Abstract
This chapter aims to review and highlight some examples of challenges and limitations of formulating prodrugs for clinical and commercial development. The reader should note that the existing literature on the formulation and pharmaceutical development of prodrugs is somewhat limited as pharmaceutical companies tend to not publish pharmaceutical development data. While the prodrug strategy has been used to overcome various drug delivery issues, it tends to present various formulation challenges. These challenges arise from various physicochemical properties of the prodrug as compared to the parent drug such as:
-
Lack of chemical stability, often the drug-promoiety linker
-
Potential for the formation of degradation by-products that are reactive intermediates resulting in secondary degradation pathways
-
Aqueous solubility
-
Aqueous solubility of degradation products
-
Disruption of solid state crystallinity
-
•|Polymorphism
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Ansel HC, Allen LV, Jr., and Popovich NG. Pharmaceutical Dosage Forms and Drug Delivery Systems. New York, NY, Lippincott Williams & Wilkins
Arimilli M, Kim C, and Bischofberger N. Synthesis, In Vitro Biological Evaluation and Oral Bioavailability of 9-[2-(Phosphonomethoxy)propyl]adenine (PMPA) Prodrugs. Antivir Chem Chemother 1997; 8:557–564
Badawy SI, Williams RC, and Gilbert DL. Chemical Stability of an Ester Prodrug of a Glycoprotein IIb/IIIa Receptor Antagonist in Solid Dosage Forms. J Pharm Sci 1999; 88:428–433
Badawy SI, Williams RC, and Gilbert DL. Effect of Different Acids on Solid-state Stability of an Ester Prodrug of a IIb/IIIa Glycoprotein Receptor Antagonist. Pharm Dev Technol 1999; 4:325–331
Constantinides PP, Tustian A, and Kessler DR. Tocol Emulsions for Drug Solubilization and Parenteral Delivery. Adv Drug Deliv Rev 2004; 56:1243–1255
Digenis GA, Gold TB, and Shah VP. Cross-linking of Gelatin Capsules and its Relevance to their In Vitro-In Vivo Performance. J Pharm Sci 1994; 83:915–921
Ennis RD, Pritchard R, Nakamura C, Coulon M, Yang T, and Lee W. Glass Delamination in Small Volume Parenterals. PDA Spring Conference 1997
Gu L, and Strickley RG. Diketopiperazine Formation, Hydrolysis, and Epimerization of the New Dipeptide Angiotensin-converting Enzyme Inhibitor RS-10085. Pharm Res 1987; 4:392–397
Gu L, and Strickley RG, A Profound Solvent Effect on the Diketopiperazine Formation of the New Dipeptide Angiotensin-converting Enzyme Inhibitor, Moexipril. Int J Pharm 1990; 60:99–107
Gu L, Strickley RG, Chi L-H, and Chowhan ZT. Drug-excipient Incompatibility Studies of the Dipeptide Angiotensin-converting Enzyme Inhibitor, Moexipril Hydrochloride: Dry Powder vs Wet Granulation. Pharm Res 1990; 7:379–383
Lee JW, Lu JY, Low PS, and Fuchs PL. Synthesis and Evaluation of Taxol-Folic Acid Conjugates as Targeted Antineoplastics. Bioorg Med Chem 2002; 10:2397–2414
Lundberg BB, Risovic V, Ramaswamy M, and Wasan KM. A Lipophilic Paclitaxel Derivative Incorporated in a Lipid Emulsion for Parenteral Administration. J Control Release 2003; 86:93–100
Narisawa S, and Stella VJ. Increased Shelf-life of Fosphenytoin: Solubilization of a Degradant, Phenytoin, through Complexation with (SBE)7m-beta-CD. J Pharm Sci 1998; 87:926–930
Rose WC, Clark JL, Lee FYF, and Casazza AM. Preclinical Antitumor Activity of Water-soluble Paclitaxel Derivatives. Cancer Chemother Pharmacol 1997; 39:486–492
Safadi M, Oliyai R, and Stella VJ. Phosphoryloxymethyl Darbamates and Darbonates—novel Water-soluble Prodrugs for Amines and Hindered Alcohols. Pharm Res 1993; 10:1350–1355
Shaw J-P, Sueoka CM, Oliyai R, Lee WA, Arimilli MN, Kim CU, and Cundy KC. Metabolism and Pharmacokinetics of Novel Oral Prodrugs of 9-[(R)-2-(Phosphonomethoxy)propyl]-adenine (PMPA) in Dogs. Pharm Res 1997; 14:1824–1829
Stevens PJ, Sekido M, and Lee RJ. A Folate Receptor-targeted Lipid Nanoparticle Formulation for a Lipophilic Paclitaxel Prodrug. Pharm Res 2004; 21:2153–2157
Strickley RG. Parenteral Formulations of Small Molecules Therapeutics Marketed in the United States (1999)—Part I. PDA J Pharm Sci Technol 1999; 53:324–
Strickley RG. Solubilizing Excipients in Oral and Injectable Formulations. Pharm Res 2004; 21:201–230
Strickley RG, Visor GC, Lin L-H, and Gu L. An Unexpected pH Effect on the Stability of Moexipril Lyophilized Powder. Pharm Res 1989; 6:971–975
Versluis AJ, Rump ET, Rensen PCN, Van Berkel TJC, and Bijsterbosch MK. Synthesis of a Lipophilic Daunorubicin Derivative and its Incorporation into Lipidic Carriers Developed for LDL Receptor-mediated Tumor Therapy. Pharm Res 1998; 15:531–537
Wrasidlo W, Gaedicke G, Guy RK, Renaud J, Pitsinos E, Nicolaou KC, Reisfeld RA, and Lode HN. A Novel 2′-(N-methylpyridinium acetate) Prodrug of Paclitaxel Induces Superior Antitumor Responses in Preclinical Cancer Models. Bioconjug Chem 2002; 13:1093–1099
Xiang T-X, and Anderson BD. Stable Supersaturated Aqueous Solutions of Silatecan 7-T-Butyldimethylsilyl-10-hydroxycamptothecin via Chemical Conversion in the Presence of a Chemically Modified beta-Cyclodextrin. Pharm Res 2002; 19:1215–1222
Yuan L-C, Dahl TC, and Oliyai R. Effect of Carbonate Salts on the Kinetics of Acid-catalyzed Dimerization of Adefovir Dipivoxil. Pharm Res 2000; 17:1098–1103
Yuan L-C, Dahl TC, and Oliyai R. Degradation Kinetics of Oxycarbonyloxymethyl Prodrugs of Phosphonates in Solution. Pharm Res 2001; 18:234–237
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2007 American Association of Pharmaceutical Scientists
About this chapter
Cite this chapter
Strickley, R.G., Oliyai, R. (2007). Formulation Challenges of Prodrugs. In: Stella, V.J., Borchardt, R.T., Hageman, M.J., Oliyai, R., Maag, H., Tilley, J.W. (eds) Prodrugs. Biotechnology: Pharmaceutical Aspects, vol V. Springer, New York, NY. https://doi.org/10.1007/978-0-387-49785-3_30
Download citation
DOI: https://doi.org/10.1007/978-0-387-49785-3_30
Publisher Name: Springer, New York, NY
Print ISBN: 978-0-387-49782-2
Online ISBN: 978-0-387-49785-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)
