Lipid nanoparticles with different oil/fatty ester ratios as carriers of buprenorphine and its prodrugs for injection

Buprenorphine is a promising drug for the treatment of chronic pain and opioid dependence. The aim of the present work was to evaluate the feasibility of lipid nanoparticles with different oil/fatty ester ratios for injection of buprenorphine. To improve the release properties and analgesic duration of the drug, ester prodrugs were also incorporated into the nanoparticles for evaluation. Linseed oil and cetyl palmitate were respectively chosen as the liquid lipid and solid lipid in the inner phase of the nanoparticulate systems. Differential scanning calorimetry (DSC) was performed, and the particle size, zeta potential, molecular environment, and lipid/water partitioning were determined to characterize the state of the drug/prodrug and lipid modification. The in vitro release kinetics were measured by a Franz assembly. DSC showed that systems without oil (solid lipid nanoparticles, SLNs) had a more ordered crystalline lattice in the inner matrix compared to those with oil (nanostructured lipid carriers, NLCs and lipid emulsion, LE). The mean diameter of the nanoparticles ranged between 180 and 200 nm. The in vitro drug/prodrug release occurred in a delayed manner in decreasing order as follows: SLN > NLC > LE. It was found that the release rate was reduced following an increase in alkyl ester chains in the prodrugs. The in vivo antinociception was examined by a cold ethanol tail-flick test in rats. Compared to an aqueous solution, a prolonged analgesic duration was detected after an intravenous injection of buprenorphine-loaded SLNs and buprenorphine propionate (Bu-C3)-loaded NLCs (with 10% linseed oil in the lipid phase). The Bu-C3 in NLCs even showed a maximum antinociceptive activity for 10 h. In vitro erythrocyte hemolysis and lactate dehydrogenase (LDH) release from neutrophils demonstrated a negligible toxicity of these carriers. Our results indicate the feasibility of using lipid nanoparticles, especially SLNs and NLCs, as parenteral delivery systems for buprenorphine and its prodrugs.     

The release and analgesic activities of morphine and its ester prodrug, morphine propionate, formulated by water-in-oil nanoemulsions

In this study, we examined the feasibility of water-in-oil (w/o) nanoemulsions as sustained-release systems for morphine, following subcutaneous administration in rats. The ester prodrug of morphine, morphine propionate (MPR), was also utilized in this study. A variety of nanoemulsions were prepared using soybean oil or sesame oil as the external phase. Span 80, Tween 80, Plurol diisostearique and Brij 98 were used as surfactants in the w/o interface. The effects of the formulation variables on the characteristics of the nanoemulsions, such as inner droplet size, zeta potential, viscosity, drug partitioning, drug release and pharmacological effect, were evaluated. Mean sizes of nanoemulsions of 50-200 nm were obtained. The initial surface charge of the emulsions was found to be around - 3 to - 4 mV, except that the Plurol-containing vehicle showed a highly negative charge of - 23 mV. The loading of morphine and MPR into the nanoemulsions resulted in slower sustained-release behavior as compared with the drug/prodrug in aqueous solution. The rate of morphine released across the membrane was found to be highly dependent on the choice of oil and surfactant types. On the other hand, discrepancies in MPR release rates among the various formulations were minimal. The in vivo analgesic duration of morphine by targeting the drug to central nerve system could be prolonged from 1 to 3 h by incorporating the drug into nanoemulsions using Span 80 or Tween 80 as the surfactant. These results suggest that w/o nanoemulsions are well suited to provide sustained morphine delivery for therapeutic purposes.     

The release and analgesic activities of morphine and its ester prodrug,morphine propionate,formulated by water-in-oil nanoemulsions

