The document presents a project on water soluble and insoluble prodrugs by Sunil Saini. It defines prodrugs as pharmacologically inactive derivatives of active drugs that are designed to maximize the amount of active drug that reaches its site of action. The project discusses how various prodrugs are used to increase drug absorption, improve site-specific delivery, prolong drug action, and decrease side effects.

1. WELCOME
Project Presentation by
Sunil Saini

2. WATER SOLUBLE
PRODRUGS
Supervised by:
Mr. Sandeep Kumar Yadav
Assistant Professor
(Pharmacology)
Submitted by:
Sunil Saini
Enroll. No. 10/373
May, 2014
LACHOO MEMORIAL COLLEGE OF SCIENCE AND TECHNOLOGY
(PHARMACY WING), JODHPUR-342003
Affiliated to
RAJASTHAN UNIVERSITY OF HEALTH SCIENCES, JAIPUR, INDIA

3. Contents :
1. Introduction
2. Water soluble prodrugs
3. Water insoluble prodrugs
4. Summary and conclusion

4. 1. Introduction
Prodrugs
Prodrugs are pharmacologically inactive derivatives of active
drugs that are designed to maximize the amount of active drug
that reaches its site of action, through manipulation of
physicochemical, biopharmaceutical and pharmacokinetic
properties of drug.
They are converted into active drug within the body
through enzymatic or non-enzymatic reactions. Also called drug
latentiation.

5. The prodrug concept is used for following purpose
• Increasing absorption of drugs. eg: Ampicillin esters.
• Improve site specific drug delivery. eg; Epinephrin.
• Prolongation of drug action eg; Testosterone.
• Decrease side effect and toxicity eg; NSAID
• Improve taste and odour eg; Chloramphenicol palmitate
• Delivery to brain eg; Dopamine to L-dopa

6. 2. Water Soluble Prodrugs
• As the name suggests water soluble prodrugs are formulated
using the aqueous solubility of the drug and for enhancing the
oral drug delivery, generally includes the addition of an
ionizable progroup to the parent compound (such as phosphate
group).
• Formation of water-soluble ester prodrugs has long been
considered an efficient way to improve the aqueous solubility
of poorly soluble drugs that contain a hydroxyl group.
• The most commonly used esters for forming prodrugs are
those containing ionizable groups such as dicarboxylic acid
hemiesters.
For example, Amprenavir is an HIV protease inhibitor

7. • Water soluble prodrugs for improved oral absorption
Phosphate esters offer one way to increase the oral
bioavailability of many sparingly water soluble drugs, but only
few phosphate prodrug for oral administration have been
marketed to date. The challenges to the development of oral
phosphate prodrug, are related to poor enzymatic
bioconversion
Ex : Estramustine phosphate is a phosphate ester prodrug of
estramustine, for the treatment of prostate carcinoma

8. • Water soluble prodrugs for improved intravenous
administration
The most commonly used approach to increase the water
solubility by prodrugs is to introduce an ionizable polar
promoiety into the parent drug. A number of phosphate esters
have been developed as potential water-soluble prodrugs for
i.v. administration
Ex : Fosphenytoin is a phosphate ester prodrug of poorly water
soluble phenytoin for the acute treatment of seizures

9. • Water soluble prodrug to treat systemic fungal infection
The treatment of systemic fungal infections normally involves
slow intravenous infusion of antifungal drugs, as formulations
may be limited by low drug solubility. To overcome this, the
phosphate ester prodrugs of fluconazole and voriconazole
were prepared improving water solubility 1000 fold

10. • Some Different Water Soluble Prodrugs
• Paclitaxel - antineoplastic agent
• Adenosine A2A receptor antagonists, such as
Istradefylline - for the treatment of Parkinson’s disease
• Combretastatin -potent antimitotic agent
• 2R-γ-Tocotrienol - group as tocopherols vitamin E family
• 17β-Estradiol - estrogenic hormone
• Endocannabinoid Noladin Ether – use for reduction of
intraocular pressure

11. 2. Water InSoluble Prodrugs
• When it in desired to decrease water solubility, a non-polar
alcohol or carboxylic acid is chosen as the prodrug moiety.
Decreasing the hydrophilicity of the compound may yield a
number of benefits, including increased absorption, decreased
dissolution in the aqueous environment of the stomach and a
longer duration of action.
• Water insoluble prodrug can be used for CNS targeted
drug delivery
Levodopa can be considered as a prodrug which achieves
targeted delivery into central dopaminergic neurones where
levodopa is rapidly converted to dopamine by enzymes only
present in nerves

12. • Prodrugs for prolonged duration of drug action
Very lipophilic prodrugs of several steroids (e.g. testosterone
nandrolone) and neuroleptics fluphenazine generally appears
between 24 to 72 hours after injection of its lipophilic
decanoate ester prodrug, and thus gradual release continues for
1 to 8 weeks with an average duration of 3 to 4 weeks.

13. 4. Summary and conclusion
A prodrug also defined as a pharmacological substance (drug) that
is administered in an inactive form. Once administered, the
prodrug is metabolized in-vivo and converted into an active
metabolite. The various factors affecting the action of prodrug are
absorption, distribution, metabolism and excretion (ADME), as
optimization of these factors enhance the bioavailability of
prodrug. Prodrugs are usually designed to improve oral
bioavailability, with poor absorption from the gastrointestinal tract
usually being the limiting factor, often due the chemical properties
of the drugs.

14. Instead of synthesizing new compounds which is a time
consuming and too costly an affair, the designing of derivatives
of existing drug is definitely an interesting and promising area of
research. Moreover, as the metabolic profile of the liberated
parent drug (after cleavage of the derivative in the body) would
be already known, it could be advantageous to design derivatives
of parent drug.