HK1144548B - Sterilised dialysis solutions containing pyrophosphates - Google Patents

Description

Dialysis solution comprising pyrophosphate

Background

The present disclosure relates generally to medical treatment. More specifically, the present disclosure relates to solutions for dialysis therapy.

Failure of the renal system of a human may occur due to disease, injury, or other causes. In renal failure of any cause, there are several physiological disorders. In renal failure, the balance of water, minerals, and excreta of the daily metabolic burden may no longer exist. During renal failure, toxic end products of nitrogen metabolism (e.g., urea, creatinine, uric acid, etc.) can accumulate in blood and tissues.

Renal failure and reduced kidney function have been treated by dialysis. Dialysis removes waste, toxins and excess water from the body that would have been removed by a properly functioning kidney. Dialysis treatment to replace kidney function is critical to many people because the treatment is life-saving. People with renal failure cannot continue to survive without replacing at least the renal filtering function.

Past studies have shown that patients with End Stage Renal Disease (ESRD) are deficient in pyrophosphate. For example, pyrophosphate is thought to help prevent soft tissue calcification, and pyrophosphate deficiency may be a risk factor for calcification defense. Plasma and cell-bound (erythrocyte) pyrophosphate is reduced by about 30% in dialysis patients relative to normal individuals, although kidneys that normally clear pyrophosphate from circulation do not function. These levels are below levels previously indicated to prevent vascular calcification of blood vessels in culture. Replacement of pyrophosphate in dialysis patients can inhibit the formation of calcium deposits in blood vessels and thus inhibit vascular calcification. Therefore, a stable dialysis solution comprising such a compound may be very advantageous.

Disclosure of Invention

The present disclosure generally relates to dialysis solutions and methods of production and use thereof. More specifically, the present disclosure relates to dialysis solutions comprising a stable and therapeutically effective amount of pyrophosphate. For example, the dialysis solution can be adapted for peritoneal dialysis and/or hemodialysis to replace the deficient amount of pyrophosphate or to supplement a therapeutically effective amount of pyrophosphate. The dialysis solution can be used, for example, as a separate dialysis solution in a single container or as a dialysis part of a separately housed or multi-chambered container.

In one embodiment, the present disclosure provides a dialysis solution comprising a therapeutically effective amount of pyrophosphate. The dialysis solution can be sterilized, for example, using techniques such as autoclave, steam, high pressure, ultraviolet light, filtration, or combinations thereof. The dialysis solutions can be in the form of one or more concentrates that can be combined to form the final dialysis solution. The dialysis solution/concentrate can be specially formulated such that the pyrophosphate in the dialysis solution remains stable (e.g., does not degrade) during sterilization and over extended periods of time (e.g., during storage).

In another embodiment, the present disclosure provides a peritoneal dialysis solution comprising a therapeutically effective amount of pyrophosphate, an osmotic agent, a buffer agent, and an electrolyte. For example, the osmotic agent can include glucose, glucose polymers (e.g., maltodextrin, icodextrin), glucose polymer derivatives, cyclodextrins, modified starches, hydroxyethyl starch, polyols, fructose, amino acids, peptides, proteins, amino sugars, glycerol, N-acetyl glucosamine (NAG), or combinations thereof. The buffer may include bicarbonate, lactate, pyruvate, acetate, citrate, tris (i.e., tris), amino acids, peptides, or combinations thereof. The electrolyte may include sodium, potassium, magnesium, calcium, and chloride ions.

In alternative embodiments, the present disclosure provides a dialysis solution comprising two or more separate dialysis parts (e.g., separate concentrates), each dialysis part comprising one or more dialysis components, e.g., the one or more dialysis components are combined and administered to a patient. The first dialysis part comprises an osmotic agent and the second dialysis part comprises a buffer. At least one of the first and second dialysis parts comprises one or more electrolyte salts and pyrophosphate.

In yet another embodiment, the present disclosure provides a method of producing a multi-part dialysis solution. The method includes providing two or more dialysis parts, each dialysis part comprising one or more dialysis components, such as an osmotic agent, a buffer, an electrolyte, or a combination thereof. Pyrophosphate is added to at least one of the dialysis parts and sterilized with the dialysis part. Sterilization may be performed, for example, using heat (e.g., steam), high pressure, ultraviolet light, or filtration. The dialysis parts are mixed to form the final dialysis solution.

