Prodrug Design
UMANG H SHAH
ASSISTANT PROFESSOR – RAMANBHAI PATEL COLLEGE OF PHARMACY
CHAROTAR UNIVERSITY OF SCIENCE AND TECHNOLOGY - CHANGA
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What is Prodrug???
In simplified terms, prodrugs are masked forms of active drugs that
are designed to be activated after an enzymatic or chemical reaction
once they have been administered into the body.
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o Almost all drugs possess some undesirable physicochemical and biological
properties.
o Drug candidates are often discontinued due to issues of poor pharmacokinetic
properties or high toxicities.
o Their therapeutic efficacy can be improved by eliminating the undesirable
properties while retaining the desirable ones.
oProdrugs are considered to be inactive or at least significantly less active than
the released drugs; therefore, salts of active agents and drugs, whose
metabolites contribute to the overall pharmacological response.
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Prodrug effect can be achieved through biological,
physical or chemical means.
Biological approach is to alter
the route of administration
which may or may not be acceptable
to patient.
Best approach in enhancing drug Physical approach
selectivity while minimizing
is to modify the design of
toxicity, is the chemical dosage form
approach for design of such as controlled drug delivery
prodrugs. of drug.
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Objectives of Prodrug Design
Pharmaceutical Objectives:
o To improve solubility, chemical stability, and organoleptic
properties
o To decrease irritation and/or pain after local
administration,
o To reduce problems related with the pharmaceutical
technology of the active agent.
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Pharmacokinetic Objectives:
o To improve absorption (oral and by non-oral routes).
o To decrease pre-systemic metabolism to improve time
profile.
o To increase organ/ tissue-selective delivery of the active
agent.
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Pharmacodynamic Objectives:
o To decrease toxicity and improve therapeutic index.
o To design single chemical entities combining two drugs
(co-drugs strategy) eg. Sulfasalazine
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Classification of Prodrug:
Bipartite
Prodrug
Carrier-linked Tripartite
Prodrug Prodrug
Bioprecursors Mutual
Prodrug
Prodrug Prodrug
Polymeric
Prodrug
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Carrier-linked Prodrugs:
Carrier linked prodrug consists of the attachment of a carrier group to the
active drug to alter its physicochemical properties.
The subsequent enzymatic or non-enzymatic mechanism releases the active
drug moiety.
The carrier group must be non-toxic and biologically inactive when detached
from drug
Inert
Inert
Chemical Prodrug Formation Carrier
Carrier
Active Chemical/Enzymatic cleavage Active
Drug in vivo Drug Covalent Bonding
Inert Carrier
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Bipartite Prodrug
It is composed of one carrier (group) attached to the drugs.
Such prodrugs have greatly modified lipophilicity due to the attached carrier. The active drug
is released by hydrolytic cleavage either chemically or enzymatically.
E.g. Prednisolone
More Polar
and Aqueous
Solubility
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2. Latanoprost: Bipartite Prodrug Concept
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Tolmetin-glycine Prodrug:
H
C O
3
N
OH
N
O C
H
3
H
O
Glycine – Improve Lipophilicity of Tolmetin
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Tripartite Prodrugs:
Structure of most prodrugs is bipartite in nature, in which parent drug is
attached directly to promoiety. However, in some cases bipartate prodrug may
be unstable due to inherent nature of the drug promoiety bond. The problem
can be overcome by designing a tripartate prodrug, utilizing a spacer or
connector group between the drug and promoiety.
Spacer/
Drug Linker
Carrier
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Eg: Bacampicillin- Improved Oral Bioavaibility
Linker/Spacer
Carrier
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Mutual Prodrug:
Generally in a prodrug the carrier group or promoiety used is inert or non-toxic.
However in certain cases the prodrug consists of two pharmacologically active
agents coupled together in the form of a single molecule so that each acts as
promoiety for the other agent. Such derivatives have been termed as mutual
prodrugs
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Sulphasalazine
Sulphasalazine was introduced in 1942 for the treatment of
rheumatoid arthritis. Azo
Reductase
The 5-aminosalicylic acid (5-ASA) and sulfapyridine used in
the treatment of ulcerative colitis.
Sulfapyridine – good carrier molecule to target 5-ASA to
colon but Sulfapyridine produced systemic toxicity.
The above disadvantage of Sulphasalazine can overcome by
olsalazine (mutual prodrug is actually a dimer of 5-ASA,
where 5-ASA is linked through azo linkage to another
molecule of 5-ASA)
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Bioprecursors:
The bioprecursor does not contain a temporary linkage between the
active drug and carrier moiety, but designed from a molecular
modification of an active principle itself.
Eg: Phenylbutazone: Phenylbutazone gets metabolized to
oxyphenbutazone that is responsible for the anti inflammatory
activity of the parent drug
Upon administration many compounds are metabolized by
molecular modification into new compounds that are active in
principle or can be metabolized further into the active drugs.
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Five types of reactions can be involved in bioprecursor activation
1. Oxidative reaction, catalyzed by CYP450 such as (i) O and N dealkylation; _e.g bioprecursor
prodrug for alprazolam) , (ii) oxidative deamination; e.g. (cyclophosphamide activation),
(iii) N-oxidation; e. g (procarbazine activation)
2. Reductive activation such as (i) disulfide reaction; e. g (activation of thiamine prodrug) and
(ii) bioreductive alkylation; e.g. (activation of anticancer antibiotic, mitomycin c).
3. Nucleotide activation.
4. Phosphorylation activation; e. g (antiviral drug, acyclovir activation).
5. Decarboxylation activation; e. g (Nabumetone).
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Polymeric Prodrugs:
Also known as macromolecular prodrug, the drug is dispersed or incorporated
into the polymer (both naturally occurring and synthetically prepared) system
without formation of covalent bond between drug and polymer.
