O

Myers (1985) presented results showing that the N-oxides of these compounds were converted to nalbuphine or naltrexone after oral administration to animals, and that oral bioavailability was markedly increased when dosed as the N-oxide. Nalbuphine bioavailability was increased 10-fold in dogs and more than 5-fold in rats when administered as nalbuphine N-oxide (4). This indicates that the prodrug approach does not necessarily require direct blocking at the site of metabolism on the molecule,...

Prodrug Info Vanco

(i) LiOH (i) EDC, DM AP,2-mercaptothiazoline (Mi) 3,5-dlmethyl-4-hydroxyl benzol alcohol, DMAP Scheme 5 ( V)OSC, pyridine (v) vancomycin, TEA, DMF Scheme 5 (Choe et al., 2002b). For instance, conjugation of the activated tetra-acid derivative 63 with 4-hydroxyl-3, 5-dimethyl benzyl alcohol followed by activation of the benzyl alcohol moiety with NHS produced the tetra-substituted 1,6-BE linker, 68. Reaction of one equivalent of 68 with 4 equivalents of vancomycin, as shown in Scheme 5, gave the...

What Are The Unmet Needs

Prodrug research is viewed by many as simply the application of old and tried techniques to newly identified problematic drugs. Rarely does one see truly innovative ideas being put forward. This is because many organizations prefer to utilize chemistries with known biological and toxicological endpoints that have historical precedence. Few major organizations can muster the support for new creative prodrug studies in either chemistry groups or groups needed for their biological evaluation. That...

Model Based Simulations

Stella and Himmelstein demonstrated that for successful drug targeting via prodrugs there are at least three properties required of the prodrug and parent drug (Stella and Himmelstein, 1985a,b) 1. The prodrug must be readily transported to the target site and uptake must be reasonably rapid. 2. Once at the site, the prodrug must be selectively cleaved to the active drug relative to its conversions at other sites in the body. 3. The active drug, once selectively generated at the site, must be...

References

Ahmed I, Gokhale RD, Shah MV and Patton TF. Physicochemical Determinants of Drug Diffusion across the Conjunctiva, Sclera, and Cornea. J Pharm Sci 1987 76 583-586 Alexander J, Cargill R, Michelson SR, and Schwam H. (Acyloxy)alkyl Carbamates as Novel Bioreversible Prodrugs for Amines Increased Penetration through Biological Membranes. J Med Chem 1988 31 318-322 Anand BS, and Mitra AK. Mechanism of Corneal Permeation of L-Valyl Ester of Acyclovir Targeting the Oligopeptide Transporter on the...

Equations For Prodrug Design In Medicine

In these equations, dQ dt indicates the flux or mass of material of material crossing the membrane, D is the diffusion coefficient across the membrane (cm2 s), P is the partition coefficient between the membrane and the donor phase, h is the thickness of the membrane (cm), A is the membrane surface area (cm2), and CD and CA are the initial concentrations of the compound in the donor and acceptor compartment, respectively. Papp (cm s) can then be defined as the apparent permeability coefficient...

C2

Examples of structures of polymeric transport vectors (macromoles) containing multiple OH-functional groups dextran (a) poly N5-(2-hydroxyethyl)glutamine (b1), leucine copolymer (b2) poly N-(2-hydroxypropyl)methacrylamide (c1), methacrylamide copolymer (c2) used in the preparation of macromolecular prodrugs. In principle, macromolecular prodrugs may provide extended duration of drug action after various routes of administration (Table 1). After i.v. injection conjugates exhibiting...

Info

Melting points (mp C), solubilities in mixtures of ethanol water (Cv), partition coefficients (K) and fluxes of total species from suspensions in ethanol water through rat skin (J) in vitro. Table 4. Melting points (mp C), solubilities in mixtures of ethanol water (Cv), partition coefficients (K) and fluxes of total species from suspensions in ethanol water through rat skin (J) in vitro. Solubilities in mixtures of ethanol water in units of mM where the value in parentheses is ethanol...

Hooc

Of the phosphinic acid group meant that the molecule was still effectively ionized throughout the pH values seen in the GIT. Blocking the charge on the phosphinic acid group did prove successful (see case study in Section 5 of this book) with the desired prodrug being an acyloxyalkyl ester of the type discussed earlier for phosphonic acid derivatives. A difference was that the acyl function was a proprionyl group and, in place of the formaldehyde, isobutryaldehyde was used. Such a double ester...

Bimatoprost

Effects, i.e., conjunctival hyperemia and irritation (Bito, 1987 and references cited therein). Thus, the main objective of PGF2a research became an effort to design a non-irritating ophthalmic drug delivery system. To achieve this, two approaches were adopted (Woodward et al., 1994). One approach was to increase the ocular absorption of PGF2a by making a prodrug and thereby reduce the exposure of the drug on the ocular surface. The other approach was based on the design of more selective...

Y

General structure of a water-soluble prodrug and its intramolecular cyclization-elimination reaction releasing the parent drug and an imide fragment (adapted from Matsumoto et al., 2000). Recent in vivo and in vitro studies detailed the generation of the parent drug KNI-727, an HIV-1 PR inhibitor that is sparingly soluble, from designed prodrugs with variable solubilizing moieties and spacer lengths. These studies suggest that a prodrug with a conversion time around 35 min was...

