HK1159489A - Buffered compositions for dialysis - Google Patents

Abstract

Acid concentrates, and dialysate compositions prepared therefrom, contain citric acid and an effective amount of a buffering agent selected from acetate and/or lactate. The buffering agent allows a physiologically acceptable amount of citrate to maintain the desired pH of the dialysate.

Description

Buffered compositions for dialysis

Cross reference to related applications

This application is a continuation-in-part application of U.S. patent application No.09/421,622, filed on 10/19/1999, which is now pending and entitled to the benefit of U.S. provisional patent application No.60/105,049, filed on 10/20/1998, the entire contents of which are incorporated herein by reference.

Background

Technical Field

The present invention relates to therapeutic compositions, and in particular to dialysate compositions.

Description of the Related Art

When functioning properly, the kidneys help the body maintain a normal internal environment known as homeostasis. The kidneys help achieve this normal balance by removing excess fluid and metabolic waste products (toxins) from the body and maintaining accurate levels of glucose and electrolytes. Renal failure can be caused by a number of factors. However, regardless of how a person's kidneys fail, kidney failure will result in the accumulation of excess fluid and poisons in the person. Uremic intoxication ultimately leads to death if these waste products are not removed by some manual means. Hemodialysis is the most common treatment modality for people whose kidneys no longer perform their blood purification function. Another common type of dialysis is Peritoneal Dialysis (PD).

Dialysate is the fluid used in dialysis, where the dialysate serves to "clean" the blood of patients with renal failure. During hemodialysis, a patient's blood circulates on one side of a membrane within a dialyzer (i.e., an artificial kidney), while dialysate flows on the other side of the membrane. Since the blood and the dialysate are separated by the semi-permeable membrane, molecules can move between the blood and the dialysate. Although the membrane pores are too small for blood cells and proteins to leave the blood, these pores allow waste products to be transferred from the blood to the dialysate.

Peritoneal dialysis uses the patient's peritoneum as a dialysis membrane. When a volume of peritoneal dialysis solution is loaded into the peritoneal cavity, the osmotic pressure causes the fluid and waste products to exit the blood through the peritoneal membrane and pool in the peritoneal cavity containing the solution. After a sufficient dwell time, the spent peritoneal dialysis solution is drained from the peritoneal cavity along with the excess fluid and waste products collected.

Today, almost all hemodialysis dialysate is made at the treatment site (in the hemodialysis machine) by mixing (1) treated water, (2) acid concentrate, and (3) base concentrate. Since the base concentrate typically contains sodium bicarbonate as the primary alkaline substance, the dialysate made by mixing these components is commonly referred to as bicarbonate dialysate. Bicarbonate dialysate is almost always made in hemodialysis machines by using a "three-stream" proportional pumping mechanism, in which treated water, a liquid "acid concentrate" and a liquid bicarbonate (base) concentrate are mixed. A patient typically requires more than 120 liters of dialysate in a hemodialysis treatment. Chronic renal failure patients are treated 3 times a week for 52 weeks each year.

These concentrates are supplied to dialysis clinics in two forms; the "acid concentrate" is usually supplied as a liquid and the bicarbonate is usually transported as a dry powder. The acid concentrate typically contains sodium chloride, calcium chloride, potassium chloride, magnesium chloride, glucose and sufficient acid (acetic acid) for pH balancing. The precise composition of the acid concentrate used in a particular dialysis procedure is determined by the physician's prescription.

Prior to the patient treatment period, a pot of liquid acid concentrate was obtained. Typically, this pot of concentrate is drawn from a larger tank or cartridge of acid concentrate. Some dialysis clinics also prepare a pot of sodium bicarbonate concentrate by mixing a quantity of sodium bicarbonate powder with a specific quantity of treated water. Since mixing of the acid concentrate and the alkali concentrate will cause precipitation of calcium carbonate and magnesium carbonate, it is necessary to separate the "acid" concentrate from the bicarbonate concentrate. After appropriate mixing, the final dialysate has the concentration specified by the physician.

As mentioned above, patients with renal failure accumulate excess fluid and normally excreted substances in their blood, most notably Blood Urea Nitrogen (BUN) and creatinine. In fact, often the blood concentration reduction of these two substances is used to assess the efficiency and combined efficacy of dialysis. Dialysis efficiency is often compromised by a number of factors, one of which is that dialyzer membrane pores can become blocked by coagulated blood.

In addition, many renal failure patients suffer from chronic acidosis due to the inability of their kidneys to remove acid. Conventionally, one of several indicators in hemodialysis treatment is to correct acidosis by buffering excess acid in the blood by providing bicarbonate in the dialysate in higher than normal amounts. However, despite the infusion of "extra" bicarbonate during hemodialysis, many patients still fail to maintain normal blood bicarbonate levels during hemodialysis treatment.

Accordingly, there is a need in the art for improved dialysate formulations to increase the efficiency of dialysis treatments in need thereof. The present invention directly fulfills this need and provides other related benefits disclosed herein.

Brief summary of the invention

The present invention provides compositions, referred to as dialysate precursor compositions, that can be diluted with water and mixed with a base, thereby forming a dialysate composition. The dialysate precursor composition, and dialysate compositions prepared therefrom, contain citric acid and an effective amount of a buffer selected from acetate and/or lactate. The buffer requires a physiologically acceptable amount of citrate to maintain the desired pH of the dialysate.

In one embodiment, the present invention provides a dialysate precursor composition. The composition contains water in a minimum amount; chloride at a concentration ranging from about 1000 to about 7000 mEq/L; citrate at a concentration ranging from about 20 to about 900 mEq/L; at least one buffering anion selected from acetate and/or lactate at a concentration ranging from about 0.01 to about 150 mEq/L; and at least one physiologically acceptable cation. In a related embodiment, the present invention provides a dry dialysate precursor composition that, upon mixing with water, provides an aqueous composition having the above-described components at the above-described concentrations. In one embodiment, the dry dialysate precursor composition is a pellet or tablet, while in another embodiment, the dry dialysate precursor composition is a powder.

In another embodiment, the present invention provides a dialysate composition. The composition contains treated water in a minimum amount; chloride at a concentration ranging from about 20 to about 200 mEq/L; citrate at a concentration ranging from about 0.5 to about 30 mEq/L; at least one buffering anion selected from acetate and/or lactate at a concentration ranging from about 0.01 to about 4.5 mEq/L; a base comprising bicarbonate; and at least one physiologically acceptable cation. In a related embodiment, the present invention provides a dry dialysate composition that, when mixed with water, provides an aqueous composition having the above-described components at the above-described concentrations. In one embodiment, the dry dialysate composition is a pill or tablet, while in another embodiment, the dry dialysate composition is a powder.

In another embodiment, the invention provides a method of forming a dialysate precursor composition. The method comprises the following steps: mixing the treated water, chloride, citrate, at least one buffering anion selected from acetate and/or lactate, and at least one physiologically acceptable cation to provide a composition comprising chloride at a concentration ranging from about 1000 to about 7000mEq/L, citrate at a concentration ranging from about 20 to about 900mEq/L, and at least one buffering anion selected from acetate and lactate at a concentration ranging from about 0.01 to about 150 mEq/L. In a related embodiment, the present invention provides a method of forming a dialysate precursor composition, the method comprising the steps of: water is mixed with the dry dialysate precursor composition comprising the above components to provide an aqueous composition having the above component concentrations. In one embodiment, the dry dialysate precursor composition is a pellet or tablet, while in another embodiment, the dry dialysate precursor composition is a powder.

In another embodiment, the invention provides a method of forming a dialysate composition. The method includes the step of mixing the dialysate precursor composition with an aqueous bicarbonate-containing solution. The dialysate precursor composition contains, in a minimum amount, treated water, chloride, citrate, at least one buffering anion selected from acetate and lactate, and at least one physiologically-acceptable cation to provide a concentrate having a chloride concentration ranging from about 44 to about 143mEq/L, citrate concentration ranging from about 1.5 to about 30mEq/L, and at least one buffering anion selected from acetate and lactate concentration ranging from about 0.01 to about 3.6 mEq/L.

In another embodiment, the present invention provides a composition prepared according to the above method.

In another embodiment, the present invention provides an aqueous acid concentrate composition comprising water, chloride at a concentration of from about 1000 to about 7000mEq/L, citrate at a concentration ranging from about 20 to about 900mEq/L, and sufficient physiologically acceptable cations to provide a neutral composition. The acid concentrate composition has a pH of less than 4 and is free of any of acetate, bicarbonate, or lactate.

