penetration Of Drugs Through The Mucous Membrane Of Penetration Of Drugs Through The Mucous Membrane Of The Nose, Throat, Trachea, Buccal Cavity, Lungs ,Vaginal The Nose, Throat, Trachea, Buccal Cavity, Lungs ,Vaginal

And Rectal SurfacesAnd Rectal Surfaces

The barrier for the drug absorption is the capillary endothelial The barrier for the drug absorption is the capillary endothelial membrane which is lipoidal and consists of pores . membrane which is lipoidal and consists of pores .

Thus, lipid soluble drugs can easily penetrate by diffusion and smaller Thus, lipid soluble drugs can easily penetrate by diffusion and smaller drug molecules can penetrate by pore transport.drug molecules can penetrate by pore transport.


pH Membrane Blood Supply Surface Area Transit Time By-pass liver

BUCCAL approx 6 thin Good, fast absorption with

low dose

small Short unless controlled

yes

ESOPHAGUS 6 Very thick, no absorption

- small short -

STOMACH 1 – 3 NormalLipophilic,acidic and neutral drugs

good small 30 - 40 minutes, reduced absorption

no

DUODENUM 5 – 7 NormalMainly lipohilic and neutral drugs

good large very short (6" long)

no

SMALL INTESTINE

6 -7 NormalAll types of drugs

good very large 10 - 14 ft, 80 cm 2 /cm

about 3 hours no

LARGE INTESTINE

6.8 - 7 - good not very large 4 - 5 ft

long, up to 24 hr lower colon, rectum yes

Gastrointestinal (GI) Physiology


SMALL INTESTINE :SMALL INTESTINE :• Major site for absorption of most drugsMajor site for absorption of most drugs due to its large surface area (0.33 due to its large surface area (0.33

mm2 )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 The Folds in small intestine called as folds of kerckring,folds of kerckring, result in result in 3 fold3 fold

increase in surface area ( 1 mincrease in surface area ( 1 m2)2)..• These folds possess finger like projections called These folds possess finger like projections called Villi Villi which increase which increase

the surface area the surface area 30 times30 times ( 10 m( 10 m2)2)..• From the surface of villi protrude several From the surface of villi protrude several microvilli microvilli which increase the which increase the

surface area surface area 600 times600 times ( 200 m( 200 m2)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. All these factors make intestine the best site for absorbtion of most drugs.


INFLUENCE OF DRUG pKa AND GI PH ON INFLUENCE OF DRUG pKa AND GI PH ON DRUG ABSORBTIONDRUG ABSORBTION

Drugs Site of absorption

Very weak acids (pKa > 8.0) Unionized at all ph valuesAbsorbed along entire length of GIT

Moderately weak acids (pKa 2.5 – 7.5) Unionized in gastric phIonized in intestinal phBetter absorbed from stomach

Strong acids (pKa <2.5) Ionized at all ph valuesPoorly absorbed from git

Very weak bases (pKa < 5) Unionized at all ph valuesAbsorbed along entire length of GIT

Moderately weak bases (pKa 5 – 11 ) Ionized in gastric phUnionized in intestinal phBetter absorbed from intestine

Strong bases (pKa >11) Ionized at all ph valuesPoorly Absorbed from GIT


GIT BLOOD FLOWGIT BLOOD FLOW

It plays an imp. role in drug absorption by continuously maintaining It plays an imp. role in drug absorption by continuously maintaining the conc. Gradient across the epithelial membranethe conc. Gradient across the epithelial membrane

Polar molecules that are slowly absorbed show no dependence on Polar molecules that are slowly absorbed show no dependence on blood flowblood flow

The absorption of lipid soluble drugs and molecules that are small The absorption of lipid soluble drugs and molecules that are small enough to easily penetrate through Aq. pores is rapid and highly enough to easily penetrate through Aq. pores is rapid and highly dependent on rate of blood flowdependent on rate of blood flow


