METHODS AND APPARATUSES FOR MANUFACTURING A PLURALITY OF CARTRIDGES OF MEDICAL BUFFERING SOLUTION WITH A COMMON PH

Abstract

The pH of a buffer or other medical solution in a plurality of containers can be adjusted and maintained by partially filling each container with a sodium bicarbonate solution so that a headspace remains over the solution. The headspace is filled with gas having a known CO2 concentration, and a fixed and precise pH will result after the CO2 is dissolved and the solution fully equilibrates.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application claims the benefit of prior provisional application No. 61/517,811 (Attorney Docket No. 36312-711.101), filed on Apr. 26, 2011, the entire contents of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

A buffer solution is a solution that, when mixed with another solution, tends to bring the pH of other solution toward the pH of the buffer. Medical buffer solutions are frequently used in antidotes, dialysates, body replacement fluids, body irrigating solutions, and cardiac perfusates. One of the most commonly used medical bicarbonate buffer solutions consists of sodium bicarbonate (NaHCO₃) mixed with water, often called “sodium bicarbonate solution.” A common use for sodium bicarbonate solution is to raise the pH of local anesthetics toward physiologic pH in order to hasten the onset of analgesia and reduce injection pain.

Sodium bicarbonate solutions are often more or less effective for medical purposes depending on their pH. Accordingly, if a sodium bicarbonate solution is intended for a particular use, if would be best to manufacture and maintained the solution at the optimum pH for such use.

Commercially produced medical sodium bicarbonate solutions fall far short of this objective. For example, commercially available buffering solutions set the pH range from pH 7.0 to pH 8.5. An assay of a sample of commercially available sodium bicarbonate solutions conducted by the inventors herein showed a pH range from 7.62 to 8.26; presumably the actual range of the product available in the marketplace is even wider than the range shown in this sample assay.

It must be appreciated in this context that a medical buffer having an actual pH of 7.0 may perform significantly differently than a medical buffer having an actual pH of 8.5. This is true whether the medical buffer is designed to buffer the pH of the body's fluids, for instance in the treatment of acidosis, or the medical buffer is designed to buffer the pH of a parenteral solution prior to its use, for instance to buffer a local anesthetic injection. In the latter example, the ratio of buffer solution to anesthetic solution would necessarily vary significantly if the pH of the bicarbonate solution were 7.0 compared to 8.5. Prior art methods of combining buffering solution with parenteral solutions do not use buffering solution having a precisely known pH in order to consistently add the same ratio of buffering solution to the parenteral solution, nor do they include manufacturing and storage methods and apparatuses designed to establish and maintain the pH of the buffering solution in an optimal range.

U.S. Patent Publication 2011/0005958, commonly owned and invented with the present application, describes a method and system for adjusting the pH of a sodium bicarbonate buffer solutions in small cartridges or containers. The cartridges are completely filled with a buffer solution, and the containers are maintained in a controlled environment of an equilibration chamber with a high carbon dioxide content. The containers are maintained for an extended period of time, typically hours or longer, in order for full equilibration to occur and for the pH to stabilize. While very effective, these methods often require a lengthy period for full equilibration which increases the cost of the process. Moreover, the degree to which the pH can be lowered is limited by the pressure in the equilibration chamber which is usually kept at or near ambient pressure.

For these reasons, it would be desirable to provide improved and alternative methods for producing a plurality of containers of buffering solutions having the same precisely controlled pH, where the pH in each container package is substantially identical and consistent, and so that medical practitioners can utilize buffers that are more specifically tailored for their medical uses than the buffers available at present. It would be further desirable to provide methods and systems for producing packaged buffer solutions which allow for the preparation of unlimited numbers of packages, such as cartridges, capsules, carpules, vials, and other containers, each of which contains a stable and precisely known pH. Such methods will preferably be capable of being performed rapidly with minimum processing time necessary to allow for CO₂ absorption into the buffer, and will further preferably allow for a higher pressure equilibration to lower the final pH of the solution. At least some of these objectives will be met by the inventions described below. Such methods and systems should provide for the economical preparation of such buffer solution containers, should allow the containers to be for long periods of time while maintaining pH stability, and should be compatible with sterilization protocols and systems. At least some of these objectives will be met by the inventions described below.

Description of the Background Art. U.S. Patent Publication 2011/0005958 has been described above. Glass vials and cartridges for storing medical solutions are described in U.S. Pat. Nos. 1,757,809; 2,484,657; 4,259,956; 5,062,832; 5,137,528; 5,149,320; 5,226,901; 5,330,426; and 6,022,337. Exemplary disposable drug cartridge that could be loaded with buffer solution in accordance with the present invention are described in U.S. Pat. No. 5,603,695 and in commonly owned, co-pending application US2009/0292271 (U.S. Ser. No. 12/406,670), both of which are incorporated herein by reference. Devices for maintaining a dissolved gas in solution in a pouch are described in U.S. Pat. Nos. 5,690,215; 5,610,170; and 4,513,015, and U.S. Patent Publ. No. 2007/0265593. Other patents and applications of interest include U.S. Pat. Nos. 2,604,095; 3,993,791; 4,154,820; 4,630,727; 4,654,204; 4,756,838; 4,959,175; 5,296,242; 5,383,324; 5,603,695; 5,609,838; 5,779,357; and U.S. Patent Publ. No. 2004/0175437.