Tumorassociated Enzyme Targets and Prodrugs pH Hypoxia and Glucuronidase Targeted Prodrugs

Under normal physiological conditions, the pH of plasma and tissues is maintained slightly above neutral pH. Many tumors, however, possess hyperme-tabolic activity and or may be in a hypoxic state (decreased oxygen level). These phenomena induce a localized decrease of pH, which can be 0.7 to 1.0 pH units lower than the normal physiological pH. This difference in pH can be exploited for drug targeting. Recent research in the area of pH-sensitive prodrugs has been performed mostly with...

Parenteral Dosing

Parenteral or injectable drug dosing is the desired route of drug administration under a number of clinical circumstances. In some countries, such as Italy, patients often prefer this route to oral dosing, while in countries like the USA the parenteral drug market is more limited. The most obvious reasons for a parenteral dosage form are when a drug cannot be taken orally due to oral absorption limitations, e.g., insulin for the treatment of diabetes, or when the patient cannot swallow oral...

H3c Ch3

Examples of vinyl-type copolymer conjugates exhibiting significant aqueous solubility at physiological pH. a conjugate formed by copolymerization of methacrylic acid and NSAID esters of 2-hydroxyethyl methacrylate (Wang and Chang, 1999) b conjugate formed by copolymerization of 1-vinyl-2-pyrrolidone, dexamethasone 21-crotonate and 2-(diethylamino)ethylcrotonate (Timofeevski et al., 1996) c conjugate formed by reacting a styrene maleic anhydride copolymer and...

Excretion and Toxicity

CPT derivatives conjugated with PEG 8,000, 20,000 or 40,000 diacid (Martinez and Greenwald, 1997) were administered as single i.v. injections to mice. All mice received the same amount of active CPT (25 mg kg) however, considerable differences in levels of toxicity were demonstrated. Lethality was approximately 50 , 10 and 0 for the PEG-CPT 40,000 Da, 20,000 Da and 8,000 Da constructs, respectively, and is due to continued release of CPT (LD50, 7 nm) over time (Greenwald et al., 2003a). The...

Application to Functional Groups

There are four functional groups found in drug molecules for which the greatest number of promoieties have been designed, synthesized, characterized (solubility, stability, purity), and evaluated in diffusion cell experiments. These four functional groups are the amide or imide (O C-NH), the thioamide (S C-NH), the hydroxy group (OH) substituted on aliphatic or aromatic carbons, and the carboxylic acid (O C-OH) mentioned above. For each functional group there are two general types of...

Criteria for an Ideal Ophthalmic Prodrug

The major goal in designing prodrugs is to overcome various physico-chemical, biopharmaceutical, and or pharmacokinetic problems that may be associated with the parent drug molecules, which would otherwise be of limited clinical use. The most common barriers in ophthalmic drug formulation and delivery that may be overcome by a prodrug are which prevents the development of aqueous eye-drops which results in low corneal permeation and low ophthalmic 3) Short duration of action (due to rapid drug...

PEG Prodrugs of Amines

PEG Tripartate Prodrugs Benzyl Elimination (BE) system While most amine drugs can be solubilized as acid salts, their rate of renal excretion is high. When converted to neutral small prodrug species, the ability to form salts is lost, and solubility may again become problematic. Not so in the case of PEG-drug conjugates, where PEG confers water solubility on insoluble small organic compounds without the need for forming salts. PEG prodrugs of amino-containing compounds also constitute the basis...

Obstacles to Success

Some of the previously described examples appear to be remarkably successful in improving oral bioavailability or having the potential to improve bioavailability. However, the majority of these cited prodrugs studies were preclinical studies and, unfortunately, many of these prodrugs have so far not become products for humans. Undoubtedly, many other prodrug strategies must have been attempted that have not been successful in preclinical studies and have not been described in the literature....

Lipid Solubility Is Important For Topical Delivery

The objective of any prodrug approach is to transiently mask a particular functional group in a drug and thus change its physicochemical properties (solubility profile, degree of ionization), protect it from premature chemical or biological metabolism, or facilitate its active or passive transport across a biological barrier, to name only a few of the more obvious applications. In the example of the use of a prodrug approach to enhance topical delivery, a change in the physicochemical...

List of Abbreviations

enzyme prodrug therapys under the concentration-time curve clearance for parent drug clearance for prodrug transport rate in to target organ transport rate out of target organ concentration targeting index enzyme prodrug therapy constant parent drug related volume enzyme prodrug therapy prodrug conversion rate central volume prodrug conversion rate target volume prodrug related volume site parent drug related volume site prodrug related volume

Rationale

Presystemic Metabolism

One of the most important pharmacokinetic characteristics of a drug or new drug candidate is its oral bioavailability. The oral route is the preferred means of administration for most drug therapies, particularly those self-administered by the patient on an ongoing basis. Unless a drug is intended to treat a condition of the gastrointestinal tract, its effectiveness after oral administration requires attaining adequate and consistent systemic exposure. The extent of bioavailability determines...

Twostep prodrug therapies

In two-step prodrug therapy, the enzyme that is supposed to activate the prodrug administered in the second step of the therapy must be targeted to tumor tissue in the first step. Enzymes can be directed to the tumor site or be expressed selectively at the tumor site in several manners. In the concept of antibody-directed enzyme prodrug therapy (ADEPT) (Bagshawe, 1987, 1995 Senter et al., 1988), a specific enzyme can be localized in the first step using an antibody-enzyme conjugate. The...