In an alternative embodiment, the present disclosure provides a method of providing dialysis, such as peritoneal dialysis or hemodialysis, to a patient in need of dialysis. The method includes administering a sterilized dialysis solution to the patient. The dialysis solution includes an osmotic agent, an electrolyte, a buffer, and pyrophosphate. In another embodiment, the method comprises providing two or more separately housed dialysis parts, each part comprising one or more dialysis components, such as, for example, osmotic agents, buffers, electrolytes, and combinations thereof. At least one of the dialysis parts comprises pyrophosphate. One or more of the dialysis parts are sterilized. The dialysis parts are then mixed to form a final sterilized dialysis solution, and the sterilized dialysis solution is administered to the patient. The mixing may be performed in situ by a mixing system or may be performed by the patient or health care worker.

In yet another embodiment, the present disclosure provides a method of treating a dialysis patient. The method provides providing a sterilized dialysis solution comprising a therapeutically effective amount of pyrophosphate to a dialysis patient suffering from vascular calcification.

It is an advantage of the present disclosure to provide improved dialysis solutions.

Another advantage of the present disclosure is to provide a sterilized dialysis solution comprising pyrophosphate.

Yet another advantage of the present disclosure is to provide improved dialysis methods for patients.

Another advantage of the present disclosure is to provide an improved method of producing a dialysis solution.

Another advantage of the present disclosure is to provide a sterilized ready-to-use dialysis solution comprising a stable amount of pyrophosphate.

Yet another advantage of the present disclosure is to provide sterilized, ready-to-use dialysis solutions comprising a therapeutically effective amount of pyrophosphate.

Furthermore, it is an advantage of the present disclosure to provide improved treatment for patients in need of dialysis.

Additional features and advantages of the invention are set forth in the description which follows, and in part will be apparent from the description.

Detailed Description

The present disclosure relates generally to dialysis solutions and methods of making and using the same. More specifically, the present disclosure relates to dialysis solutions comprising pyrophosphate and methods of making and using the same. For example, the dialysis solutions in embodiments of the present disclosure are designed to reduce or prevent vascular calcification due to pyrophosphate deficiency in patients undergoing dialysis treatment. In addition, the amount of pyrophosphate in the dialysis solution can remain stable (e.g., not readily degraded) before, during, or after sterilization, or over a specified period of time (e.g., during storage).

In a general embodiment, the present disclosure provides a dialysis solution or dialysis concentrate comprising one or more dialysis components (e.g., components or constituents of the dialysis solution) and a stable and therapeutically effective amount of pyrophosphate. The dialysis solution may be suitable for peritoneal dialysis, hemodialysis or any other dialysis treatment. In one embodiment, the dialysis solution comprises pyrophosphate in the range of about 0.1 μ M to about 1000 μ M. In another embodiment, the dialysis solution comprises pyrophosphate in the range of about 1 μ M to about 15 μ M. In alternative embodiments of the present disclosure, the dialysis solution may be used as a separate dialysis solution, for example in a single container, or as a dialysis part of a separately housed or multi-chambered container.

In an alternative embodiment, the present disclosure provides a dialysis solution/concentrate comprising pyrophosphate that is stable under sterile conditions. For example, it has been surprisingly found that heat sterilization of a dialysis solution comprising pyrophosphate at a higher pH (e.g., greater than 6) and with the use of specific dialysis components such as buffers reduces the amount of pyrophosphate degradation during sterilization. In addition, non-thermal sterilization methods such as autoclaving, ultraviolet light, or filtration provide a sterilized dialysis solution that includes a stable amount of pyrophosphate at a lower pH (e.g., less than 6). Thus, a greater amount of the original pyrophosphate remains in the sterilized dialysis solution, which can be stored for later use.

The dialysis solution can be sterilized using any suitable sterilization technique such as, for example, autoclave, steam, autoclaving, ultraviolet light, filtration, or a combination thereof. The dialysis solution can also be sterilized before, during, or after combining the one or more dialysis components and the one or more pyrophosphate salts.