In this study, we examined the feasibility of water-in-oil (w/o) nanoemulsions as sustained-release systems for morphine, following subcutaneous administration in rats. The ester prodrug of morphine, morphine propionate (MPR), was also utilized in this study. A variety of nanoemulsions were prepared using soybean oil or sesame oil as the external phase. Span 80, Tween 80, Plurol diisostearique and Brij 98 were used as surfactants in the w/o interface. The effects of the formulation variables on the characteristics of the nanoemulsions, such as inner droplet size, zeta potential, viscosity, drug partitioning, drug release and pharmacological effect, were evaluated. Mean sizes of nanoemulsions of 50–200 nm were obtained. The initial surface charge of the emulsions was found to be around ? 3 to ? 4 mV, except that the Plurol-containing vehicle showed a highly negative charge of ? 23 mV. The loading of morphine and MPR into the nanoemulsions resulted in slower sustained-release behavior as compared with the drug/prodrug in aqueous solution. The rate of morphine released across the membrane was found to be highly dependent on the choice of oil and surfactant types. On the other hand, discrepancies in MPR release rates among the various formulations were minimal. The in vivo analgesic duration of morphine by targeting the drug to central nerve system could be prolonged from 1 to 3 h by incorporating the drug into nanoemulsions using Span 80 or Tween 80 as the surfactant. These results suggest that w/o nanoemulsions are well suited to provide sustained morphine delivery for therapeutic purposes.     

Enhancement of transdermal apomorphine delivery with a diester prodrug strategy

Diester prodrugs of apomorphine, diacetyl apomorphine (DAA), and diisobutyryl apomorphine (DIA) were synthesized, and their partition coefficients, capacity factor (log K′), enzymatic hydrolysis, and in vitro permeation across nude mouse skin were characterized. The lipophilicity of the diesters was between that of apomorphine HCl and the apomorphine base. The prodrugs were chemically stable, but enzymatically unstable in esterase medium, skin homogenate, and human plasma. DAA showed a faster hydrolysis in plasma compared to DIA. Total fluxes (nmol/cm²/h) of the parent drug and prodrug were significantly greater after topical treatment with the diesters in aqueous solutions (water, 30% polyethylene glycol in water, and 30% glycerol in water) compared to treatment with HCl and base forms of apomorphine. DIA flux from deionized water was 51 nmol/cm²/h, which exceeded the flux of apomorphine HCl by 10-fold. The extent of parent drug regeneration after topical application ranged 51-88% and 34-61% for DAA and DIA, respectively, depending on the vehicles selected. Permeation measurements using intact and stratum corneum-stripped skins demonstrated that the viable epidermis/dermis was an important barrier to prodrug permeation. Nano-sized lipid emulsions were also used as carriers for apomorphine and its prodrugs. Diester prodrugs exhibited superior skin permeation compared to the parent drug when formulated into the emulsions. DAA and DIA fluxes from lipid emulsions were 11- and 3-fold higher than that of apomorphine HCl. The results in the present work suggest the feasibility of diester prodrugs for the transdermal delivery of apomorphine.     

Pancreatic Lipase-Catalyzed Hydrolysis of Esters of Hydroxymethyl Phenytoin Dissolved in Various Metabolizable Vehicles,Dispersed in Micellar Systems,and in Aqueous Suspensions

Lipase-catalyzed hydrolysis of fatty acid esters of 3-hydroxymethyl phenytoin was studied in various triglyceride and ethyl oleate emulsions, dispersed in micellar solutions, and suspended in an aqueous buffered solution. Phenytoin release from ethyl oleate emulsions of the prodrugs show apparent first-order kinetics with the pentanoate to nonanoate derivatives and sigmoidal kinetics with the long-chain fatty acid derivatives (stearate and oleate). A transition in the kinetic behavior, between the short- and the long-chain acyl prodrugs, was observed with the decanoate derivative. These observations are accounted for by a proposed kinetic model. Phenytoin release from the solid prodrugs follows zero-order kinetics and is independent of the total amounts of suspended material but directly proportional to the lipase concentration. Lipolysis of the solid suspended prodrugs was dependent on the length of the acyl side chain of the prodrug, with maxima for the pentanoate and the octanoate derivatives. The short-chain derivatives, acetate and propionate, as well as the long-chain prodrug, stearate, showed the slowest lipolysis rate when present as solid dispersions. The zero-order rate is qualitatively correlated with the melting point of the prodrugs. This result might be expected if the melting point is taken as a measure of the cohesivity or packing of the molecules at the surface of a crystal.     