GASTRIC EMPTYINGGASTRIC EMPTYING The process by which food leaves the stomach and enters the The process by which food leaves the stomach and enters the

duodenum.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. SedativesRapid onset of action is desired eg. Sedatives Dissolution occurs in the intestine eg. Enteric coated tabletsDissolution occurs in the intestine eg. Enteric coated tablets Drugs not stable in gi fluids eg. penicillin GDrugs not stable in gi fluids eg. penicillin G Drug is best absorbed from small intestine eg. Vitamin B12Drug 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. GresiofulvinFood promotes drug dissolution and absorbtion eg. Gresiofulvin Disintegration and dissolution is is promoted by gastric fluidsDisintegration and dissolution is is promoted by gastric fluids


Factors affecting Gastric EmptyingFactors 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 Meal Gastric emptying rate: carbohydrates > proteins > fats

Temperature of Food

Increase in temperature, increase in emptying rate

Body Position Lying on the left side decreases emptying rate and right side promotes it

Git PH Retarded at low stomach PH and promoted at higher alkaline PH

Emotional state Anxiety promotes where as depression retards it

Disease states gastric ulcer, hypothyroidism retards it, while duodenal ulcer, hyperthyroidism promotes it.


DISEASE STATESDISEASE STATES

CHF decreases blood flow to the Git, alters GI PH, CHF decreases blood flow to the Git, alters GI PH, secretions and microbial flora.secretions and microbial flora.

Cirrhosis influences bioavailability mainly of drugs that Cirrhosis influences bioavailability mainly of drugs that undergo considerable 1st pass metabolism eg. Propranololundergo considerable 1st pass metabolism eg. Propranolol

Git infections like cholera and food poisoning also result Git infections like cholera and food poisoning also result in malabsorbtion.in malabsorbtion.


PHYSIO-CHEMICAL FACTORS

PHYSICAL FACTORS

PHYSIO-CHEMICAL FACTORS


PHYSICAL FACTORS1. 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.


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.


1. PARTICLE SIZE

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 08/10/201008/10/2010 7777KLECOP, NipaniKLECOP, Nipani

Finally drug size reduction and subsequent increase in surface area and dissolution rate is always not useful.

Ex. of such drugs are Penicillin G & ErythromycinThese 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.


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.


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 solubilityThe 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.


3. Solvates And Hydrates

Many drugs associate with solvent and forms solvatesSolvent 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. ComplexationThis 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.


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 GITDrugs 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 pH2So it means Penicillin G is stable at less acidic pH Erythromycin and its esters are unstable at gastric fluid (T½=Less than 2 min.)


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 SurfactantUse 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. DissolutionDisintegration 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


SOLID DRUG

DRUG AT ABSORPTIONSITE

DRUG IN SYSTEMIC

CIRCULATION

DISSOLUTION

ABSORPTION


NOYES AND WHITNEY’S EQUATION

dc/dt = KS(CS-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


PHYSICOCHEMICAL FACTORSPHYSICOCHEMICAL 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.


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 bothDissociation 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.


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.


eg. Pivampicilin, the pivaloyloxy-methyl ester of ampicilin isMore lipid soluble than ampicilin.

Lipid solubility is provided to a drug by its partition coefficient betweenAn 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%)


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)


Improvement of solubility:

Addition of acidic or basic excipientEx: 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.


PHARMACEUTICAL FACTORS MEANS Absorption rate depends on the dosage Form which is administred,ingredients used, proceduresUsed 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.


SOLUTIONS

Shows maximum bioavailability and factors affectingAbsorption 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. Viscosity5. Type of solution: Whether aqueous or oily solution.


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.


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.


CAPSULES

Two types of capsule

1.Hard gelatin capsule

2. Soft gelatin capsule


HARD GELATIN CAPSULEThe rate of absorption of drugs from capsule is functionOf some factors.1.Dissolution rate of gelatin shell.2.The rate of penetration of GI fluids into encapsulated mass3.The rate at which the mass disaggregates in the GI fluid4. The rate of dissolution.5. Effect of excipients;a).Diluentsb).Lubricantsc). Wetting characteristics of drugd).Packing density


SOFT GELATIN CAPSULESGS 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 HGCAnd are equivalent to emulsions.

Eg. Quinine derivative was better absorbed from SGC Containing drug base compared with HGC containingHCl salts.

Grieseoflavin exhibited 88% absorption from soft gelatinCapsules compared to HGC(30%)08/10/201008/10/2010 9898KLECOP, NipaniKLECOP, Nipani

TABLETS

1.Compressed tablets

2. Coated tablets


Compressed tabletsBioavailability are more due to large reductionin surface area.