The pyrophosphate salt may be, for example, pyrophosphate, a salt of pyrophosphate, or a combination thereof. The salt of pyrophosphate includes sodium pyrophosphate, potassium pyrophosphate, calcium pyrophosphate, magnesium pyrophosphate and the like. The dialysis component can be any one or more of an osmotic agent, a buffer, an electrolyte, or a combination thereof, as discussed in detail below.

The dialysis solution may further comprise one or more electrolytes in the following ranges: about 100 to about 140mEq/L of Na⁺About 70 to about 130mEq/L of Cl^-0.1 to about 4mEq/L of Ca²⁺0.1 to about 4mEq/L of Mg²⁺And/or K of 0.1 to about 4mEq/L⁺。

In another embodiment, the dialysis solution/concentrate can include two or more dialysis parts (e.g., separate solutions/concentrates that when mixed constitute the final dialysis solution), each dialysis part including one or more dialysis components. Pyrophosphate may be added to one or more of the dialysis parts and sterilized with the dialysis part. The two or more dialysis parts may be stored and sterilized separately, e.g. in separate containers or in a multi-chamber container.

A variety of different and suitable acidic and/or alkaline agents may be used to adjust the pH of the osmotic, buffer and/or electrolyte solutions or concentrates. For example, various inorganic acids and bases that can be used include hydrochloric acid, sulfuric acid, nitric acid, hydrogen bromide, hydrogen iodide, sodium hydroxide, and the like, or combinations thereof.

In another embodiment, the present disclosure provides a multi-part dialysis solution comprising at least a first dialysis part comprising an osmotic agent and a second dialysis part comprising a buffer. One or more of the separate dialysis parts comprises electrolytes. In one embodiment, the pH of the first dialysis part is from about 2 to about 6. In alternative embodiments, the pH of the first dialysis part is from about 2 to about 2.5, from about 3 to about 3.5, and from about 4 to about 4.5. The electrolytes can be equilibrated between the first dialysis part and the second dialysis part. In one embodiment, the second dialysis part comprises a therapeutically effective amount of pyrophosphate. The first and second dialysis parts may comprise a variety of other suitable dialysis components to ensure that the first and second parts can be mixed, e.g., easily and aseptically, to form a ready-to-use dialysis formulation, which can then be administered to a person in need thereof.

Additional ready-to-use formulations in embodiments of the present disclosure can be prepared in a variety of ways. In one embodiment, the first and second (or more) separate portions of dialysis solution are stored separately from each other, such as separately in separate and liquid-tight connected (hydraulicy) chambers in a multi-chamber container, until mixed together to form a mixed solution. In this regard, the ready-to-use formulation may be prepared in a container by mixing the separate dialysis parts in the container. This may effectively eliminate the need to manually inject all or at least a portion of the dialysis part into a container to form a mixed solution, thereby ensuring that a ready-to-use formulation can be readily prepared under sterile conditions.

Additionally, the container may be configured such that one of the dialysis parts may be configured to be in direct fluid communication with the patient prior to mixing, while the other dialysis part is not configured to be in direct fluid communication with the patient prior to mixing. This may provide a further level of safety in the preparation and administration of the ready-to-use formulations of the present disclosure, as a separate part, which cannot be configured to be in physical direct fluid communication with the patient, cannot be supplied to the patient unless it is first mixed with another part. In this regard, if, unexpectedly, a separate dialysis part that is not physically configured for direct fluid communication with the patient has an undesirable concentration of a dialysis component (such as potassium, sodium, etc.), such a configuration necessarily ensures that the undesirable level of the component is not provided or administered to the patient.

In an alternative embodiment, the present disclosure provides a peritoneal dialysis solution comprising a stable and therapeutically effective amount of pyrophosphate, an osmotic agent, a buffer agent, and an electrolyte. For example, the osmotic agent can include glucose, glucose polymers, glucose polymer derivatives, cyclodextrins, modified starches, hydroxyethyl starch, polyols, fructose, amino acids, peptides, proteins, amino sugars, glycerol, N-acetyl glucosamine (NAG), or combinations thereof. The buffer may include bicarbonate, lactate, pyruvate, acetate, citrate, tris (i.e., tris), amino acids, peptides, or combinations thereof. The electrolyte may include sodium, potassium, magnesium, calcium, and chloride ions. The peritoneal dialysis solution comprising a therapeutically effective amount of pyrophosphate can be sterilized in any suitable manner, such as, for example, heat sterilization.