In a related embodiment, the present invention provides a dry acid concentrate precursor composition comprising the above-described components (without water) which, when mixed with water, provides an aqueous acid concentrate composition having the indicated components at the indicated concentrations. In one embodiment, the dry acid concentrate precursor composition is a pellet or tablet, while in another embodiment, the dry acid concentrate precursor composition is a powder.

The concentration of magnesium is preferably less than or equal to 2mEq/L, the concentration of calcium is preferably less than or equal to 4.5mEq/L, and the concentration of bicarbonate is preferably in the range of 25 to 40 mEq/L. As the amount of citrate in the composition increases, the calcium and magnesium concentrations should be adjusted to higher values in order to compensate for the binding with citrate of serum calcium and/or magnesium.

In another embodiment, the present invention provides sterile compositions particularly suitable for use in peritoneal dialysis. According to one embodiment, the present invention provides a peritoneal dialysis solution composition comprising treated water, citrate at a concentration ranging from about 0.5 to 30 mEq/L; chloride at a concentration ranging from about 20 to 200 mEq/L; bicarbonate at a concentration ranging from about 5 to 100mEq/L (assuming all carbonate-containing species are in the bicarbonate form), glucose at a concentration of about 10 to 100g/L, and sufficient physiologically acceptable cations to neutralize all citrate, chloride, bicarbonate, and any other anionic species that may be present in the composition. In another embodiment, the present invention provides a composition for peritoneal dialysis as described above, but containing no water. This embodiment thus provides a dry composition to which sterile water may be added in order to form a peritoneal dialysis solution.

Brief Description of Drawings

The figure is a graph of dialysate pH (y-axis) versus sodium acetate concentration (x-axis) showing the effect on pH of the addition of sodium acetate to the dialysate when the initial pH of the bicarbonate concentrate solution is 8.14.

Detailed description of the invention

In one aspect, the present invention provides a composition, referred to as a dialysate precursor composition, that contains, or is made from, water, chloride, citrate, at least one buffering anion, preferably selected from acetate and/or lactate, and at least one physiologically-acceptable cation. The dialysate precursor composition is mixed with a base and diluted to form a biocompatible composition that can be used for hemodialysis or peritoneal dialysis. In a related embodiment, the present invention provides a dry dialysate precursor composition that, upon mixing with water, provides an aqueous composition having the above-described components. In one embodiment, the dry dialysate precursor composition is a pellet or tablet, while in another embodiment, the dry dialysate precursor composition is a powder.

As discussed in more detail below, the presence of some buffering anions, for example anions selected from acetate and/or lactate, in the dialysate precursor composition allows the dialysate precursor composition to be used as an acid concentrate in a standard three-stream dialysis machine, along with a standard base (i.e., bicarbonate) concentrate, thereby mitigating problems associated with pH fluctuations in the dialysate during dialysis treatment. In the absence of the buffering anion, the dialysate may have pH and/or conductivity properties outside of the ranges considered acceptable by health care professionals. Before the composition of the present invention and its properties are discussed more closely, the main components of the composition will be described.

As used herein, "chloride" refers to an anionic chloride. Thus, the term "chloride" includes anionic chlorides and their salt forms, such as may be formed from a chloride anion and a physiologically acceptable cation. The term "chloride" does not include compounds in which a chlorine atom is covalently bound to, for example, a carbon atom in an organic molecule. Examples of physiologically acceptable cations include, but are not limited to, hydrogen ions (i.e., protons), metal cations, and ammonium cations. Metal cations are generally preferred, with suitable metal cations including, but not limited to, sodium, potassium, magnesium, and calcium in cationic form. Of these, sodium and potassium are preferred, and sodium is more preferred. When it is desired to include iron or trace elements in the composition, the metal cation package can be an iron cation (i.e., an iron or ferrous cation), or can be a cation of a trace element, such as a selenium or zinc cation. Compositions containing chloride salts may contain mixtures of physiologically acceptable cations.

In one embodiment, chloride is present in the precursor dialysate composition at a concentration of about 1000 to about 7000mEq/L, preferably about 2000 to about 5000 mEq/L. Generally, the concentration of the components in the precursor dialysate composition of the invention is individually determined by the physician to reduce, increase, or normalize the concentration of the different components in the blood, plasma, or serum of the patient. Thus, the precise concentration of chloride in the precursor dialysate composition, and dialysate compositions prepared therefrom, will be determined by the physician in accordance with principles known in the art.

As used herein, "citrate" refers to citrate anion in any form, including citric acid (citrate anion complexed with 3 protons), salts containing citrate anion, and partial esters of citrate anion. The citrate anion is an organic, tricarboxylic acid having the formula:

(chemical formula on page 7 of the original text.)

Assigned chemical Abstract registration number77-92-2 citric acid with molecular formula of HOC (CO)₂H)(CH₂CO₂H)₂Having a molecular weight of 192.12 g/mol. Citrate salts (i.e., salts containing citrate anions) consist of one or more citrate anions in combination with one or more physiologically acceptable cations. Examples of physiologically acceptable cations include, but are not limited to, protons, ammonium cations, and metal cations. Suitable metal cations include, but are not limited to, sodium, potassium, calcium and magnesium, with sodium and potassium being preferred and sodium being more preferred. Compositions containing citrate anions may contain mixtures of physiologically acceptable cations.

The partial ester of the citrate anion will have 1 or 2, but not necessarily 3, carboxylates of the citrate anion in the form of an ester (i.e., -COO-R where R is an organic group) (i.e., -COO^-) A group. In addition to 1 or 2R groups, the partial ester of citrate anion will comprise 1 or 2 physiologically acceptable cations (such that the total of R groups and cations equals 3). The R group is an organic group, preferably a lower alkyl group.

The citrate is preferably bound to a proton and/or a metal cation. Examples of such citrate compounds are, but are not limited to, citric acid, sodium dihydrogen citrate, disodium hydrogen citrate, trisodium citrate dihydrate, potassium dihydrogen citrate, dipotassium hydrogen citrate, calcium citrate, and magnesium citrate. In one embodiment, the citrate is present in the dialysate precursor composition in the form of one or more of citric acid, sodium dihydrogen citrate, disodium hydrogen citrate, potassium dihydrogen citrate, or dipotassium hydrogen citrate.

In a preferred embodiment, citric acid provides a source of citrate anion. In this embodiment, citric acid functions as the primary acidulant in the precursor composition. Citric acid is a relatively inexpensive physiological acid that is in the form of a dry chemical powder, crystals, pellets or tablets under ambient conditions. Any physiologically tolerable form of citric acid may be used to introduce citrate anions to the composition. For example, citric acid may be in the form of a hydrate, including a monohydrate.

It was previously thought that citrate could act as an anticoagulant in the bloodstream by binding calcium. Thus, the concentration of citrate in the dialysate precursor composition should be selected with a view to its anticoagulant properties. Unless other measures are taken, the citrate concentration should not exceed about 900mEq/L, preferably not more than about 200 mEq/L. When using citric acid concentrations of 200 to 900mEq/L, it is necessary to increase the magnesium and/or calcium concentration in the dialysate precursor composition.

Although the concentration of citrate should not be so great as to adversely affect the clotting properties of the blood, the concentration of citrate should be sufficiently high that it will effectively reach and maintain the pH of the final dialysate composition at a physiologically acceptable pH. Typically, a citrate concentration of 1/4 or less required to achieve anticoagulation can provide a physiologically acceptable pH for the dialysate composition. Thus, the dialysate precursor composition of the invention should have a minimum citrate concentration of about 20mEq/L in order to provide the desired dialysate pH. In one embodiment, the dialysate precursor composition contains citrate at a concentration ranging from about 20 to about 900mEq/L, and in a preferred embodiment, the composition contains citrate at a concentration ranging from about 70 to about 150 mEq/L. In a related embodiment, the present invention provides a dry dialysate precursor composition that, when mixed with water, produces a dialysate precursor composition that contains citrate at a concentration ranging from about 20 to about 900mEq/L, and in a preferred embodiment, from about 70 to about 150 mEq/L.

While citrate functions as an acidifying agent that lowers the pH of the dialysate composition, in one aspect the present invention introduces a buffering anion into the dialysate precursor composition in order to maintain the pH of the final dialysate composition within a physiologically acceptable range. As used herein, "buffering anion" refers to a physiologically acceptable anion that adjusts and regulates the pH of the composition. Suitable buffering anions include, for example, acetate, lactate, and mixtures thereof (i.e., acetate and/or lactate), which are compounds that will minimize variations in hydrogen ion concentration in the dialysate composition. The phrase "lactate and/or acetate" as used herein is meant to indicate that lactate alone, acetate alone, or a mixture of lactate and acetate may be used in the composition.

