Saltbased prodrugs

The design of salt forms of prodrugs is associated most commonly with solubility and stability enhancement in various dosage forms. Ester prodrugs often are converted to salts to provide the desired balance of hydrophilic lipophilic properties.45 For example, fosphenytoin is designed as a disodium salt ester prodrug of phenytoin (Fig. 3.9) to overcome parenteral delivery problems related to the low aqueous solubility (20 to 25 g mL) of the parent compound.46 The sodium salt of phenytoin...

Oral cavity

Drug delivery via this route is promising owing to ease of administration and a rich supply of blood and lymphatic vessels. In addition, this route offers high permeability to drugs and good reproducibility. Drugs absorbed via the buccal mucosa enter the systemic circulation directly through the jugular vein. This ensures a rapid onset of action and avoids first-pass liver metabolism, gastric acid hydrolysis, and intestinal enzymatic degradation.89-91 Buccal tissue is a robust tissue owing to...

Lectindirected enzymeactivated prodrug therapy LEAPT

Lectin-directed enzyme-activated prodrug therapy (LEAPT) is a bipartite drug delivery system that first exploits endogenous carbohydrate-to-lectin binding to localize glycosylated enzyme conjugates to specific, predetermined cell types, followed by administration of a prodrug activated by the predelivered enzyme at the desired site.121 For example, the carbohydrate structure of an a-L-rhamnopyranosidase enzyme was modified through enzymatic deglycosylation and chemical reglycosylation. Ligand...

Info

That may provide dual therapeutic benefits against cancer, e.g., accelerating tumor cell death while protecting normal tissues from damage. However, D609 contains a dithiocarbonate (xanthate) group O C( S)S(-) O C( S)SH that is chemically unstable, being readily oxidized to form a disulfide bond with subsequent loss of all biological activities. A series of S-(alkoxyacyl)-D609 prodrugs that connect the xanthate group of D609 to an ester via a self-immolative methyleneoxyl group was designed...

Esterbased prodrugs

Owing to the properties of carbonyl group, esters generally are more hydrophobic (and consequently more lipophilic) than their parent compounds. Using specifics of their chemical structure, properties of ester prodrugs can be broadly modulated to achieve particular stability and solubility profiles, provide good transcellular absorption, resist hydrolysis during the initial phase of absorption, and transform rapidly and efficiently at the site of action.18-21 Biotransformation of an ester...

Vaginal mucosa

The potential of vaginal drug delivery is under investigation because of the advantages of prolonged, less frequent administration, low dose requirements, and continuous release. A drug delivered by the vaginal route does not face stability and degradation barrier issues.122 Anatomy and physiology. The vagina, also called the birth canal, is a thin-walled fibromuscular tubular structure, 8 to 12 cm in length, that lies inferior to the uterus, posterior to the urethra and bladder, and anterior...

M kt1

Where MWp and Xp denote the molecular weight and weight fraction of polymer in the formulation, respectively, and Mp is the polymer release profile. Interestingly, the release profile of polymer (Eq. 4.27) resembles that for the erosion-controlled system of Eq. (4.25). Note that Cpdis is the intrinsic value of pure polymer, whereas (Cpdis)eq is an equivalent Cpdis of polymer in a formulation. One can consider Cp dis as the equivalent solubility of polymer because it defines the concentration at...

James A Uchizono

Long School of Pharmacy and Health Sciences University of the Pacific Stockton, California 1.2 Pharmacokinetics and Pharmacodynamics 3 of Pharmacokinetic Parameters 4 1.3.1 Maximum concentration, time to maximum 4 concentration, and first-order absorption rate constant 1.3.3 Volume of distribution Vd 6 1.3.5 First-order elimination rate constant K 1.4 Pharmacokinetics and Classes of Models 7 1.4.1 Linear versus nonlinear pharmacokinetics 8 1.4.2 Time- and state-varying...

Rationale for Prodrug Design

A large number of the new molecular entities with promising therapeutic profiles are dropped from the screening stage because of their inferior physicochemical and biopharmaceutical properties. These undesired properties result in poor absorption, extensive metabolism, and low bioavailability because of physical, biological, or metabolic barriers. If the chemical structure of the drug or lead compound can be modified to overcome these barriers and then revert to the pharmacologically active...

Principles of Prodrug Design

Successful design of prodrug-based controlled delivery systems is generally based on efficient transformation of the promoiety into the active drug in vivo at the desired organ or tissue. Despite the diversity in chemical structure, most prodrugs can be classified on the basis of a common chemical linkage (e.g., esters, amides, and salts). In addition to these common types of prodrugs, recent prodrug approaches include conversion of promoieties into primary and secondary amines, imides,...

Lung

The lung as a drug delivery site offers many advantages. Drugs can be delivered noninvasively via lung for systemic effects. A rich blood supply and large effective surface area (140 m2) contributes to a high bioavailability and a quick onset of action.117 Delivery of proteins and peptides may be feasible owing to the low metabolic activity of this surface.117 Anatomy and physiology. The human respiratory system is divided into upper and lower respiratory tracts. The upper respiratory system...