It should be understood that the separate dialysis parts of the multi-part dialysis solution can be contained or contained in any suitable manner such that the dialysis solution can be effectively prepared and administered. Various containers may be used to house the two or more dialysis parts, such as separate containers (e.g., flasks or bags) connected by a suitable fluid communication mechanism. Two or more separate portions of the dialysis solution can be sterilized and stored in containers, respectively. Pyrophosphate may be added to at least one of the dialysis parts and sterilized with the dialysis part. The dialysis part not comprising pyrophosphate may also be sterilized.

In one embodiment, the dialysis parts may be stored separately, e.g. in separate compartments or chambers in the same container (e.g. a multi-chamber or dual-chamber bag), and combined prior to or during dialysis treatment. Activation of a barrier such as, for example, a peel seal or a frangible object between the chambers may allow the contents of the two chambers to mix. The container may be covered with an outer container that is gas impermeable. Alternatively, the sterilized dialysis parts can be combined at any time to form the complete, ready-to-use dialysis solution discussed previously.

In yet another embodiment, the present disclosure provides a method of producing a stable multi-part dialysis solution comprising pyrophosphate. The method comprises providing two or more dialysis parts, each dialysis part comprising one or more dialysis components such as osmotic agents, buffers, electrolytes. Pyrophosphate is added to one or more of the dialysis parts and sterilized with the dialysis part. The dialysis parts are mixed to form the final dialysis solution. The sterilization may be performed by autoclave, steam, autoclaving, uv, filtration or a combination thereof. Sterilization may be performed at a temperature and pH that does not cause significant decomposition of pyrophosphate in the dialysis solution. For example, a suitable buffer may be used to maintain the pH at a level that minimizes pyrophosphate degradation. In an alternative embodiment, the method comprises preparing a single dialysis solution comprising pyrophosphate and one or more of an osmotic agent, an electrolyte, and a buffer, and sterilizing the dialysis solution.

In one embodiment, the pH of the dialysis solution or separate dialysis part comprising pyrophosphate is 6 or more during sterilization. In another embodiment, the pH of the dialysis solution or separate dialysis part comprising pyrophosphate is 7 or more during sterilization. In an alternative embodiment, the pH of the dialysis solution or separate dialysis part comprising pyrophosphate is 8 or more during sterilization. In yet another embodiment, the pH of the dialysis solution or separate dialysis part comprising pyrophosphate is 9 or more during sterilization. Preferably, during sterilization, the dialysis solution or dialysis part comprising pyrophosphate further comprises a suitable buffer.

In an alternative embodiment, the present disclosure provides a method of providing dialysis to a patient in need of dialysis. For example, the patient may have suffered from or be predisposed to vascular calcification, or have a phosphate or pyrophosphate deficiency. The method includes administering a sterilized dialysis solution to the patient. The dialysis solution comprises pyrophosphate and one or more of an osmotic agent, an electrolyte, and a buffer. In one embodiment, pyrophosphate salts can be administered to a patient in amounts of about 0.01 μ M/day to about 20 mM/day.

In an alternative embodiment, the present disclosure provides a method of providing dialysis to a patient. The method includes providing two or more separately housed dialysis parts, each part including a dialysis component, such as, for example, an osmotic agent, a buffer, an electrolyte, and combinations thereof. At least one dialysis part comprises pyrophosphate. One or more of the dialysis parts are sterilized using any suitable sterilization technique. The dialysis parts are then mixed to form a final sterilized dialysis solution, and the sterilized dialysis solution is administered to the patient. The mixing may be performed in situ by any suitable mixing system or may be performed by the patient or healthcare professional. For example, the dialysis parts may be stored in separate chambers of the container, and a barrier between the chambers, such as for example a peel seal or a frangible, may be broken to allow the parts to mix.

