Prodrug. Introduction of prodrug. Classification of prodrug. Rational for the use of prodrug. Prodrug for oculary. Prodrug for buccal delivery. Prodrug for brain targeting. Recent advancement. Antibody directed enzyme prodrug. gene directed enzyme prodrug therapy. Virus directed enzymes prodrug therapy. prodrug in novel drug delivery.

1. PRODRUGS
Presentedby
JyotsanaBhatt
M.Pharm(pharmaceutics)
Targeted drug delivery system

2. CONTENT
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 Introduction
 Targeteddrugdeliverysystem
 Prodrug
 Classificationofprodrug
 Rationalforuseoftheprodrug
 Strategiesfordesigningprodrug
 RequirementsforprodrugdesignedforTDDS.
 Variousapproachesoftheprodrug
 Recentadvancement
 Conclusion

3. Introduction
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The term prodrug was introduced by Albert who used ‘’prodrug’’ or
‘’proagent’’ to refer to a pharmacologically inactive compound that is
transformed by the mammalian system into an active substance by either
chemical or metabolic means.
Another term drug latentiation was coined by Herper which implies
prodrug is converted into active drug within the body through enzymatic or
non-enzymatic reactions.
The prodrug approach used as a tool for the over coming various
obstacles to the drug formulation and targeting such as a chemical instability,
poor aqueous solubility, inadequate brain penetration, insufficient oral
absorption, local irritation and toxicity.

4. Targeted drug delivery system
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The concept of designing targeted delivery system has been given by Paul
Enrich, a microbiologist, who proposed idea of delivering drug in the form of
magic bullet.
Targeted drug delivery means-
 Delivery of the drugs in a specific part of the body
 Reduce overall drug toxicity
 Improve bioavailability
 Improve therapeutic index of the drug.
for example- peptide drugs
High dosing required due to transport factors including widespread
disposition, rapid metabolism and excretion.

5. Prodrug
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Prodrug is defined as a biologically inactive derivative of a parent drug
molecules that usually requires a chemical or enzymatic transformation
within the body to release the active drug and posses improved delivery
properties over the parent molecule.
These inactive derivatives are designed through manipulation of
physicochemical, biopharmaceutical and pharmacokinetic properties of drug.

6. Classification of the prodrug
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 CARRIER LINKED PRODRUG -
Active drug is covalently linked to an inert carrier or transporter
moiety. They have enhanced lipophilicity due to attached carrier. The active
drug is released by hydrolytic cleavage, either chemically or enzymatically.
 TRIPARTITE PRODRUGS -
Structure of most prodrugs is bipartite in nature (parent moiety
directly attached to premoiety). Tripartite prodrugs can be designed by
utilising a spacer or connector group between the drug and premoiety. This
system is used to overcome the instability problems.
Ex- N–tert butyloxy carbomyl lysine group is promoiety,
P–amido benzyloxy carbonyl group is spacer group and P–nitro aniline
is the drug.

7.  MUTUAL PRODRUGS-
The prodrug comprises of two pharmacologically active agents coupled
together to form a single molecule such that each act as the carrier for the
other drug.
Ex-Benorylate is mutual prodrug of NSAIDs aspirin and paracetamol.
Ex- Emcyt is a mutual prodrug containing estramustine and nornitrogen
mustard linked to each other
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Actual alkylating species
CH3
OH
OH
NH
Cl
Cl
NH+Cl-
Cl
Nornitrogen mustard
Aziridine
Sodium phosphate
and
Carbon dioxide
CH3
OPO3Na2
ON
O
Cl
Cl Estermustine Sodium Phosphate
Emcyt® - Pharmacia & Upjohn

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 POLYMERICPRODRUGS–
Also called as the macromolecular prodrug. The drug is dispersed or
incorporated into the polymer (both naturally occuring and synthetically
prepared) system without formation of covalent bond between drug and
ploymer,

9. CLASSIFICATION OFPRODRUG
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10. Rational for the use of prodrug
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A drug exert its desired pharmacological action when it reaches its site of
action. The three major phases involved in the drug receptor interaction that
include the –
Pharmaceutical phase- the phase of development which involve the
identification of new chemical entity with measured therapeutic potential
and incorporation into delivery system.
Pharmacokinetic phase- the phase involve absorption, distribution,
metabolism, and excretion of the drug.
Pharmacodynamic phase- this phase involve physiological and biochemical
effect of drug at organ system.

