3. Defination
• Prodrug is medication or a compound when administered, but after
administration it get metabolized and converted into pharmacologically
active drug.
• Prodrug is pharmacologically inactive chemical moiety which are used to
change physicochemical properties of drug temporarily for improving
efficacy and reducing their toxicity.
4. History
• Adrien Albert first introduced the term ‘Prodrug’ in 1958.
• The first intentionally designed prodrug is mostly ‘Methenamine’ was
introduced in 1899 by Schering.
5. Importance of Prodrug Development
• The development of prodrug gives strategy to improve the physicochemical,
biopharmaceutical and pharmacokinetic properties of drug.
• Prodrug development has great application in aqueous solubility, chemical
instability, insufficient oral absorption, rapid pre-systemic metabolism,
inadequate brain penetration, toxicity & local irritation.
6. Designing Of Prodrug
• Design of prodrug structure should be decided at early stages of pre-clinical
development because after that it may alter tissue distribution, efficacy and
toxicity of parent drug.
• For designing of prodrug following factors should be considered before
developing a prodrug structure.
a) Parent Drug
b) Promoiety(Carrier)
7. a)Parent Drug :-
It should be checked that what type of functional groups are able to
chemical prodrug derivation.
b) Promoiety (Carrier) :-
i. This should be ideally safe & rapidly excreted from body.
ii. The selection of promoiety should be based on disease state, dose and duration
of therapy.
+ Prodrug
Parent
Drug Carrier
8. Degradation of Prodrug
• These can affect chemical & physical stability and lead too formation of degraded
product.
Drug Carrier
B
A
R
R
I
E
R
Drug Carrier
Drug
Carrier
9. Ideal Properties Of Prodrug
1)Pharmacologically inertness.
2)Rapid Transformation (Chemically and
Enzymatically).
3)Non-toxic metabolic fragments.
10. Classification
• Depending upon constitution of lipophilicity method of bioactivation &
catalyst used they are classified as-
PRODRUG
Carrier-linked
Prodrug
Bio Precursor
Prodrug
11. A. Carrier linked Prodrug
• In this type active drug is covalently linked with the inert carrier.
• They are generally ester or amide.
• They have high modified lipophilicity due to joined carrier.
• Chemical prodrug formation
• covelent bond
•
• Chemical or Enzymatic clevage
Active Drug
Inert Carrier
12. Advantages
1.
• It increases absorption &decreases toxicity.
2.
• It eliminates unpleasant taste.
3.
• It reduces injection site pain.
13. B.Bioprecursor Prodrug
• They are inert molecule obtained by chemical modification of
active drug but do not contain carrier.
• Such moiety have some lipophilicity as that of parent drug and
bioactivated generally using redox biotransformation only
enzymatically.
• Bioprecursor doesn’t posses any temporary linkage between active
compound and carrier but result in molecular modification of
active drug.
14. Application
• Prodrug have wide range of applications such as to enhance pharmaceutical ,
organoleptic & chemical properties of parent drug with enhanced stability
and patient compliance.
Applications
Pharmacokinetic
Pharmaceutical
15. 1)Pharmacokinetic Applications
I. Prodrug for improvement of bioavailability.
II. Prodrug for site selective drug delivery.
III.Prodrug for longer duration of action.
IV.Prodrug for minimizing toxicity.
V. Prodrug for protection from pre-systemic metabolism.
16. a) Prodrug for improvement of bioavailability
• Chemical modification of drug is used to improve physicochemical
properties such as solubility, lipophilicity, polarity & stability.
For
Improvement of
Bioavailability
Prodrug to increase
Lipophilicity
Prodrug to increase
Polarity
17. I)Prodrug to increase lipophilicity
• The main reason behind the designing is to increase it’s bioavailability &
intestinal absorption.
• Eg - Valacyclovir
18. II)Prodrug to increase Polarity
• Prodrugs are designed to increase aqueous solubility.
• This can be done by esterification with amino acid or phosphate group.
• Eg - Sulindac (NSAID)
19. b)Prodrugs for Site Selective Drug Delivery
Site Selective Drug Delivery
Tumor targeted
drug delivery
• Prodrugs are applied for targeting drugs to a specific organ or tissue used in
chemotherapy.
• Prodrugs are applied for targeting drugs to a specific organ or tissue used in
Membrane Transporter
prodrug targeting
20. 1.Tumor Targeted Drug Delivery
• Cancer chemotherapeutics are toxic & non-selective which limits their use
for cancer therapy.
• In this method a gene encoding the activating enzyme is delivered to tumor
cells, as first step.
• In second step inactivated prodrug is administered & converted to toxic drug
by tumor enzyme.
• Eg - Doxorubicin
21. 2.Membrane Transporter Prodrug Targeting
• They target specific transporters which have an important role in drug
absorption, distribution & elimination via prodrug.
Eg- Acyclovir
22. c)Prodrug for Longer Duration of Action
• Drugs with short half life require frequent dosing to maintain blood
concentration, which leads to poor patient compliance & fluctuation in the
drug concentration.
• Eg – Fluphenazine decanoate
23. d)Prodrug Minimizing Toxicity
• For therapeutically active drug, it should be have minimum or no toxicity.
• Prodrugs have great application in minimizing the toxicity of drug.
• Eg – PEG conjugated paclitaxel 2 glycinate ( show antitumor effect by
reducing toxicity)
24. e)Prodrug for protection from Pre-systemic
metabolism
Pre-systemic metabolism causes low oral bioavailability of drugs.
Certain sites or groups in molecules are subjected to pre-systemic
metabolism.
Prodrugs can used to block these sites & increase oral bioavailability.
Eg – Estradiol
25. Pharmaceutical Application
• For understanding organoleptic properties & physicochemical properties
associated with them are resolved by prodrug formation.
1. Taste Masking
2. Odour Masking.
3. Change of Physical form of drug.
4. Reduction of GI Irritation.
5. Minimizing Pain at injection site.
6. Enhancement of Solubility & Dissolution Rate of Drug.
7. Enhancement of Chemical Stability.
26. 1.Taste Masking
• Taste is an important factor in developing dosage form & masking bitter
taste of oral drug , is crucial for patient especially for pediatric and geriatric
patient.
• Eg – Various types of coating agents are used such as bees wax, shellac.
27. 2.Odour Masking
• Odour is an aesthetic concern for drugs with high vapour pressure or low
boiling point which makes them difficult to formulate.
• Eg – Ethyl mercaptan
28. 3.Change of Physical form of Drug
• Some drug which are in liquid form are unsuitable for formulation as
compared to solid dosage form, especially if there is high dose.
• The method of converting liquid form into solid form involves formation of
symmetrical molecules having tendency to crystalize.
• Eg - Trichlorethanol
29. 4.Reduction of GI Irritation
• Several drugs cause irritation damage to gastric mucosa through direct
contact, increased stimulation of acid secretion.
• Eg- Salsalate
30. 5.Minimizing Pain at Injection Site
• Pain at the injection site is caused by precipitation of drug that causes lysis &
tissue injury.
• The problem may related to vehicle composition needed for formulation
purpose.
• Eg- Fosphenytoin
31. 6.Enhancement of Solubility & Dissolution
Rate
• The prodrug approach is also made useful for rectification of solubility
problem & for better gastrointestinal absorption.
• Solubility can be enhanced by using phosphate ester.
• Eg – Chloramphenicol succinate
32. 7.Enhancement of Chemical Stability
• A drug may destabilize during it’s shelf life.
• The commonest conventional method is to lyophilize the solution into
powder.
• The prodrug design of such agents is a good alternative to improve stability.
• Eg - Pivampicillin