In addition to the aforementioned pyrophosphate salts, the sterilized dialysis solutions and separate dialysis parts of the present disclosure can contain any number, type, and amount of dialysis components typically used as part of or during dialysis treatment. For example, the dialysis component can include one or more suitable osmotic agents, buffers, electrolytes, and combinations thereof. Examples of osmotic agents include glucose, glucose polymers (e.g., maltodextrin, icodextrin), glucose polymer derivatives, cyclodextrins, modified starches, hydroxyethyl starch, polyols (e.g., xylitol), fructose, amino acids, peptides, proteins, amino sugars, glycerol, N-acetyl glucosamine (NAG), and the like, and combinations thereof. Examples of buffers include bicarbonate, lactate, pyruvate, acetate, citrate, tris, amino acids, intermediates of the krebs cycle, and the like, and combinations thereof. Examples of electrolytes include calcium, magnesium, sodium, potassium, chlorine particles, and the like, and combinations thereof.

The peritoneal dialysis solution can preferably include components such as an osmotic agent to maintain the solution's osmotic pressure greater than physiological osmotic pressure (e.g., greater than about 285 mOsmol/kg). For example, glucose may be a preferred osmotic agent because it provides a rapid ultrafiltration rate. Other suitable types of osmolytes, such as amino acids, may be used in addition to or as a substitute for glucose. The dialysis solution can then be sterilized after combining the osmotic agent and the pyrophosphate.

Another family of compounds that can be used as osmotic agents in peritoneal dialysis solutions are glucose polymers or their derivatives such as icodextrin, maltodextrin, hydroxyethyl starch, and the like. Although these compounds are suitable for use as osmotic agents, they can be sensitive to low and high pH, particularly during sterilization and long term storage. Glucose polymers such as icodextrin may be used in addition to or in place of glucose in the peritoneal dialysis solution. In general, icodextrin is a polymer of glucose derived from the hydrolysis of corn starch. The molecular weight is 12-20,000 daltons. Most glucose molecules in icodextrin are linked linearly (> 90%) by alpha (1-4) glycosidic linkages, while a small (< 10%) are linked by alpha (1-6) linkages.

The sterilized dialysis solutions of the present disclosure can be used in a variety of suitable applications. For example, the dialysis solution can be used during peritoneal dialysis, such as automated peritoneal dialysis, continuous ambulatory peritoneal dialysis, continuous flow peritoneal dialysis, and the like. It should be understood that the present disclosure can be used with a variety of different and suitable dialysis treatments for treating renal failure.

While the present disclosure may be used in one embodiment in a method of providing dialysis treatment for a patient with chronic renal failure or disease, it should be understood that the present disclosure may be used in acute dialysis needs, such as in an emergency room setting. Finally, as will be appreciated by those skilled in the art, intermittent treatments (e.g., hemofiltration, hemodialysis, peritoneal dialysis, and hemodiafiltration) can be performed in a central, self-care/intensive care, and home environment.

The dialysis component can also include bicarbonate and an acid. The bicarbonate may include an alkaline solution so that the bicarbonate may be maintained stable without using a gas barrier cover film (gas barrier over), or the like. The bicarbonate solution alone may have a pH greater than about 8.6, preferably about 9. Any suitable type of ingredient, such as sodium hydroxide or the like, may be used to adjust the pH of the bicarbonate solution portion. Illustrative examples of BICARBONATE SOLUTIONs of the present disclosure may be found in U.S. patent 6,309,673 entitled "BICARBONATE-BASED SOLUTION in wo PARTS FOR particulate catalyst system OR SUB catalyst in continuous use RENAL REPLACEMENT THERAPY", published 30/10/2001, the disclosure of which is incorporated herein by reference.

The acid may include one or more physiologically acceptable acids such as lactic acid, pyruvic acid, acetic acid, citric acid, hydrochloric acid, and the like. The acid can be a separate solution having a pH of about 5 or less, about 4 or less, about 3 or less, about 2 or less, about 1 or less, as well as a separate solution having any other suitable acidic pH. According to one embodiment, the use of an organic acid such as lactic acid alone or in combination with another suitable acid (such as a suitable inorganic acid, including hydrochloric acid), another suitable organic acid (e.g., lactate, pyruvate, acetate, citrate/citrate), and the like in an acidic solution may make the solution more physiologically tolerable.

