WELCOME

Project Presentation by Sunil Saini

WATER SOLUBLE PRODRUGS

Supervised by:Mr. Sandeep Kumar YadavAssistant Professor(Pharmacology)

Submitted by:Sunil SainiEnroll. 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

Contents :

1. Introduction

2. Water soluble prodrugs

3. Water insoluble prodrugs

4. Summary and conclusion

1. IntroductionProdrugs

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.

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

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

• 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

• 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

• 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

• 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

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

• 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.

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.

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.