STUDY OF PRODRUGS IN PROBLEM RELATED TO BIOAVAILABILITY AND ELEGANCE OF FORMULATION

Presented by:Mankaran Singh M.Pharmacy CT Institute of Pharmaceutical Sciences Punjab, India

Introduction
What is a prodrug ? The term prodrug refers to a pharmacologically inactive compound that is converted to an active drug by a metabolic biotransformation. Prodrug is formed by linking drug to an inert chemical by covalent bond which is broken down in vivo to release drug. The biotransformation of a prodrug may occur prior, during, and after absorption, or at specific target sites within the body.
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Principle of prodrug Approach

DRUG

PRO MOIETY

DRUG

ENZYMES

PRO

DRUG

PRO

DRUG

Prodrug design may be useful in circumventing problems associated with:

Solubility Absorption and distribution Site specificity (Diethylstilbestrol diphosphate ) Instability (hemisuccinate ester of propanolol) Prolonged release(Haloperidol decanoate)(cns depressant) Toxicity (aspirin) Poor patient acceptability Formulation problems
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Classification of Prodrugs
Carrier-linked prodrug: contain a group that can be easily removed enzymatically (such as an ester) to reveal the true drug. Ideally, the group removed is pharmacologically inactive and nontoxic while the connecting bond must be labile for efficient activation in vivo. Bioprecursors: Metabolized into a new compound that may itself be active or further metabolized to an active metabolite (e.g. amine to aldehyde to carboxylic acid).
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Carrier-linked prodrugs can be further subdivided into: 1. Bipartate: Composed of one carrier (group) attached to the drug. 2. Tripartate: Carrier group is attached via linker to drug 3. Mutual prodrugs: Two drugs linked together

Steps in Prodrug Design

Identification of drug delivery problem

Identification of desired physicochemical properties

Selection of transport moiety which will

give prodrug desired transport properties

be readily cleaved in the desired biological compartment

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Rationale in prodrug formation

The process of drug development occur in 3 phases:1.Pharmaceutical a. Physical properties like odour,taste etc b. Physiochemical properties (hydrophilicity etc) 2. Pharmacokinetic ( ADME of drug) 3. Pharmacodynamic Drug receptor interaction and is not usually not a phase in which prodrug play a major role.

A. Pharmaceutical barriers
1. Drug Solubility
Formulation of insoluble compounds may be improved by the use of phosphate or hemisuccinate prodrugs Examples: Insoluble glucocorticoids such as dexamethasone, prednisolone, betamethasone, hydrocortisone etc.

Dexamethasone disodium phosphate water soluble phosphate of Dexamethasone

Prodrug of Dexamethasone
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2. Organoleptic properties Unpleasant tastes and odors can be improved by using prodrug concept Example: Chloramphenicol
Chloramphenicol
OH OH Cl Cl O O-Na+ O O O H N O H O Cl Cl

H N O

Esterase

O2 N

O2 N

or Water
OH O-Na+ O

Chloramphenicol Succinate

Sodium succinate

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3. Drug stability Breakdown or degradation of active drugs on prolonged storage Common problem of oral drugs which are unstable in gastric acid 5-Aminosalicylic acid (mesalazine) ;
Treatment of ulcerative colitis Unstable in gastric acid in stomach Site of action is ileum/colon

Eg : Hetacillin a prodrug of Ampicillin which is stable in aq solution

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4. Reduction of pain at site of injection Pain at site of injection is related to various factors like viscosity, pH, isotonicity, precipitation at site of injection etc. Clindamycin hydrochloride produces pain at site of action due to precipitation of free clindamycin but its prodrug Clindamycin phosphate which is higher soluble produces no irritation at site of injection.

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B. Pharmacokinetic barriers 1. Increasing bioavailability Many drugs are poorly or unpredictably absorbed from gastrointestinal tract Prodrug design has been utilized in a number of cases to optimize the absorption of such drugs thereby improving their bioavailability Example: Ampicillin is used as their lipophilic esters like pivampicillin & bacampicillin to improve drug absorption Ampicillin R=H
Pivampicillin R= CH2-O-CO-C(CH3)3 Bacampicillin R= CH(CH3)-O-COOC2H5

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a. Preventing first pass metabolism Prodrugs may protect a drug from 1st-pass effects. Propranolol (antihypertensive drug) suffers from firstpass elimination resulting in decreased bioavailability of oral doses compared to i.v. injections. One of the major metabolites is the O-glucuronide. The hemisuccinate ester was designed to block glucuronide formation resulting in an 8-fold increase of plasma levels of propranolol.

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b. Intestinal absorption Eg: Sulindac ( NSAID) its bioavailability is increased due to increased solubility in GI track. c. Buccal absorption Eg: Phenolic compound of ketobemidone increased lipophilicity of drug. d. Dermal transport Eg : Morphine ester have more than 2000folds higher dermal absorption than morphine
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e. Rectal absorption Eh : Bacampicillin a prodrug of ampicilin have more rectal absorption( 40% more). f. Ocular absorption Eg. Dipivefrin a prodrug of adrenaline have more ocular absorption.

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2. Drug distribution The modification of a drug to a prodrug may lead to enhanced efficacy for the drug by differential distribution of the prodrug in body tissues before the release of the active form. Example: L-dopa is formulated as prodrug of dopamine to enhance the dopamine level in the brain tissues
HO HO CO2H NH2 HO

Decarboxylase
HO

NH2

Dopamine
Brain has a specific transport system for L-amino acids

Dopamine does not cross the blood brain barrier efficiently, is rapidly metabolized by oxidative deamination, and can cause peripheral side effects

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C. Other application of prodrugs 1. Reduction in Toxicity The prodrug that is converted to the active drug at the target site itself greatly reduced side effects of highly toxic drugs.
Derivative of salicylic acids are one of the oldest example that are characterized by lesser toxicity than their parent drugs. Salicylic acid is a good pain-killer but causes gastric irritation and bleeding because of carboxyl group. It accumulates in the gastric mucosal cells. Aspirin, esters of salicylic acid, suppresses gastric irritation.
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Targeted Prodrug design represents a strategy for directed and efficient drug delivery Site activated prodrugs Site directed prodrugs

For example:- tumor cells posses higher concentrations of phosphatases and amidases than normal cells. Diethylstilbestrol diphosphate was designed for such site-specific delivery of diethylstilbestrol in the treatment of breast cancer
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 A common strategy for slow release is to include a longchain aliphatic ester to slow hydrolysis. It is particularly useful for the treatment of psychoses where patients require medication for extended periods and patient compliance is low.

EG: Haloperidol: potent orally active CNS depressant, sedative, tranquilizer. peak plasma levels between 2-6 hr after administration Haloperidol decanoate: injected i.m. as a solution in sesame oil Antipsychotic activity lasts ~ 1 month.
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CONCLUSION
Prodrugs are used to overcome several undesirable properties in order to achieve the best clinical drug application Site specificity is central to the prodrug development strategy

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THANK YOU
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