As used herein, "acetate" refers to any form of acetate anion, including acetic acid and salts of acetic acid. Acetate is of the formula H₃C-COO^-Organic, monocarboxylate. The acetate salt consists of one or more acetate anions in combination with one or more physiologically acceptable cations. Examples of physiologically acceptable cations include, but are not limited to, protons, ammonium cations, and metal cations, with metal cations being preferred. Suitable metal cations include, but are not limited to, sodium, potassium, magnesium and calcium, with sodium and potassium being preferred and sodium being more preferred.

Examples of acetate compounds of the present invention include, but are not limited to, acetic acid, sodium acetate trihydrate, potassium acetate, calcium acetate monohydrate, magnesium acetate, and magnesium acetate tetrahydrate. In one embodiment, the acetate in the dialysate precursor composition is present in the form of sodium acetate or potassium acetate, and in a preferred embodiment, the acetate is in the form of sodium acetate.

As used herein, "lactate" refers to any form of lactate anion, including lactic acid and salts of lactic acid. Lactate is of the formula H₃C-CH(CH)-COO^-An organic, monocarboxylic acid salt of (a). Lactate consists of one or more lactate anions in combination with one or more physiologically acceptable cations. Examples of the physiologically acceptable cation include, but are not limited to, protons, ammonium cations, and metal cations, with metal cations being preferred. Suitable metal cations include, but are not limited to, sodium, potassium, magnesium and calcium, with sodium and potassium being preferred and sodium being more preferred. When it is desired to include iron or trace elements in the composition, the metal cation package may be an iron cation (i.e., an iron or ferrous cation), or may be a trace amountCations of elements, such as selenium or zinc cations.

Examples of lactate compounds of the present invention include, but are not limited to, lactic acid, sodium lactate, potassium lactate, calcium lactate, and magnesium lactate trihydrate. In one embodiment, lactate is present in the dialysate precursor composition in the form of sodium lactate or potassium lactate, most preferably lactate is in the form of sodium lactate. When it is desired to include iron or trace elements in the composition, the lactate may be complexed with iron (i.e., iron or ferrous cations), or may be complexed with trace elements, such as selenium or zinc cations.

In general, the dialysate precursor composition will typically contain a greater number of equivalents of citrate than the number of equivalents of buffering anion. The precursor composition preferably contains a number of equivalents of citrate greater than the number of equivalents of acetate, lactate, or acetate + lactate. In one embodiment, the dialysate precursor composition contains citrate at a concentration ranging from about 20 to about 900mEq/L and a buffering anion selected from acetate and/or lactate at a concentration ranging from about 0.01 to about 150 mEq/L. In a preferred embodiment, the composition contains citrate at a concentration ranging from about 70 to about 150mEq/L and a buffering anion selected from acetate and/or lactate at a concentration ranging from about 0.3 to about 125 mEq/L. In a related embodiment, the present invention provides a dry composition (e.g., pill, tablet, powder) that, upon mixing with water, provides the dialysate precursor composition described above.

As the amount of citrate in the dialysate precursor composition increases, it tends to decrease the pH of the dialysate made from the precursor. As the dialysate pH decreases, there is no need to buffer the precursor as such to ensure that the dialysate pH does not rise to physiologically unacceptable levels. Thus, conventionally, the higher the equivalent amount of citrate used in the dialysate precursor composition, the less equivalent amount of buffering anion is required. In contrast, the lower the equivalent amount of citrate used in the dialysate precursor composition, the more equivalent amount of buffering anion is required.

The phrase "physiologically acceptable" as used hereinBy cation "is meant a cation typically found in the blood, plasma or serum of a mammal, or a cation that is tolerated when introduced into a mammal. Suitable cations include protons, ammonium cations, and metal cations. Suitable metal cations include, but are not limited to, the cationic forms of sodium, potassium, calcium and magnesium, with sodium and potassium being preferred and sodium being more preferred. Ammonium cations, i.e. of the formula R₄N⁺The compound of (1), wherein R is hydrogen or an organic group, can be used as long as it is physiologically acceptable. In a preferred embodiment, the cation is selected from the group consisting of H (i.e., proton), sodium, potassium, calcium, magnesium, and combinations thereof.

When the pH of the dialysate composition begins to increase (i.e., the dialysate becomes more alkaline) during the course of a dialysis treatment, the buffering anion, present in an effective amount, prevents the pH of the dialysate composition from rising outside of a physiologically acceptable range. In order for the composition to have the citrate concentrations described above and provide the desired buffering effect, the precursor composition should contain from about 0.01 to about 150mEq/L of a buffering anion, preferably selected from acetate, lactate, and mixtures thereof. In a preferred embodiment, the precursor composition contains from about 0.3 to about 125mEq/L of acetate and/or lactate. In one embodiment, the buffering anion is a mixture of acetate and lactate. In another embodiment, the buffering anion is acetate and lactate is absent from the composition. In another embodiment, the buffering anion is lactate and acetate is absent from the composition.

In the case of peritoneal dialysis solutions, in order to promote diffusion between the blood and the dialysis solution, it is desirable to maintain an osmotic gradient between the fluids by adding a permeation agent to the dialysis solution. The presence of osmotic agents in the peritoneal dialysis solution will encourage excess fluid and metabolic waste by-products to flow out of the blood and into the dialysate. A suitable osmotic agent for use in the precursor dialysate composition is sugar. The sugar is preferably selected from glucose (e.g. dextrose), poly (glucose) (i.e. a polymer made from repeating glucose residues, e.g. icodextrin made from repeating dextrose units) or fructose. Although it is possible to prepare a dialysate precursor that does not contain sugar, if sugar is to be added to the dialysate composition, the sugar is typically dextrose. It should be further understood that any biocompatible, non-sugar osmotic agent that functions equivalently may be a useful alternative. The sugar is typically present in the dialysate precursor composition at a concentration of less than about 2700 g/L.

The serum of a patient contains a variety of components including, for example, proteins, carbohydrates, nucleic acids, and various ions. Typically, the dialysate composition prescribed by the physician is selected to reduce, increase, or normalize the concentration of a particular component in the serum. Several cations may be routinely included as part of the precursor dialysate composition. Suitable cations may include, for example, sodium, potassium, calcium, and magnesium. In the dialysate precursor composition, the preferred concentration of sodium ranges from about 2000 to about 5000 mEq/L. The preferred concentration range for potassium is less than about 250 mEq/L. The preferred concentration range for calcium is less than about 250 mEq/L. The preferred concentration range for magnesium is less than about 100 mEq/L. Concentrations below about the stated values as used herein include zero. In related embodiments, the invention provides dry compositions (e.g., tablets, pills, powders) that, when mixed with water, provide dialysate precursor compositions having the above-described sodium, potassium, calcium, and magnesium concentrations.

As used herein, "mEq/L" refers to the concentration of a particular dialysate constituent (solute) present versus the amount of water present. More specifically, mEq/L refers to the number of milliequivalents of solute per liter of water. Milliequivalents per liter are calculated by: the number of moles per liter of solute is multiplied by the number of charged species (radicals) per mole of solute and then by a factor of 1000. For example, when 10 grams of citric acid is added to 1 liter of water, the concentration of citric acid is 10 g/L. The molecular weight of the anhydrous citric acid is 192.12 g/mol; thus, the number of moles of citrate anion per liter of citric acid and caused (due to 1 mole of citrate anion per mole of citric acid) is 10g/L divided by 192.12g/mol, which is 0.05 mol/L. Citrate anions have three negatively charged species in the form of carboxylate groups. Thus, a citrate concentration of 0.05mol/L is multiplied by 3 and then by 1000 to provide a citrate concentration in mEq/L, in this example a citrate anion concentration of 156 mEq/L.

Preferred water of the present invention is treated so that it is substantially pyrogen free and sterile and at least meets the purity requirements established by the medical Association for the advancement of medical instrumentation (AAMI) for dialysate compositions. Water may also be referred to as treated water or AAMI-quality water. A monograph describing the water treatment of dialysate, monitoring of water treatment systems, and adjustment of water treatment systems is available from AAMI ("Standards Collection)" column 3, dialysis, section 3.2 quality of water for dialysis, 3 rd edition, 1998, AAMI, 3330 Washington Boulevard, Arlington, VA 22201) or via the Internet at http:// www.aami.com. Furthermore, all other components of the precursor dialysate composition of the invention are preferably at least United States Pharmacopeia (USP) -grade purity, which is typically about 95% purity. The purity of the component is preferably at least about 95%, more preferably at least about 98%, more preferably at least about 99%.

