Prodrug : A Sustained Chemical Drug Delivery Approach

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Swarnlata Saraf

Swarnlata Saraf

The organic drugs are chemical moiety used for therapeutic effects but the targeting of this drug moiety are difficult due to presence of pharmaceutical/ physiological barrier  so there is need of  change in physicochemical properties of  drug.

For targeting of drug many novel approaches used such as vesicular system, micro emulsion, nanotechnology etc. but most of these approaches suffer from entrapment efficiency and stability problem. To overcome this problem an approach i.e. conversion of drug entity to drug conjugate has been developed. These prodrug is converted in to active drug moiety either by enzymatic or by bioconversion inside the body. The present article discusses about prodrug incorporated delivery system, ideal properties, limitation and targeting of prodrug.


The drug gives pharmacologic response by binding with receptor at the site of action and factor that limits its optimum entering into this site is considered as barrier. The barrier can be overcome by chemically linking promoiety to form prodrug which undergoes biotransformation to release the parent drug, so prodrug is a chemically modified inert drug precursor which upon biotransformation converted into the pharmacologically active parent compound3.

Classificastion Of Prodrug

• Carrier Linked Prodrug: -

In this type of prodrug, the active drug is covalently linked to an inert carrier or transport moiety. Such prodrug has modified lipophilicity due to attached carrier. The active drug is released by hydrolytic cleavage either chemically or enzymaticaly. The used moiety is ester or amides.

• Bioprecursor: -

These are obtained by chemical modification of active drug but do not contain a carrier. Such type of prodrug has almost the same lipophilicity as the parent drug and is bioactivated generally by redox biotransformation2,3.

Ideal Property Of Prodrug:

It should not have intrinsic pharmacological activity that means it should not change receptor configuration that is necessary for pharmacological response. It should rapidly transform into the active form where desired and metabolic fragment, apart from the active drug should be nontoxic4

Prodrug Incorporated Delivery System:

The colloidal drug delivery system works as a controlled  and sustained delivery by releasing the encapsulated drug while in circulation or after the recognition by cell , so it is necessary  that the delivery system must contain maximum quantity of drug for optimum efficacy .The encapsulation depends upon the physicochemical properties which can suitably modified by linking with promoiety  and altering as prodrug2,5.


Liposomes are consisted of lipid (mainly phospholipids) bilayer in which between lipid bilayer intervening water molecules are present. The drug is incorporated into either aqueous compartment or in the lipid bilayer as the drug has its physicochemical property. The less hydrophobic drug exhibit low entrapment efficiency and making them more hydrophobic by derivative of fatty acids , improves the entrapment efficiency of delivery system e.g. the triamcinolone 21 palmitate (prodrug) showed 85% entrapment efficiency as compared to triamcinolone acetonite which has 5%entrapment efficiency2,6.


Lipoprotein are endogenous transporter of lipids in the circulation , they are nonimmunogenic escapes recognition by reticuloendothelial system. Their structural component are NeoHDL particles consisting of apolar triglyceride core surrounded by phospholipids monolayer in which specific apoprotein are imbedded .Since apoprotein are necessary for the recognition of L.D.L. so drug should be into the lipid moiety but most of the drug has not sufficient lipophilic  so there is need of to prepare lipophilic prodrug2,8.


The oil in water emulsion are used as sustained drug delivery ,by passing targeted to macrophages  and active  targeting by ligand attachment, so in this case the lipophlicity of the drug is necessary to make as oil in water emulsion as sustained delivery system.e.g. Esterified phenolic 4 hydroxy derivative of etoposide is used as lipophilic prodrug which is soluble in lipid emulsion in which cholesteryl ester oil used as oil component2,10.

Solid Lipid Nanoparticle:

Solid lipid nanoparticle consisted of high melting point triglyceride aas the solid core and a phospholipids coating .Its advantage over the other system are use of natural lipid and incorporation of drug in triglyceride core which may be applicable for prolonged release .For prolonged release it is desirable to incorporate the drug into triglyceride phase of emulsion e.g. Azidothymidine palmitate ester prodrug incorporation increases as compared to Azidothymidine.