Intact tablets a granules primary drug particlesA B

Drug in GI fluid

Drug absorbed in body

K1K2

K3

K4


The rate constants decrease in the following order.

K3>>K2>>K1

The overall dissolution rate and bioavailability of a poorSoluble drugs is influenced by1.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


1.Effect of diluents : Na Salicylates + starch = Faster dissolution Na salicylates + lactose=Poor dissolution.

2.Effect of Granulating agent:Phenobarbital + Gelatin solution=Faster dissolutionPhenobarbital+PEG 6000= poor dissolution.

3.Effect of lubricants:Magnesium stearate will retard the dissolution of aspirin tablet Whereas SLS enhance the dissolution.


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:


COATED TABLETS:There are three types of coatingSugar coatingFilm coatingEnteric coating

SUGAR COATING:Sugar,Shellac,fatty glycerides, bees wax, silicone resinSub coating agent: Talc,acacia,starch.

FILM COATING:Polymers, dispersible cellulose derivatives like HPMCCMC.

ENTERIC COATING:Shellac, cellulose acetate phthalate etc.


Factors affecting the drug release are1.Thickness of coatinge.g.. Quinine shows decrease in rate of absorptionif coated with cellulose acetate phthalate.

2.The amount of dusting powder:

3.Effect of ageing:e.g. The shellac coated tablets of Para amino salicylicacid when given after two years plasma concentrationof 6-7mg/100ml. However the tablets stored for 3½ yearsshowed plasma concentration of only 2mg/100ml which is the sub therapeutic effect.


SUBLINGUAL / BUCCAL ROUTESUBLINGUAL / BUCCAL ROUTE

SUBLINGUAL ROUTE: the dosage form is placed SUBLINGUAL ROUTE: the dosage form is placed beneath the tongue.beneath the tongue.

BUCCAL ROUTE: Dosage form is placed between BUCCAL ROUTE: Dosage form is placed between the cheek and teeth or In the cheek pouch.the cheek and teeth or In the cheek pouch.

Drugs administered by this route are supposed to Drugs administered by this route are supposed to produce systemic drug effects, and consequently, they produce systemic drug effects, and consequently, they must have good absorption from oral mucosa.must have good absorption from oral mucosa.

Oral mucosal regions are highly vascularised Oral mucosal regions are highly vascularised therefore rapid onset of action is observed.therefore rapid onset of action is observed.

For Eg, anti-anginal drug Nitroglycerin.For Eg, anti-anginal drug Nitroglycerin.08/10/201008/10/2010 106106KLECOP, NipaniKLECOP, Nipani



Blood perfuses oral regions drains directly into the general Blood perfuses oral regions drains directly into the general circulation.circulation.

Barrier to drug absorption from these routes is epithelium of Barrier to drug absorption from these routes is epithelium of oral mucosa.oral mucosa.

Passive diffusion is the major mechanism of absorption of Passive diffusion is the major mechanism of absorption of most drugs.most drugs.

In general, sublingual tablets are designed to dissolve In general, sublingual tablets are designed to dissolve slowly to minimize possibility of swallowing the dose.slowly to minimize possibility of swallowing the dose.

Exception include: Nitroglycerin, Isosorbide dinitrate tablets Exception include: Nitroglycerin, Isosorbide dinitrate tablets which dissolves within minutes in buccal cavity to provide which dissolves within minutes in buccal cavity to provide prompt treatment of acute anginal episodes.prompt treatment of acute anginal episodes.


Factors to be considered:Factors to be considered:

Lipophilicity of drugLipophilicity of drug: The lipid solubility should be : The lipid solubility should be high for absorption.high for absorption.

1.1. Salivary secretionSalivary secretion: drug should be soluble in : drug should be soluble in buccal fluid.buccal fluid.

2.2. pH of salivapH of saliva: pH of saliva is usually 6.: pH of saliva is usually 6.3.3. StorageStorage compartmentcompartment: some drugs have storage : some drugs have storage

compartment in buccal mucosa. Eg, Buprenorphinecompartment in buccal mucosa. Eg, Buprenorphine4.4. Thickness of oral epitheliumThickness of oral epithelium: : SSublingual ublingual absorption is faster than buccal, because former absorption is faster than buccal, because former

region is thinner than that of buccal mucosa.region is thinner than that of buccal mucosa.


