Amino Acid Prodrug

58 o Na

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 to 2.7 mg/mL in an aqueous solution of 72 mg/mL of 52 at pH 11.8. This projects a shelf life of 1.7 years, and the solubility of 53 would be greater at pH 7.4 than pH 11.8, so that the actual shelf life of a ready-to-use parenteral dosage form of 52 formulated at pH 7.4 may very well exceed 2 years (Krise et al., 1999b).

The bioreversion of 52 and 54 has been evaluated in rats and dogs by Krise et al. (1999c). Prodrugs were administered IV and IM to rats and dogs. Plasma levels of the prodrugs drop rapidly with a half-life of approximately 1 min and fall below limits of detection 5 min after infusion in rats and dogs. 52 was not observed in detectable levels in the plasma following IM administration to rats. The mean AUC values of 53 and 55 following IV and IM dosing of the parent drugs are not statistically different than AUC values of 53 and 55 produced from equivalent doses of their respective prodrugs. An example of the PK profile of 55 following IV administration of 55 as a cyclodextrin solution and its prodrug 54 to a beagle dog can be seen in Figure 3. The plasma concentration profile of 55 from 54 is nearly identical to that from equivalent dose of 55. These results are consistent with the rapid and complete conversion of the prodrug to parent drug following IV and IM administration to rats and dogs. Enzyme saturation of enzymes responsible for the bioreversion is not observed when the IV dose of 54 is tripled from 6.2 |imol/kg to 18.6 |imol/kg in rats (Krise et al., 1999c).

These prodrugs are shown to be substrates for alkaline phosphatase, which facilitates the release of parent drug from their respective prodrugs (Krise et al.,

Time (hours)

Figure 3. Plasma concentration of cinnarizine (55) following IV administration of equimolar (3 |imol/kg) doses of 54 (•) and 55 (•) to beagle dog (Krise et al., 1999c).

Time (hours)

Figure 3. Plasma concentration of cinnarizine (55) following IV administration of equimolar (3 |imol/kg) doses of 54 (•) and 55 (•) to beagle dog (Krise et al., 1999c).

1999b). The in vivo conversion of these prodrugs is extremely rapid compared to the relatively slow in vitro hydrolysis in the presence of alkaline phosphatase. It is likely that a significant fraction of the enzymes responsible for the rapid in vivo conversion are arterial and venous membrane-associated (Krise et al., 1999c).

The success of the POM prodrug strategy with fosphenytoin and other drugs has led to its utilization in more recent applications. Propofol (Diprivan®, 61) is an IV sedative-hypnotic agent widely used for anesthesia and sedation (Bryson et al., 1995). 61 is an oil, and is only sparingly soluble in water. It is currently formulated as an oil-in-water emulsion, which has several disadvantages including poor physical stability, potential for emulsion-induced embolism, and a risk of infection due to bacterial contamination (Prankerd and Stella, 1990; Bennett et al., 1995). Pain at the site of injection is also a major adverse effect (Nakane and Iwama, 1999).

GPI 15715 (Aquavan®) (60), is a water-soluble phosphonooxymethyl ester prodrug of propofol. It is reported to have an aqueous solubility of approximately 500 mg/mL and is converted to 61 by alkaline phosphatase in vitro (Stella et al., 2000). Furthermore, 60 is nontoxic in rats and produces anesthesia in dogs similar to 61. In rats, 61 from 60 showed a slightly delayed onset (as expected), longer apparent half-life, increased volume of distribution, greater potency, and sustained duration of action compared to that of known formulations of 61 (Schywalsky et al., 2003).

In the first study in humans by Fechner et al. (2003), 60 was well tolerated with no signs of pain on injection. Two of the nine subjects reported a transient unpleasant tingling or burning sensation in the groin area at the start of infusion. The pharmacokinetics of 60 were best described by a two-compartment model, and the hydrolysis half-life was 7.2 ± 1.1 min (central volume of distribution, 0.07 L/kg; clearance, 7 mL ■ kg1 min1; terminal half-life, 46 min). The PK parameters of 61 produced from 60 were somewhat different than parameters reported in the literature for lipid emulsion formulations of 61. Due to the conversion process of 60 to 61, the time to achieve peak concentration of 61 after bolus injection of 60 was longer than that from 61, and the time for elimination of 61 after infusion of 60 was longer than for 61 from the lipid emulsion formulation.