Summary

The examples cited in this brief overview were selected to illustrate various aspects of the macromolecular prodrug approach to controlled drug release. Despite the substantial amount of knowledge gained about the behaviour of macromolecular prodrugs in vitro, relatively little information is available on the pharmacokinetic fate of such conjugates after different routes of administration. Although few in number, the published pharmacokinetic studies imply that application of macromolecular...

Prostaglandins

The most recent achievements for prodrug technologies in ophthalmology have been with prostaglandin prodrugs for the reduction of IOP in patients with open angle glaucoma or ocular hypertension. The first prostaglandin prodrug, latanoprost (3) (Xalatan ), was approved by the FDA in 1996, followed by bimatoprost (4) (Lumigan ), travoprost (5) (Travatan ) and unoprostone isopropyl (6) (Rescula ) in the early 2000s. Although some of these compounds are reviewed in case histories at the end of this...

Table of Contents

Phosphate Prodrugs that Enhance Drug Absorption 165 Phosphate Prodrugs that Fail to Enhance Drug Absorption 166 Challenges with Phosphate Esters Prodrugs 167 Phosphate Prodrugs Case Examples 168 TAT-59, Miproxifene Phosphate 168 Dose, Solubility and Dissolution Rate Considerations 176 The Dose Number as a Tool in Selection of Parent Drugs 176 Solubility and Dose Numbers for Parent Drugs and Prodrugs 176 Low Do Drugs (Do< 1) with high Permeability 177 Low Do Drugs (Do< 1) with low...

Can Prodrugs Be Used To Overcome The Limited Permeation Of Drugs That Are Efflux Candidates

One can make a case for efflux candidacy being a major cause for the poor permeation characteristics of many new drug candidates. Lipinski's guidelines (Lipinski et al., 1997, 2000 Horspool and Lipinski, 2003) related to size, lipophilicity and numbers of hydrogen-bond acceptors and donors and the observations of Veber et al. (2002) on rotatable bonds in many new molecules speak to this issue to some extent. The relatively promiscuous nature of many efflux systems makes them particularly...

Mechanism of CR for Lipophilic Esters for Parenteral Depots

Water-soluble small molecular weight molecules are absorbed rapidly upon IM administration. Even relatively larger sized carbohydrate molecules are rapidly absorbed after injection in a rabbit hind leg perfusion model (Nara et al., 1992). Similarly, rapid absorption transport should be expected for lipophilic molecules after IM administration either via the lymphatics or directly into the blood from the interstitial aqueous space in the muscle since it is highly vascularized. In a SC and IM...

Nadolol Prodrugs

Nadolol (18) is a hydrophilic (log D'oc4t -0.82, pK 9.39), nonselective blocker (Schoenwald and Huang, 1983). The low corneal permeation of nadolol is probably the main reason for its poor clinical efficacy. Diacetyl nadolol (19) is about 20 times more lipophilic than nadolol, and this prodrug enhanced the in vivo ocular absorption of nadolol in rabbits by about 10-fold compared to nadolol (Duzman et al., 1982). Despite the improved ocular absorption of nadolol with a prodrug, both diacetyl...

Facilitated Permeability By Utilizing A Gastrointestinal Tract Transporter

The intestinal peptide transport system has been a key target for prodrug approaches some by design, some by serendipity. For example, the intestinal peptide transport system has broad substrate specificities and is involved in the transport of natural di- and tripeptides. The most cited transporter is PepT-1 (Liang et al, 1995 Tsuji and Tamai, 1996 Adibi, 1997 Yang et al., 1999). This transport system also absorbs various orally administered peptidomimetic drugs, including some -lactam...

Prodrug Monotherapy

Anticancer prodrug monotherapy is defined as chemotherapy in which prodrugs are used that are designed for direct activation or recognition by a tumor-associated factor, such as hypoxia, an enzyme or a receptor. In prodrug monotherapy, the administered prodrug is directly and site-specifically cleaved to yield the parent compound (Figure 2). The difference between this and other prodrug therapies, discussed in the next paragraph, is that monotherapy is a one-step therapy only the prodrug is...

Isomer Paclitaxel 187 Water

Paclitaxel and the triphosphonate 184 under physiological conditions, while the conversion of 185 to 184 and 153 is much slower. A recent somewhat unique example of a paclitaxel prodrug with increased solubility has been reported by Hayashi et al. (2003). This prodrug (187) is a structural isomer of paclitaxel, which has a free amine group. The water solubility of 187 as its HCl salt is 0.45 mg mL and it is relatively stable in pH 4 citrate buffer at room temperature (< 3 release of 153 after...

Circulatory Retention Molecular Weight Considerations of the Polymer

Yamaoka et al. (1994) conducted a detailed study that measured the distribution and tissue uptake of PEG of different molecular weights after i.v. administration to mice. Yamaoka reported that the renal clearance of PEG decreased with an increase in molecular weight, with the most dramatic change occurring at 30,000 Da. The t1 2 of PEG circulating in blood also showed a concomitant and dramatic increase. For example, the t1 2 for PEG went from approximately 18 min to 16.5 h as the molecular...