FACTORS LIMITTING DRUG FACTORS LIMITTING DRUG ADMINISTRATION:ADMINISTRATION:

1.1. Limited mucosal surface area.Limited mucosal surface area.

2.2. Taste of medicament and discomfort.Taste of medicament and discomfort.

EXAMPLES: Nitroglycerin, Isosorbide dinitrate, EXAMPLES: Nitroglycerin, Isosorbide dinitrate, Progesterone, Oxytocin, Fenosterol, Morphine.Progesterone, Oxytocin, Fenosterol, Morphine.


RECTAL ADMINISTRATION:RECTAL ADMINISTRATION:

Absorption across the rectal mucosa occurs by Absorption across the rectal mucosa occurs by passive diffusion.passive diffusion.

This route of administration is useful in children, old This route of administration is useful in children, old people and unconscious patients.people and unconscious patients.

Eg., drugs that administered are: aspirin, Eg., drugs that administered are: aspirin, acetaminophen, theophylline, indomethacin, acetaminophen, theophylline, indomethacin, promethazine & certain barbiturates.promethazine & certain barbiturates.


PARENTERAL ROUTES:PARENTERAL ROUTES:

.


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


INTRAVENOUS ROUTE:

INTRAVENOUS ROUTE: This route is used when a rapid clinical response is This route is used when a rapid clinical response is

required like treatment of epileptic seizures, acute required like treatment of epileptic seizures, acute asthmatic and cardiac arrhythmias.asthmatic and cardiac arrhythmias.

There may also be a danger of precipitation of drug in There may also be a danger of precipitation of drug in the vein if the inj. is too rapidly. This could result in the vein if the inj. is too rapidly. This could result in thrombophlebitis.thrombophlebitis.

This mode of administration is required with drugs This mode of administration is required with drugs having short half lives and narrow therapeutic index.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.


Intra arterial injectionIntra arterial injection

In this route the drugs are injected directly into the In this route the drugs are injected directly into the artery.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 It increased drug delivery to the area supplied by the

infused artery and decreased drug delivery to infused artery and decreased drug delivery to systemic circulation.systemic circulation.


INTRA MUSCULAR INJECTIONINTRA MUSCULAR INJECTION

Absorption of drug from muscles is rapid and Absorption of drug from muscles is rapid and absorption rate is perfusion rate limited.absorption rate is perfusion rate limited.

Polypeptides of less than approx 5000 gram per mole Polypeptides of less than approx 5000 gram per mole primarily pass through capillary pathwayprimarily pass through capillary pathway

Greater than about 20000 g/mol are less able to Greater than about 20000 g/mol are less able to traverse capillary wall, they primarily enter blood via traverse capillary wall, they primarily enter blood via lymphatic pathway.lymphatic pathway.


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.


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.08/10/201008/10/2010 119119KLECOP, NipaniKLECOP, Nipani

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.


Skin consist of three layers Skin consist of three layers :: EpidermisEpidermis Dermis Dermis Subcutaneous fat tissueSubcutaneous fat tissue The main route for the penetration of the drugs is The main route for the penetration of the drugs is

generally through epidermal layergenerally through epidermal layer Stratum corneum is the rate limiting barrier in passive Stratum corneum is the rate limiting barrier in passive

percutaneous absorption of drug.percutaneous absorption of drug.


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).


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. 08/10/201008/10/2010 125125KLECOP, NipaniKLECOP, Nipani

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.


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%


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. 08/10/201008/10/2010 129129KLECOP, NipaniKLECOP, Nipani

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


FACTOR INFLUENCING FACTOR INFLUENCING PERCUTANEOUS ABSORPTIONPERCUTANEOUS ABSORPTION

1.1. Drug release from dosage form Drug release from dosage form

2.2. Drug concentration in the formulationDrug concentration in the formulation

3.3. Drug oil water partition coefficient.Drug oil water partition coefficient.

4.4. Drug affinity to the skin tissueDrug affinity to the skin tissue

5.5. Surface areaSurface area

6.6. Site of applicationSite of application

7.7. Hydration of skinHydration of skin

8.8. Nature of vehicle used Nature of vehicle used


FACTOR INFLUENCING FACTOR INFLUENCING PERCUTANEOUS ABSORPTIONPERCUTANEOUS ABSORPTION

99. Rubbing. Rubbing

10. Contact period10. Contact period

11. Permeation enhancers11. Permeation enhancers


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 flowParticles larger than 20 micron and the particles impact in the mouth and throat. Smaller than 0.5 micron and they aren't retained.


