Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-09-29
2001-04-03
Cintins, Marianne M. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
active
06211169
ABSTRACT:
This is a non-provisional utility patent application filed by the inventor, Dr. Edward Shinal, of Holmdel, N.J., for a “Stable Calcitriol Solution for Packaging Into Vials.”
FIELD OF THE INVENTION
The invention relates to liquid calcitriol formulations, particularly calcitriol formulations for intravenous administration. More specifically, the invention relates to a calcitriol solution, and a method for preparing the solution, which is suitable for packaging into vials.
BACKGROUND OF THE INVENTION
Calcitriol, also known as 9,10-Secocholesta-5,7,10(19)-tricne-1,3,25-triol, 1 &agr;, 25-dihydroxycholecalciferol, or 1&agr;, 25-dihydroxyvitamin D
3
, is the biologically active form of vitamin D
3
which promotes intestinal calcium transport and bone calcium resorption. It is formed in the kidney during the second of two successive hydroxylations of vitamin D, and is administered therapeutically for the treatment of vitamin D-dependent rickets, osteoporosis, hypocalcemia (particularly when associated with hypoparathyroidism), and calcium metabolism disorders associated with renal failure.
Calcitriol is supplied commercially in two forms. Rocaltrol® (calcitriol) capsules (Roche Labs) provide a solid form for oral administration, while Calcijex® (calcitriol) (Abbott Labs) provides a solution for intravenous administration, which is particularly useful for chronic renal dialysis patients. The intravenous solution is supplied as 1 ml ampules containing either 1 mcg or 2 mcg of calcitriol. The ampules are stored at 15-30° C. (59-86° F.) and are formed of amber glass to protect the solution from light.
Calcitriol is a colorless compound which can be degraded by light and oxygen. Therefore, it is supplied in combination with a metal ascorbate salt antioxidant, such as sodium ascorbate, and a chelating agent. The headspace of the calcitriol ampule is filled with nitrogen gas to provide an inert atmosphere. However, even in the airtight ampule, the solution retains some oxygen and the reaction of the metal ascorbate antioxidant with the residual oxygen ultimately causes the clear solution to turn yellow. Since drug products are periodically inspected for discoloration, a significant amount of therapeutically useful product is discarded due to antioxidant discoloration.
A calcitriol composition which is stored in an ampule has previously been described by Conway et al. (U.S. Pat. No. 4,308,264, issued Dec. 29, 1981). Although the sealed glass ampule provides the advantage of product storage with nitrogen gas in the headspace to provide a more inert environment, this form of drug packaging has even more significant disadvantages for clinical use. For example, sealed glass ampules must be broken open in order to access the medication, exposing the health care provider to risk of injury from broken glass. Glass fragments can enter the solution as the ampule is broken, often requiring the use of a sterile filter, with additional effort and expense, to remove the solution from the open ampule. Breaking the ampule requires that it be handled, usually not within a sterile environmnent, increasing the risk of both microbial and blood contamination. The ampule has broken glass edges which are difficult to sterilize before the needle is inserted. Once the ampule is broken the entire contents must be used or, if only a part of the contents are used, the remainder must be discarded. It is also not unusual for an ampule to shatter completely upon opening, spilling the contents and potentially causing injury to the individual trying to open it. Ampule packaging is therefore used only when the physical and chemical stability of the contents requires it.
There is currently a need for alternative packaging systems that can maintain the stability of aqueous calcitriol solutions.
SUMMARY OF THE INVENTION
The invention provides a therapeutic aqueous calcitriol solution which has a molecular oxygen concentration of less than about 1 ppm, and more preferably less than about 0.5 ppm or less, the solution being resistant to antioxidant discoloration. The invention also provides said solutions packaged into containers such as ampules or pharmaceutical vials. Suitable vials are those comprising a closure means comprising a septum (i.e., a closure means that is penetrable and self-sealing).
The invention also provides a method for limiting discoloration of a therapeutic calcitriol solution by preparing the solution with water which has been purged of oxygen, to yield an oxygen concentration of less than 1 ppm, and more preferably less than about 0.5 ppm.
Further, the invention also provides a novel dosage form for calcitriol comprising an aqueous calcitriol solution packaged in a pharmaceutical vial, such as the pharmaceutical vials described by Etheredge (U.S. Pat. No. 5,230,429, issued Jul. 27, 1993, and incorporated herein by reference), the stopper preferably being at least partially coated with an inert polymer, such as polytetrafluoroethylene (Teflon®(polytetrafluoroethylene), DuPont®, Wilmington, Del.), so as to prevent chemical interaction between any of the other stopper components and the calcitriol 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®, DuPont®, 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 (X
Aesgen, Inc.
Cintins Marianne M.
Jagoe Donna
Schwegman Lundberg Woessner & Kluth P.A.
LandOfFree
Stable calcitriol solution for packaging into vials does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Stable calcitriol solution for packaging into vials, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Stable calcitriol solution for packaging into vials will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2550483