Polyethylene glycol Ester Prodrugs

Polyethylene glycol (PEG) is a polyether diol manufactured by the aqueous anionic polymerization of ethylene oxide. Polymerization is initiated using anhydrous alkanols such as methanol or derivatives including methoxyethoxy ethanol, which result in a mono alkyl, capped poly(ethylene glycol) such as methoxy PEG (mPEG). mPEG is acceptable for drug modification because of its low potential reactivity. The polymerization can be controlled and a variety of linear or branched neutral polymers...

Phosphate Ester Prodrugs

Phosphate prodrugs offer several advantages for formulation and development of poorly water-soluble compounds. Phosphate prodrugs are chemically stable, their synthesis is usually straightforward in the presence of a hydroxyl moiety (Kearney and Stella, 1993), and the increases in solubility imparted by the dianionic phosphate group are often several orders of magnitude (Stella, 1996 Rodriguez et al., 1999 Zhu et al., 2000 Heimbach, 2003 Furfine et al., 2004). For oral dosage forms, the...

Introduction

It is estimated that 40 of active new chemical entities (NCEs) identified in combinatorial screening programs employed by many pharmaceutical companies are poorly water soluble, i.e., these compounds have an aqueous solubility less than 10 M (5 g mL for a compound with a molecular weight of 500) (Lipinski, 2002, 2004). When these poorly soluble NCEs are further advanced in discovery and ultimately brought into development they are often plagued by incomplete absorption and low, erratic...

Background

Site-specific delivery is the ultimate goal in all drug delivery research programs, where the optimal therapeutic benefit of a drug is obtained and unwanted effects are minimized. Site-specific delivery is particularly desirable for highly toxic compounds, such as those employed in the treatment of cancer this topic is covered in greater depth elsewhere in this book. Two parameters commonly discussed in the assessment of the efficiency of drug targeting are therapeutic advantage and drug...

Rice Husks As Prodrug

Various strategies used to convert linear peptides with both a free N-terminus amino group and a C-terminus carboxyl group to cyclic peptides. Also shown is the metabolic pathway for conversion of an acyloxyalkoxy-based prodrug of DADLE (Tyr-D-Ala-Gly-Phe-D-Leu) to DADLE mimetics may be well absorbed, depending on the degree of paracellular transport or their ability to be recognized by a transporter. It is also possible to deliver these polar drugs orally if they are converted to...

Amino Acid Prodrug

The loxapine POM prodrug (52) is approximately 15,000 times more soluble at pH 7.4 than 53, and is very stable in aqueous solution. However, precipitation of parent drug from concentrated prodrug solutions is expected to be the limiting factor in shelf-life. The solubility of 52 at pH 7.4 is only 30 g mL, which would only allow for 0.06 degradation before 53 would theoretically precipitate, resulting in a shelf-life limited to about 6.7 days. However, the intrinsic solubility of 53 is increased...

Corneal Barrier

The cornea is generally considered to be a major, but not exclusive, pathway for ocular permeation of a topically applied drug (Doane et al., 1978). Compared to many other epithelial tissues (e.g., bronchial, intestinal, nasal, tracheal), the corneal epithelium is relatively impermeable but less so than the stratum corneum of the skin (Rojanasakul et al., 1992). The conjunctiva, which is mainly responsible for the non-corneal absorption of drugs, is significantly more permeable than the cornea...

Dissolution Controlled Depots Based on Prodrugs

The attempt in this type of depot formulation is to control the appearance of drug in systemic circulation by controlling its release from the depot through slowing the dissolution rate of the drug. The Noyes-Whitney equation predicts that dissolution rate is directly proportional to solubility under steady-state conditions. If the solubility of a drug is high at physiological pH, slow release may require the use of sparingly soluble salts and or poorly soluble complexes of the drug to provide...

Route of Administration

The oral controlled drug delivery concept may embrace dosage forms that release the active agent in a predictable manner over a desired period of time as well as delivery systems designed to liberate the drug locally at specific sites within the gastrointestinal tract. To justify the high costs of developing a macromolecular prodrug for oral drug delivery, the prodrug must provide a superior solution to a drug delivery problem not easily resolved by conventional formulation techniques. Drug...

Clinical Trial Results for PEG Prodrugs

A phase I clinical trial of 3 has been carried out and a human PK study was reported (Beeram et al., 2002) in which it was determined that the MTD (maximum tolerated dose) was in excess of 5,184 mg m2, but most treatments were performed at 4,320 mg m2 (approximately 235 mg m2 of paclitaxel). Similarly to Taxol neutropenia was the predominant hematological toxicity observed, while others consisted of peripheral neuropathy, vomiting, and diarrhea. Preliminary PK monitoring of free and conjugated...

Acyclovir Prodrugs

Acyclovir (25) is a potent and selective anti-herpes drug (Schaeffer et al., 1978) that could offer a means for topical treatment of herpes simplex virus (HSV) keratitis. However, the delivery characteristics of acyclovir are far from optimal, which can be attributed to its limited aqueous solubility (1.4 mg mL) and moderate lipophilicity (logP -1.47) (Bundgaard et al., 1991). Thus, acyclovir cannot be given as eye drops, which would be the most practical formulation for the treatment of ocular...

Timolol Prodrugs

Timolol is a base with a pKa value of 9.2 (Schoenwald and Huang, 1983). At physiological pH, 98 of timolol is protonated, and it therefore shows low lipophilicity with a log-Dj> '4t of -0.04 (Bundgaard et al., 1988a). Due to its low lipophilicity, less than 5 of the instilled timolol dose gains access to internal eye structures (Urtti et al., 1990). Various alkyl, cycloalkyl, and aryl esters and a carbamate ester have been synthesized by esterifying the hydroxyl group of timolol (Table 2)...

