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D
Department of Pharmaceutics
KLE Universitys College of Pharmacy
BELGAUm 590010, Karnataka, India
Cell No: 00919742431000
E-mail: bknanjwade@yahoo.co.in
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CONTENTS
Introduction of absorption.
Structure of the Cell Membrane.
Gastro intestinal absorption of drugs.
Mechanism of Drug absorption.
Factors affecting drug absorption
Absorption of drugs from non-per oral routes
Methods of determining absorption
References.
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Introduction of Absorption
Definition :
The process of movement of unchanged
drug from the site of administration to systemic
circulation.
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Therapeutic success of a
rapidly & completely
absorbed drug.
Plasma
Drug
Therapeutic failure of a
slowly absorbed drug.
Conc.
Subtherapeutic level
Time
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CELL MEMBRANE
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LIPID BILAYER
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LIPID BILAYER
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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 )
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CHOLESTEROL
Amount in membrane is 20 %.
Insert in membrane with same orientation as
phospholipids molecules.
Polar head of cholesterol is aligned with polar head of
phospholipids.
FUNCTION:
Immobilize first few hydrocarbons groups
phospholipids molecules.
Prevents crystallization of hydrocarbons &
phase shift in membrane
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OH
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GLYCOLIPIDS
FUNCTIONS:
Protective
Insulator
Site of receptor binding
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COMPOSITION OF PROTEINS
PROTEINS
INTEGRAL
PROTEINS
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LIPID
ANCHORED
PROTEINS
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PERIPHERAL
PROTEINS
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INTEGRAL PROTEINS
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Ex. G Proteins.
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PERIPHERAL PROTEINS
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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.
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Small Intestine :
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Small
Intestine
: transit time to be about 3 to
Newer studies
suggest the
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.
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Large intestine :
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MECHANISM OF DRUG
ABSORPTION
1)
2)
3)
4)
5)
6)
Passive diffusion
Pore transport
Carrier- mediated transport
a) Facilitated diffusion
b) Active transport
Ionic or Electrochemical diffusion
Ion-pair transport
Endocytosis
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1) PASSIVE DIFFUSION
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a)
D A Km/w
h
(CGIT C)
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b)
c)
d)
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2) Pore transport
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.
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.
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dc = N. R2. A . C
dt () (h)
where,
dc = rate of the absorption.
dt
N = number of pores
R = radius of pores
C = concentration gradient
= viscosity of fluid in the pores
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a) Facilitated diffusion
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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.
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b) Active transport
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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.
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4) IONIC OR ELECTROCHEMICAL
DIFFUSION
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It is another
mechanism is
able to explain
the absorption of
such drugs
which ionize at
all pH condition.
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6) ENDOCYTOSIS
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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.
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A)
Phagocytosis
B)
Pinocytosis
C)
Transcytosis
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A) Phagocytosis
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B) Pinocytosis
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This process is
important in the
absorption of oil
soluble vitamins & in
the uptake of
nutrients.
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C) Transcytosis
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BIOLOGICAL FACTORS:
PHYSIOLOGICAL FACTORS:
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1. PASSIVE DIFFUSION
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2. PORE TRANSPORT
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3. FACILITATED DIFFUSION
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4. ACTIVE TRANSPORT
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5. PINOCYTOSIS
Pinocytosis ("cell-drinking")
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BLOOD BRAIN
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ROUTES OF PENETRATION
2.
3.
4.
Innuction
Iontophoresis
Sonophoresis
Magnetophoresis
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Thus, lipid soluble drugs can easily penetrate by diffusion and smaller
drug molecules can penetrate by pore transport.
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Membrane
Transit Time
By-pass liver
BUCCAL
approx 6
thin
Good, fast
absorption with
low dose
small
Short unless
controlled
yes
ESOPHAGUS
Very thick, no
absorption
small
short
STOMACH
13
Normal
Lipophilic,acidic
and neutral drugs
good
small
30 - 40 minutes,
reduced absorption
no
DUODENUM
57
Normal
Mainly lipohilic
and neutral drugs
good
large
no
SMALL
INTESTINE
6 -7
Normal
All types of drugs
good
very large 10 - 14
ft, 80 cm 2 /cm
about 3 hours
no
LARGE
INTESTINE
6.8 - 7
good
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lower colon,
rectum yes
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SMALL INTESTINE :
Major site for absorption of most drugs due to its large surface area (0.33
m2 ).
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 m2).
These folds possess finger like projections called Villi which increase
the surface area 30 times ( 10 m2).
From the surface of villi protrude several microvilli which increase the
surface area 600 times ( 200 m2).