The dialysate precursor composition of the invention will typically have a pH of from about 1 to about 6.5, more typically from about 1 to about 4, more typically from about 2 to about 4, at a temperature of from about 15 ℃ to about 40 ℃, prior to dilution with treated water and base to provide a dialysate composition.

In a preferred embodiment, the dialysate precursor composition contains the following components: chloride is included at a concentration ranging from about 2000 to about 5000 mEq/L; citrate at a concentration ranging from about 70 to about 150 mEq/L; acetate and/or lactate at a total concentration ranging from about 0.3 to about 125 mEq/L; at least one physiologically acceptable cation selected from the group consisting of hydrogen, sodium at a concentration ranging from about 2000 to about 5000mEq/L, potassium at a concentration ranging less than about 250mEq/L, calcium at a concentration less than about 250mEq/L, and magnesium at a concentration less than about 100 mEq/L; and glucose (preferably dextrose) at a concentration of less than about 2700g/L, wherein the composition meets or exceeds the AAMI standards set for dialysate. In one embodiment, the above listed ingredients are only active ingredients in the composition. In a related embodiment, the present invention provides a dry composition that, upon mixing with water, provides a dialysate precursor composition having the above-described components and component concentrations.

The present invention provides a method of forming a precursor dialysate composition as described above. In the method, ingredients are mixed together to obtain the dialysate precursor composition. Thus, a chloride source, a citrate source, and a source of buffering anions (e.g., acetate and/or lactate) are mixed with the treated water in amounts that ultimately provide the respective desired concentrations as listed above. The non-aqueous components of the precursor dialysate composition can be pre-mixed and in powder, pellet, tablet, or other dry form, and then easily mixed with water to form the precursor dialysate composition. Suitable sources for these ingredients are well known in the art. Indeed, the chemical characteristics of the compounds used in the present invention, such as molecular weight and solubility, are available in the art, so that one of ordinary skill in the art would know how to prepare the compositions of the present invention. See, e.g., Sigma-Aldrich catalog from Sigma-Aldrich (Milwaukee, Wis.; http:// www/sial. com.).

For example, the chloride source may be any of hydrochloric acid, sodium chloride, potassium chloride, magnesium chloride, ammonium chloride, and the like. The citrate source can be any one of citric acid, sodium dihydrogen citrate, disodium hydrogen citrate, trisodium citrate dihydrate, potassium dihydrogen citrate, dipotassium hydrogen citrate, calcium citrate, magnesium citrate, etc. The acetate source may be any one of acetic acid, sodium acetate trihydrate, potassium acetate, calcium acetate monohydrate, magnesium acetate tetrahydrate, and the like. The lactate source can be any one of lactic acid, sodium lactate, potassium lactate, calcium lactate, magnesium lactate trihydrate, etc. Any or all of these chemicals are commercially available (if desired, in USP-grade) from a number of chemical suppliers including, for example, Aldrich chemical company, Milwaukee WI. The treated water may be obtained by standard purification techniques including, for example, distillation and reverse osmosis. Alternatively, the treated water may be purchased commercially. Such treated water is used in all or almost all dialysis clinics and is therefore well known to those skilled in the art.

In one embodiment, the present invention provides a method of forming a dialysate precursor composition, the method comprising the steps of: mixing water, chloride, citrate, at least one buffering anion selected from acetate and/or lactate, and at least one physiologically acceptable cation to yield a composition having a chloride concentration ranging from about 1000 to about 7000mEq/L, citrate concentration ranging from about 20 to about 900mEq/L, and at least one buffering anion selected from acetate and/or lactate at a total concentration ranging from about 0.01 to about 150 mEq/L. The non-aqueous components of the dialysate precursor composition can be pre-mixed and in the form of a dry powder, pellet, tablet, such that the method requires mixing water with the dry pre-mixed composition.

In a preferred embodiment, water, chloride, citrate, acetate, and a source of physiologically acceptable cations are mixed to provide a chloride having water at a concentration ranging from about 2000 to about 5000 mEq/L; citrate at a concentration ranging from about 70 to about 150 mEq/L; acetate at a concentration ranging from about 0.3 to about 125 mEq/L; at least one physiologically acceptable cation selected from the group consisting of hydrogen, sodium at a concentration ranging from about 2000 to about 5000mEq/L, potassium at a concentration of less than about 250mEq/L, calcium at a concentration of less than about 250mEq/L, and magnesium at a concentration of less than about 100 mEq/L; and glucose at a concentration of less than about 2700g/L, wherein the composition meets or exceeds an AAMI-quality criterion set for dialysate.

In another aspect, the present invention provides a dialysate composition. The dialysate composition can be made from the dialysate precursor composition described above, for example, by adding treated water and a base, preferably bicarbonate, to the precursor composition. After addition of the base and water, the dialysate precursor composition provides a composition suitable for dialysis. Alternatively, the dry composition, also described above, can be mixed with water and a base to prepare a dialysate composition.

For example, a bicarbonate concentrate or a diluted bicarbonate concentrate can be added to a dialysate precursor composition or a diluted dialysate precursor composition to provide a dialysate composition of the invention. Typically, 1 part by volume of the dialysate precursor composition is diluted with 33 to 45 parts of the diluted base concentrate to give the dialysate composition. The dialysate precursor will contain citrate (as the main acidic component of the acid concentrate), bicarbonate (as the main basic component of the base concentrate) and a buffering anion preferably selected from acetate and/or lactate.

In one embodiment, the dialysate composition contains the following components: comprises treated water; chloride at a concentration ranging from about 20 to about 200 mEq/L; citrate at a concentration ranging from about 0.5 to about 30 mEq/L; at least one buffering anion selected from acetate and/or lactate at a concentration ranging from about 0.01 to about 4.5 mEq/L; bicarbonate radical; and at least one physiologically acceptable cation.

In one embodiment, the dialysate composition includes one or more sugars selected from the group consisting of glucose (preferably dextrose), poly (glucose) (preferably poly (dextrose), such as icodextrin), and fructose at a concentration of less than about 45 g/L. Alternatively, or in addition to sugar, the dialysate composition can contain one or more amino acids. Preferably, the dialysate composition contains water that meets or exceeds the purity requirements established by AAMI for dialysate, and all other components have at least USP-grade purity. In another preferred embodiment, the dialysis composition has a pH of about 5 to about 8.5 at a temperature of about 25 ℃ to about 40 ℃, more typically a pH of about 6.4 to 7.6, preferably a pH of about 7.2 to about 7.4, within this temperature range.

In other embodiments, the dialysate composition contains the following ingredients: water, chloride at a concentration ranging from about 40 to about 150 (more preferably from about 60 to about 120) mEq/L; citrate at a concentration ranging from about 1.5 to about 4.5 (more preferably from about 2 to about 3) mEq/L; acetate and/or lactate at a total concentration in the range of about 0.01 to about 4.0 (more preferably about 0.2 to 0.5) mEq/L; bicarbonate at a concentration ranging from about 25 to about 45 mEq/L; at least one physiologically acceptable cation selected from the group consisting of hydrogen, sodium at a concentration ranging from about 60 to about 190 (more preferably from about 70 to about 150) mEq/L, potassium at a concentration of less than about 5mEq/L, calcium at a concentration of less than about 5mEq/L, and magnesium at a concentration of less than about 2 mEq/L; and glucose (preferably dextrose) at a concentration of less than about 45 (preferably less than about 8) g/L, wherein the mixed composition meets or exceeds the AAMI-quality criteria set for dialysate.

In the dialysate composition of the invention, including precursors thereof, for hemodialysis or peritoneal dialysis, in one embodiment of the invention the composition comprises iron. Patients undergoing dialysis are often iron deficient, where iron deficiency is associated with anemia and other adverse medical conditions. Currently, iron deficiency is most commonly addressed by oral iron supplement programs or by parenteral administration of iron. However, oral iron supplement programs sometimes cause poor gastrointestinal effects and also have the difficulty that patients do not follow the program rigorously. Parenteral administration of iron overcomes some of the difficulties associated with oral administration of iron and is the standard procedure in the case of patients undergoing peritoneal dialysis. For hemodialysis patients, it is injected into the venous blood flow of the dialysis machine during treatment, which adds inconvenience and cost. One aspect of the present invention solves these problems by providing a dialysis composition comprising iron. As used herein, the term "iron" refers to the iron and ferrous forms of iron, as well as complexes of iron.