Prodrugs for Parenteral SR Formulations

Parenteral sustained release (SR) formulations, conventionally known as depots, in contrast to oral CR formulations are generally designed to maintain plasma levels for more than a few weeks duration, preferably for a month or longer (Chien, 1981 Murdan and Florence, 2000). These formulations are usually administered by either a subcutaneous (SC) or an intramuscular (IM) injection, which provides sustained plasma levels for weeks to months. The parenteral route of administration thus precludes...

Prodrugs of Adrenergic Antagonists

P-Adrenergic antagonists ( -blockers) are effective ocular hypotensive agents that act by decreasing the formation of aqueous humor (Sugrue, 1989). Timolol, a nonselective P-adrenergic antagonist, was introduced in 1978 for the treatment of glaucoma. Today, timolol is one of the most frequently prescribed drugs for this disease. In addition to timolol, betaxolol, carteolol, levobunolol and metipranolol are currently in clinical use. Additionally, various other P-blockers, such as atenolol,...

Use Of Morflux Drug

Melting points (mp), molecular weights (MW), solubilities in IPM (SIPM), mineral oil (SMO) and pH 7.0 and 7.4 buffers (S7.0 and S7.4), and fluxes from suspensions of morphine (MOR) and naltrexone (NTX) prodrugs in IPM (JIPM), pH 7.0 buffer (J7.0) and mineral oil (JMO) through human skin in vitro. aUnits of mM. bUnits of nmol cm-2 h-1. cC1, C2, etc. refer to number of carbons in alkyl chain. d Units of C. eData from a combination of fresh and previously frozen skin. Data from previously...

High Do Do100 Drugs with Low Permeability

While these drugs are not likely to be suitable candidates for oral delivery, they can be ideal prodrug candidates for the parenteral route. An example of such a BCS Class IV parent drug is the echinocandin B analog LY303366 targeted for systemic fungal infections. LY303366 has poor intestinal permeability as measured in the Caco-2 model (Li et al., 2001) (Table 1), in spite of a favorable log octanol water partition coefficient of 2.0 and a solubility less then 0.005 mg mL. The low...

Estramustine Phosphate

Estramustine phosphate (EMP) is the phosphate ester prodrug of the practically insoluble, non-ionizable parent drug estramustine, shown in Figure 7 (Wadsten and Lindberg, 1989). Emcyt (Pharmacia, Pfizer) is a cytotoxic drug that has long been used in the treatment of advanced prostatic carcinoma and is available in both injectable and oral formulations (Bergenheim and Henriksson, 1998). The oral prodrug is a high-dose compound with suggested dosages from 140 mg to 1400 mg day divided in 2-3...

Prodrug Strategies to Increase Solubility for Parenteral Formulations

The most widely cited examples of parenteral prodrugs are water-soluble prodrugs of steroids. Adrenal corticosteroids such as prednisolone, methylpred-nisolone, hydrocortisone, betamethasone, and dexamethasone exhibit poor aqueous solubility. They are all commercially available as water-soluble sodium hemisuccinate esters and or sodium phosphate esters. These water-soluble prodrugs are used in the emergency treatment of bronchial asthma, acute adrenal cortical insufficiency, and allergic drug...

Phenylephrine Prodrugs

Phenylephrine (1) is an a-adrenergic agent that is used clinically for pupil dilation either in eye examinations or in ocular surgery. It has a low ocular bioavailability due to its hydrophilic nature (log Dj,4t -1.89) (Schoenwald et al., 1987) and, therefore, concentrated eyedrops (up to 10 ) are required to produce mydriasis. The large topical dose of phenylephrine may cause adverse systemic side effects, such as severe hypertension, ventricular arrhythmia, and possible myocardial infarction...

Summary on Solubility and Dose

To summarize, parent drugs with a high targeted oral dose and low solubility (high Do, > 100), such as DP-TAT-59, are well suited for a phosphate prodrug strategy. For successful oral delivery, high intestinal permeability of parent drugs is required, i.e., they are BCS Class II drugs. A phosphate prodrug strategy has been utilized on occasion for BCS Class I drugs (low Do, i.e., Do < 1), but no biopharmaceutical advantage is achieved. For BCS Class III and IV (low permeability) parent...

Oh O

Structures of amino acid ester prodrugs of (A) CAM 4451, (B) CEP-5214, and (C) quercetin. These prodrugs are hydrolysed in vivo at the arrowed oxygen to release the parent drugs and their corresponding amino acids. membrane of the GI tract. The time of conversion to the parent drug is important to the success of this approach since rapid hydrolysis could result in parent compound precipitation in the intestine. To be successful, the prodrug should escape hydrolysis in the lumen and...

Effect of Systemic Prodrug Clearance on Target Site Drug Concentration

One of the aspects that was not investigated in the earlier manuscripts is the effect of the systemic clearance rate of prodrug on the target site levels of drug. We know intuitively that systemic prodrug clearance will have an impact on target site drug exposure. Through model simulations we can investigate at what levels systemic prodrug clearance makes a significant impact on target site drug levels. Figure 3 illustrates the effect of systemic prodrug clearance (ClPDelim) on the AUC ratio...