Blood flow is 6-10 times that of stomach.
PH Range is 57.5 , favourable for most drugs to remain unionised.
Peristaltic movement is slow, while transit time is long.
Permeability is high.
All these factors make intestine the best site for absorbtion of most drugs.
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Site of absorption
Unionized in gastric ph
Ionized in intestinal ph
Better absorbed from stomach
Ionized in gastric ph
Unionized in intestinal ph
Better absorbed from intestine
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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
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GASTRIC EMPTYING
The process by which food leaves the stomach and enters the
duodenum.
It is a RDS in drug absorbtion.
Rapid Gastric Emptying Advisable when :
Rapid onset of action is desired eg. Sedatives
Dissolution occurs in the intestine eg. Enteric coated tablets
Drugs not stable in gi fluids eg. penicillin G
Drug is best absorbed from small intestine eg. Vitamin B12
Delay in Gastric Emptying recommended when
Food promotes drug dissolution and absorbtion eg. Gresiofulvin
Disintegration and dissolution is is promoted by gastric fluids
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Git PH
Emotional state
Disease states
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DISEASE STATES
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PHYSIO-CHEMICAL FACTORS
PHYSICAL FACTORS
PHYSIO-CHEMICAL FACTORS
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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.
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1. PARTICLE SIZE
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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 - polymorph in
the suspension. The form is more soluble and better absorbed.
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5.Adsorption
It is a physical and surface phenomena where the drug
molecules are held on the surface of some inert substances by
vanderwalls 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.
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7. Salts
Na or K salts of weak acid dissolves rapidly than free acid.
ex. Na salts of Novobiocin shows improved bioavailability
Certain salts also may have low solubility and dissolution rate.
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
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SOLID DRUG
DISSOLUTION
DRUG AT ABSORPTION
SITE
ABSORPTION
DRUG IN
SYSTEMIC
CIRCULATION
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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.
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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.
1)Basic drug
2)Acidic drug
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soluble
1) Acidic medium( stomach)
2) basic medium( intestestine)
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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.
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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.
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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.
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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.
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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.
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CAPSULES
Two types of capsule
1.Hard gelatin capsule
2. Soft gelatin capsule
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TABLETS
1.Compressed tablets
2. Coated tablets
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Compressed tablets
Bioavailability are more due to large reduction
in surface area.
Intact tablets
granules
K1
K2
K3
Drug in GI fluid
K4
Drug absorbed in body
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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.
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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:
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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.
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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.
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RECTAL ADMINISTRATION:
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PARENTERAL ROUTES:
.
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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
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INTRAVENOUS ROUTE:
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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.
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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.
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OCULAR ADMINISTRATION
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OCULAR ADMINISTRATION
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Composition of eye
Water - 98%
Solid -1.8%
Organic element
Protein - 0.67%, sugar - 0.65%, Nacl - 0.66%
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Characteristics required to
optimize ocular drug delivery system
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Advantages
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FACTOR INFLUENCING
PERCUTANEOUS ABSORPTION
1.
2.
3.
4.
5.
6.
7.
8.
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FACTOR INFLUENCING
PERCUTANEOUS ABSORPTION
9. Rubbing
10. Contact period
11. Permeation enhancers
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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.
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cont
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Advantages
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Disadvantages
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Enhancement in absorption
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Enhancement in absorption
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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.
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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.
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PULMONARY ADMINISTRATION
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.
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
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PULMONARY ADMINISTRATION
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Advantages
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IN-VITRO METHODS
Circulation technique.
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Mucosal side
(intestinal segment before eversion)
Serosal side
Buffer solution
Ligature
Mucosal side
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(after eversion)
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Advantages
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cannula
Plain buffer
Buffer solution
with drug
Water
maintained at
aerator
37o C
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(FIG: EVERTED SAC MODIFICATION)
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Procedure
Animal fasted for 20-24hrs
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Advantages
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Disadvantages
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Circulation technique
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Advantages
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Advantages
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In-situ methods
Perfusion technique.
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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
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Replacement of intestine.
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Figure
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Contd..
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Advantages
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Contd.
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In-vivo methods
Direct method.
Indirect method.
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Direct method
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Procedure
A blank urine or blood sample is taken for the
test animal before the experiment.
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Indirect method
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Log dose
d
Fka/2.303
x
Duration of response time
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Where,
F= bioavailability.
Ka= the absorption rate constant.
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REFERENCES
1.
2.
3.
4.
5.
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Thank you
Cell No: 00919742431000
E-mail: bknanjwade@yahoo.co.in
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