Ueda et al. (2003) have reported the synthesis and biological evaluation of a new POM prodrug of ravuconazole, BMS-379224 (62). Ravuconazole (63) is a potent broad-spectrum antifungal agent, which exhibits excellent activity against fungal pathogens such as Candida albicans and Cryptococcus neformans and, especially, against Aspergillus species (Arikan and Rex, 2002). Bristol-Myers Squibb is developing 63 as an oral agent, but its overall usefulness is limited by its poor aqueous solubility (0.6 |g/mL). An IV formulation would be of considerable benefit for the treatment of serious systemic fungal infections. 62 has an aqueous solubility of >30 mg/mL, and is relatively stable in solution and very stable in its solid form. 62 was rapidly converted to 63 in vivo following IV administration to rats, dogs, and monkeys, and shows efficacy comparable to that oral 63 against systemic C. albicans infection in mice. BMS-379224 appears to be in late stage clinical trials.

Amino Acid Prodrugs

Amino acids and amine-containing derivatives have been used for parenteral prodrug strategies, such as the previously mentioned steroid and chloramphenicol examples. They have been explored further for their use as promoieties for parenteral prodrugs, and metronidazole provides several good examples of amino acid ester type prodrug strategies. Metronidazole (64) is a drug used for the treatment and prevention of infections caused by anaerobic bacteria (Tally and Sullivan, 1981; Edwards, 1983). It is usually administered orally, but can also be administered by IV infusion for rapid onset; however, because of its relatively poor solubility, administration typically requires the infusion of 100 mL of a 5 mg/mL solution (Bundgaard et al., 1984a). There appears to be some interest in developing a prodrug of 64 for parenteral administration. Bundgaard et al. (1984a) synthesized and evaluated a number of amino acid esters of metronidazole (65-72), among them, metronidazole N,N-dimethylglycinate (66) appeared to be the most promising.

The hydrochloride salt of metronidazole N,N-dimethylglycinate (66) has an aqueous solubility of >50% w/v, and is rapidly cleaved (t1/2, 12 min) to give 64 in human plasma at 37°C (Bundgaard et al., 1984a). This prodrug is apparently rapidly and quantitatively hydrolyzed to 64 following IV administration to beagle dogs (Bundgaard et al., 1984b). The plasma-concentration time curve of 64

68 R =

Structures 64-72.

produced from 66 following IV administration is very similar to that from 64. While 66 does not exhibit sufficient aqueous stability to formulate as a ready-to-use solution, it has adequate stability to prepare a freeze-dried dosage form that could be reconstituted up to several hours prior to use.

Several other prodrug strategies have been applied to 64. The phosphate ester of metronidazole (73) was evaluated by Cho et al. (1982). The solubility of 73 is >730 mg/mL at pH 7 and 25°C, more than 50 times the solubility of the parent drug. Subcutaneous administration of the 73 to rats produces blood levels of 64, are only slightly less than that from an equivalent 64 dose (0.88:1.00 AUC ratio). It is possible that some of the prodrug may be excreted unchanged prior to enzymatic conversion. Maleic acid, succinic acid, and glutaric acid hemiesters (74-76) of metronidazole have also been examined to establish the kinetics of o Na+

regeneration of 64 in buffered solutions, 80% human plasma, and pig liver homogenate (Larsen et al., 1988). This study was performed as part of an investigation of the potential of using dextrans as carriers for drugs, which is discussed in the macromolecular prodrug chapter of this book.

The reason for the unfavorable high instability of amino acid ester prodrugs such as 66 even at low pH values where the prodrug is most soluble and stable is due to the proximity of the amino group to the ester linkage. The neighboring amino group can participate in intramolecular catalysis or assistance of ester hydrolysis, and the strong electron-withdrawing effects of the protonated amino group activate the ester bond linkage toward hydrolysis (Bundgaard et al., 1984b, and references there in). In an effort to overcome this problem, Bundgaard et al. (1989) synthesized a number of aminomethylbenzoate esters of metronidazole (77-79) and other drugs in which a phenyl group is placed between the ester bond linkage and the solubilizing amino group to distance the ester bond from the electron-withdrawing and catalytic effects associated with the promoiety. Elevated temperature stability studies predict a shelf life (t90) of 12 to 14 years for compounds 77-79 with consideration given to precipitation of formed drug (Jensen et al., 1990). These prodrugs are very soluble at low pH and show excellent solution stability. Furthermore, these prodrugs are rapidly cleaved in 80% human plasma with t1/2 values of 0.4 and 0.6 min for prodrugs 78 and 79, respectively.

This aminomethylbenzoate ester prodrug approach has been applied to a number of other drugs that suffer from poor aqueous solubility with similar success. N-substituted 3- or 4-(amino —methyl)benzoate 21-esters of hydrocor-

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