It should be understood that the dialysis solution of the present disclosure may comprise any other components/ingredients suitable for use in dialysis treatment in addition to those described above. In one embodiment, the pH of the (mixed) dialysis solution can be in a wide range, preferably from about 4 to about 9. In another embodiment, the pH of the (mixed) dialysis solution can be in a wide range, preferably from about 5 to about 8.

Examples

By way of example, and not limitation, the following examples are illustrative of various embodiments of the present disclosure and further illustrate experimental tests performed using dialysis solutions comprising pyrophosphate.

Example 1: pyrophosphate stability in dialysis solutions

Will contain disodium pyrophosphateAndperitoneal Dialysis (PD) solution (Baxter Healthcare Corporation) was used as the test article in this study.

A 2.5 millimolar (mM) stock solution of pyrophosphate (PPi) was prepared using disodium pyrophosphate and carbon dioxide free deionized water. This stock solution was diluted to 1L of a predetermined volume with a separate volume of PD solution to give 1L of solution containing PPi (see table 1) in a "ready-to-use" product.

For each test sample (i.e., 1L PD solution containing PPi), an aliquot was placed in a containerAutoclavedIn a bottle. The remaining solution volume of each test sample was retained as T-0 for analysis.

Data analysis

The study evaluated the change in pyrophosphate concentration when steam sterilization was performed in different autoclaves and with different sterilization times. PPi analysis was performed using a modified ion chromatography method. The method provides results in parts per million (ppm). The results of the PPi levels of the test samples contained in table 1 were converted to ppm and reported as micromoles per liter (μmol/L) and percent recovery of pyrophosphate (% PPi) relative to the initial.

Table 1: pyrophosphate recovery in PD solutions before and after steam sterilization

The results demonstrate that:

·steam sterilized test samples with PPi showed a reduction in PPi concentration.

·Steam sterilized samples with PPi showed small changes in PPi levels. This stability may be attributed toCompared to the high pH state of the test sample.

Example 2: effect of buffering Agents on Folum phosphate stability

Introduction: this study was conducted to evaluate the stability of pyrophosphate salts with different buffers in the pH range of 4-10 during steam sterilization and after storage at 40 ℃. Two pyrophosphates and four buffers were obtained for this study. Tris was added to all solutions as a pH stabilizer. Two solutions without tris were prepared for comparison. The pH of the solution is adjusted to pH 4-10 with 1N HCl or 1N NaOH. The solution was sterilized at 121 ℃ for 40 minutes. Pyrophosphate concentrations were determined before and after sterilization and after storage. The pH was also determined after sterilization and after storage.

The salts tested were:

1. disodium pyrophosphate (Na)₂H₂P₂O₇)

2. Tetrapotassium pyrophosphate (K)₄P₂O₇)

The sodium and potassium salts of pyrophosphoric acid were used in conjunction with the buffers shown below. No solutions with a pH below 7 were prepared with bicarbonate, as bicarbonate decomposes at lower pH.

1. Sodium lactate

2. Sodium bicarbonate

3. Citric acid sodium salt

4. Pyruvic acid sodium salt

The concentrations of the solution components are shown in table 2 below.

TABLE 2

Results and discussion

The results of this study are summarized in the following four tables:

table 3: recovery of disodium pyrophosphate (unsterilized)

Unsterilized disodium pyrophosphate (table 3):

recovery was 95% or greater for all buffers at pH 6 and higher.

The recoveries at pH4 and 5 using citrate were 81% and 89%, respectively, while the other buffers were 90-102% at this low pH range.

There was no difference in recovery between bicarbonate with or without TRIS and the values with lactate were similar to TRIS, or slightly higher.

Table 4: recovery of disodium pyrophosphate (sterilized) at time zero and after storage at 40 ℃

Sterilized disodium pyrophosphate (table 4):

for all solutions, there was no change in pH after sterilization, with a change of less than 0.1pH units after storage at 40 ℃ up to two months.

Recovery of pyrophosphate after sterilization was less than 20% for all buffers at pH 6 and lower and less than 20% at pH 7 and 8 using lactate, TRIS and pyruvate.

