Transcript Enhancing Drug Bioavailability by Overcoming Intestinal Metabolism Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D Professor of Pharmaceutics Department of Pharmaceutics KLE University, Belgaum, India E-mail: [email protected] Cell No:

Enhancing Drug Bioavailability by
Overcoming Intestinal Metabolism
Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D
Professor of Pharmaceutics
Department of Pharmaceutics
KLE University, Belgaum, India
E-mail: [email protected]
Cell No: 00919742431000
INTRODUCTION
• Drugs may be given in a number of ways
• Oral administration is the most common and
the easiest way to give a drug
• The amount of drug reaching the general
circulation will depend on a number of factors
• The proportion of drug that reaches the target
organs and tissues, which is expressed as a %
of the dose administered.
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Intestinal Absorption of Oral Drugs
Passive Diffusion
• Most approved oral drugs
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Active Transport
• Nutrients (small peptides, amino acids,
vitamins, fatty acids, etc.)
• Selected drugs: valacyclovir, ACE inhibitors
cephalosporins, pravastatin, etc.
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Drug Absorption
• The drug is absorbed from the GI tract and
passes via the portal vein into the liver where
some drugs are metabolized
• Sometimes the result of first pass metabolism
means that only a proportion of the drug
reaches the circulation
• First pass metabolism can occur in the gut and
liver
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Drug Absorption
• Absorption is the process by which a drug
enters the bloodstream without being
chemically altered
or
The movement of a drug from its site of
application into the blood or lymphatic
system
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Drug Absorption
• Factors which influence the rate of
absorption
– types of transport
– the physicochemical properties of the drug
– protein binding
– routes of administration
– dosage forms
– circulation at the site of absorption
– concentration of the drug
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Drug Absorption
• The rate at which a drug reaches it site of
action depends on:
– Absorption - involves the passage of the drug
from its site of administration into the blood
– Distribution - involves the delivery of the drug
to the tissues
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Drug Absorption
• Mechanisms of solute transport across
membranes
– passive diffusion
– filtration and bulk flow
– endocytosis
– ion-pairing
– active transport
Drug Absorption animaton
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Bioavailability
Definition: the fraction of the administered
dose reaching the systemic circulation
for i.v.: 100%
for non i.v.: ranges from 0 to 100%
e.g. lidocaine bioavailability 35% due to
destruction in gastric acid and liver metabolism
First Pass Effect
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Bioavailability
Destroyed
in gut
Not
absorbed
Destroyed
by gut wall
to
systemic
circulation
Dose
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Destroyed
by liver
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The enterohepatic shunt
Drug
Liver
Bile formation
Bile
duct
Hydrolysis by
beta glucuronidase
Biotransformation;
glucuronide produced
gall bladder
Portal circulation
Gut
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First-pass Effect
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Bioavailability
=
(AUC)o
(AUC)iv
Plasma concentration
i.v. route
oral route
Time (hours)
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Enzymatic status
• Luminal enzymes of the small intestine
- Pepsin is the primary enzyme found in gastric fluid.
- Other enzymes such as lipases, amylases and
peptides are secreted into the small intestine via the
pancreas in response to ingestion of food.
- Pepsins and proteases are responsible for the
breakdown of protein and peptide drugs in the
lumen.
- Drugs which resemble nutrients such as fatty acids
and nucleotides are susceptible to enzymatic attack.
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Enzymatic status
• Colon
- Presence of bacterial enzymes in the colonic region
of the gastrointestinal tract, which digest material
not yet digested in the small intestine.
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First-pass Effect
• The first-pass effect is the term used for the
hepatic metabolism of a pharmacological
agent when it is absorbed from the gut and
delivered to the liver via the portal circulation.
• The greater the first-pass effect, the less the
agent will reach the systemic circulation when
the agent is administered orally
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First-pass Effect cont.
Magnitude of first pass hepatic effect:
Extraction ratio (ER)
ER = CL liver / Q ; where Q is hepatic blood
flow (usually about 90 L per hour).
Systemic drug bioavailability (F) may be
determined from the extent of absorption (f)
and the extraction ratio (ER):
F = f x (1 -ER)
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Bypassing First Pass Metabolism
• Two ways to bypass first pass metabolism
involve giving the drug by sublingual and
buccal routes
• The drugs are absorbed by the oral mucosa in
both methods
• In sublingual administration the drug is put
under the tongue where it dissolves in salivary
secretions
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Bypassing First Pass Metabolism
• Nitroglycerine is administered in this way
• In buccal administration the drug is placed
between the teeth and the mucous
membrane of the cheek
• Sublingual and buccal methods both avoid
destruction by the GI fluids and first pass
effect of the liver
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Improving oral Bioavailability
• Particle Size Reduction
- Jet-milling, high energy ball milling
- Spray drying
- Super critical fluid extraction
- High supersaturation crystallization
• Solid Form Thermodynamics
- Amorphous
- Salts
- High Free Energy Polymorphs
• Improve Solubility
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Attempted oral delivery systems
• Enzyme inhibition
- Difficult to target large variety of enzymes
- Interferes with natural metabolism
• Permeation enhancement
- Leads with non-specific paracellular transport
• Enteric coatings
- pH dependent solubility
- Maintain integrity through stomach, degrade in
intestine
- Modest success, but
still very low transport
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Complexation hydrogels
• Poly(methacrylic acid-g-ethylene glycol), P(MAA-g-EG)
– MAA backbone grafted with terminally functional PEG chains
– Forms a water swollen, cross-linked polymer network
– Exhibits environmentally responsive pH dependent swelling
PMAA
CH3
CH3
H3C
CH3
H3C
CH3
O
O
O
H
H3C
O
O
O
O
O
H
pKa ~ 4.8
Low pH
Insulin
O
O
O
High pH
H
O
PEG
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Approach
• Improve bioavailability of the oral delivery
system by modifying the network of the
P(MAA-g-EG) hydrogel and combining it with
chemically modified insulin species
• Insulin modification:
- PEGylated insulin can resist enzymatic attack
- Use Vitamin B12 to enhance transport across
intestinal wall
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Insulin conjugation
• PEGylation: Covalent attachment of PEG to a protein
– Reduces enzymatic degradation of protein
– Increases circulation time
– Increases solubility of protein
• Would help overcome enzymatic barrier in intestine
• May enhance interaction between hydrogel and insulin
• PEG could be used as a linking agent for Vitamin B12
• Vitamin B12 is actively transported across epithelial cells
• May provide pathway to overcome physical barrier in the
intestines
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Summary of Polymers used in pharmaceutical
formulations as coating materials.
Polymer
Trade name
Application
Shellac
EmCoat 120 N
Marcoat 125