BRIEF SUMMARY OF THE INVENTION

The present invention provides for the manufacture of a plurality of buffering or other medical solution containers where the solution within each container will have a precise and uniform pH. The pH of a sodium bicarbonate buffer or other solution depends upon the partial pressure of CO₂ in the solution. In accordance with the present invention, a plurality of containers are partially filled with a predetermined volume of solution selected to leave a specific preselected headspace volume of above the buffer. The headspace is filled with a gas rich in CO₂, and the container is then sealed. The amount of CO₂ in the headspace is selected so that the pH of the solution is fixed at a target value after the CO₂ has dissolved into the aqueous solution. By maintaining the aqueous solution and the gas within headspace under a known temperature, e.g. room temperature or 20° C., and pressure (usually elevated above ambient pressure) after the container is sealed, the partial pressure of the CO₂ in the headspace and the solution within the container will equilibrate. The method allows the manufacturer to control the pH of the solution in the container by adjusting any one or more of the temperature, the pressure under which the contents of the containers are held, and the volume and concentration of CO₂ gas that is placed in the headspace during manufacture.

Methods of the present invention are particularly advantageous in that they simplify the pH adjustment process, shorten the time required for the containers to be maintained in a processing environment, and allow for large volumes of CO₂ to be dissolved in the solution to lower the pH of the solution after equilibration. In particular, when compared to the process described in U.S. Patent Publication 2011/0005958, the process of the present invention is simplified since the containers do not need to be completely filled. Moreover, the time required to maintain the containers in a processing environment can be shortened since, after the containers are sealed, they may be removed from the processing environment and simply stored until being shipped for use. Additionally, lower pH's may be achieved without having to maintain higher pressures throughout a large equilibration chamber.

In specific aspects of the present invention, a method for adjusting the pH of a medical or other solution in the container comprises filling the container with a preselected volume of bicarbonate solution. The volume of the bicarbonate solution is selected to leave a predetermined volume of headspace over the buffer in the container. The headspace is the space or open volume below an open top of the container and above the surface of the solution in the container when the container is held vertically. The volume of the headspace is equal to the interior volume of the container less the preselected volume of the bicarbonate solution which is added to the container.

After the container is filled with the preselected volume of the bicarbonate solution, the headspace will be filled with a carbon dioxide (CO₂)-rich gas. The container is then sealed, and the CO₂-rich gas dissolves into the buffer solution to lower the pH of the buffer to a desired value, typically in the range from 7.4 to 8, preferably in the range from 7.6 to 7.8. The volume of bicarbonate buffer is typically in the range from 1.6 ml to 2.1 ml, typically in the range from 1.8 ml to 1.9 ml, and the headspace volume is typically in the range from 0.16 ml to 2.1 ml, usually from 0.18 ml to 0.19 ml. The CO₂-rich gas will typically have a CO₂ concentration of at least 75% by volume, usually being at least 98% by volume, and frequently being essentially pure CO₂ gas.

The pH of the buffer or other medical solutions which is achieved will depend on a number of factors, including the volume of the CO₂-rich gas, the concentration of CO₂ in the CO₂-rich gas, the temperature, and the pressure under which the gas is maintained within the container. While the CO₂-gas may be maintained at ambient pressure, often it will be maintained at a pressure above ambient. For example, the container may have a movable plug or other barrier with a force being applied against the plug or barrier in order to raise the pressure on the solution and CO₂-gas inside the container. For example, the force may be applied by a spring element, a screw element, or the like.

One advantage of the present invention is that by dissolving CO₂ from the headspace into the solution, the amount of CO₂ in the buffer may be higher than can be achieved by the ambient pressure equilibration provided by a U.S. Patent Publication 2011/0005958. In some instances, however, it may be desirable to initially treat the containers with buffers and other solutions using the methods described in U.S. Patent Publication 2011/0005958, followed by the methods of the present invention. For example, the cartridges may be partially filled with the bicarbonate buffer as described herein, and then placed in a controlled equilibration environment filled with a CO₂-rich gas prior to sealing the openings. The controlled equilibration environment is typically a large enclosure holding many open cartridges and having elevated CO₂ levels, as taught in U.S. Patent Publication 2011/0005958. After the open cartridges are left within the controlled equilibration environment for a preselected duration so that the pH is initially stabilized at a target value, the containers may be sealed and pressure applied to the buffer within the containers, typically using a spring element and movable plug as described in detail hereinafter, so that additional CO₂ is dissolved within the buffer to further lower the pH beyond that achieved by the initial equilibration. In such methods, the filling step of the present invention is achieved during the initial pre-equilibration, which occurs in the controlled equilibration environment which is filled with the CO₂-rich gas.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a cartridge useful in the practice of the present invention.