Iron may be introduced into the composition in a convenient form that is also compatible with the patient' S well being (see, e.g., "NKF-DOQ 1 clinical practice guidelines for the treatment of emission of bacterial crude failure" Am J. kit Dis.30.S192-S237, 1997). For example, Iron dextran (Iron hydroxide dextran complex, CAS registry No. 9004-66-4) is currently administered to hemodialysis patients by parenteral administration (see, e.g., "Iron dextran treatment in personal dialysis patents on erythropoetin" Perit. Dial. Bull.8: 464-466, 1992; and Goldberg, L., "Pharmacology of personal ir preparations" Iron in Clinical Medicine 78: 74-92, 1958). Instead of or in addition to dextran, iron may be complexed with other sugars or polysaccharides, such as iron glucarate or gluconic acid complex. Any of these iron sugar complexes may be included in the dialysate composition of the invention. As another example, iron may be introduced via ferric pyrophosphate (see, e.g., Gupta, A., et al, "analysis iron therapy: Infusion of soluble polymeric phosphate via the catalyst reduction catalysis" reagent International 55: 1891-1898.1999). To produce ferric pyrophosphate in a water-soluble form, ferric pyrophosphate can be prepared by chemical reaction with citric acid and sodium hydroxide. As a final example, the dialysate composition can be introduced via either or both ferric citrate (CAS registry No. 3522-50-7) or ferrous citrate. In one aspect of the invention, iron is introduced into the dialysate via the iron salt of citric acid.

Regardless of the form of iron added to the dialysate, the amount of iron added should be a therapeutically effective amount. This amount will vary to some extent depending on the particular circumstances of the patient and the goals of the attending physician. Generally, however, iron concentrations in the dialysate that vary between 0.1 and 300 mg/dl will be suitable concentrations. Because this amount will typically vary from patient to patient, a commercial citrate-containing product can be prepared that does not contain any iron, and this product can be "blended" with the desired amount of iron in the hospital or elsewhere where the patient is undergoing dialysis treatment.

In the dialysate composition of the invention, including precursors thereof, for hemodialysis or peritoneal dialysis, in one embodiment of the invention the composition includes one or more trace elements. Studies have shown that dialysis, particularly maintenance dialysis, results in the loss of trace elements in patients undergoing dialysis. The present invention provides compositions and methods for compensating for such loss of trace elements by incorporating trace elements into the compositions of the present invention.

Any one or more Trace elements may be included in the compositions of the present invention (see, e.g., Zima, T., et al, Blood plasma 17 (4): 187-. For example, selenium may be included in the compositions of the present invention (see, e.g., Krzek, M. et al, "infilling of hematology on selenium blocks" Sb Lek 101 (3): 241-248, 2000; and Napolino G., "Thyroid function and plasma in bacterial activities on hematology procedure" biol. Trace Elem. Res.55 (3): 221-30, Dec. 1996). Another trace element that may be included in the compositions of the present invention is zinc. Chromium, manganese, and molybdenum are three additional trace elements that may be included in the dialysate composition of the invention.

Trace elements may be added to the composition via any salt or complex of the elements. For example, trace elements may be added to the compositions of the present invention via their citrate salts in one aspect of the invention, regardless of their identity. However, other suitable forms may be used, for example zinc sulphate for zinc and selenium sulphide for selenium. The amount of trace metals to be included in the compositions of the present invention will be selected according to the particular circumstances of the patient and the goals of the attending physician. However, in general, Recommended daily (or Dietary) supplementation (RDA) of trace elements is a good guideline to comply, as proposed by The Food and Nutrition Board of The National Academy of Sciences/National Research Council (see, e.g., Recommended diet Allowances: National Academy of Sciences; 10 th edition, 1989; see also Diet Reference Intakes (DRIs): National Academy of Sciences, 1997). Because this amount can vary from patient to patient, a commercial citrate-containing product can be prepared that does not contain any trace elements, and can be "blended" with desired amounts of desired trace elements in a hospital or elsewhere in a patient undergoing dialysis treatment.

In another aspect, the inventionA method of forming a dialysate composition is provided. In a preferred embodiment, the method comprises mixing a dialysate precursor composition as described above with a base concentrate, preferably a bicarbonate base concentrate, and, if desired, treated water to provide a solute at the concentration described in the dialysate. The base concentrate contains water, bicarbonate and has a pH greater than 7. The pH is greater than 7 due to the presence of one or more "bases" in the concentrate. Base concentrates are currently used in most dialysis clinics. The base in a typical base concentrate is bicarbonate, also known as bicarbonate, of the formula HCO₃. Bicarbonate carries a net negative charge, so it will bind to a positively charged species. Suitable positively charged species include physiologically acceptable metal cations such as sodium, potassium, calcium and magnesium in cationic form.

The base used in preparing the base concentrate in almost all dialysis clinics is sodium bicarbonate and it is the preferred base in the compositions and methods of the present invention. The bicarbonate concentrate in the dialysate is preferably about 25 to 40 mEq/L. Acetate base is not a preferred base.

Optionally, the sodium bicarbonate in the base concentrate may be partially replaced with a different physiologically acceptable base. Suitable anionic moieties in place of sodium bicarbonate can be, for example, carbonate, lactate, citrate, and acetate. Thus, the base used in the base concentrate may be selected from the salt forms of bicarbonate and optionally any of carbonate, lactate, citrate and acetate. Also present in salt form will be one or more physiologically acceptable cations selected from sodium, potassium, calcium and magnesium. These salts and acids are electrically neutral, i.e., the number of positive and negative charges are equal.

Preferably, the dialysate precursor composition and the base concentrate are mixed so as to obtain a dialysate composition comprising: water, chloride at a concentration ranging from about 40 to about 150 (more preferably from about 60 to about 120) mEq/L; citrate at a concentration ranging from about 1.5 to 15.0, preferably from about 1.5 to about 4.5 (more preferably from about 2 to about 3) mEq/L; acetate and/or lactate at a total concentration in the range of about 0.01 to about 4.0 (more preferably about 0.2 to 0.5) mEq/L; bicarbonate at a concentration ranging from about 25 to about 45 mEq/L; at least one physiologically acceptable cation selected from the group consisting of hydrogen, sodium at a concentration ranging from about 60 to about 190 (more preferably from about 70 to about 150) mEq/L, potassium at a concentration of less than about 5mEq/L, calcium at a concentration of less than about 5mEq/L, and magnesium at a concentration of less than about 2 mEq/L; and glucose (preferably dextrose) at a concentration of less than about 45 (preferably less than about 8) g/L, wherein the mixed composition meets or exceeds the AAMI-quality criteria set for dialysate. Higher concentrations of citrate may typically be used when the patient is simultaneously infused with excess calcium.

In the dialysate composition of the invention, the citrate-containing dialysate precursor composition is mixed with an alkali concentrate to achieve a physiological range of pH of the final dialysate composition of 5 to 8.5, preferably about 7.2 to about 7.4.

In another aspect, the present invention provides an aqueous acid concentrate composition suitable for hemodialysis that contains water, chloride, citrate, and cations in minimal amounts to provide a neutral (i.e., no net charge) composition, but does not contain any of bicarbonate, acetate, or lactate. Water is "treated water" or even higher purity water as defined herein, and the chloride and citrate are each USP-grade quality or better (e.g., reagent grade, preferably at least 99% purity). In a related aspect, an aqueous acid concentrate composition is prepared from water and a solid composition that, when mixed with water, results in an aqueous acid concentrate composition having the above-described components. Accordingly, in one aspect the present invention also provides such solid compositions.

The aqueous acid-concentrate composition contains chloride in a concentration of from about 1000 to about 7000, preferably from about 2000 to about 5000 mEq/L; citrate at a concentration ranging from about 20 to about 200, preferably from about 70 to about 150 mEq/L; and sufficient physiologically acceptable cations to provide a neutral (i.e., no net charge) composition, wherein the composition has a pH of less than 4, preferably between about 2 and about 3, more preferably between about 2.2 and 2.8, and is free of any of bicarbonate, acetate, or lactate. The present invention also provides the same composition in anhydrous form which, when mixed with water, will form the above-described aqueous acid concentrate composition. The anhydrous form may be in the form of, for example, pellets, tablets, or powders.

Although the aqueous acid concentrate composition does not contain any of bicarbonate, acetate or lactate, it is still suitably used in dialysate production. For example, it provides a convenient stock solution to which a base and/or salt may be added. Since it is a liquid, it is conveniently used as an acid concentrate in a conventional dialyzer that uses a three-stream proportional pumping mechanism to prepare dialysate. However, care should be taken when mixing the base (e.g., bicarbonate) with the aqueous acid-concentrate composition in order to obtain the desired pH of the final dialysate.