11. PHARMACEUTICAL PHASE
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The phase of development which involve the identification of new chemical
entity with measured therapeutic potential and incorporation into delivery
system
Two main barriers identified in the development phase of commercial usable
drug product are-
Aesthetic properties such as odour, taste, pain upon injection site,
gastrointestinal irritability of the new molecule.
Drug formulation problems, stability problems, undesirable physicochemical
properties like- polarity, partition coefficient etc.

12. USE OF PRODRUG TO OVERCOMEPHARMACEUTICAL
BARRIERS
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1. MASKINGTASTEORODOUR- undesirable taste or odour arises due to adequate
solubility and interaction of drug with taste receptor which can be solved by
lowering the solubility of drug or prodrug in saliva.
Lipase
O2N CH
CH3
CH
NH
O
CHCl 2
CH2 OHO2N CH
CH3
CH
NH
O
CH3
CH2OC
O
(CH2)14CH3
Chloramphenicol palmitate chloramphenicol

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2. MINIMIZING PAIN AT SITE OF INJECTION- Pain caused at injection site due to weekly
acidic nature or poor aqueous solubility of drugs.
for example- phosphate ester of phenytoin a prodrug of phenytoin has
improved aqueous solubility as compared to its active drug. Thus, reduced pain.
3. ALTERATION OF DRUG SOLUBILITY- prodrug approach can be used to increase or
decrease the drug solubility.
for example- chloramphenicol succinate and chloramphenicol
palmitate, ester prodrugs of chloramphenicol have enhanced and reduced drug
solublity.
4.ENHANCEMENTOFCHEMICAL STABILITY- It can be achieved by-
 Modification of the functional group responsible for instability.
 Change the physical property of the drug.
Parent drug Prodrug with enhanced stability
azacytidine Azacytidine bisulfite
erythromycin Stearate, ethyl succinate and estolate prodrugs

14. PHARMACOKINETICPHASE
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The pharmacokinetic phase can be considered as the phase involving
absorption, distribution, metabolism, and excretion of the drug.
The principle barrier identified in the pharmacokinetic phase are :-
 Incomplete absorption of drug from the delivery system
 Incomplete systemic delivery of an agent due to pre-systemic metabolism.
 Toxicity problems associated with local irritation.
 Poor site specificity of drugs.

15. 1. OVERCOME ABSORPTION PROBLEMS – poor absorption of drug may be due to
physicochemical properties of drug itself. Bioavailability after oral dosing of
water insoluble drugs mainly depend upon dissolution of drug and for
polar drugs they depends on permeability.
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2. ENHANCEMENTOFORALABSORPTION-various therapeutics agents such as water
soluble vitamins, natural purines, dopamine etc. have poor gastrointestinal
absorption and can be enhanced by conversion into prodrug.
for example- The absorption of water soluble vitamin was enhanced
by derivatization of thiolate ion to form lipid soluble Prodrugs.
on contrary, gitoxin, a cardiac glycoside has very poor oral
bioavailability due to limited aqueous solubility.

16. 3.PREVENTIONOFPRE-SYSTEMICMETABOLISM- Phenolic moiety, ester cleavage and
peptide degradation are responsible for the pre-systemic metabolism of
various drug.
The first pass metabolism of a drug can be prevented if the
functional group susceptible to metabolism is protected temporarily by
derivatization.
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4.TODIMINISH LOCALANDSYSTEMICTOXICITYOF DRUG- Various non steroidal anti
inflammatory drugs like salicylic acid and indomethacin severely
damage the GI mucosa due to presence of free carboxylic group, problem can
be solved by conversion of the pure drug into derivative form.
Active drug Prodrug with reduced toxicity
Salicylic acid aspirin
Adriamycin Adriamycin 14- octanoate
Indomethacin Aldehyde prodrug of Indomethacin

17. 5. PROLONGATIONOFDURATIONOFACTION-The two rate controlling steps in the
enhancement of duration of action –
:- rate of release of prodrug from site of application,
:- rate of conversion of prodrug into active form.
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For example- bambuterol is a biscarbonate ester prodrug of terbutalline
in the treatment of asthma. Slowly converted into active form by action of
cholinestrease.
 It bypass pre-systemic circulation.
 Maximum plasma concentration of terbutaline occurs approximately 4-
7hrs after bambuterol administration and efficacy lasts for 24hrs.
 Therefore dose is reduced from thrice a day to once a day.