INTRA NASAL ADMINISTRATIONINTRA NASAL ADMINISTRATION Drugs generally administered by intra nasal route for Drugs generally administered by intra nasal route for

treatment of local condition such as perennial rhinitis, treatment of local condition such as perennial rhinitis, allergic rhinitis and nasal decongestion etc.allergic rhinitis and nasal decongestion etc.

Absorption of lipophilic drugs through nasal mucosa Absorption of lipophilic drugs through nasal mucosa by passive diffusion and absorption of polar drugs by by passive diffusion and absorption of polar drugs by pore transport.pore transport.

Rate of absorption of lipophilic drugs depend on their Rate of absorption of lipophilic drugs depend on their molecular weight.molecular weight.

Drugs with molecular weight less than 400 daltons Drugs with molecular weight less than 400 daltons exhibit higher rate of absorption.exhibit higher rate of absorption.


cont…cont…

Drugs with molecular weight 1000 daltons show Drugs with molecular weight 1000 daltons show moderate rate of absorption.moderate rate of absorption.

Presently nasal route is becoming popular for Presently nasal route is becoming popular for systemic delivery of peptide and proteins, this is systemic delivery of peptide and proteins, this is because of high because of high permeabilitypermeability of nasal mucosa with of nasal mucosa with vasculature.vasculature.


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.08/10/201008/10/2010 137137KLECOP, NipaniKLECOP, Nipani

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.


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


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.


Various mechanisms involved in absorption enhancements are:-

Increased drug solubility

Decreased mucosal viscosity

Decrease enzymatic degradation

Increased Paracellular transport

Increased transcellular transport



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.



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.


Applications of nasal drug deliveryA. 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.


Applications of nasal drug deliveryB. 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.


PULMONARY ADMINISTRATIONPULMONARY ADMINISTRATION The drugs may be administered for local The drugs may be administered for local

action of bronchioles or their systemic effects action of bronchioles or their systemic effects through absorption of lungs.through absorption of lungs.

Inhalation sprays and aerosols are used to Inhalation sprays and aerosols are used to deliver the drugs to the lungs.deliver the drugs to the lungs.

Larger surface area of alveoli, high Larger surface area of alveoli, high permeability of alveolar epithelium for drug permeability of alveolar epithelium for drug penetration, and a rich vasculature are penetration, and a rich vasculature are responsible for rapid absorption of drugs by responsible for rapid absorption of drugs by this routethis route


PULMONARY ADMINISTRATIONPULMONARY ADMINISTRATION

In general particles greater than 10mm are In general particles greater than 10mm are retained in the throat and upper airways whereas retained in the throat and upper airways whereas fine particles reach the pulmonary epitheliumfine particles reach the pulmonary epithelium

Drugs generally administered by this route are Drugs generally administered by this route are bronchodilators (e.g.. Salbutamol, isoproterenol), bronchodilators (e.g.. Salbutamol, isoproterenol), antiallergic (e.g.. Cromolym sodium), and antiallergic (e.g.. Cromolym sodium), and antiinflammatory (e.g.. Betamethasone, antiinflammatory (e.g.. Betamethasone, dexamethasone).dexamethasone).


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


IN-VITRO METHODSIN-VITRO METHODS

Everted small intestine sac method.Everted small intestine sac method.

Everted sac modification.Everted sac modification.

Circulation technique.Circulation technique.

Everted intestinal ring or slice technique.Everted intestinal ring or slice technique.


Why in-vitro studiesWhy in-vitro studies

Because of economical & ethical limitations of in-vivo Because of economical & ethical limitations of in-vivo studies.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 Procedures are of great value during screening of new

drug candidates.drug candidates. Carried out outside the body.Carried out outside the body. Used to assess permeability of drug using animal Used to assess permeability of drug using animal

tissues.tissues.