Application: Targetting Of Prodrug

Brain Targeting:

The high selectivity and poor permeability of blood brain barrier limits the delivery of hydrophilic drug to the brain and thus therapeutic concentration is difficult to achieve .Conversion into their lipophilic forms leads to simultaneous enhancement of  transport of drug to other tissue ,there by greatly increasing the chance of systemic toxicity. For this reason dihydropridine pyridinium type redox system was developed for brain specific sustained delivery of drug. The drug containing amine group is made lipophilic by coupling to dihydropyridine promoiety that facilitate penetration of prodrug through the blood brain barrier. In the CNS dihydropridine group oxidize to polar pyridinium salt, thus becomes poorly permeable to blood brain barrier and causes retention at the site and cleavage provides sustained release for action .The same process in periphery due to high hydrophilicity rapidly excreted and toxicity eliminates.

Kidney Targeting:

For the treatment of renal hypertension Dopamine is used because of binding to specific receptor present in the kidney but its therapeutic index is small as it precipitate high blood pressure by interaction with the α-adrenergic receptor. This can be overcome by the advantage of fact that their glutamil derivative of amino acid and peptides selectively accumulate in the kidney. Such derivative on reaching kidneys is acted upon by two enzymes that present in high concentration in the renal tissue, γ glutamyl transpeptidase and L-aromatic amino acid decarboxylase to release active drug. The release of dopamine levels produces marked increases in renal blood flow.

Colon Targeting:

The polar prodrug decreasing the absorption in the stomach and intestine while selective cleavage by bacterial enzyme present in colon to more lipophilic drug follows fast absorption through the membrane of colon, thus targeting to colon is achieved, e.g. sulphasalazine which is formed by coupling of diazotized sulphanilamide pyridine with s-amino salicylic acid (ASA). On oral administration intact sulphasalazine reaches the colon .The azo reductase associated with colonic microflora  convert sulphasalazin to its constituents entities, the active species 5ASA  available for absorption in colon, while precolonic absorption responsible for side effects is reduced.

Antibody Based Targeting:

Monoclonal antibody is ideal way of targeting tumor cells. Two approaches is used for targeting and activating a prodrug at the tumor site.These are called antibody drug conjugate and antibody directed enzyme prodrug therapy (ADEPT).

  • Antibody drug immunoconjugate formed by linking cytotoxic agent to monoclonal antibodies active with tumor associated antigen. The immunoconjugate  bind to specific cells leading to internalization of conjugate and drug is cleaved from the antibody  intracellularly (lysosomal degradation).The limiting factor for this approach is heterogeneity in expression of antigen by cancer cells, insufficient internalization of the antigen antibody complex or inefficient cleavage of linker moiety to release the free drug.
  • The second approach involves administration of enzyme that is covalently linked to a monoclonal antibody, which bind selectively to the respective tumor associated antigen. After the antibody enzyme conjugate has localized within the tumor and has cleaved from non target sites, a prodrug that is substrate for the enzyme is administered, when prodrug contact with enzyme, it is converted to active drug species at the tumor site2,6.

Targeting The Viruses:

The antiviral drug Acyclovir has been targeted through  site selective activation by the herpes virus encoded enzyme pyrimidine deoxynucleoside (thymidine) kinase, responsible for converting acyclovir to its monoester form. Again monoester converted into triester by cellular kinase.The triester is pharmacologically active form .The enzymatic  conversion of triester form is found in the herpes infected cells ,so Acyclovir shows high therapeutic activity against herpes virus and low activity against uninfected host cells2,6.

Limitation Of Prodrug:

The problem associated with prodrug design is its toxicity which is due to

·Formation of unexpected metabolite from the total drug conjugates.

