Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Utility Patent
1999-03-31
2001-01-02
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S064000, C536S001110, C536S018700, C536S124000, C568S006000
Utility Patent
active
06169076
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the preparation of salt-free or essentially salt-free p-boronophenylalanine complexes with enhanced solubility.
BACKGROUND OF THE INVENTION
Neutron capture therapy (NCT), first postulated by Locher in 1936 (Locher,
Am. J. Roenten. Rad. Ther.
36: 1-13 [1936]) and Sweet (Javid et al.,
J. Clin. Invest.
31: 603 [1952]); Sweet et al.,
N. Engl. J. Med.
245: 875 [1951]), is a binary system for treating tumors in which a chemical agent and thermal or isothermal neutrons are directed to a tumor where they combine to release a lethal dose of radiation to the cell. A commonly used chemical agent usually includes at least one
10
B atom, although other compounds (i.e.,
157
Gd) have also been investigated (Shi et al.,
Med. Phys.
19: 733 [1992]; Miller and Horton, in
Advances in Neutron Capture Therapy, Vol II
, Larsson et al., eds., Elsevier Science B. V., pp. 545-546 [1997]). The neutron source is typically generated by a nuclear reactor, accelerator or generator, although other sources (i.e.,
252
Cf) have been explored (See e.g., Maruyama et al.,
Int. J. Radiat. Oncol. Biol. Phys.
11: 1475 [1985]; Shpikalov et al.,
Nucl. Sci. Appl.
4: 419 [1991]; Lorvidhaya et al., in
Advances in Neutron Capture Therapy, vol II
, page 540, Larsson et al., eds., Elsevier Science B. V. [1997]; Miller et al., in
Advances in Neutron Capture Therapy, vol. II
, pp. 545-546, Larsson et al., eds., Elsevier Science B. V. [1997]; Barth et al.,
Cancer Res.
50: 1061-1070 [1990]; Allen et al., in
Advances in Neutron Capture Therapy, vol. I
, pp. 271-274, Larsson et al., eds., Elsevier Science B. V. [1997]).
Boron neutron capture therapy (BNCT) is a form of radiochemotherapy that is becoming increasingly important for the treatment of malignant gliomas, malignant melanomas and other forms of cancer. BNCT involves administration of a boron compound (
10
B) followed by neutron irradiation of the tumor cells or organ. The boron captures a neutron (n
th
), which results in the release of ionizing helium and lithium ions that are highly damaging and usually lethal to the host cell (Kobayashi et al.,
Radiation Res.
91: 77-94 [1982]; Garth et al.,
Radiation Res.
111: 14-25 [1987]). For BNCT to be successful, a large number of
10
B atoms must be localized on or preferably within the target cells, and a sufficient number of thermal neutrons must reach and be absorbed by the
10
B atoms to sustain a lethal reaction.
Targeted delivery of boron to tumors is a critical prerequisite for successful BNCT. Thus, the development of tumor-localizing boron compounds continues to be of interest to researchers in this field. (See e.g., Saris et al.,
Cancer Res.
52: 4672-4677 [1992]; Mehta and Lu,
Pharm Res.
13:344-351 [1996]; Barth et al.,
Cancer Invest.
14: 534-550 [1996]; Chadha et al.,
Int. J Radiat. Oncol. Biol. Phys.
40: 829-834 [1998]; Fairchild et al.,
Int. J Radiation Oncology Biol. Phys.
11: 831-840 [1985]).
p-Boronophenylalanine (p-BPA) was initially proposed as a boron delivery drug for BNCT of malignant melanoma because it was postulated that this amino acid would selectively accumulate in melanoma cells by mimicking phenylalanine, an amino acid precursor of melanin. p-Boronophenylalanine has been shown to be selectively taken up by melanoma cells (See e.g., Packer et al.,
Invest Ophthalmol. Vis. Sci.
33: 395-403 [1992]; Coderre et al.,
Cancer Res.
47: 6377-6383 [1987]). Intravenous infusion of p-BPA was a possible route for delivering p-BPA to tumor cells, but was not widely used because p-BPA exhibits poor water solubility at physiological pH (7.4). (See e.g., U.S. Pat. No. 5,492,900 to LaHaan; LaHaan et al., in
Advances in Neutron Therapy
, pp. 513-517, Soloway et al., eds., Plenum Press, New York [1993]). p-Boronophenylalanine has a solubility of 1.6 g/L in water, which is insufficient for medical uses (Mori et al.,
Pig. Cell Res.