18. STRATEGIESFOR DESIGNOF PRODRUG
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1.Carriers:
 Carrier is an inert molecule or the promoiety attached to the active drug
moiety through a metabolically labile linkage.
 The carrier imparts some desirable property to the drug such as increased
lipid or water solubility.
2.Specifiers:Carriers that help in directing the active moiety to the target site is
called as specifier.Targeting unit part of the prodrug which directs the active
moiety to the target site.
 Antibody Directed Enzyme Prodrug Therapy
 Gene Directed Enzyme Prodrug Therapy
 Polymer Directed Enzyme Prodrug Therapy/ Macromolecule

19. LINKERS- A releasable linker or spacer is placed between the carrier or
specifier and active drug moeity.
Reason for application of a linker-
incorporation of appropriate linkage between premoeity and active drug.
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SIMPLESPACER-

20. PRODRUG LINKAGEAND ENZYMESINVOLVED
IN HYDROLYSIS OFLINKAGE
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21. REQUIREMENTS FOR PRODRUG DESIGNFOR
TARGETED DRUG DELIVERY SYSTEM
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1. The tissue associated biomolecule must be present in significantly elevated
levels in that particular tissue compared to normal tissue.
2. Prodrug level must be high enough to generate therapeutic levels of free
drug in the target tissue.
3. Prodrug activation at the other sites must be minimal.
4. Prodrugs must be good substrate or possess high binding affinity for tissue
associated molecule.
5. It must not be rapidly eliminated from the body and must not enter cells
randomly.

22. VARIOUSAPPROACHESOF THE PRODRUG
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TUMORTARGETING-
Most effective chemotherapeutic agents are –
1. Highly toxic with narrow therapeutic index.
2. Also effect normal dividing cells
3. Undesirable side effects:- nausea, vomiting, hair loss, diarrhoea etc.
4. Development of multidrug resistance by the tumor cells.
5. Hypoxic cells are resistance to radiotherapy.
Irregular blood flow to tumor cells leads to reduced supply of glucose and other
nutrient. Thus, decrease their rate of cell division, making it difficult for
chemotherapeutic agents to target.

23. TUMOR ASSOCIATED FACTOR FOR TARGETING
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 HYPOXIA- hypoxic selective cytotoxic agent used in combination therapy
with conventional anticancer chemotherapeutic agents.
Hypoxic selective drugs kill hypoxic tumor cells and other agents kill
aerobic tumor cells.
EX- N- oxide bioreductive triapazamine (phase-III clinical trials) is
used in treatment of lung cancer along with cisplatin.
 FOLATE- folate are low molecular weight vitamins required by all eukaryotic
cells for carbon metabolism and nucleotide synthesis. Folate receptor is
known to be expressed on the surface of many malignant cells and fully
accessible to parentrally administered folate drug conjugate.

24. PRODRUG FOR OCULAR DELIVERY
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Major challenges in ocular drug delivery include tightness of corneal
epithelium, pre-corneal drug elimination. As a result, less than 10% of drug
reaches the intraocular tissues.
Measures taken in improving the bioavailability of the ocular delivery-
 First, extending the drug residence time in the conjunctival sac.
 Second improving penetration of drug across corneal barrier.
Ocular absorption of a drug can be enhanced substantially by increasing its
lipophilicity, which can be achieved with prodrug applications . Key requirements
for ocular Prodrugs involve good stability and solubility in aqueous solutions to
enable formulation, sufficient lipophilic properties to penetrate through the
cornea, low irritation profile, and ability to release the parent drug within the eye
at a rate that meets the therapeutic need.

25. PRODRUGS FOR OCULAR DRUG DELIVERY
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26. PRODRUG FOR BUCCAL DELIVERY
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 Buccal delivery route has generated interest lately because it offers a non
invasive route of delivery for proteins and peptides that cannot tolerate the
harsh acidic environment of the GI tract.
 Prodrugs in buccal delivery generally improve drug solubility and stability
using polymers.
 Prodrugs provides a constant drug release rate, resulting in a reduced total
amount of drug and increased patient comfort.
 Buccal delivery of opioid analgesics and antagonists can improve
bioavailability relative to the oral route. Eg. oxymorphone, butorphanol.