In a related embodiment, the present invention provides a method of preparing a dialysate wherein a basic solution containing water and at least one of bicarbonate, carbonate, acetate, lactate, and citrate, at a pH greater than 7, is mixed with the above-described aqueous acid concentrate composition (i.e., an acidic solution having a pH less than 4 containing chloride, citrate, and cations in minimal amounts that provide an electrically neutral composition, wherein the acidic solution is free of any of bicarbonate, acetate, or lactate). According to this method, the relative amounts of the basic and acidic solutions that are combined should be carefully tailored to achieve the desired dialysate pH over the entire time during the dialysis treatment. Typically, the desired dialysate pH is 6.8 to 7.8.

Although hemodialysis compositions containing citric acid are known in the art (see Ahmad et al, U.S. Pat. No. 5,252,213), such compositions are disclosed in the form of dried pellets (or other similar solid forms) that are dissolved in water to provide a hemodialysis composition. These compositions provide a convenient source of all the components of the hemodialysis compositions, need to be combined with water prior to use in hemodialysis treatment, and are substantially free of other ingredients. Thus, each pill contains both the acidic component and the basic component of the hemodialysis solution composition, which ensures the pH of the resulting hemodialysis solution.

The present invention produces an aqueous acid concentrate that can be used to prepare a hemodialysis or peritoneal dialysis solution. As currently practiced in dialysis clinics, citric acid concentrate is mixed with treated water and base concentrate to provide a dialysate composition. In the clinic, the pH of the base concentrate, which typically contains sodium bicarbonate, can vary widely and affect the resulting dialysate pH. Thus, when using an acid concentrate comprising citric acid in the manner of the present invention, the concentrate should contain a buffer in order to maintain the pH of the resulting dialysate within a predetermined physiologically acceptable range throughout the duration of the dialysis treatment. Buffering is required because increasing the amount of citric acid by lowering the dialysate pH can result in a significant decrease in serum calcium concentration. This need for a buffer using citric acid concentrate is contrary to the practice in the art.

Most dialysate in use today uses acetic acid as an acidifying agent to maintain the pH of the final dialysate within an acceptable physiological range. As mentioned above, the "acid concentrate" used in most hemodialysis treatments today is transported in liquid form. Since acetic acid is a liquid acid, the concentrate is in liquid form. Although this solution is much more concentrated (perhaps 45 times more concentrated) than the final dialysate actually used to purify the patient's blood, three-quarters of its weight and volume is still water. The present invention utilizes citric acid, rather than acetic acid, as the primary acidic material in the acid concentrate.

In an acid concentrate containing citrate, the citrate will be predominantly in the form of citric acid. There are certain ramifications of using citric acid for acid concentrates for dialysate. For example, citric acid forms citrate in blood, which binds to free magnesium and calcium. In fact, blood banks utilize the strong binding of calcium to citrate to prevent coagulation of donated blood. Although the level of citric acid used in the dialysate of the invention is only a fraction (less than a quarter) of the amount required to achieve measurable anticoagulation, medical caution has prompted the use of the least amount of citric acid in the dialysate possible to minimize undesirable calcium binding in the blood. When the dialysate is prepared 45-fold diluted from the precursor dialysate, and the citrate concentration in the precursor dialysate is 200 to 900mEq/L, the precursor preferably has elevated levels of calcium and/or magnesium to compensate for the extent to which citrate will bind serum calcium and magnesium.

The amount of citrate in the acid concentrate of the invention should be the minimum amount necessary to achieve a final dialysate pH of 7.2 to 7.4. We have found that using about 7 grams of citric acid per liter of water in the acid concentrate (to a concentration equal to 2.4mEq/L) will minimize calcium binding and achieve an acceptable dialysate pH.

However, the use of citrate in the acid concentrate causes intermittent problems when such dialysate is used in a clinical setting. Typically, some dialysis machines will alarm because of high pH later in the dialysis session (often during the last 1 hour of treatment). This problem is traced to the alkaline solution.

Bicarbonate is the basic material in most alkaline solutions. In most dialysis clinics, the bicarbonate solution is prepared by the clinic staff just prior to use. The method may often include pouring a predetermined amount of sodium bicarbonate (typically 1 pack) into a pot, adding a measured amount of water and mixing manually (often by shaking the container). Any, some or all of the following factors may cause the pH of the bicarbonate to deviate from the desired standard: the amount of water added may be more or less than the prescribed amount, mixing may be insufficient to completely dissolve all of the sodium bicarbonate powder into solution, the container may be left for a period of time before use, or the patient may undergo a prolonged dialysis treatment.

When the bicarbonate is carefully measured and mixed well, the pH of the concentrated solution is 7.85(± 0.05). However, in practice, samples of bicarbonate concentrate prepared by office workers have a pH ranging from 7.78 to 8.13. Furthermore, the residual bicarbonate concentrate just used for hemodialysis treatment was found to have a pH of 7.9 to 8.24. We speculate that this change in pH, which is most clearly observed in "spent" dialysate, may be due to any one or a combination of the following factors:

● the water added to the base concentrate is insufficient to make it more concentrated than the bicarbonate concentration required.

● the powder is not mixed well with the water, causing some powder to precipitate, so the bicarbonate solution is more concentrated and the pH rises later in the dialysis treatment (when the powder is completely dissolved).

● bicarbonate concentrate releases carbon dioxide over time, thereby resulting in a slow increase in pH.

One way to ensure that the pH does not rise above the alarm threshold during dialysis treatment is to increase the amount of acid used, which results in a more acidic dialysate. However, increasing the amount of citric acid will also increase the amount of calcium bound thereby, which must be used with care. Another approach taken by the present invention is to mitigate the effects of increased dialysate pH caused by an increase in the pH of the bicarbonate concentrate by including a buffer in the acid concentrate.

Acetate and/or lactate are selected as preferred buffering agents for the present invention. Each of these anions is naturally present in the blood of dialysis patients. Sodium acetate is a preferred buffer since it contains the same components, i.e., sodium and acetate, which are present in virtually all dialysis solutions today (supplied by sodium chloride and acetic acid).

Surprisingly, there was no linear relationship between the amount of sodium acetate buffer present in the acid concentrate and the pH of the final dialysate solution. It might be expected that adding an increased amount of this acidic buffer to the acid concentrate would result in a linear decrease in the pH of the final solution. However, this is not the case. Within a narrow range, sodium acetate causes a significant decrease in the pH of the dialysate. However, this buffering effect of sodium acetate is only observed when the pH of the bicarbonate concentrate exceeds 8.0. The higher the pH of the bicarbonate concentrate, the more pronounced the buffering effect of acetate.

This effect is shown in the figure. The graph in the figure illustrates the dialysate pH obtained using a relatively high bicarbonate concentration of pH 8.14 mixed with treated water and using a dialysate precursor of the invention with 2.4mEq/L citrate and increasing the sodium acetate concentration from 0 to 3.5 g/L. As shown in the figure, increasing the concentration of sodium acetate above a certain point, the buffering effect of sodium acetate is no longer increased, nor is the buffering effect evident at lower bicarbonate pH values. While not wishing to be bound by theory, it is suggested that the following explains the surprising effect of using acetate in the acid concentrate of the present invention.

Citric acid is a polyprotic acid. It contains three labile hydrogen atoms that can cause the solution to be acidic. There is a separation equilibrium associated with each hydrogen ion release:

wherein A represents a citrate anion. When the pH is greater than 7, almost all of the citric acid is dissociated, with H as the main species⁺And A^3-。

Acetic acid is a monoprotic acid, i.e., it contributes only one labile hydrogen atom to the solution and has only one equilibrium constant for the following equilibrium:

wherein Ac represents an acetate anion. When sodium acetate (NaAc) is added to the aqueous solution, it is completely dissolved as sodium ions (Na)⁺) And acetate ion (Ac)^-). The sodium is considered a "bystander" ion-it does not participate in any equilibrium. Acetate (Ac)^-) The anion is hydrolyzed:

a buffer is a solution whose composition is designed to resist pH changes. A small amount of acid or base may be added to the buffer and the pH change is very small. These statements mean that the buffer solution can be reacted with H⁺(also commonly written as H)₃O⁺) Can react with OH^-And (4) ion reaction. Two common types of buffer solutions are those containing (1) a weak acid + a salt of such a weak acid and (2) a weak base + a salt of such a weak base. A rare class contains a weak acid (e.g., citric acid) and a salt of another weak acid (e.g., sodium acetate from acetic acid).

In the case of simple aqueous solutions, the buffering action can generally be calculated on the basis of available data, in particular: acid concentration, salt concentration, temperature and appropriate equilibrium constant K_i. The situation of acid concentrates and the dialysis fluid of the invention is more complicated. Other equilibria are introduced by adding calcium (Ca) and magnesium (Mg) to the dialysate. These metal ions have their own equilibrium with carbonate, acetate and citrate ions. For some of these balances, the balance constant K_iAre not available and therefore their effect on dialysate formulation pH cannot be absolutely predicted. In this dialysate preparation, direct measurement of solution pH by titrimetric analysis can be used. The main equilibria in the solution are as follows (non exhaustive):

wherein A represents a citrate anion.