Recovery after sterilization increases with increasing pH from pH 7-10 for all buffers.

Bicarbonate at each pH of 7-10 gave the highest recovery after sterilization and reached 99% at pH 10. Bicarbonate without TRIS gave higher recovery than bicarbonate with TRIS at pH 7 and 8.

At pH 7-10, the recovery of lactate was similar to TRIS and pyruvate after sterilization.

At pH 9 and 10, higher recovery was observed after sterilization than lactate with TRIS. At pH 7 and 8, the recovery of lactate and citrate without TRIS after sterilization was similar.

Pyrophosphate was stable at 40 ℃ for 1 week at pH 7-10 for all buffers except lactate without TRIS at pH 7. Solutions of pH4-6 were not tested after one week due to low recovery after sterilization.

Table 5: recovery of tetrapotassium pyrophosphate (unsterilized)

Unsterilized tetrapotassium pyrophosphate (table 5):

recovery of tetrapotassium pyrophosphate was similar to that of disodium pyrophosphate for all buffers at all pH.

Table 6: tetrapotassium pyrophosphate (sterile) and recovery after storage at 40 ℃ C

Sterilized tetrapotassium pyrophosphate (table 6):

no change in pH after sterilization, a change of less than 0.1pH units after 1 week of storage.

Recovery of pyrophosphate after sterilization with all buffers was lower than recovery at pH 6 and lower, as seen for sodium pyrophosphate.

Recovery after sterilization with all buffers increased with increasing pH from pH 7-10, as seen with disodium phosphate.

At each pH of 7-10, bicarbonate gave the highest recovery after sterilization, as seen with disodium pyrophosphate.

Pyrophosphate was stable at 40 ℃ for 1 week at pH 7-10 for all buffers. Solutions at pH4-6 were not tested after one week due to low recovery after sterilization.

And (4) conclusion:

the pH of the solution of sodium or potassium salt did not change after sterilization and after storage at 40 ℃ for one week. At pH 6 and below, significant loss of pyrophosphate occurred with both sodium and potassium salts during sterilization with all buffers. Sodium and potassium salts are most stable during sterilization with bicarbonate at pH 9-10. The sodium and potassium salts remained unchanged at pH 7-10 when stored with all buffers at 40 ℃ for 1 week.

It should be understood that various changes and modifications to the presently preferred embodiments described herein may be made as will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the disclosed subject matter and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered by the appended claims.

Claims (34)

1. A heat-sterilized dialysis solution comprising a dialysis component selected from the group consisting of an osmotic agent, an electrolyte, and combinations thereof, a therapeutically effective amount of pyrophosphate, a buffer, and a pH of greater than 9, wherein the bicarbonate buffer and the pH of greater than 9 thermally stabilizes the pyrophosphate.

2. The dialysis solution of claim 1, wherein the dialysis solution comprises a concentrate.

3. The dialysis solution of claim 1, wherein the sterilization is performed by a technique selected from the group consisting of autoclaving, steam, and combinations thereof.

4. The dialysis solution of claim 1, wherein the pyrophosphate salt is selected from the group consisting of pyrophosphoric acid, salts of pyrophosphoric acid, and combinations thereof.

5. The dialysis solution of claim 1, wherein the osmotic agent is selected from the group consisting of glucose, glucose polymers, cyclodextrins, modified starches, polyols, fructose, amino acids, peptides, proteins, amino sugars, and combinations thereof.

6. The dialysis solution of claim 1, wherein the buffer additionally comprises a component selected from the group consisting of lactate, pyruvate, acetate, citrate, tris, amino acids, peptides, intermediates of the krebs cycle, and combinations thereof.

7. The dialysis solution of claim 1, comprising at least two separately housed dialysis parts, and pyrophosphate is present with at least one of said dialysis parts and is sterilized with said dialysis part.

8. The dialysis solution of claim 7, wherein the dialysis part comprising pyrophosphate has a pH of greater than 9.

9. The dialysis solution of claim 7, wherein the electrolyte is in equilibrium between the first dialysis part and the second dialysis part.