Ester prodrugs of morphine improve transdermal drug delivery: a mechanistic study

Two alkyl esters of morphine, morphine propionate (MPR) and morphine enanthate (MEN), were synthesized as potential prodrugs for transdermal delivery. The ester prodrugs could enhance transdermal morphine delivery. The mechanisms of this enhancing effect were elucidated in this study. Both prodrugs were more lipophilic than their parent drug as evaluated by the skin/vehicle partition coefficient (log P) and capacity factor (log K'). The in-vitro skin permeation of morphine and its prodrugs from pH 6 buffer was in the order of MEN > MPR > morphine. MPR and MEN respectively enhanced the transdermal delivery of morphine by 2- and 5-fold. A contrary result was observed when using sesame oil as the vehicle. The prodrugs were stable against chemical hydrolysis in an aqueous solution, but were readily hydrolysed to the parent drug when exposed to skin homogenate and esterase. Approximately 98% MPR and approximately 75% MEN were converted to morphine in an in-vitro permeation experiment. The viable epidermis/dermis contributed to a significant resistance to the permeation of ester prodrugs. According to the data of skin permeation across ethanol-, alpha-terpineol-, and oleic acid-pretreated skin, MEN was predominantly transported via lipid bilayer lamellae in the stratum corneum. The intercellular pathway was not important for either morphine or MPR permeation.     

A novel prodrug approach for tertiary amines. 2. Physicochemical and in vitro enzymatic evaluation of selected N-phosphonooxymethyl prodrugs.

Quaternary amine prodrugs resulting from N-phosphonooxymethyl derivatization of the tertiary amine functionality of drugs represents a novel approach for improving their water solubility. Separate reports have demonstrated the synthetic feasibility and rapid and quantitative prodrug to parent drug conversion in rats and dogs. This work is a preliminary evaluation of the physicochemical and in vitro enzymatic reversion properties of selected prodrugs. The loxapine prodrug had over a 15 000-fold increase in aqueous solubility relative to loxapine free base at pH 7.4. The loxapine prodrug was also shown to be quite stable at neutral pH values. The time for degradation product (parent drug) precipitation from an aqueous prodrug formulation would be expected to dictate the shelf life. Using this assumption, together with solubility and elevated temperature chemical stability studies, the shelf life of a parenteral formulation of the loxapine prodrug was projected to be close to 2 years at pH 7.4 and 25 degrees C. In addition, the prodrugs of cinnarizine and loxapine have been shown to be substrates for alkaline phosphatase, an enzyme found throughout the human body, and revert to the parent compound in its presence. The results from these evaluations demonstrate that the derivatives examined have many of the ideal properties required for potential clinical application.     

Characterization of liposomes and an emulsion containing mitomycin C or lipophilic mitomycin C prodrugs

The characteristics of liposomes and an oil-water emulsion containing either mitomycin C (MMC) or its lipophilic prodrugs were investigated. Prodrugs were incorporated into liposomes and oil droplets of an oil-water emulsion, and this incorporation was dependent on the lipid content of the liposomes and droplets. A good correlation was observed between the calculated lipid:water partition ratios and partition coefficients in chloroform:water. The prodrugs were rapidly distributed between the lipid and aqueous phases when they were injected into the dispersion medium of empty liposomes and an oil-water emulsion, or when the formulations incorporating prodrugs were diluted with water. Addition of prodrugs to liposomes containing perylene resulted in a decrease of fluorescence. Based on these findings, prodrugs were concluded to be incorporated into lipidic dispersion formulations based on their partitioning behavior. N1a-[(Nonyloxy)carbonyl]MMC (7) showed the highest incorporation into lipidic formulations, while prodrugs with moderate lipophilicities were rapidly released from lipid particles. Liposomes incorporating 7 maintained their multilamellar vesicular form as shown by electron microscopy and by examining their entrapping capacity for water soluble marker dyes. The release of prodrug 7 from both formulations was slow in a buffer solution, but considerable release and conversion to the parent drug were observed when rat plasma was added to the same system. These results suggest that the stability of MMC could be improved by incorporation into lipidic formulations and that a suitable release rate in vivo could be accomplished by use of a prodrug.     

药物载体脂肪乳的研究与应用

综述作为药物载体的脂肪乳的分类、制备方法和工艺、存在的问题和解决方法、应用及发展前景。以甘油三酯和磷脂为主要成分的脂肪乳除可用作肠外营养外,近年来其用作药物载体的研究备受关注。     

Water-soluble gambogic acid PEGylated prodrugs: synthesis, characterization, physicochemical properties and in vitro hydrolysis

A series of poly(ethylene glycol) (PEG) prodrugs of gambogic acid (GA) with different molecular weight which used L-leucine as spacer were synthesized and characterized by FT-IR, 1H NMR and TOF MS. Drug loading capability, analyzed by UV spectrum, was 17.48, 9.26, 3.99, and 1.79%, aqueous solubility of the prodrugs was determined to be 1750, 1250, 800, and 645 mg/ml, respectively. The drug release from prodrugs was investigated under simulated in vivo conditions whose half-time (t1/2) in plasma ranged from 1.26 to 6.12 h. The effect of temperature on drug release was studied at four different temperatures and activation energy was determined as well. The stability of the prodrugs was improved in parallel with increasing molecular weight of PEG while prodrug yields and drug loading capability were reduced.     