Wherein Ac represents an acetate anion.

Due to A^3-The pH of the species is predominantly above 7.0 and is therefore not considered with the lower citrate ion (HA)^2-And H₂A^-) The calcium and magnesium are in equilibrium.

If all constants and concentrations at 37 ℃ are known, the above equation can be set as a model and the pH and buffering effects can be obtained by calculation. This situation is further limited by the requirement to maintain the pH in the physiological range (especially towards the end of dialysis, where the pH of the bicarbonate concentrate tends to rise). Typically, this can be achieved by adding more (citric) acid, however, this is excluded because the concentration of citrate ions (from citric acid) needs to be kept as low as possible. This is again desirable due to the tendency of calcium and magnesium to bind to citrate ions, thereby reducing the serum levels of calcium and magnesium to clinically unacceptable levels, as discussed below. The applicant has found a solution to this problem by selecting a buffer.

Sodium citrate is not used in the buffer due to the aforementioned need to keep the total concentration of citrate ions at an acceptably low level. Acetate or lactate may be used because of (1) its appropriate buffering action, (2) cost, (3) acetate ions (from acetic acid) have been (preferably) used in the dialysate formulation and thus do not introduce new changes to the chemistry of the dialysate.

The buffering action manifests itself by lowering the pH of the dialysate to a physiological, non-alarm level when the pH of the bicarbonate is high-caused by incorrect mixing or elapsed time after mixing. When the bicarbonate pH is appropriate, a buffer is present, but is apparent to the operation of the dialysate. When using bicarbonate concentrate solutions with a pH < 8.0, the buffering effect is not significant. The buffering effect is evident when using bicarbonate concentrate solutions with a pH of 8.1 < pH < 8.3 (see FIG.). The buffering effect is particularly pronounced for sodium acetate concentrations in the range of 0.5 to 3.0 grams per liter of acid concentrate, which is the preferred range for the acid concentrate of the present invention.

In another aspect, the present invention provides citrate-containing compositions that are particularly useful in Peritoneal Dialysis (PD). These compositions may be in solid form or may be in liquid form, i.e., either a mixture of dry components that are precursors to the peritoneal dialysis solution or a solution of different solutes that are themselves the peritoneal dialysis solution. The dry ingredient mixture contains, in minimum amounts, chloride, citrate, bicarbonate, and dextrose, as well as one or more cationic species that provide a neutral (i.e., no net charge) composition. Solutions of the PD compositions contain water in a minimum amount in addition to the minimum amounts of ingredients described above required for the dry composition. Citrate (acid) -containing compositions suitable for peritoneal dialysis are sterile, whether in solid or liquid form.

The peritoneal dialysis solution (i.e., PD solution dialysate) of the present invention contains water and the following components in the amounts (the amounts are in mEq/L PD solution): citrate (0.5 to 6, preferably 1.5 to 4.5, more preferably 2 to 3), chloride (20 to 200, preferably 40 to 150, more preferably 60 to 120) and bicarbonate (5 to 100, preferably 10 to 70, more preferably 30 to 40). Further, the PD composition in the form of a solution contains glucose at a concentration of 10 to 100, preferably 20 to 80, more preferably 40 to 60 in g/L solution. In addition, the PD composition in solution form contains a sufficient amount of physiologically acceptable cations to neutralize all of the citrate, chloride, bicarbonate, and any other anionic species that may be present in the composition. The PD solution dialysate is sterile as required by all dialysate approved by the U.S. food and drug administration for peritoneal dialysis.

In a preferred embodiment, the PD composition in solution form contains acetate and/or lactate, wherein the total amount of these two anions is 0.01 to 10, preferably 0.1 to 1, more preferably 0.25 to 0.75, calculated as mEq/L PD solution. The cationic species present in the PD fluid are substantially within the same concentration ranges as previously listed herein for the cationic species (i.e., sodium, magnesium, calcium, and potassium) in the hemodialysis composition.

The present invention provides a dry composition which, when mixed with sterile water, will yield the PD solution dialysate described above. The dry composition itself is sterile. According to one approach, such dry compositions may be described in terms of grams of a particular ingredient per (one) gram of citrate. Using these terms, the dry composition contains chloride in an amount of 5 to 50, preferably 10 to 40, more preferably 20 to 30; bicarbonate in an amount of 1 to 50, preferably 5 to 30, more preferably 10 to 20; and glucose in an amount of 100 to 600, preferably 150 to 500, more preferably 200 to 350, where each of these values is grams per gram of citrate. In calculating these amounts, the molecular weights of citrate, chloride and bicarbonate are 189.1g/mol, 35.5g/mol and 61.0g/mol, respectively, where chloride and bicarbonate each have one charge and citrate has three charges. The dry PD composition contains sufficient cationic species to provide a neutral (no net charge) composition. Furthermore, the pH of the resulting solution will be in a physiologically tolerable range, preferably in the range of 6.4 to 7.6.

According to another approach, the contents of a dry PD composition can be described in terms of milliequivalents of a particular charged species present in the composition per (one) milliequivalent of citrate present in the composition. In these terms, the dry composition contains chloride in an amount of from 1 to 200, preferably from 10 to 100, more preferably from 30 to 50 mEq; and bicarbonate in an amount of 1 to 50, preferably 5 to 30, more preferably 10 to 20 mEq. Further, the dry PD composition contains glucose in an amount of 100 to 600, preferably 150 to 400, more preferably 200 to 300, where each of these values is grams per gram of citrate.

To be suitable for peritoneal dialysis, both the peritoneal dialysis solution and its dry precursors must be sterile. Therefore, each of the preparations thereof must be carried out under aseptic conditions, and/or the resulting composition must be sterilized by an appropriate sterilization treatment. According to one embodiment, the dry PD composition is prepared by the following steps: sodium chloride (5.67g), calcium chloride dihydrate (0.26g), magnesium chloride hexahydrate (0.10g), sodium bicarbonate (2.94g), anhydrous citric acid (0.15g), sodium acetate trihydrate (0.041g) and dextrose (42.5g) were mixed (with each chemical listed in sterile form) and the mixing step was carried out under sterile conditions. The dry composition contained 0.15g citrate, 3.6g chloride, 2.1g bicarbonate and 42.5g glucose, 24g chloride, 14g bicarbonate and 283g dextrose per gram citrate, 42mEq chloride and 14.5mEq bicarbonate per milliequivalent of citrate.

Since each anionic species can be introduced into the composition in any anhydrous form that is physiologically acceptable and contains the anionic species of interest, the dry PD composition and the peritoneal dialysis solution prepared therefrom are described as anionic species. Thus, for example, "citrate" may be incorporated into the dry composition in any anhydrous form that contains citrate. Examples are citric acid (anhydrous), citric acid monohydrate, trisodium citrate, disodium citrate sesquihydrate, monosodium citrate, tripotassium citrate monohydrate, and the like. Likewise, both bicarbonate and chloride may be introduced simultaneously with cations selected from sodium, potassium, magnesium and calcium, and may be in anhydrous or hydrated form. Thus, the dry composition is described by the terms "chloride", "citrate", and "bicarbonate", without indicating any particular salt or protonated form thereof.

The chloride is present in the dry composition in the form of a salt. Suitable chloride salts include, but are not limited to, sodium chloride, potassium chloride, calcium chloride, and magnesium chloride. The preferred chloride salt is sodium chloride.

The citrate is present in the dry composition in the form of an acid and/or a salt. Citric acid is a suitable acid form of citrate. Trisodium citrate, tripotassium citrate and calcium citrate (i.e., tricalcium dicitrate) are all suitable salt forms of citrate. The citrate may be in the form of a mixed acid/salt, i.e., complexed with both one or more protons and one or more metal cations. Typical examples of citrate in the mixed acid/salt form include, but are not limited to, potassium dihydrogen citrate, dipotassium hydrogen citrate, and disodium hydrogen citrate. Preferably, the citrate is citric acid.

The bicarbonate is present in the dry composition in the form of a salt. Suitable bicarbonate salts include, but are not limited to, sodium bicarbonate and potassium bicarbonate. The preferred bicarbonate is sodium bicarbonate.