Everted small intestine sac Everted small intestine sac techniquetechnique

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…08/10/201008/10/2010 152152KLECOP, NipaniKLECOP, Nipani

Flask & its contents oxygenated & agitated at 37oC for specific period of

time

After incubation, the serosal content is assayed for drug

content


Figure( reverted sac technique)Figure( reverted sac technique)

Serosal side

Mucosal side(intestinal segment before eversion)

Buffer solution

Ligature

Mucosal side

Serosal side

(after eversion)08/10/201008/10/2010 154154KLECOP, NipaniKLECOP, Nipani

AdvantagesAdvantages Prolongs the viability & integrity of the Prolongs the viability & integrity of the

preparation after removal from the animal.preparation after removal from the animal. Convenience & accuracy with respect to drug Convenience & accuracy with respect to drug

analysis. analysis. The epithelial cells of the mucosal surface are The epithelial cells of the mucosal surface are

exposed directly to the oxygenated mucosal exposed directly to the oxygenated mucosal fluid.fluid.

Difficulty in obtaining more than one sample per intestinal segment


Everted sac modificationEverted sac modification

Crane & Wilson modification.Crane & Wilson modification.

Essential features of simple sac methods are Essential features of simple sac methods are retained.retained.

ModificationModification- - the intestine is tied to a the intestine is tied to a cannula. cannula.


cannula

Plain buffer

Buffer solution with drug

Water maintained at 37o C

(FIG: EVERTED SAC MODIFICATION)

aerator08/10/201008/10/2010 157157KLECOP, NipaniKLECOP, Nipani

ProcedureProcedure

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….


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


How to determine the rate How to determine the rate of drug transferof drug transfer

The entire volume of serosal solution is The entire volume of serosal solution is removed from the sac at each time interval removed from the sac at each time interval with the help of syringe & it is replaced with with the help of syringe & it is replaced with fresh buffer solution.fresh buffer solution.

The amount of drug that permeates the The amount of drug that permeates the intestinal mucosa is plotted against time to intestinal mucosa is plotted against time to describe the absorption profile of the drug at describe the absorption profile of the drug at any specific pH.any specific pH.


AdvantagesAdvantages A number of different solutions may be A number of different solutions may be

tested with a single segment of the intestine tested with a single segment of the intestine unlike in the sac technique.unlike in the sac technique.

Simple & reproducible.Simple & reproducible. It distinguishes between active & passive It distinguishes between active & passive

absorption.absorption. It determines the region of the small It determines the region of the small

intestine where absorption is optimal, intestine where absorption is optimal, particularly in the case of active transport.particularly in the case of active transport.

Also used to study the effect of pH, surface Also used to study the effect of pH, surface active agents, complexation & enzymatic active agents, complexation & enzymatic reaction.reaction.


DisadvantagesDisadvantages

The intestinal preparation is removed The intestinal preparation is removed from the animal as well as from its blood from the animal as well as from its blood supply. Under these conditions, the supply. Under these conditions, the permeability characteristics of the permeability characteristics of the membrane are significantly altered.membrane are significantly altered.

The rate of transport of drug as The rate of transport of drug as determined from the everted sac determined from the everted sac technique, may be slower than in the technique, may be slower than in the intact animal.intact animal.


Circulation techniqueCirculation 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 In this method either entire small intestine of

small lab animal or a segment is isolated.small lab animal or a segment is isolated. Oxygenated buffer containing the drug is Oxygenated buffer containing the drug is

circulated through the lumen.circulated through the lumen. Drug free buffer is also circulated on the Drug free buffer is also circulated on the

serosal side of the intestinal membrane & serosal side of the intestinal membrane & oxygenated.oxygenated.

Absorption rate from the lumen to the outer Absorption rate from the lumen to the outer solution are determined by sampling both the solution are determined by sampling both the fluid circulating through the lumen.fluid circulating through the lumen.


AdvantagesAdvantages

This is applicable to kinetic studies of This is applicable to kinetic studies of the factors affecting drug absorption.the factors affecting drug absorption.

Both surface are oxygenated.Both surface are oxygenated.

Eversion is not necessary.Eversion is not necessary.


