Prodrug and its application in different fields

1. PRODRUG
Presented By:
Ramit Sharma
M.Pharm (2nd sem)
Department of Pharmacology
ISF College of Pharmacy
Moga, Punjab
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2. CONTENT
 Introduction
 History
 Classification
 Applications
 Improved Patient Acceptability
 Solubility Enhancement Of Drugs Using Pro-drugs
 Enhancement of Bio-availability
 Pro-drugs for Site Specificity 2

3. INTRODUCTION
 Pro-drug is a chemically modified inert precursor of the drug which
liberates active parent compound on biotransformation.
 Pro-drug is not having intrinsic pharmacological activity.
 It is generally prepared by combining a carrier with a potent drug
through suitable linkage.
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4. HISTORY
In 1958 Albert initially coined the term pro drug and used it to refer to “A
pharmacologically inactive compound that is transformed by the mammalian
system into an active substances by either chemical or metabolic means.”
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5. PRO-DRUGS
CHEMICAL
MODIFICATION
• ACTIVE DRUG
METABOLIC
TRANSFORMATION
• PRO DRUG
• (INACTIVE)
NONTOXIC
METABOLITES
• ACTIVE DRUG
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6. PRODRUG CONCEPT
 A pro-drug is a pharmacological substance (drug) administered in an
inactive (or significantly less active) form.
 Once administered, the pro drug is metabolized in vivo into an active
metabolite, a process termed bio activation.
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7. PURPOSE OF PRODRUG DESIGN
 Improve absorption.
 Improve dissolution.
 Enhance bioavailability
 improving the solubility that may limit dissolution in the gastro-
intestinal tract
 Improving permeability across biological membranes
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8.  Avoid the first-pass metabolism/pre systemic
metabolism.
 Site specific delivery.
 Decrease toxicity.
 Improved patient compliance.
 Control drug release
CONTD..
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9. CLASSIFICATION
1. Carrier-linked Pro-drugs.
2. Bio Precursor Pro-drugs.
3. Mutual Pro-drugs.
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I. CARRIER LINKED PRODRUGS

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E.g - Levodopa for Dopamine
Levodopa is formulated as a prodrug for dopamine to improve
its membrane permeability in brain.
Dopamine
 Useful in treating Parkinson’s
Disease
 Too polar to cross cell
membranes and BBB
Levodopa
 Lipophilic prodrug and cross cell
membrane
 Carried across cell membranes by
carrier proteins for amino acids
 Decarboxylated in cell to dopamine
OH
OH
NH2
CO2
H
OH
OH
NH2
Decarboxylase
DopamineLevodopa

12. II. BIO-PRECURSOR PRODRUGS
 It does not contain a temporary linkage between the active drug & a
carrier moiety but designed from a molecular modification of the active
principle itself.
 It is a compound that is converted to active drug by a Metabolic
biotransformation.
 Types of activation-
 Oxidation (most common method)
 Reduction
 Phosphorylation (For antiviral agents)
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13. Oxidation Example –
Nabumetone, which is a Non-steroidal anti-inflammatory prodrug
used in arthritis
CH3
O
CH3
O
OH
CH3
O
O
series of oxidative
decaboxylation
Active form of the drug
that inhibits Prostaglandin
biosynthesis by cyclo-oxygenase
Nabumetone
Contd…
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14. C
O
O
NH C
O
CH3OCOCH3
COOH
OCOCH3
OH
NHCOCH3
+
prodrug
ParacetamolAsprin
(Benorylate)
III. MUTUAL PRODRUG
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15. 1. IMPROVED PATIENT ACCEPTABILITY
 For poor patient compliance, particularly in case of children is
 Bitterness.
 Acidity
 Two approaches can be utilized to overcome the bad taste of the
drug:
 Reduction of drug solubility in saliva .
 lower the affinity of drug towards taste receptor.
APPLICATIONS OF PRODRUG APPROACH
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16. Parent Drug Pro-drug with
improved taste
1.chloramphenicol Palmitate ester
2.Clindomycin Palmitate ester
3.Sulfoxazole Acetyl ester
CONTD….
 Pro-drug with improved taste.
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17. 2. SOLUBILITY ENHANCEMENT OF DRUGS USING
PRO-DRUGS
 Pro-drugs can increase the aqueous solubility of the parent drug molecule:
 By decreasing hydrogen bonding and consequent crystal lattice
packing, which lead to lower melting point of the parent drug
molecule.
 By increasing the polarity of the drug molecule.
 Pro-moieties can be connected to drug molecules:
 Depending upon the functional groups present in the drug molecule and
the desired way to release the parent compound.
 Eg. Tocopherol sodium succinate ester
 Metronidazole amino acid esters.
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18. 3. ENHANCEMENT OF BIO-AVAILABILITY
 Most drugs are absorbed by passive diffusion for which lipo-philicity is
an important requirement.
 A big advantage of increased bioavailability through increased lipo-
philicity is the reduction in dosing.
 For example: Bacampicillin is as effective as Ampicillin in just one-
third of the dose of latter.
 Pro-drug approaches for improved oral bioavailability:
 1) Increased aqueous solubility.
 2) Increased lipo-philicity.
 3) Transporter-mediated drug delivery.
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19. 4. PRO-DRUGS FOR SITE SPECIFICITY
 Brain targeting
 Kidney targeting
 Liver targeting
 Virus targeting
 Tumor targeting
 Lymphatic targeting
 Colon targeting
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20. TARGETING TO BRAIN
 In a brain targeting, delivery of drug is limited by Blood Brain
Barrier (BBB).
 The Blood Brain Barrier can allows only small, non-ionic and lipid
soluble molecules, which can diffuse the BBB from systemic
circulation.
 But the larger, more water soluble and ionic molecules do not
readily cross BBB.
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21. Example: Progabide
GABA is too polar to cross BBB so it is not an effective
anticonvulsant drug.
Progabide is a lipophilic analog of GABA which cross BBB.
Then release GABA inside brain and shows anticonvulsant activity.
IN BRAIN
NH2
OH
O
GABA
OH
N
NH2
O
CI
F
PROGABIDE
BBB
PROGABIDE
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22. TARGETING TO COLON
 Drug targeting to colon is achieved by preparing the polar
prodrug.
 There by decreasing the absorption in stomach & intestine within
upper GIT.
 The prodrug is activated by bacterial enzymes presents in colon
follows fast absorption through colonic membrane.
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23. E.g – Sulfasalazine
 Which formed by coupling of diazotized 2-sulfanilamide
pyridine with 5-amino salicylic acid (ASA)
 When administered orally, very limited extent absorbed in upper
GIT due to its polar nature.
 Large percent of intact sulfasalazine reaches to the colon.
 The azo reductase associated with anaerobic colonic bacteria
which converts sulfasalazine to 5- ASA
SULFASALAZINE 5- ASA
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24. REFERENCES
 Https://pubs.Acs.Org/doi/pdf/10.1021/jm00186a001.
 Alagarsamy v., Text book of medicinal chemistry, vol. 1, section
II, chapter no. 6, pg no. 71-81.
 Google scholar.
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