2: 273-277 [1989]).
Hydrochloric acid salts of p-BPA have been used to increase p-BPA solubility (See e.g., Ichihashi et al.,
J. Invest. Dermatol.
78: 215 [1982]; Yoshino et al.,
Proc.
2
nd International Symp. on Neutron Capture Therapy
, p. 291 [1986]). However, the acidity imparted by hydrochloric acid salts of p-BPA (e.g., a 0.1 M solution is reported to have a pH value of approximately 1.5), causes pain to patients injected with p-BPA solution of this acidity (Mori et al., supra; Yoshino et al.,
Strantenthen Onkol.
165: 127-129 [1989]). Therefore, it is desirable to find methods of increasing the solubility of p-BPA at physiological pH.
One method for increasing p-BPA solubility is the use of organic complexes. Complex formation of boric acid, borate and aromatic boronic acids with different polyols has been known for some time (See e.g., Kuivila et al.,
J. Org. Chem.
19: 780 [1954]; Lorand et al.,
J. Org. Chem.
24: 769 [1959]; Aronoff et al.,
Carbohydrate Res.
40: 299-309 [1975]; van Duin et al.,
Tetrahedron
40: 2901-2911 [1984]; van Duin et al.,
Tetrahedron
41: 3411-3421 [1985]; Shinkai et al.,
J. Chem. Soc., Chem. Commun.
, pp. 1039-1041 [1991]; Verchere et al.,
Polyhedron
6: 1415-1420 [1987]; Kondo et al.,
Tetrahedron
48: 8239-8252 [1992]; Shiomi et al.,
J. Chem. Soc. Perkin Trans.
, pp. 2111-2117 [1993]; Tsukagoshi et al.,
J. Org. Chem.
56: 4089-4091 [1991]; James et al.,
Angew. Chem. Int. Ed. Engl.
35: 1910-1922 [1996]; Wood et al.,
Carbohydrate Res.
36: 247-256 [1974]; James et al.,
J. Chem. Soc., Chem. Commun.
, pp. 477-478 [1994]; Kinoshita et al., in
Progress in Neutron Capture Therapy for Cancer
, pp. 243-246, Allen et al., eds., Plenum Press, New York [1992]). The solubility effects of monosaccharides and polyols allow for more efficient intravenous use of p-BPA (See e.g., Mori et al., supra; U.S. Pat. No. 5,492,900, supra; Honda et al., in
Progress in Neutron Capture Therapy for Cancer
, Allen et al., eds., Plenum Press, page 421 [1992]; Mishima et al., in
Progress in Neutron Capture Therapy for Cancer
, Allen et al. (eds.), Plenum Press, page 577 [1992]; Matalka et al.,
Cancer Res.
53: 3308 [1993]). For example, studies have shown that systemic administration of p-BPA-fructose complex increases the
10
B uptake in a murine melanoma model (Coderre et al.,
Int. J. Radiation Oncology Biol. Phys.
30: 643-652 [1994]).
Furthermore, p-BPA exists in different forms at different pH values, and complexing of p-BPA with monosaccharides is a pH dependent process. Recent studies have reported a method of solubilizing p-BPA at neutral pH using fructose, to yield a p-BPA-fructose complex (See, Mori et al., supra; U.S. Pat. No. 5,492,900, supra). These methods involve mixing equimolar amounts of p-BPA and fructose in water, increasing the pH to about 10 to dissolve all solids, and subsequent pH adjustment to 7.4 using a concentrated acid (i.e., hydrochloric acid). However, the current methods produce roughly one equivalent of NaCl (depending on how high the pH is raised), thus greatly exceeding its iso-osmotic point with blood and may be partially responsible for the toxicity observed when administered intravenously (LaHann et al., in
Advances in Neutron Capture Therapy
, Soloway et al., eds. Plenum Press, page 513 [1993]). Additionally, the solution must be used within two days of its preparation and requires a trained technician working with concentrated solutions of HCl and NaOH in an aseptic laboratory environment in close proximity to the treatment area.
Thus, it is desirable to find methods of making p-BPA complexes that are free of NaCl salts. Additionally, by understanding the chemical nature of the complex of p-BPA with f
Head Gerald
Shull Brian
Spielvogel David
Glcosyn Pharmaceuticals, Inc.
Medlen & Carroll LLP
Peselev Elli
LandOfFree
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