10. A stable heat sterilized peritoneal dialysis solution comprising a therapeutically effective amount of pyrophosphate, an osmotic agent selected from the group consisting of glucose, glucose polymers, cyclodextrins, modified starches, polyols, fructose, amino acids, peptides, proteins, amino sugars, and combinations thereof, a buffer agent comprising bicarbonate, and an electrolyte comprising sodium, potassium, magnesium, calcium, and chloride, and a pH greater than 9, wherein the bicarbonate buffer and the pH greater than 9 thermally stabilizes the pyrophosphate.

11. A method of producing a dialysis solution, the method comprising:

preparing a dialysis solution comprising pyrophosphate, a buffer comprising bicarbonate, and at least one dialysis component selected from the group consisting of an osmotic agent, an electrolyte, and combinations thereof, and having a pH greater than 9, wherein the bicarbonate buffer and the pH greater than 9 thermally stabilize the pyrophosphate; and

the dialysis solution was heat sterilized.

12. The method of claim 11, wherein the dialysis solution comprises a concentrate.

13. The method of claim 11, wherein the sterilizing is performed by a technique selected from the group consisting of autoclaving, steam, and combinations thereof.

14. The method of claim 11, wherein the dialysis solution comprises at least two separately housed dialysis parts, each dialysis part comprising at least one dialysis component selected from the group consisting of an osmotic agent, a buffer, an electrolyte, and combinations thereof, at least one of the dialysis parts comprising pyrophosphate, and wherein at least one of the dialysis parts is sterilized.

15. The method of claim 14, comprising mixing the dialysis parts to form a final dialysis solution.

16. The method of claim 14, wherein the dialysis part comprising pyrophosphate is sterilized and has a pH greater than 9.

17. The method of claim 16, wherein the dialysis part comprising pyrophosphate further comprises a buffer selected from the group consisting of lactate, pyruvate, acetate, citrate, tris, amino acids, peptides, intermediates of the krebs cycle, and combinations thereof.

18. Use of the dialysis solution of claim 1 in the manufacture of a medicament for the treatment of renal failure and reduced kidney function.

19. Use of the dialysis solution of claim 1 in the manufacture of a medicament for the treatment of vascular calcification.

20. Use according to claim 19, wherein the dialysis is peritoneal dialysis.

21. A multi-part dialysis product comprising:

at least two separately housed dialysis parts, each dialysis part comprising at least one dialysis component selected from the group consisting of an osmotic agent, an electrolyte, and combinations thereof, at least one of the dialysis parts being heat sterilized and comprising pyrophosphate, a buffer comprising bicarbonate and having a pH greater than 9, wherein the bicarbonate buffer and the pH greater than 9 heat stabilize the pyrophosphate.

22. A heat sterilized solution comprising pyrophosphate, a buffer comprising bicarbonate, and a pH greater than 9, wherein the bicarbonate buffer and the pH greater than 9 heat-stabilizes the pyrophosphate.

23. The solution of claim 22, wherein the solution comprises a concentrate.

24. The solution of claim 22, wherein the sterilization is performed by a technique selected from the group consisting of steam, high pressure, ultraviolet light, filtration, and combinations thereof.

25. The solution of claim 22 wherein the pyrophosphate salt is selected from the group consisting of pyrophosphoric acid, salts of pyrophosphoric acid, and combinations thereof.

26. The solution of claim 22 comprising from 0.1 μ Μ to 1000 μ Μ pyrophosphate.

27. The dialysis solution of claim 1, wherein the osmotic agent is hydroxyethyl starch.

28. The stable heat sterilized peritoneal dialysis solution of claim 10, wherein the osmotic agent is hydroxyethyl starch.

29. The dialysis solution of claim 5, wherein the polyhydric alcohol is glycerol.

30. The stable heat sterilized peritoneal dialysis solution of claim 10, wherein the polyol is glycerol.

31. The dialysis solution of claim 1, wherein the osmotic agent is N-acetylglucosamine.

32. The dialysis solution of claim 1, wherein the sterilization is performed by an autoclave.

33. The method of claim 11, wherein the sterilization is performed by an autoclave.

34. The solution of claim 22, wherein the sterilization is performed by an autoclave.