Skin permeation of buprenorphine and its ester prodrugs from lipid nanoparticles: lipid emulsion,nanostructured lipid carriers and solid lipid nanoparticles

The aim of this study was to develop and characterize lipid nanoparticle systems for the transdermal delivery of buprenorphine and its prodrugs. A panel of three buprenorphine prodrugs with ester chains of various lengths was synthesized and characterized by solubility, capacity factor (log K′), partitioning between lipids and water and the ability to penetrate nude mouse skin. Colloidal systems made of squalene (lipid emulsion, LE), squalene + Precirol (nanostructured lipid carriers, NLC) and Precirol (solid lipid nanoparticles, SLN) as the lipid core material were prepared. Differential scanning calorimetry showed that the SLN had a more-ordered crystalline lattice in the inner matrix compared to the NLC. The particle size ranged from 220–300 nm, with NLC showing the smallest size. All prodrugs were highly lipophilic and chemically stable, but enzymatically unstable in skin homogenate and plasma. The in vitro permeation results exhibited a lower skin delivery of drug/prodrug with an increase in the alkyl chain length. SLN produced the highest drug/prodrug permeation, followed by the NLC and LE. A small inter-subject variation was also observed with SLN carriers. SLN with soybean phosphatidylcholine (SLN-PC) as the lipophilic emulsifier showed a higher drug/prodrug delivery across the skin compared to SLN with Myverol, a palmitinic acid monoglyceride. The in vitro permeation of the prodrugs occurred in a sustained manner for SLN-PC. The skin permeation of buprenorphine could be adjusted within a wide range by combining a prodrug strategy and lipid nanoparticles.     

Absorption characteristics of the lipophilic prodrug of mitomycin C from injected liposomes or an emulsion

Mitomycin C (MMC) is amphiphilic and so cannot be incorporated into lipoidal delivery systems. To develop a lipoidal delivery system, its prodrug, nonyloxycarbonyl MMC, was formulated in liposomes and in o/w emulsions and the usefulness of these formulations was evaluated. After injection into the rat thigh muscle, MMC was rapidly absorbed regardless of the dosage form. However, the prodrug was retained at the injection site for considerably longer when formulated in a lipid dispersion system. The accumulation of MMC at regional lymph nodes was also investigated and whereas free MMC arrived at and disappeared from the lymph nodes almost immediately after injection, the prodrug arrived at an early stage and its concentration decreased only gradually, remaining fairly high 2 h after injection. Liposomal lipids appeared to accumulate at the lymph nodes to a greater degree than o/w emulsions. It is suggested that the combination of lipidic carrier devices with lipophilic prodrugs may be a useful adjunct to cancer chemotherapy.     

Pure redox-sensitive paclitaxel–maleimide prodrug nanoparticles: Endogenous albumin-induced size switching and improved antitumor efficiency

A commercial albumin-bound paclitaxel nano-formulation has been considered a gold standard against breast cancer. However, its application still restricted unfavorable pharmacokinetics and the immunogenicity of exogenous albumin carrier. Herein, we report an albumin-bound tumor redox-responsive paclitaxel prodrugs nano-delivery strategy. Using diverse linkages (thioether bond and disulfide bond), paclitaxel (PTX) was conjugated with an albumin-binding maleimide (MAL) functional group. These pure PTX prodrugs could self-assemble to form uniform and spherical nanoparticles (NPs) in aqueous solution without any excipients. By immediately binding to blood circulating albumin after intravenous administration, NPs are rapidly disintegrated into small prodrug/albumin nanoaggregates in vivo, facilitating PTX prodrugs accumulation in the tumor region via albumin receptor-mediated active targeting. The tumor redox dual-responsive drug release property of prodrugs improves the selectivity of cytotoxicity between normal and cancer cells. Moreover, disulfide bond-containing prodrug/albumin nanoaggregates exhibit long circulation time and superior antitumor efficacy in vivo. This simple and facile strategy integrates the biomimetic characteristic of albumin, tumor redox-responsive on-demand drug release, and provides new opportunities for the development of the high-efficiency antitumor nanomedicines.KEY WORDS: Paclitaxel, Abraxane, Redox-sensitive, Disulfide bond, Maleimide, Prodrug-based nano-drug delivery systems, Prodrug/albumin nanoaggregates, Breast cancer treatment     