Everted intestinal ring or Everted intestinal ring or slice technique 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

37oCContd…08/10/201008/10/2010 165165KLECOP, NipaniKLECOP, Nipani

Contents are continuously agitated & aerated.

At selected time intervals, the tissues slices are assayed for drug

content


AdvantagesAdvantages 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.


In-situ methodsIn-situ methods

Absorption from small intestine.Absorption from small intestine.

Perfusion technique.Perfusion technique.

Intestinal loop technique.Intestinal loop technique.

Absorption from the stomach.Absorption from the stomach.


Why in-situ studies.Why in-situ studies.

In this method the animals blood supply remains In this method the animals blood supply remains intact & thus the results of rate of absorption intact & thus the results of rate of absorption determined may be more realistic than those from determined may be more realistic than those from in-vitro techniques.in-vitro techniques.

Alternative means to in-vivo models in evaluating Alternative means to in-vivo models in evaluating the relative contribution of GI absorption to oral the relative contribution of GI absorption to oral bioavailability.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 Mimic the in-vivo physiological process with

significant reduction in cost & time.significant reduction in cost & time.08/10/201008/10/2010 169169KLECOP, NipaniKLECOP, Nipani

ABSORPTION FROM ABSORPTION FROM SMALL INTESTINESMALL INTESTINE

Adult male rats fasted for about 16-24hrs.

Animal anesthetized, a midline abdominal incision

is made.

isolation & cannulation of Small intestine


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)


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


FigureFigure


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..08/10/201008/10/2010 174174KLECOP, NipaniKLECOP, Nipani

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.


AdvantagesAdvantages Simple & reproducibleSimple & 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.


Absorption from the stomachAbsorption 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….08/10/201008/10/2010 177177KLECOP, NipaniKLECOP, Nipani

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 absorbed08/10/201008/10/2010 178178KLECOP, NipaniKLECOP, Nipani

In-vivo methodsIn-vivo methods

Direct method.Direct method.

Indirect method.Indirect method.


Why in-vivo studiesWhy in-vivo studies

Only method to assess the importance of many Only method to assess the importance of many factors like-factors like-

Gastric emptying.Gastric emptying. Intestinal motility.Intestinal motility. Effect of drug on GIT.Effect of drug on GIT.

The influence of dosage form variables on The influence of dosage form variables on drug absorption can also be studied.drug absorption can also be studied.


Direct methodDirect method

The drug level in blood or urine is The drug level in blood or urine is determined as a function of time.determined as a function of time.

Absorption studies on experimental Absorption studies on experimental animals & clinical trials.animals & clinical trials.

Selection of experimental animals- pigs, Selection of experimental animals- pigs, dogs, rabbits, rat.dogs, rabbits, rat.


ProcedureProcedureA 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.


Indirect methodIndirect method Adopted when the measurement of drug Adopted when the measurement of drug

concentration in blood or urine is difficult concentration in blood or urine is difficult or not possible.or not possible.

Pharmacological response is taken as the Pharmacological response is taken as the index of drug absorption.index of drug absorption.

LD 50 appears to be dependent on the rate LD 50 appears to be dependent on the rate of absorption of drug & hence on the rate of absorption of drug & hence on the rate of dissolution.of dissolution.

A plot of log dose vs. duration of response A plot of log dose vs. duration of response time is plotted.time is plotted.


Log

dos

e

Duration of response time

Fka/2.303

x

y

Where, F= bioavailability.Ka= the absorption rate constant.d= threshold dose

d


REFERENCESREFERENCES

1.1. Biopharmaceutics & pharmacokinetics by Biopharmaceutics & pharmacokinetics by D.M.Brahmankar & Sunil B. Jaiswal.D.M.Brahmankar & Sunil B. Jaiswal.

2.2. Biopharmaceutics & pharmacokinetics by Biopharmaceutics & pharmacokinetics by P.L.Madan.P.L.Madan.

3.3. Biopharmaceutics & pharmacokinetics by Biopharmaceutics & pharmacokinetics by G.R.Chatwal.G.R.Chatwal.

4.4. Human anatomy & physiology by Tortora.Human anatomy & physiology by Tortora.

5.5. www.google.com.www.google.com.


Thank youThank youCell No: 00919742431000

E-mail: [email protected]


Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of Pharmaceutics KLE University’s...

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