FIG. 2 illustrates another embodiment of a cartridge useful in the practice of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

A first embodiment of this invention is shown in FIG. 1. A container 10 comprises a glass cartridge with a pierceable septum 12 at one end and a slideable plunger 13 at the other end. The interior of the container 10 has been filled to 85% of its volumetric capacity with sodium bicarbonate solution 14 having a concentration of 8.4% CO₂ by weight. The remaining 15% of the cartridge volume is filled with CO₂ gas 15 at a concentration of 98%-100% by volume. The gas and liquid contents of the container 10 are maintained under pressure by the slideable plunger 13, which applies ambient pressure (typically 1 atm.) to the contents of the cartridge. Over the course of 48 hours, the partial pressure of the CO₂ gas in the headspace 15 will equilibrate with the partial pressure of the CO₂ in the sodium bicarbonate solution 14, and the pH of a plurality of cartridges manufactured using this method will be approximately 7.50.

In another embodiment shown in FIG. 2, container 10′ comprises a spring 18 or similar mechanism which presses against the plunger 13 in order to create an above-atmospheric pressure inside container 10′. The higher pressure is exerted against both the gas in the headspace 15 and the liquid sodium bicarbonate buffer 14. If the other variables set forth in the first embodiment (above) are the same, then the pH of the plurality of cartridges manufactured using this method would equilibrate to a common, more acidic, pH. The specific pH would depend on the amount of spring force selected and implemented using this method. The upper limit (corresponding to lowest pH) occurs when the pressure is sufficient to drive all of the CO₂ gas into solution at the storage temperature. That is, at some point, all of the CO₂ gas initially present in the headspace 15 would be driven into solution, leaving no headspace 15 with plunger 13 moved fully to the right so that solution 14 would entirely fill the interior of cartridge 10′, including all the volume between plunger 13 and cap 12. In that state, the pH of the solution could go no lower regardless of the amount of force exerted by spring 18.

In still another embodiment not shown in a figure, the CO₂ concentration of gas initially in the headspace may be less than the 98%-100% set forth in the earlier example with all the other variables may remain the same. In such an embodiment, the partial pressure of CO₂ in solution after equilibration would be lower, and the pH of the fully equilibrated bicarbonate buffer solution would be higher (more basic) than in the first example. The actual post-equilibration pH would be determined by the concentration of the CO₂ gas in the headspace.

Other embodiments of the invention may include different combinations of spring force, temperature, and concentrations of CO₂ gas which can be selected to achieve different targeted pH levels.

The present invention would also include containers having other mechanisms for applying pressure to the contents of the container, such as gas springs, screw mechanism, and the like.

The foregoing methods and apparatuses may be used to create containers having a common pH for any medical solution having the characteristic that the pH of the solution changes based on the partial pressure of CO₂ in solution, where CO₂ can enter or leave solution. Accordingly, among other solutions and medical uses, the foregoing method and apparatuses could be used to create medical bicarbonate solutions that would have a consistent pH, which would optimize their use in treating, among other things, metabolic acidosis.

While the above is a description of preferred embodiments of the invention, various alternatives, modifications, and equivalents may be used. Therefore, the above description should not be taken as limiting the scope of the invention which is disclosed.

While the above is a complete description of the preferred embodiments of the invention, various alternatives, modifications, and equivalents may be used. Therefore, the above description should not be taken as limiting the scope of the invention which is defined by the appended claims.

Claims

1. A method for adjusting the pH of a medical solution in a container, said method comprising:

filling the container with a preselected volume of a bicarbonate solution to leave a predetermined volume of headspace over the buffer;

filling the headspace with a CO2-rich gas;

sealing the container to allow the CO2-rich gas to dissolve in the buffer to adjust a pH of the buffer to a desired value.

2. A method as in claim 1, wherein the volume of bicarbonate buffer is in the range from 1.6 ml to 2.1 ml and the headspace volume is in the range from 0.16 ml to 0.21 ml.

3. A method as in claim 1, wherein the CO2-rich gas has a CO2 concentration of at least 75%.

4. A method as in claim 3, wherein the CO2 concentration is at least 98%.

5. A method as in claim 1, wherein the contents of the container are maintained at ambient pressure after sealing.

6. A method as in claim 5, wherein the cartridge has a moveable plug.

7. A method as in claim 1, wherein the contents of the container are maintained at a pressure above ambient after sealing.

8. A method as in claim 7, wherein the container has a moveable plug and the pressure is maintained by applying a spring-force to the plug.

9. A method as in claim 1, further comprising holding the containers in a controlled atmosphere after filling, but before sealing so that the buffer pre-equilibrates with the atmosphere.

10. A method as in claim 9, wherein the controlled atmosphere comprises the CO2-rich gas, wherein the headspace fills with the CO2-rich gas while the buffer pre-equilibrates.