Eg: 1. p–phenylene diamine mustard is covalently attached to polyamino
polymer backbone polyglutamic acid.
2. Polymeric prodrug for prolonged drug release of nitrofurazone (NF) on the
skin, with chitosan as the carrier.
Most commonly used polymers are proteins as antibodies and lipoproteins,
polypeptides as polylysine and polyglutamic acid, synthetic polymers as
copolymers of N-vinyl pyrrolidine and polysaccharides as dextran, starch, gum
etc. are used
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Novel Classification:
Type I prodrugs are bioactivated inside the cells
(intracellularly). Examples of these are anti-viral nucleoside
analogs that must be phosphorylated and the lipid-lowering
statins.
Type II prodrugs are bioactivated outside cells
(extracellularly), especially in digestive fluids or in the
body's circulation system
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Purpose of Synthesis of Prodrugs:
Enhancing site-specific drug delivery.
Enhancing bioavailability and biomembrane passage.
Improvement of aqueous solubility.
Improvement of lipophilicity.
Prolongation of drug action.
Reduction of toxicity and adverse reaction.
Improvement of drug formulation.
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PHARMACEUTICAL BARRIERS
Barrier for Drug Prodrug (Reference)
efficient
application
Patient Compliance Problems:
Taste Chloramphenicol Chloramphenicol palmitate
Odour Ethylmercaptan Dithylthiophthalte (Davies et al. 1956)
Painful or Clindamycin Clindamycin Hydrogen Phosphate(Gray et al. 1974)
Irritating Injection Phenytoin Acyclic Derivative of Phenytoin (Deehan et al. 1952;
Varial et al. 1984)
Solubilization Paclitaxel Poly(ethylene glycol) paclitaxederiv. (Arpicco et al. 2013)
Chloramphenicol Chloramphenicol sod. Succinate (Glazko et al. 1957)
Erythromycin Erythromycin esteolate
Amprevavir Fosamprenavir (Chapman et al. 2004; Wire et al. 2006)
Formulation Barriers
Stability Sulindac Sulindac sulphide
Ampicillin Polymerized Ampicillin
Hetacillin
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SITE SPECIFIC DRUG DELIVERY
Barrier for Drug Prodrug (Reference)
efficient
application
Lungs Isoniazid Isoniazid sod. Mesylate
Liver Adefovir Pradefovir (Erion et al. 2006)
5-fluorouracil N-galactosylated-chitosan-5fluorouracil acetic acid Conjugate (GC-FUA)
Brain Dopamine Dopa
Tacrine (THA) Dihydropyridine carriermutual prodrug of tacrine
Morphine Diamorphine
Colon Sulphapyridine Sulphasalazine
Salicylic acid Mesalazine
Fexofenadine Fexofenadine-D-glucosamine (Dhaneshwar and Gautam in 2012)
Kidney L- Dopa γ-glutamoyl -L-Dopa
Stomach Omperazole Sulphenamide Intermediate
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PHARMACOKINETIC BARRIERS
Barrier for Drug Prodrug (Reference)
efficient
application
Bio-availability Improvement
Oral Oseltamivir carboxylate Oseltamivir (Tamiflu®)
Oleanolic acid Propylene glycol-linked amino acid prodrug of Oleanolic acid
Dopamine Dopa (Cohen et al.1972)
Ampicillin Becampicillin, Telampicillin and Pivampicillin
Ophthalmic Epinephrine Dipivifrin
Prostaglandin Latanoprost (Xalatan®Introduction)
Transdermal Nicotinic acid Dodecyl nicotinate (Tashtoush et al. 2013)
Mefenide Mefenide acetate salt (Beyer et al.1945)
Tazarotenic acid Tazarotine (Dando and Wellington 2005)
Diclofenac Diclofenac ammonium salt 17 and 21 acetonide
Metabolism Morphine Diamorphine
Retardation Terbutaline Ibuterol
Enhancement in Testosterone Testosterone cypionate
Duration of Fluphenazine Fluphenazine heptanoate (Ebert etal. 1965)
Action
Decrease in Toxicity Cytarabine , Taxol , Salicylic acid, Cyclocytidine, Taxol-chlormethine derivatives
Adriamycin, Camptothecin Acetyl Salicylic acid, Adriamycin-14-octanoate, Cyclodextrin-
Camptothecin conjugates
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Chemical approaches for formation of Prodrugs
Most common
(biologically labile)
functional groups
utilized in prodrug
design are shown
above.
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Chemical approaches for formation of Prodrugs
Derivative Drug (Group Utilized for Formation of Prodrug
Prodrug)
Esterification Paracetamol (Phenolic) Paracetamol ester of NSAIDs
Salicylic Acid (Phenolic) Aspirin
Gitoxin (Alcoholic) Gitoxin Penta acetate
Mefenamic Acid (-COOH) Mefenamic Acid ester of menthol
Amidation 4- amino salicylic acid (-COOH) Amide Prodrug of 4-ASA
Ibuprofen (-COOH) Amide of Ibuprofen
Ampicillin Azlocillin
5-Fluorouracil (Cyclic Ureide) N- Acetyl-5- Fluorouracil
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Chemical approaches for formation of Prodrugs
Derivative Drug (Group Utilized for Formation of Prodrug
Prodrug)
Disulfide Paclitaxel Disulfide Prodrug of Paclitexel
Formation
Thiazolidine Hydrocortisone Thiazolidine derivative of Hydrocortisone
Formation
Oxazolidine Phenylephrine Oxazolidine prodrug of Phenylephrine
Formation
N- DOPA Gama – glutamyl- DOPA
Acyloxyalkoxyc
arbonylation
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