Cellulose acetate
Aquacoat CPD®
Sepifilm™ LP
Klucel®
Aquacoat® ECD
Metolose®

Polyvinylacetate phthalate
Sureteric®

Methacrylate
Eudragit®

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Enteric Coatings
 Taste/Odor Masking
Enteric Coatings
 Taste masking
 Sustained release coating
 Sub coat moisture and barrier
Sealant pellet coating
Enteric Coatings
Enteric Coatings
 Sustained Release Coatings
 Taste Masking
 Moisture protection
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Anatomical Considerations
Gut Lumen
Portal Vein
Liver
Gut Wall
Systemic
Circulation
Metabolism
Metabolism
Release + Dissolution
Permeation
Elimination
Absorption
Bioavailability
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Gabapentin Has a Limited GI Absorption
Window
Limited Capacity
Absorption Window
Stomach
1 to 6 hours
Small Intestine
2 to 4 hours
Colon
8 to 18 hours
Transit Time in Humans
• Saturable uptake – exposure not proportional to dose
• Variable capacity/transit times - inter-subject variability in PK
• No colonic absorption - SR formulation not possible
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Overcoming a Limited Absorption
Window
Modify the drug for recognition by high capacity
transporters located throughout the intestine:
High Capacity Transporter
Stomach
1 to 6 hours
1.
2.
3.
4.
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Small Intestine
2 to 4 hours
Colon
8 to 18 hours
Increased bioavailability
Greater dose proportionality
Lower inter-patient variability
Reduced dosing frequency (sustained release)
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THANK YOU
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