·Toxicity may be due to inert carrier generated by cleavage of promoiety and drug conjugate which is converted into toxic metabolite.

·The prodrug might consume a vital cell constituent such as glutathione during its activation stage which causes depletion of prodrug11.


The modification of basic drug molecules by chemical methods improves the physicochemical and biological properties. Physicochemical property such as patition –coefficient, solubility, pH, effects the absorption, distribution, and ultimately metabolism.further excretition of the drugs changes by these properties.By the prodrug approaches we can target at particular site for sustained delivery of drug.


1.Gennaro .R. Alfanso et al,Remington:The science and practice of pharmacy, 20 ,1 ,913-914.

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2.Jain N.K. ,Advances in Controlled and Novel drug delivery,2001,1 , 268-283

3.Brahmankar D.M., Jaiswal S.B., Biopharmaceutics and pharmacokinetics –A treaties,1,159-176.

4.Stella V.J., Himmel stein K.J., prodrug and site specific drug delivery,J med. chem1980, 23 1275-1282.

5.Bagshawe K.D., Antibody  directed enzyme prodrug(ADEPT), Adv Pharmacol 1993,24 99-121.

6.Sharma S.K., melton R.G.,Sherwood R.F., Human immune response to monoclonal antibody-enzyme conjugate in ADEPT pilot clinical trial, cell Biophy. 1992 ,2 109-120.

7.Lebach F.H. Ganupathy V., Prptide transporter in the intestine and kidney , Annu, rev.Nutr 1996, 16, 99-119

8.Suginoshit  et al J. controlled release , 2002, 83 ,75- 88.

9.Hasuda H., kwon O.H., Kang I.N. Biomaterials, 2005:26,2401-2406.

10.Bansal A.K., Khar R.K., Dubey R.,Sharma A.K.,Alkyl ester prodrug for improved topical delivery of Ibuprofen,J Exp. Bio.2001 39(3) 280-283

11.Jha V.Chang K.S., Drug induced renal diseases, J. Assoc., Physician India 1995, 43,407-21     

About Authors:

Swarnlata Saraf

Dr.(Mrs.)Swarnlata Saraf has nearly 14 years of research and teaching experience. She is a leading scientist and well-known in the field of herbal cosmetics. Mrs. Saraf did her doctoral research at the Dept. of Pharmacy, Dr. H. S. Gour University, SAGAR. She has over 40 publications to her credit published in international and national journals. She is an active member of IPA, APTI and ISTE. Her research interest extends from Herbal Cosmetics to transdermal drug delivery (especially Iontophoresis), New Drug Delivery Systems for biological and therapeutic agents. She has Co-authored 1 book on cosmeceuticals. Presently, She is working as a Reader at Institute of Pharmacy Pt. Ravishankar Shukla University, Raipur, (C.G.) INDIA.

* For correspondence

Dr. (Mrs.)Swarnlata Saraf , Reader, Institute of Pharmacy , Pt. Ravishankar Shukla University, Raipur (C. G.) - 492010

e-mail- swarnlata_saraf@rediffmail. com

Shailendra Saraf

Prof.S.Saraf has nearly 17 years of research and teaching experience at both U.G. and P.G. levels. He is a leading scientist and well-known academician . Prof. Saraf did his doctoral research at the Dept. of Pharmacy, Dr. H. S. Gour University, SAGAR. under the supervision of Prof. V. K. Dixit, a renowned Pharmacognosist. He has over 50 research publications to his credit published in international and national journals. He has delivered invited lectures and chaired many sessions in several National Conferences and Symposia in India. His research interest extends from Herbal Cosmetics to Herbal drug standardization Modern analytical techniques, New Drug Delivery Systems with biotechnology bias. He has authored 1 books. Presently, he is Professor and Director Institute of pharmacy and Dean, Faculty of Technology, Pt. Ravishankar Shukla University, Raipur , (C.G.).

Shashikant Chandrakar

Shashikant Chandrakar

Gyanil Kumar Sahu

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