Disposition characteristics of emulsions and incorporated drugs after systemic or local injection

Lipid emulsions are useful tools for controlling the in vivo disposition of drugs and plasmid DNA. The dispositions of lipid emulsions are determined by their tissue interaction depending on the anatomical and physiological characteristics of each tissue and the physicochemical and biological properties of lipid emulsions. In addition, the retention of drugs is another issue, as too rapid a release of the drug would lead to failure of exerting its therapeutic potency. This review presents an overview about the disposition profiles and various physicochemical properties of lipid emulsions and incorporated drugs after systemic or local injection. Controlled biodistribution of lipid emulsions and incorporated drugs are also discussed.     

Characterization of lipophilic gemcitabine prodrug-liposomal membrane interaction by differential scanning calorimetry

Gemcitabine is an anticancer agent rapidly deaminated to the inactive metabolite 2',2'-difluorodeoxyuridine. Its stability as well as bioavailability can be increased by making prodrugs. A series of lipophilic prodrugs of gemcitabine were synthesized by linking the 4-amino group with valeroyl, lauroyl, and stearoyl linear acyl derivatives. We studied, by the differential scanning calorimetry technique, and compared the interaction of pure gemcitabine and its prodrugs with dimyristoylphosphatidylcholine and distearoylphosphatidylcholine vesicles with the aim of demonstrating if the gemcitabine prodrug is more able than the pure gemcitabine to interact with lipid vesicles employed both as model biomembranes and as carriers in the transport of antitumor drugs. These studies, carried out by static and kinetic calorimetric measurements, give evidence that the increase of the prodrug's lipophilic character improves the interaction with lipid bilayers, favoring the absorption through the lipid barriers and allowing the liposomes to work (when the prodrug is inserted inside the vesicles) as a lipophilic carrier which is able to deliver the drug near the cell surface. The use of different prodrugs modified in their lipophilic character, of different kinds of vesicles (multilamellar and unilamellar), and of different kinds of vesicles forming phospholipids permitted us to determine the better equilibrium between in-vesicle solubility and through-vesicle diffusion of the drug, important in the preformulative studies of antitumor carriers based on phospholipid formulations. Such studies suggest that the prodrug lipophilic tail should modulate the transport and the release of gemcitabine inside the cellular compartments, and the efficiency of the liposomal system is related to the length of the prodrug's acyl chain which has to match the phospholipid acyl chain allowing or retarding the migration through the lipid release device.     

Phenytoin prodrugs VI: In vivo evaluation of a phosphate ester prodrug of phenytoin after parenteral administration to rats

Tissue damage caused by subcutaneous and intramuscular administration of three phenytoin prodrugs to rats was assessed. Since two of the prodrugs caused significant irritation, only 3-(hydroxymethyl)-5,5-diphenylhydantoin disodium phosphate ester might be useful as a nonirritant phenytoin prodrug suitable for parenteral administration. To confirm the release of phenytoin from this prodrug, phenytoin availability after intramuscular and intravenous administrations of the phosphate prodrug was evaluated in rats and compared with sodium phenytoin. The prodrug quantitatively released phenytoin after intravenous administration, and phenytoin levels from intramuscular administration of the prodrug were far superior to those generated from similarly administered sodium phenytoin. Based on this and earlier studies, it was concluded that this prodrug should be further assessed as a parenteral form of phenytoin.     

A novel prodrug approach for tertiary amines. 3. In vivo evaluation of two N-phosphonooxymethyl prodrugs in rats and dogs.