27. PRODRUG FOR BRAIN TARGETING
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28. PRODRUG FOR BRAIN TARGETING
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Dihydropyridine-pyridinium salt redox system:
 The drug to be delivered to brain is covalently linked to the lipophilic
dihydropyridine carrier to form a prodrug which partitions across the BBB.
 Ex: Another inert carrier used to target drugs to brain is dihydro
trigonelline. It can be linked to dopamine and targeted to brain.

29. RECENT ADVANCEMENT
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 TARGETINGSPECIFICENZYMES-
These therapies include activation of prodrug by exogenous enzymes
delivered to tumor cells via monoclonal antibodies, or generated in tumor
cells from DNA construct containing the corresponding gene.
The selective activation of prodrug in tumor tissues by exogenous
enzyme for cancer therapy can be accomplished by several ways-
1. Antibody directed enzyme prodrug therapy(ADEPT)
2. Gene directed enzyme prodrug therapy(GDEPT)
3. Virus generated enzyme prodrug therapy(VDEPT)
4. Polymer directed enzyme prodrug therapy(PDEPT)

30. ANTIBODY DIRECTEDENZYME PRODRUG THERAPY
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 An antitumor- antibody is conjugated to an enzyme not normally
present in extracellular fluid or carrier cell membrane and than these
conjugates are localized in the tumor cell.
 After allowing the conjugate to clear from blood.
 Prodrug is administered that is normally inert but is activated by the
enzyme delivered to the tumor cell.
Ex- Amygdalin as prodrugs which
Is activated by enzyme beta-glycosidase
Associated with monoclonal antibody.

31. GENE DIRECTED ENZYME PRODRUGTHERAPY
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This therapy include the use of gene expressing the foreign enzyme is
delivered.
1. In the first step, a gene is used to deliver enzyme associated in activation
of prodrug to the respective tumor cell.
2. Second step include. Administration of prodrug that is converted to
active form by enzyme.
Ex-combination of herpes simplex virus- thymidine kinase(HSV-TK) and
ganciclovir(GCV). Ganciclovir is an antiviral drug, which is phosphorylated
by HSV-TK and then cellular kinase to produce GCV triphophate which
disrupt, DNA synthesis and cause cell death.

32. VIRUS DIRECTED ENZYMESPRODRUG THERAPY
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 Both GDEPT and VDEPT involve physical delivery of genes
encoding prodrug-activating enzymes to the tumor cells for
site-specific activation.
 The only notable difference between the two strategies is
GDEPT uses non viral vectors for intracellular delivery of genes,
whereas VDEPT uses viral vectors for achieving the same
purpose.
 This therapy relies on use of viral vectors for the efficient
delivery to tumor cells of a ‘suicide gene’ encoding enzyme,
which convert a non- toxic prodrug to a cytotoxic agent.

33. PRODRUGS INNOVEL DRUG DELIVERY SYSTEM
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A number of carrier systems used to deliver drug into its active site in its
intact form
few examples are Nanoparticle, niosomes, and liposomes. They have the
ability to protect drug and increase its solubility and permeability . Thus, this
is a burning topic for research and gaining lot of interest.
liposomes nanoparticles
(using phospholipid) (triglyceride core)

34. CONCLUSION
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 Recent advances in biotechnology have made it possible to utilize pro-drug
design to develop site specific drug delivery systems which provide various
means of targeting the delivery of parent drugs to specific sites within the
body.
 Clearly, the increasing demands for more efficacious and less toxic drugs will
ensure that prodrug approaches continue to be exploited in the development
of future drug substances.

35. REFERENCES
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•John H. Block and John M. beale, Jr. ,Wilson and Gisvold’s textbook of Organic
medicinal and Pharmaceutical chemistry, eleventh edition, pg: 142-155.
•Biopharmaceutics and Pharmacokinetics by D.M.Brahmankar and Sunil B.Jaiswal, pg:
159-176.
•Advances in Controlled and Novel Drug Delivery by N.K.Jain, pg: 269-285.
•Xiaoling Li, Ph.D, Bhaskara R. Jasti, Ph.D,
Design of Controlled Release Drug Delivery
Systems, pg: 75-105.
•Binghe Wang, terune Siahaan, and Richard A.
Soltero’s Drug delivery principles and
applications

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