EP0215925A4

EP0215925A4 - Supplemental calcium addition unit.

Info

Publication number: EP0215925A4
Application number: EP19860902230
Authority: EP
Inventors: John C Miller; Robin Dawe; Albert Stone; Shanker L Gupta
Original assignee: Baxter Travenol Laboratories Inc
Current assignee: Baxter International Inc
Priority date: 1985-03-27
Filing date: 1986-03-24
Publication date: 1987-10-26
Also published as: WO1986005688A1; JPS62502261A; AU5628386A; ZA862326B; EP0215925A1

Abstract

A supplemental calcium addition unit for providing calcium to a container of phosphate-containing intravenous amino-acid solution. The unit comprises an ampule, plus means on the ampule for facilitating substantially aseptic fluid flow connection with the interior of the container, for example a needle pierceable latex membrane. The ampule comtains a solution of an intravenously metabolizable calcium compound typically at a pH of 2 to 5.5.

Description

SUPPLEMENTAL CALCIUM ADDITION UNIT

TECHNICAL FIELD

Amino acid in solutions suitable for injection are used with critically ill patients to provide nu- trition. For example, TRAVASOL *^■=^■ (amino acid) Injection is currently sold by Travenol Laboratories, Inc. of Deerfield, Illinois. Typically, the injectable amino acid solutions are sold without certain electrolytes which may be needed by a patient. In that circumstance, it becomes desirable for the doctor to add appropriate electrolytes to the container of amino acid solution immediately prior to intravenous administration to the patient. Among the electrolytes often added are phos¬ phate and calcium, as well as other physiologica] elec- trolytes.

Amino acid solutions have been provided in glass bottles, where they may have a relatively low pH. In this circumstance, small amounts of phosphate and calcium may be added to the amino acid solution without the risk of forming a precipitate, because the pH of amino acid solutions currently sold in bottles is sufficiently low to prevent the precipitation of, for example, dibasic calcium phosphate.

It has been deemed desirable to provide amino acid solutions in collapsible plastic containers to ob¬ tain the many advantages which collapsible plastic con¬ tainers can provide over glass containers. These advan¬ tages have caused glass containers to be substantially replaced by collapsible plastic containers in most other large volume parenteral products. However, technical factors have required that the amino acid solutions which are marketed in collapsible containers must have a pH of about 6.0-8.0 (and typically at least 6.5), which tends to be higher than the pH of amino acid so- lutions sold in glass containers, which usually have a pH of about 5 to 6.5.

In this circumstance, when one has added phosphate to the amino acid solution, and one attempts to add a standard unit of calcium gluconate injection, USP, which has a pH of 6.0-8.2, there is a risk that a precipitate of typically dibasic calcium phosphate will form. The formation of such a precipitate renders the solution unfit for intravenous administration to a patient.

Also, when larger amounts of calcium and phosphate are required by a patient, for example a pediatric patient, there arises a risk that a precipitate will form even in lower pH amino acid injection solutions.

By this invention, a way is provided in which more metabolizable calcium and phosphate can be added to amino acid formulations without the risk of causing precipitation.

DESCRIPTION OF THE INVENTION

By this invention a supplemental calcium addition unit is provided for administering dissolved calcium to a container of phosphate-containing intravenous amino acid solution. The unit comprises an ampule, plus means carried on the ampule for facilitatingsubstantially aseptic fluid flow connection with the interior of said container. This may constitute any of various conventional means for transferring an ampule of material in aseptic manner to a larger container. For example the ampule may carry a needle-pierceable latex wall, which may be penetratedin conventional manner with a needle and syringe.

The ampule contains a solution of intravenously metabolizable calcium compound at a pH of 2 to 5.5. Accordingly, sufficient acidity may be provided by the contents of the ampule, so that when the calcium cαπpound is added to phosphate-containing intravenous amino acid solution, no precipitation takes place. The solution inside the ampule may typically con- tain from 5 to 25 weight percent of calcium gluconate, a known metabolizable calcium compound, plus sufficient gluconic acid to provide to the solution a preferredpH of 3 to 4. The solution may also contain from 4 to 6 mg. of calcium d-saccharate per ml. of solution whichis present, as a precipitation inhibitor as well as a source of added calcium and as a stabilizer.

Other forms of metabolizable calcium which may be used in the supplemental calcium addition unit include calcium chloride, calcium acetate, calcium lactate, cal¬ cium ascorbate, or calcium succinate.

Other acids besides gluconic acid may also be used to provide a pH within the desired range, for example acetic acid, hydrochloric acid, ascorbic acid, lactic ac- id, succinic acid, or any other desired acid which would be suitable for use in an injectable solution at the appropriate pH.

For the manufacture of a specific example of the invention, the solution may be prepared by adding the desired amount of calcium gluconate (preferably 10 to 20 percent by weight) to rapidly boiling water for in¬ jection, which may be present in about 80 percent of the total volume of solution required, with constantstirring. In the case where a 10 percent solution of calcium glu- conate is being prepared five mg. , per ml. , of calcium d-saccharate may be added. Twice this amount of calcium d-saccharate may be added for a 15 percent solution of calcium gluconate.

