Enhancing Drug Bioavailability by Overcoming Intestinal Metabolism

1
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 bknanjwade_at_yahoo.co.in
• Cell No 00919742431000

2
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.

3
Intestinal Absorption of Oral Drugs
Active Transport
Passive Diffusion

• Nutrients (small peptides, amino acids, vitamins,
  fatty acids, etc.)
• Selected drugs valacyclovir, ACE inhibitors
  cephalosporins, pravastatin, etc.

• Most approved oral drugs

4
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

5
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

6
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

7
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

8
Drug Absorption

• Mechanisms of solute transport across membranes
• passive diffusion
• filtration and bulk flow
• endocytosis
• ion-pairing
• active transport

Drug Absorption animaton
9
(No Transcript)
10
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
11
Bioavailability
Destroyed by gut wall
Destroyed in gut
Destroyed by liver
Not absorbed
to systemic circulation
Dose
12
The enterohepatic shunt
Drug
Liver
Bile formation
Bile
duct
Biotransformation glucuronide produced
Hydrolysis by beta glucuronidase
gall bladder
Portal circulation
Gut
13
First-pass Effect
14
(AUC)o (AUC)iv
Bioavailability

i.v. route
Plasma concentration
oral route
Time (hours)
15
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.

16
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.

17
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

18
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)
19
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

20
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

21
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

22
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

23
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
PEG
24
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

25
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

26
Summary of Polymers used in pharmaceutical
formulations as coating materials.
Polymer Trade name Application
Shellac EmCoat 120 N Marcoat 125 Enteric Coatings Taste/Odor Masking
Cellulose acetate Aquacoat CPD  Sepifilm LP Klucel Aquacoat ECD Metolose Enteric Coatings Taste masking Sustained release coating Sub coat moisture and barrier Sealant pellet coating
Polyvinylacetate phthalate Sureteric Enteric Coatings
Methacrylate Eudragit  Enteric Coatings Sustained Release Coatings Taste Masking Moisture protection Rapidly disintegrating Films
27
(No Transcript)
28
Anatomical Considerations
Gut Lumen
Portal Vein
Liver
Gut Wall
Systemic Circulation
Metabolism
Metabolism
Release Dissolution
Permeation
Elimination
Absorption
Bioavailability
29
Gabapentin Has a Limited GI Absorption
Window
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

30
Overcoming a Limited Absorption Window
Modify the drug for recognition by high capacity
transporters located throughout the intestine

1. Increased bioavailability
2. Greater dose proportionality
3. Lower inter-patient variability
4. Reduced dosing frequency (sustained release)

31

• THANK YOU