Amino Acid Ester Prodrugs

Additional strategies to enhance drug solubility include amino acid ester prodrugs. In general, amino acid pro-groups introduce a cation or anion to the parent drug. At physiological pH, the prodrugs are ionized and have greater water solubility than the parent. In the literature, a few investigations have been reported with only a limited number of prodrugs reaching clinical stages. Examples of amino acid ester prodrugs are listed in Table 3, and their structures are shown in Figure 13. CAM...

Bispilocarpic Acid Mono and Diesters

Bispilocarpic acid mono- and diesters are dimeric pilocarpine prodrugs with two pilocarpine units attached via a carbon chain, which minimizes the molecular weight contribution of the promoieties (Jarvinen et al., 1991a,b,1992a). Bispilocarpic acid monoesters were prepared by esterifying pilocarpic acid with appropriate di-halogenated alkyls aryls (Jarvinen et al., 1992a). Bispilocarpic acid monoesters spontaneously cyclized to pilocarpine in aqueous solution (Scheme 2). Unfortunately, the...

Challenges with Phosphate Esters Prodrugs

There are several limiting attributes of phosphate prodrugs with respect to their oral delivery. Phosphate groups impart negative charges to drug compounds. For that reason they are functionally extremely polar and thus are thermodynamically unlikely to passively cross the GI-membrane (Krise and Stella, 1996). Passively absorbed drugs are thought to be absorbed primarily in their neutral, non-ionized form (Winne, 1977). This principle is captured in the so-called pH-partition hypothesis (Shore...

Estimation of Dissolution Rates and Ratios

To evaluate or rank-order solubility enhancing prodrugs, it is useful to calculate the estimated dissolution times of prodrugs and parent drugs relative to the GI residence time. Here, the dissolution times (TDiss) for selected (phosphate) prodrugs were calculated based on Eq. 4 published by others (Yu, 1999 Zhang and Yu, 2004). p drug density (which is generally near 1200 mg cm3), h aqueous diffusion layer thickness set to 30 im, r0 initial particle size set to 25 im, D diffusion coefficient...

A

90. mono-PEGyiated 92. mono-PEGyiated 91. heavily PEGyiated 93. heavily PEGyiated release was compatible with the circulating t1 2 of permanently PEGyiated proteins, which typically ranges from a few hours to several days (Witt et al., 2001). For an rPEG protein conjugate to demonstrate effective drug delivery, activity must be regenerated before the protein is eliminated from the body by renal and hepatic clearance pathways. rPEG-lysozyme conjugates were relatively stable in pH 7.4 buffer for...

Solubility and Dose Numbers for Parent Drugs and Prodrugs

Phosphate prodrugs had solubilities higher than that of the corresponding parent drugs by 10-100000-fold (Table 1), as expected. Most prodrugs are highly soluble compounds, as defined in the Biopharmaceutical Classification System (BCS), and their Do is < 1 (data not shown) (Kasim et al., 2004). For example, fosphenytoin has a Do of 0.003 for a 100 mg dose, which compares to a Do of 21 for phenytoin, the parent drug (Table 1). Parent drugs were classified based on their measured aqueous...

Soft Quaternary Salts of Pilocarpine

Soft quaternary ammonium salts of pilocarpine are water-soluble prodrugs that release pilocarpine via enzymatic and spontaneous chemical hydrolysis (Scheme 3) (Bodor, 1977 Druzgala et al., 1992). As quaternary salts, their aqueous solubility should be high, which could limit their corneal permeation. The in vivo studies, however, have shown that their bioavailability is better than that of pilocarpine. Compared to a 2 pilocarpine solution, 0.5 W-hexadecanoy-loxymethyl pilocarpinium chloride...

Promoiety

Scissile linkage subject to fission by a proenzyme-activating system Figure 6. A construct in which the recruitment of a natural proenzyme-activation system could effect cleavage of a scissile linkage to release an enzyme enzyme analog and a promoiety. See the text for further discussion. Constructs targeted on components of an activation cascade could in principle achieve unusual tissue distributions and pharmaco-kinetic characteristics. It would be an understatement to note that the...

Labeling Studies of PEG Prodrugs Fluorescent Dye Labeling

To examine cellular binding, uptake, and trafficking of PEG in cancer cells, FITC-labeled 40 kDa PEG (PEG-FITC) was synthesized employing a stable thiourea bond. This conjugate was shown to be stable under the experimental conditions. Yu et al. (2004) examined the cellular uptake and subcellular localization of PEG-FITC in various human cancer cells using FACS and confocal microscope analyses. FACS results revealed that PEG-FITC was taken up by A549 lung cancer cells in a dose- and...

Phosphate Prodrugs that Enhance Drug Absorption

Oral phosphate prodrugs may result in higher plasma levels (Cmax) and increased bioavailability compared to the parent drug form. This very outcome has been demonstrated for oxyphenbutazone phosphate (Hook et al., 1975) as well as fosphenytoin in dogs (Varia and Stella, 1984 Lai et al., 1987). Fosphenytoin also yielded lower tmax and higher Cmax in rats (Burstein et al., 1999) as shown in Figure 2. Plasma levels of a stachyflin analog were also greatly increased in rats after phosphate prodrug...

