Title:  Stable calcitriol solution for packaging into vials

United States Patent:  6,211,169

Assignee:  Aesgen, Inc. (Princeton, NJ)

Filed:  September 29, 1999

The invention provides a therapeutic calcitriol solution which is suitable for packaging into pharmaceutical vials without producing discoloration of the antioxidant component of the solution.

DETAILED DESCRIPTION

The inventor has discovered a method to stabilize the antioxidants responsible for the discoloration of a therapeutic calcitriol solution, thereby providing a solution which can be packaged into vials. Until now, it has not been practical to package calcitriol in vials, since the available molecular oxygen in the solution causes the antioxidant, which protects the drug from chemical degradation, to be degraded to form colored (usually yellow) compounds. Although the calcitriol solution is chemically stable in the presence of the antioxidant, it is perceived as being degraded when the solution turns yellow.

Applicant has discovered that calcitriol solutions prepared from water having a dissolved oxygen level of less than 1 part per million, and preferably less than about 0.5 parts per million, undergo significantly less antioxidant degradation than conventional aqueous calcitriol solutions.

The therapeutic calcitriol solution of the present invention can be packaged into ampules or into glass vials, most preferably vials of amber glass to protect the calcitriol from degradation by light. The concentration of calcitriol in the therapeutic solution is preferably from approximately 0.5 mcg/ml to approximately 3 mcg/ml, and most preferably about 1.0 mcg/ml to 2.0 mcg/ml.

Glass vials that can be used for packaging the solution of the present invention are commonly used for packaging injectable solutions and are known to those of skill in the art. Examples of glass vials which can be used to package calcitriol intravenous solution dosage forms are described, for example, in U.S. Pat. No. 5,230,429 (Etheredge, Jul. 27, 1993). The vial typically has a closure means, usually a stopper, formed of rubber or other polymeric material, which allows a needle to be inserted therethrough into the vial without requiring that any glass be broken. A preferred stopper has an inert (e.g., polytetrafluoroethylene (Teflon.RTM., DuPont.RTM., Wilmington, Del.)) coating to prevent chemical interaction between the stopper components and the calcitriol solution. The closure or stopper is typically held securely in place by a metal over-cap, which in turn has an exterior cover used to seal the vial until its initial use. The polymer closure means comprises at least one septum, or thinner area of polymer material, preferably centered in the body of the closure means, through which a needle can be inserted to contact the solution. The solution can be drawn into the needle without glass particle hazard to either the patient or the health care provider.

Although Conway et al. (U.S. Pat. No. 4,308,264) describe a process of boiling the water used to prepare an aqueous calcitriol solution, this method does not reduce the oxygen level sufficiently to provide a solution that can be packaged in vials with an antioxidant, without unacceptable degradation (yellowing) of the antioxidant.

Since water has a mole fraction solubility (X₁) at 25^oC. of 2.29x10^-5 (R. Battino, Ed. IUPAC Solubility Series, Vol.7: Oxygen and Ozone (1981), Pergamon Press, Oxford England), the inherent solubility of oxygen is therefore 409 parts per million (ppm). When efforts, such as boiling the water or sparging with nitrogen, are made to exclude oxygen, it is possible to reduce the oxygen concentration to 3 to 6 ppm. However, even 2 ppm oxygen concentration is sufficient to induce antioxidant degradation and solution discoloration. Water in a batching vessel will equilibrate above one percent, even if constant sparging of nitrogen (as is commonly practiced in the pharmaceutical industry) is performed.

The present invention provides a calcitriol solution which resists discoloration when an antioxidant is present in the solution, and a method for preparing such a calcitriol solution, by lowering and maintaining the oxygen content of the solution to about 0.5 ppm or less prior to packaging. Briefly, the calcitriol solution vial is prepared using Water for Injection, USP, which has been purged of essentially all oxygen, to a level of less than 0.5 parts per million, preferably in a closed top vessel. The closed top vessel is important to the invention, since an open top vessel allows trace oxygen from the atmosphere to redissolve in the water. The calcitriol solution is placed into a suitable vessel, where nitrogen is directed to flow through sintered dispersion heads located at or near the bottom of the liquid volume, with the only exit port being a vent for excess nitrogen. An inert atmosphere is also maintained above the solution throughout the process of mixing the solution, filling the solution into vials, and closure and sealing of vials to yield a final product with a dissolved oxygen content of less than 0.5 ppm and a headspace oxygen content of less than 0.5 ppm. Nitrogen, for example, can be used to provide the inert atmosphere.

Generally, a calcitriol solution prepared by the method of the present invention will comprise, for example, about 1 mcg to about 2 mcg calcitriol, in admixture with about 1,000 to 15,000 parts, or, for example, about 10 mg/ml, ascorbate antioxidant, about 8 to about 12,000 parts, or approximately 1 mg/ml, of a chelating agent, with approximately 400 to approximately 80,000, or approximately 4 mg, of a surfactant, and added water sufficient to produce the desired solution volume. Preferably, the added water is Water for Injection, USP, which has been sparged with nitrogen in a closed top vessel to produce an oxygen concentration of less than about 1, and preferably less than about 0.5, parts per million. The solution is maintained at a pH of approximately 6.5 to 7.8 using dibasic and monobasic sodium phosphate.

The solution is sparged with nitrogen or other noble gas, as described above, and as the vials are filled and sealed a suitable atmosphere is maintained (using nitrogen or other noble gas, for example) to keep the oxygen concentration level at or below 1 ppm, or more preferably below 0.5 ppm.

A solution such as that described above, prepared by the method of the present invention, can be stored at 15 to 30^oC. for a period of at least two years without exhibiting solution discoloration, discoloration being determined using APHA color standards by methods known to those of skill in the art.

Claim 1 of 15 Claims

What is claimed is:

1. An aqueous solution comprising calcitriol, an antioxidant, a chelating agent, and less than about 1 ppm molecular oxygen.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.