The solution becomes clear after 2 or 3 minutes of continuous boiling. The solution is then allowed to cool to room temperature. Following this, 50 percent gluconic acid may be added incrementally until the pH of the solution is, preferably, 3.4-3.5. For 10 percent calcium gluconate solution, about 56 mg./ml. of gluconic acid is required to obtain this pH.

The resulting solution is then adjusted tothe total volume required by the addition, if necessary, of up to about 10 or 20 percent of its volume of water for injec¬ tion. The solution is then filtered through a 0.2 micron filter to prevent nucleation by crystallites or contam- inants in the solution. The solution is then filled into 50 ml. glass ampules, stoppered with a conventional ampule closure, and autoclaved for 35 minutes.

The contents of one of these ampules may be trans¬ ferred by injection needle using normal aseptic technique into a flexible, collapsible container of amino acid injection solution containing dissolved phosphate and other electrolytes, the amino acid injection solution typically having a pH of 6 to 8, without formation of any precipitate. A typical pH value for such amino acid injection solutions is 7.5.

In the drawing, a typical glass ampule 10 containing a solution of this invention is shown. The ampule is closed with a conventional latex needle-piercable dia¬ phragm 12, and is autoclaved before use. If it is desired to use other calcium compounds than calcium gluconate, it is generally desirable to use the acid corresponding to the anion of the calcium com¬ pound for pH control. For example, one may use acetic acid for pH control with a calcium acetate solution, or ascorbic acid with a calcium ascorbate solution.

Claims

WHAT IS CLAIMED IS:

1. A supplemental calcium addition unit for pro¬ viding calcium to a container of intravenous amino acid solution, which comprises: an ampule, and means carried on said ampule for facilitating substantially aseptic fluid flow connection with the interior of said container, said ampule con¬ taining a solution of an intravenously metabolizable calcium compound at a pH of 2 to 5.5.

2. The unit of Claim 1 in which said solution contains 5 to 25 weight percent calcium gluconate and sufficient gluconic acid to provide to the solution a pH of 3 to 4.

3. The unit of Claim 2 which also contains from 4 to 6 g. of calcium d-saccharate per ml. of solution.

4. A supplemental calcium addition unit for pro¬ viding calcium to a flexible collapsible container of phosphate-containing intravenous amino acid solution, which comprises: an ampule, and means carried on said ampule for facilitating substantially aseptic fluid flow connection with the interior of said flexible collapsible container, said ampule containing a solution of an intravenous metabolizable calcium compound at a pH of 2 to 5.5.

5. The unit of Claim 4 which also contains from 4 to 6 mg. of calcium d-saccharate per ml. of solution.

6. The unit of Claim 5 in which said solution contains a mixture of 5 to 20 weight per cent calcium gluconate and sufficient gluconic acid to provide to the solution a pH of 3 to 4. 7. The method which comprises transferring in substantially aseptic manner the contents of an ampule which contains a solution of an intravenously metabo¬ lizable calcium compound at a pH of 2 to 5.5 into a con- tainer of intravenous amino acid solution, whereby the calcium compound remains in solution even when phos¬ phate is present.

8. The method of Claim 7 in which said container of amino acid solution is initially at a pH of at least 6.5.

9. The method of Claim 7 in which said calcium containing solution contains 5 to 25 weight per cent calcium gluconate and sufficient gluconic acid to pro¬ vide to the solution a pH of 3 to 4.

10. The method of Claim 7 in which said ampule also contains from 4 to 6 mg. of calcium d-saccharate per ml. of solution present.

11. For use as an additive to intravenous amino acid solutions, an aqueous solution of an intravenously metabolizable calcium compound at a pH of 2 to 5.5.

12. The solution of Claim 11 which contains 5 to 25 percent of calcium gluconate and sufficient gluconic acid to provide to the solution a pH of 3 to 4.

13. The solution of Claim 12 which also contains from 4 to 6 mg. of calcium d-saccharate per ml. of solu¬ tion.

14. The method which comprises adding a solution of an intravenously metabolizable calcium compound having a pH of 2 to 5.5 to an amino acid solution having a pH of 6 to 8, whereby the formation of a precipitate is prevented.

15. The method of Claim 14 in which said intra¬ venous amino acid solution contains an intravenously metabolizable phosphate compound.

16. The method of Claim 15 in which said amino acid solution is carried in a flexible, collapsible plastic container.

17. The method of Claim 16 in which said solution of intravenously metabolizable calcium compound is added to the amino acid solution under substantially aseptic conditions.

18. The method of Claim 17 in which said solution of intravenously metabolizable calcium compound contains

5 to 25 weight percent of calcium gluconate and sufficient gluconic acid to provide to said solution a pH of 3 to 4.

19. The method of Claim 18 in which said solution of intravenously metabolizable calcium compound also con¬ tains from 4 to 6 mg. of calcium d-saccharate per ml. of solution.