Fosamprenavir

Fosamprenavir (Telzir , Lexiva ) is the phosphate ester prodrug of the protease inhibitor (PI) amprenavir (Agenerase ), which was co-discovered by Vertex Pharmaceutical (VX-175) and GlaxoSmithKline (GW433908). This novel prodrug addresses several challenges. It shows improved solubility and equivalent or higher bioavailability compared to the parent drug, and permits more convenient once- or twice-daily tablet dosing instead of multiple capsules (Corbett and Kashuba, 2002 Falcoz et al., 2002...

Proenzymes and their Activation

Proenzymes are also known as zymogens, emphasizing their capacity to generate enzymes under suitable conditions. When the prodomain is removed and the enzyme part of the proenzyme released to form, in some cases by conforma-tional reorganization, the mature enzyme, the proenzyme is said to have been activated. The ways in which activation is accomplished vary from very simple processes to extraordinarily complex processes. The point can be illustrated by a few examples. Pancreatic Serine...

Low Do Drugs Do

Hydrocortisone-phosphate Do 1 is available only as the prodrug for parenteral use. For oral administration, the parent drug hydrocortisone is marketed. Hydrocortisone for oral delivery is a low dose 5-20 mg compound, and this polar steroid has a relatively high solubility near 0.3 mg mL at intestinal pH Pedersen, 2000 . Combined with its high Peff in rats Fleisher et al., 1986 and its low-dose bioavailability of 96 , hydrocortisone can be classified as a Class I compound according to the BCS...

Fludarabine Phosphate

Fludarabine phosphate Fludara , is a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-p-D-arabinofuranosyladenine ara-A , which differs only by the presence of a fluorine atom at position 2 of the purine moiety and a phosphate group at position 5 of the arabinose moiety Plunkett et al., 1993 , shown in Figure 6. These structural modifications result in increased aqueous solubility and resistance to enzymatic degradation by adenosine deaminases compared to vidarabine Brockman...

PEG Prodrugs of Indoles

The cyclin-dependent kinases CDKs are a group of enzymes that are involved in cell cycle progression regulation Kunick et al., 2000 . The CDKs activate host proteins through phosphorylation on serine or threonine using adenosine triphosphate as a phosphate donor Sielecki et al., 2000 . CDKs have attracted much attention as potential therapeutic targets, especially in treating cancer, because they are key players in the control of cell proliferation. Recently, a novel class of small molecule CDK...

Phosphate Prodrugs that Fail to Enhance Drug Absorption

Failure of phosphate prodrugs to increase drug absorption can be attributed to several potential rate-limiting factors in the drug absorption process Figure 1 . After oral administration, phosphate ester prodrugs are dephosphorylated in the GI tract by membrane-bound alkaline phosphatase AP . In theory, lipophilic parent drugs generated at the membrane surface should be well absorbed compared to their ionic polar phosphate counterparts, and there appears to be little luminal metabolism from...

Conclusions

Prodrug technology offers reasonable strategies to improve the parenteral delivery properties of poorly soluble drugs. Different prodrug strategies offer their own advantages and disadvantages. In the early days, sodium hemi-succinate prodrugs were the most common choice for poorly soluble alcohol functional group-containing drugs, but they often suffer from poor aqueous stability and slow and incomplete in vivo conversion. The phosphate prodrugs are usually much more stable, and appear to bioconvert rapidly, but there are some applications in which they are unable to be synthesized or do not bioconvert due to steric or other factors. POM prodrugs have demonstrated good stability and rapid in vivo conversion, but there are some concerns about the pruritis paresthesia noted in the clinic for these as well as other phosphate-based prodrugs. Many of the prodrugs discussed here have little or no toxicity data reported about non-naturally occurring side products formed during...

The Dose Number as a Tool in Selection of Parent Drugs

The dimensionless dose number Do as described by Amidon and colleagues Amidon et al., 1995 Kasim et al., 2004 Sun et al., 2004 can be used as a tool to evaluate the practicality of a solubility enhancing prodrug approach. The Do was calculated as the targeted oral parent equivalent dose 250 mL Csmin, where Csmin is the lowest parent drug solubility at relevant intestinal pH and 250 mL represents the 8 oz volume of fluid routinely recommended with oral drug administration. The targeted doses...

Entacapone Phosphate

Entacapone phosphate is an investigational phosphate ester prodrug of entacapone Figure 5 , a drug marketed in 1999 as Comtan by Novartis and Orion Pharma for the treatment of Parkinson's disease PD which results from low levels of dopamine in the brain. Common treatment of PD involves oral administration of levodopa, a precursor of dopamine that can cross the blood-brain barrier, combined with an inhibitor of dopa decarboxylase DDC , such as carbidopa, to inhibit decarboxylation of levodopa in...

Caco 2 Permeability And

Calculated Dissolution Ratios and Rate Limits of Parent Drags and Prodrugs. Table 2. Calculated Dissolution Ratios and Rate Limits of Parent Drags and Prodrugs. Calculations are based on earlier work by Yu Yu, 1999 Zhang and Yu, 2004 The dissolution ratios were calculated by dividing the dissolution time TDiss , by the mean small intestinal residence time, Tsi, 199 min 'Based on targeted oral dose. BCS Class I high solubility, high permeability BCS Class II low solubility, high...