N-phosphonooxymethyl derivatives of tertiary amine containing drugs have been identified as a novel prodrug approach for improving aqueous solubility. The in vivo reversion of two prodrugs to the corresponding parent compounds following iv and im administration to rats and dogs was investigated. Equimolar doses of parent drugs (loxapine or cinnarizine) and the corresponding prodrugs were each administered via a rapid iv infusion to rats and dogs. Equimolar doses of loxapine and its prodrug were each administered im to rats only. Blood samples were collected over 12 h, and plasma was assayed for both parent drug and intact prodrug by HPLC. Comparison of the plasma AUC for the parent drugs following administration of the parent drugs and prodrugs allowed estimation of the apparent bioavailability of parent drug from prodrug dosing. Plasma levels of the prodrugs fell below the limit of detection 5 min after iv infusion with an approximate half-life of 1 min. The mean AUCs following iv and im dosing of parent drugs were not statistically different from the parent drug AUCs obtained after prodrug dosing. The results are consistent with rapid and quantitative prodrug to parent drug reversion following administration of the phosphonooxymethyl prodrugs to the rats and dogs. This information, together with previous studies on the synthesis and physicochemical evaluation of the prodrugs, suggests that this novel prodrug strategy is a very promising approach for overcoming solubility limitations seen with many tertiary amine containing drugs at physiological pH values.     

Modulating the therapeutic activity of nanoparticle delivered paclitaxel by manipulating the hydrophobicity of prodrug conjugates

A series of paclitaxel prodrugs designed for formulation in lipophilic nanoparticles are described. The hydrophobicity of paclitaxel was increased by conjugating a succession of increasingly hydrophobic lipid anchors to the drug using succinate or diglycolate cross-linkers. The prodrugs were formulated in well defined block copolymer-stabilized nanoparticles. These nanoparticles were shown to have an elimination half-life of approximately 24 h in vivo. The rate at which the prodrug was released from the nanoparticles could be controlled by adjusting the hydrophobicity of the lipid anchor, resulting in release half-lives ranging from 1 to 24 h. The diglycolate and succinate cross-linked prodrugs were 1-2 orders of magnitude less potent than paclitaxel in vitro. Nanoparticle formulations of the succinate prodrugs showed no evidence of efficacy in HT29 human colorectal tumor xenograph models. Efficacy of diglycolate prodrug nanoparticles increased as the anchor hydrophobicity increased. Long circulating diglycolate prodrug nanoparticles provided significantly enhanced therapeutic activity over commercially formulated paclitaxel at the maximum tolerated dose.     

In Vitro and In Vivo Study of Poly(ethylene glycol) Conjugated Ibuprofen to Extend the Duration of Action

Ibuprofen-polyethylene glycol (PEG) conjugates (PEG-Ibu) were prepared and their potential as a prolonged release system was investigated. Two PEG-Ibu conjugates were synthesized from Ibuprofen and PEG with two different molecular weights by esterification in the presence of DCC and DMAP. The PEG-Ibu conjugates were characterized by FT-IR, (1)H NMR, Mass spectroscopy and DSC analysis. The solubility study in aqueous system showed an increase in solubility of conjugates. The dissolution / hydrolysis studies showed a specific acid-base catalysis pattern dependent on the pH of the medium. This indicated a good chemical stability in aqueous buffer solution of acidic medium and the extended release behavior was found in both prodrugs after 9 hour. The results demonstrate that, in the same condition, the rate of hydrolysis for PEG(4000)-Ibu is slower than other. The Writhing induced by acetic acid experiment and paw edema test after oral administration showed that both conjugates had extended analgesic and anti-inflammatory effects compared with Ibuprofen. These results suggest that PEG-Ibu could be a promising NSAID prodrug with an extended pharmacological effect owing to delayed-release of parent drug.     

A novel, unusually efficacious duocarmycin carbamate prodrug that releases no residual byproduct

A unique heterocyclic carbamate prodrug of seco-CBI-indole(2) that releases no residual byproduct is reported as a new member of a class of hydrolyzable prodrugs of the duocarmycin and CC-1065 family of natural products. The prodrug was designed to be activated by hydrolysis of a carbamate releasing the free drug without the cleavage release of a traceable extraneous group. Unlike prior carbamate prodrugs examined that are rapidly cleaved in vivo, the cyclic carbamate was found to be exceptionally stable to hydrolysis under both chemical and biological conditions providing a slow, sustained release of the exceptionally potent free drug. An in vivo evaluation of the prodrug found that its efficacy exceeded that of the parent drug, that its therapeutic window of efficacy versus toxicity is much larger than the parent drug, and that its slow free drug release permitted the safe and efficacious use of doses 150-fold higher than the parent compound.