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 DP-TAT-59 to increase its solubility and dissolution rates, as was done successfully with tamoxifen citrate, apparently failed.

Prodrug chemical stability was verified to confirm the viability of a phosphate prodrug strategy. TAT-59 powder was determined to be chemically stable at neutral pH over GI residence times, and formulated tablets were shown to be chemically stable in long-term stability studies. In these studies, parent drug formation was minimal (Matsunaga et al., 1993, 1994; Matsunaga et al., 1996; Heimbach, 2003), a result that is typical for most phosphate esters under ambient conditions. The degradation rate of TAT-59 was slightly higher at or near pH 3-4 due to the less stable monoanionic phosphate form that exists predominantly at that pH range,; this has also been observed for many phosphate esters (Flynn and Lamb, 1970; Kearney and Stella, 1993; Heimbach, 2003).

It is expected that a phosphate prodrug would exhibit a higher solubility and dissolution rate compared to a poorly soluble parent drug. Indeed, the TAT-59 prodrug increased the parent drug's equilibrium solubility by three orders of magnitude at pH 7.4, from 58 ng/mL (0.1 |M) for DP-TAT-59 to 52 |g/mL (~100

TAT-59, Miproxifene Phosphate (Prodrug)

Enzymatic Hydrolysis _^ HO

Enzymatic Hydrolysis _^ HO

DP-TAT-59, Miproxifene (Parent drug)

TAT-59, Miproxifene Phosphate (Prodrug)

DP-TAT-59, Miproxifene (Parent drug)

Figure 4. Structures of TAT-59, shown in its neutral, zwitterionic form, and its precursor DP-TAT-59.

|M). However, unlike other phosphate esters, TAT-59 exhibits unusually low solubility (Table 1), even though solubility and dissolution rate are increased with increasing pH. The higher solubility is promoted as the second phosphoric acid hydrogen undergoes ionization followed by deprotonation of the basic amine (Heimbach, 2003). Similarly, apparent solubility is increased from 8 |g/mL (pH 6.5) to 52 |g/mL (pH 7.4) and 830 |g/mL (pH 8.0) (Heimbach, 2003). Despite TAT-59's unusually low solubility, the prodrug did show a phosphate prodrug solubility advantage by having nearly 1000-fold higher phosphate prodrug solubility compared to that of DP-TAT-59 (Table 1), near pH 7.4. However, at pH 6.0, the prodrug did not significantly improve the solubility over that of the parent drug, and both are insoluble at 0.0037 |g/mL and 0.0040 |g/mL, respectively (Heimbach, 2003).

The low solubility of TAT-59 is surprising since most phosphate esters are freely soluble in water. In a similar case, the prodrug metronidazole phosphate had a minimal solubility at pH 2 that was attributed to zwitterion formation (Cho et al., 1982). The low aqueous solubility of TAT-59 is most likely linked to the formation of a poorly soluble zwitterion, resulting in an overall neutral molecule in much of the pH range of the GI tract. TAT-59 has a melting point of over 210°C, a relatively high value, especially when compared to that of tamoxifen citrate, at 140-142°C. High levels of crystallinity as reflected in high melting points will also adversely affect solubility since a high melting point reflects poor solubility in all solvents (Amidon, 1981).

The prodrug approach was successful because, despite the relatively low solubility of TAT-59, its solubility and dissolution rate were significantly higher than those of the parent drug (see also Table 2). This was demonstrated in a study showing that 20 mg TAT-59 tablets were completely dissolved within 30 min at pH 7.4; these results could not be achieved with the parent drug (Heimbach, 2003).

The prodrug approach was also successful from a drug delivery point of view. In Caco-2 cells, at 100 |M dosing TAT-59 increased the absorptive flux of DP-TAT-59 nearly 10-fold, which is in accordance with the increased solubility achieved by the prodrug approach (Heimbach et al., 2003b). In vivo pharmacokinetic studies showed that TAT-59 is rapidly dephosphorylated. When given as a single oral dose of 0.3 mg/kg to rats with induced carcinoma, no intact TAT-59 was detected in plasma (Toko et al., 1990), but significant levels of the parent drug were detected. The bioavailability of DP-TAT-59 after oral TAT-59 dosing was 28.8% in rats and 23.8% in dogs, and no intact prodrug was detected in the plasma of either species (Masuda et al., 1998). For humans, no bioavailability data have been published, but the tmax of DP-TAT-59 after prodrug dosing ranged from 5 to 7.3 h; and its Cmax and AUC were dose-dependent (Nomura et al., 1998a). There were no reported food effects with TAT-59 from the Phase I studies (Nomura et al., 1998a). A report from early Phase II trials recommended a daily low dose of 20 mg (Aoyama et al., 1998), and in late Phase II studies TAT-59 was found to show efficacy and safety comparable to that of tamoxifen (Nomura et al., 1998b). The development of TAT-59 was discontinued in 1999, possibly due to lack of differentiation from tamoxifen.

Phosphate Ester Prodrug

Aqueous Solubility Prodrug (mg/mL)a

Aqueous Solubility Parent Drug

Cs min, (mg/mL)a

Targeted OralDose


Dose Number (Do)c based on Parent drug solubility

Acetaminophen phosphate


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