Stable galactose injection solutions

Details Stable galactose injection solutions Stable galactose injection solutions

2002-02-19

2003-04-08

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S001110, C536S004100, C514S023000, C514S893000

Reexamination Certificate

active

06544954

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to stable galactose injection solutions for injection, which demonstrates high stability after storage at 80° C. for two weeks. The galactose injection solutions contain (1) 1 to 50% by weight of galactose, (2) a buffer solution, and (3) an antioxidant, and are at pH of 4.0 to 9.0. The preferred buffer solution is citrate buffer, preferably at a concentration of 0.01 M to 1.0 M. The preferred antioxidant is sodium bisulfite, preferably at a concentration of 0.001 to 5% by weight.
BACKGROUND OF THE INVENTION
Galactose, the C
4
-epimer of glucose, has been widely used for diagnostic and nutritional purposes. Galactose is one of the hexoses in lactose. Galactose resembles glucose in chemical structure, yet galactose differs greatly from glucose in other physical and chemical properties, such as solubility and stability.
Galactose has been widely used to assess liver function based on its enzymatic biotransformation to glucose, and as a nutrient for glucose-intolerant neonates. During the preparation of galactose solution, the solution is sterilized by autoclaving which causes the degradation of galactose to form 5-hydroxymethylfurfural (5-HMF) accompanied by development of amber to yellow coloration.
Galactose has a high affinity for the liver parenchymatous cells, which makes galactose useful for evaluating liver function. U.S. Pat. No. 4,010,251 discloses a composition of a scanning agent for imaging liver which contains a galactose moiety; U.S. Pat. No. 5,723,121 discloses an interferon having at least one galactose residue which composition has an improved accumulation in the liver and is preferably intravenously injected; U.S. Pat. No. 6,071,245 discloses the use of radioactive galactose in food as diagnostic agent for liver function; U.S. Pat. No. 6,177,274 discloses a compound for gene delivery targeted at liver which has galactose as a preferred targeting moiety.
However, galactose injection is generally prepared extemporaneously by pharmacists, particularly due to the unstable nature of the galactose solution and the absence of stability information regarding galactose injection solutions.
Bhargava et al.,
Am. J. Hosp. Pharm.,
46: 104-108 (1989), have tested the stability of galactose formulations and suggested that galactose degradation increases in relation to the increase of its concentration, temperature, and buffer concentration. Bhargava et al. proposes that galactose solution should be better kept in distilled or sterile water and the galactose solution containing pH buffer should not be sterilized by autoclaving, or it would cause significant discoloration of the solution.
Also, as indicated in Bhargava et al., many commercially supplied galactose may be pyrogenic and microbial contaminated. Thus, it is important to find galactose formulations which are pH balanced and can sustain sterilization by autoclaving while not affecting the purity and stability of galactose.
SUMMARY OF THE INVENTION
The present invention provides galactose injection solutions, which demonstrate high stability after sterilization by autoclaving and storage at 80° C. for at least two weeks.
The galactose injection solutions of the present invention contain 1-50% galactose, a buffer solution and an anti-oxidant, and are at a pH of 4.0 to 9.0. Examples of the buffer solution include, but are not limited to, citrate buffer, phosphate buffer, acetate buffer, carbonate buffer, and triethanolamine buffer. The preferred buffer solution is citrate buffer. Examples of the anti-oxidant include, but are not limited to, sodium bisulfite and vitamin C. The preferred anti-oxidant is sodium bisulfite.
In addition, it is preferred that the galactose injection solutions contain galactose at a concentration of 4% to 40% by weight, the buffer solution at the concentration of 0.01 M to 1.0 M (most favorably at about 0.01 M), and the anti-oxidant at the concentration of 0.001% to 5% by weight (most favorably at 0.01 to 1% by weight).


REFERENCES:
patent: 4010251 (1977-03-01), Green
patent: 5723121 (1998-03-01), Takenaga et al.
patent: 6071245 (2000-06-01), Kohno et al.
patent: 6177274 (2001-01-01), Park et al.
Oliver Yoa-Pu Hu et al.; Novel Galactose Single Point Method as a Measure of Residual Liver Function: Example of Cefoperazone Kinetics in Patients with Liver Cirrhosis; J Clin Pharmacol, 1995, p 250-258, vol. 35.
Oliver Yoa-Pu Hu et al.; Guest Editor's Note: Practical and Regulatory Issues on New Drug, New Dosage Form, and Generic Drug Development Drug Information Journal, 1997, p. 1145-1147, vol. 31.
Oliver Yoa-Pu Hu et al.; Determination of Galactose in Human Blood by High-Performance Liquid Chromatography: Comparison with an Enzymatic Method and Application to the Pharmacokinetic Study of Galactose in Patients with Liver Dysfunction; Journal of Pharmaceutical Sciences, 1995, p. 231-235, vol. 84, No. 2.
Oliver-Yoa-Pu Hu et al.; Pharmacokinetics of Promazine in Patients with Hepatic Cirrhosis-Correlation with a Novel Galactose Single Point Method; Journal of Pharmaceutical Sciences, 1995, p. 111-114, vol. 84, No. 1.
Vijay O. Bhargava et al.; Stability of galactose in aqueous solutions; American Journal of Hospital Pharmacy, 1989, p. 104-108, vol. 46.
Hung-Shang Tang et al.; Assessment of Liver Function Using a Novel Galactose Single Point Method; Digestion, 1992, p. 222-231, vol. 52.

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