Ki

Structures of CSA and prodrugs adapted from the literature Cho and Chung, 2004 . The insoluble nature of paclitaxel, one of the most potent chemotherapeutic agents used in the treatment of breast and ovarian cancers, has led to the formulation of this drug as a 1 1 ethanol cremophore mixture, which is diluted prior to lengthy infusions. Various hypersensitive reactions have been found in patients undergoing paclitaxel treatments, mainly due to histamine release mediated by...

D

Illustration showing that a non-polar prodrug PD of a polar drug D- may show less than complete oral availability due to premature cleavage in the GIT or the enterocytes. Despite the ceiling and a reasonable incidence of diarrhea, GlaxoSmithKline GSK did get a prodrug of cefuroxime 19 , cefuroxime axetil 20 , approved this was followed by introduction of a number of similar prodrugs of other cephalosporins both in the USA and in other countries Dellamonica, 1994 . These include...

Examples of the Prodrug Approach

There have been numerous examples of the application of the prodrug approach to improve the oral bioavailability of drugs subject to extensive presystemic metabolism, with varying degrees of success. Some selected examples of prodrugs and the results observed are summarized in Table 1 and are discussed below. Also included in Table 1 are some examples of peptides for which the prodrug approach was utilized to potentially improve oral or transmucosal delivery by reducing metabolic degradation....

Prodrugs Launched

Bortezomib Mannitol Ester

Paul Ehrlich, the 1908 Nobel Laureate, coined the term magic bullet to describe drugs or therapies that selectively acted at their site of action with minimal exposure to the rest of the body Ehrlich, 1906, 1908 . He appeared to be one of the first to talk about a receptor in molecular terms. In addition, he also studied the role of drug metabolism in activating drugs in his seminal work on arsenicals see Albert, 1985 . Effectively, Ehrlich's magic bullet concept and his work on arsenicals were...

Acid Activated PEGDrug Conjugates Hydrazone Derivatives of Doxorubicin

A novel series of HMW PEG conjugates that incorporated acid-sensitive hydrazone linkages have been synthesized using PEG 20,000 Da and 70,000 Da Rodrigues et al., 1999 . Thus, DOX maleimide derivatives containing an acid-sensitive hydrazone linker, and a stable amide linker for comparison, were coupled to PEG using thiopropionic acid spacers as shown in Figure 8. The polymer drug derivatives were designed to release DOX inside a tumor cell by acid-cleavage of the hydrazone bond, after endocytic...

Carbonic Anhydrase Inhibitor Prodrugs

Oral carbonic anhydrase inhibitors CAIs have already been in clinical use for 50 years in the treatment of increased IOP Sugrue, 1989 . The currently used oral CAIs include acetazolamide and methazolamide. However, patient compliance with systemic CAI medication is poor, due to side effects such as hypokalemia, fatigue, depression, gastrointestinal disturbances, and anorexia Epstein and Grant, 1977 Lichter et al., 1978 . Because the topical administration of CAIs was clinically ineffective,...

TAT59 Miproxifene Phosphate

TAT-59 Miproxifene Phosphate is a triphenylethylene analog of tamoxifen that was under development and in Phase II III clinical trials Nomura et al., 1998b Monograph, 1999 by the Taiho Pharmaceutical Company Tokushima, Japan when its development was discontinued. TAT-59 is the phosphate ester prodrug of the practically insoluble parent drug DP-TAT-59 Figure 4 , which has a solubility of 58 ng mL at pH 7.4 Heimbach, 2003 . Formulation strategies to identify a crystalline pharmaceutical salt of...

Model Development

In order to reflect the obvious dependence of flux on aqueous as well as lipid solubility properties of the intercellular barrier, Roberts and Sloan 1999 developed a transformation of the Potts-Guy equation Roberts-Sloan equation which could accommodate lipid vehicles and which contained parameters for solubilities in IPM log SIPM and pH 4.0 buffer log SAq log J x y log SIPM 1 - y log SAq - z MW. When this equation was fit to data from seven series of homologous prodrugs of 6-MP, 5-FU and Th...

Strategic Considerations for Orally Administered Solubility Prodrugs

Phosphate Prodrug Screening Strategy The successful identification of ideal candidates for an oral phosphate prodrug strategy requires a careful analysis of the properties of the parent drug and prodrug. These include ionization, drug and prodrug solubility dissolution, enzyme-mediated parent drug generation, transport and efflux, targeted dose, and the ratio of targeted dose relative to parent drug solubility as well as the potential for precipitation. Based on these considerations, a...

Releasable Linkers in Targeted Conjugates

In this section as well as in other sections throughout this book, tumor-activated prodrugs in which a releasable self-elimination linker or spacer is incorporated between a specifier targeting unit part of prodrug or conjugate that is enzymatically removed and the parent drug are discussed. Two main reasons for application of releasable linker systems in prodrugs and bioconjugates are facilitation of enzymatic activation, and incorporation of appropriate linkage chemistry. In a prodrug...

Prodrug Of Tertiary Amines

With the exception of 107, the HCl salts of the various L-amino acid amide and glycine prodrugs of dapsone are very soluble in water. L-lysine-dapsone 109 had an apparent solubility of gt 65 mg mL even at pH 7.4. Elevated temperature studies indicate that the predicted t90 values for the amino acid amide prodrugs of dapsone are gt 2 years at pH 4 Pochopin et al., 1995 . The stability of the L-amino acid amides and the glycine prodrugs in human blood at 37 C was found to be good, with t1 2...