Prodrugs for ocular delivery

For most ocularly applied drugs, passive diffusion is thought to be the main transport process across the cornea.67 Major challenges in ocular drug delivery include the tightness of the cornea1 epithelium barrier, rapid precorneal drug elimination, and systemic absorption from the conjunctiva.68,69 As a result, less then 10 percent and typically less than 1 percent of the instilled dose reaches the intraocular tissues. Many drugs developed for systemic use lack the physicochemical properties...

Anant Shanbhag Noymi Yam and Bhaskara Jasti

Long School of Pharmacy and Health Sciences University of the Pacific Stockton, California 3.2 Rationale for Prodrug Design 77 3.3 Principles of Prodrug Design 78 3.3.1 Ester-based prodrugs 79 3.3.2 Amide-based prodrugs 82 3.3.3 Salt-based prodrugs 84 3.3.4 Additional prodrug types 86 3.4 Prodrugs for Prolonged Therapeutic Action 88 3.5 Prodrug Design for Various Routes of Administration 89 3.5.1 Prodrugs for nasal delivery 90 3.5.2 Prodrugs for ocular delivery 91 3.5.3 Prodrugs for...

Tzuchi Rob Ju Yihong

Abbott Laboratories North Chicago, Illinois 4.1.1 Basic equations of diffusion 4.1.2 Diffusional release from a preloaded matrix 4.1.3 Diffusion across a barrier membrane 4.2 Oral Diffusion-Controlled Systems 4.2.3 Current challenges and future trends 4.3 Transdermal Diffusion-Controlled Systems 4.3.4 Current challenges and future trends 4.4 Other Diffusion-Controlled Systems 4.4.1 Intrauterine devices and intravaginal rings 4.4.3 Subcutaneous implants References

Macromoleculedirected enzyme prodrug therapy MDEPT

Macromolecule-directed enzyme prodrug therapy (MDEPT) is also referred to as polymer-directed prodrug therapy (PDEPT). It is similar to GDEPT and VDEPT, except that it applies a macromolecule conjugate of the drug to enable delivery to the tumor. This method also takes advantage of the enhanced permeation and retention (EPR) of tumors. One of the earliest examples of MDEPT involved -(2-hydroxypropyl) methacrylamide.116 The modes of delivery and activation of the prodrug by the preceding methods...

Ladme Scheme In Pharmacology

Figure 1.2 Relationship between the pharmacokinetic, link, and pharmacodynamic models. Figure 1.2 Relationship between the pharmacokinetic, link, and pharmacodynamic models. 1.3 LADME Scheme and Meaning of Pharmacokinetic Parameters The frequently used acronym LADME, which stands for liberation, absorption, distribution, metabolism, and excretion, broadly describes the various biopharmaceutical processes influencing the pharmacokinetics of a drug. Since each of aspect of LADME can influence the...

Introduction

Innovations in drug discovery and development, fueled by rapid advances in technology, have led to novel therapeutics for the prevention and treatment of diseases, greatly improving the quality of patients' lives. These innovations have been driven by increasing investments in research and development by pharmaceutical companies, which to some extent have contributed to the upward-spiraling costs of health care, especially prescription medications. The number of new molecular entities NMEs...

Zeren Wang and Rama A Shmeis

Boehringer-Ingelheim Pharmaceuticals, Inc. Ridgefield, Connecticut 5.2 Theoretical Considerations for Dissolution Controlled 140 Release Matrix and Coated Systems 5.2.1 Dissolution of solid particles 140 5.2.2 Dissolution of coated systems 142 5.2.3 Dissolution of matrix systems 146 5.3 Parameters for Design of Dissolution Controlled 149 Release Matrix and Coated Systems 5.3.1 Parameters affecting dissolution 149 of solid particles 5.3.2 Parameters affecting dissolution 150 of coated systems...

References

Principles of drug metabolism. In Abraham, D. J. ed. , Burgers Medicinal Chemistry and Drug Discovery, Vol 2, 6th ed. New York Wiley, 2003, pp. 431-498. 2. Albert, A. Chemical aspects of selective toxicity, Nature 182 421-423, 1958. 3. Harper, N. J. Drug latentiation. Prog. Drug Res. 4 221-294, 1962. 4. Sinkula, A., and Yalkowsky, S. Rationale for design of biologically reversible drug derivatives Prodrugs. J. Pharm. Sci. 64 181-210, 1975. 5. Higuchi, T., and Stella,...

Amit Kokate Venugopal P Marasanapalle Bhaskara R Jasti and Xiaoling Li

Long School of Pharmacy and Health Sciences University of the Pacific Stockton, California 2.2 Barriers to Peroral Controlled Release Drug Delivery 42 of the gastrointestinal tract 42 2.2.2 Physiological and biochemical characteristics of the gastrointestinal tract 48 2.2.3 Barriers to peroral drug delivery 52 2.3 Barriers to Nonperoral Controlled Release Drug Delivery 52 2.4 Physiological and Biochemical Barriers to Controlled Release Drug Delivery 66 Copyright 2006 by The...

Contributors

Engineering Fellow, ALZA Corporation, a Johnson amp Johnson Company, Mountain View, Calif. chap. 7 Bret Berner, Ph.D. Vice President, Depomed, Inc., Menlo Park, Calif. chap. 6 Shiladitya Bhattacharya, M. Pharm. Ph.D. Candidate, Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, Calif. chap. 13 Ramesh R. Boinpally, Ph.D. Research Investigator, OSIPharmaceuticals, Boulder, Colo....