Glucose, a component of most currently used peritoneal dialysis solutions, is added to the peritoneal dialysis solutions (and precursors thereof) of the present invention in order to provide the benefits known to be provided by glucose to peritoneal dialysis solutions. For example, as noted above, glucose is primarily used as an osmotic agent, and it is also believed to mitigate some of the undesirable side effects of peritoneal dialysis. Glucose may also provide some nutritional supplementation to subjects undergoing dialysis treatment. The most typical glucose isomer currently used in peritoneal dialysis solutions is dextrose, i.e., alpha-D-glucose. It is a well-known commercial substance and is available in both hydrated and anhydrous forms. Both forms can be used in the PD compositions of the invention.

Although the dry composition is dry to the touch, it may contain some water. For example, several salts and acids of suitable ingredients of the above-mentioned dry PD compositions are generally available in hydrated form. Such hydrated forms are suitable for use in preparing the dry PD compositions provided herein. The various ingredients of the above-described dry PD compositions are available from a number of commercial suppliers. See, e.g., Sigma-Aldrich (http:// www.sail.com). Preferably, these ingredients have a United States Pharmacopeia (USP) -grade purity or greater, which is generally considered to be at least about 95% pure.

Optional ingredients may be present in the dried PD composition. Suitable optional ingredients include, but are not limited to, amino acids.

Dry PD compositions are readily prepared simply by mixing together weighed amounts of the various dry sterile ingredients under sterile conditions. Mixing can be easily accomplished by stirring a mixture of ingredients until a homogeneous mixture is obtained. For ease of transportation, and to make it easier for the skilled person to prepare a solution form of the dry composition, the pre-weighed amount of dry mixture can be packaged in a tightly sealed package.

The dry powder dialysate technology of the present invention allows for the preparation of peritoneal dialysate. This aspect of the invention results in a unique peritoneal dialysis solution that, in a preferred embodiment, uses citric acid as an acidulant, dextrose at a concentration of greater than 2.0%, and bicarbonate as a basic anion. Other ingredients will include water as well as chloride, sodium, potassium, magnesium and calcium, all of which can be included in the concentration ranges specified for the hemodialysis dialysate. Since the volume of dialysate used for each treatment is only a small fraction of the amount used for hemodialysis, the peritoneal dialysis solution does not require a precursor (other than a dry powder). Preparing the peritoneal dialysis solution just prior to use (i.e., adding sterile water to the sterile dry PD powder) would allow the use of bicarbonate as the basic anion. Typically, bicarbonate cannot be used in PD because a solution of bicarbonate and citric acid does not have sufficient long-term stability to allow storage. To overcome this stability problem, currently used PD compositions typically contain lactate (instead of bicarbonate) as the basic anion. However, bicarbonate is preferred as the basic anion by some health care professionals, and this invention meets this need.

The precise order in which the sterile water and dry ingredients are mixed is not critical. Alternatively, sterile water may be added to the above-described dry PD composition. Alternatively, a desired volume of sterile water may be provided, and various other (sterile) ingredients of the solution PD composition may be added thereto. Typically, the final solution should be stirred or otherwise agitated, such as by shaking, to form a homogeneous composition. "Handbook of Dialysis" 2 nd edition, Dangiridas, J.T. and Ing T.S. editions (Little, Brown, Boston, 1994) provide an in-depth discussion of peritoneal Dialysis (as well as hemodialysis).

Physiological effects

Citric acid is considered a potential acidifying agent for dialysate because it is an inexpensive physiological acid. Furthermore, it has a long history of use in blood banks and has also been successfully used for regional anticoagulation in hemodialysis. These prior uses are all based on the calcium binding effect of citric acid. It has been empirically observed that if the concentration of free calcium in blood is above a certain critical concentration, the blood will coagulate. When citric acid is added to blood, citrate binds to free calcium and reduces its concentration. When the free calcium concentration is reduced to a certain point, the blood is no longer coagulated.

In the present invention, citric acid is used as an acidifying agent in the dialysate to lower the pH of the dialysate. However, the use of citric acid above about 2.4mEq/L in the dialysate may result in a decrease in the calcium concentration in the serum, which may be clinically undesirable. When the citric acid content in the dialysis fluid is 2.4mEq/L, the increase in citrate concentration in the blood is generally small enough not to have any significant detrimental effect on the clotting behavior of the blood. In fact, no increase is usually detected beyond the clotting time of patients already reached with their normal anticoagulant drug heparin.

Generally, patients with renal failure suffer from chronic acidosis. Their kidneys fail to clear H produced by the body during normal metabolic processes⁺Ions. As a result, their bodies buffer excess H with excess bicarbonate⁺Ions. Since bicarbonate neutralizing acids are used at all times, these patients have lower than normal levels of bicarbonate (carbon dioxide) when they are undergoing dialysis treatment. Traditionally, dialysis treatment is performed by using a dialysate containing bicarbonate at a higher concentration than in normal serum in an attempt to correct the acidosis problem. Thus, during the course of treatment, the treatment is carried out bySome of this excess bicarbonate diffuses into the blood helping to restore the body's total bicarbonate, and thus the blood bicarbonate increases. However, conventional dialysis using dialysate bicarbonate concentrations of about 37mEq/L is generally insufficient to maintain normal blood bicarbonate between dialysis sessions. Thus, at the next dialysis of the patient, the bicarbonate in the blood is again abnormal. The buffered citrate dialysate of the present invention has shown some efficacy in replenishing body bicarbonate levels, thereby facilitating the treatment of chronic acidosis.

The following examples are provided for purposes of illustration and not limitation.

Examples

Example 1

Acid concentrate formulations

The following amounts of indicated USP grade chemicals were carefully weighed: 262.0g sodium chloride (FW58.45), 9.70g calcium chloride (dihydrate, FW 147.02), 3.40g magnesium chloride (hexahydrate, FW 203.3), 90.0g dextrose (FW 180.16), 7.0g citric acid (anhydrous, FW192.12) and 1.75g sodium acetate (trihydrate, FW 136.08). These chemicals were placed in a large calibration beaker and AAMI quality water was added to the 900ml mark. The beaker was placed on a stir plate and the chemicals and water were stirred using a stir bar. After about 10 minutes of stirring, these chemicals were completely dissolved and the solution was "clear. The stir bar was removed and the dissolution "ended" with an additional AAMI quality of water added to the beaker with a 1 liter mark. The stir bar was reintroduced and the solution was stirred for an additional 3 minutes.

Example 2

Hemodialysis

The solution beaker prepared as in example 1 was placed in a Fresenius haemodialysis machine ready for the measurement (bypass) mode. In this configuration, the machine prepares the dialysate in the same manner as when the patient is undergoing dialysis treatment. The treated water supply line is connected to the machine and carefully prepares a container of bicarbonate concentrate. All solutions were then connected to the machine and the machine was started.

The machine was run for 10 minutes at a dialysate flow rate of 800 ml/min to ensure that the solution produced completely filled the appropriate path through the machine. In addition, the conductivity meter of the machine to which the dialysate flow line had been connected, as well as other conductivity monitors, were monitored and readings were found to be within an acceptable range (1310 to 1330 millisiemens). The pH of the machine-mixed dialysate was determined by sampling the drain effluent at several intervals, on average 10 minutes apart. The pH was 7.4, which was between the target range 7.3 to 7.5. Effluent samples were analyzed at the university of washington medical center laboratory to confirm that the final dialysate concentration was within an acceptable range for hemodialysis.

Finally, after appropriate approval, the dialysate precursors produced by the hemodialysis machine and the resulting dialysate are repeatedly tested during clinical trials of new dialysate in real patient treatment. During the whole test, even the dialysis phase continued up to 5 hours, no pH alarm occurred.

Example 3

Dialysate composition

1 liter of dialysate composition, in addition to sodium bicarbonate, contains in mEq/L: sodium, 100.3; chloride, 104.25; 2.5 parts of calcium; potassium, 1.0; 0.75 parts of magnesium; acetate, 0.3; citric acid, 2.4; and dextrose in g/L, 2.0. The total chemical composition (without sodium bicarbonate) in the dialysate composition was (in grams): NaCl (5.822); CaCl₂ 2H₂O(0.139)；KCl(0.074)；MgCl₂ 6H₂O(0.036)；NaC₂H₃O₂(0.039)；C₆H₈O₇(0.155) and C₆H₁₂O₆H₂O(2)。

From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims (10)

1. A dialysate precursor composition comprising citrate at a concentration of about 20 to about 900mEq/L, preferably about 70 to about 150 mEq/L; a buffering anion selected from acetate in the form of acetate and/or lactate in the form of lactate; water; chloride at a concentration of about 1000 to about 7000 mEq/L; at least one physiologically acceptable cation; and a therapeutically effective amount of iron.

2. An aqueous acid concentrate composition comprising water, chloride at a concentration of about 1000 to about 7000mEq/L, citrate at a concentration of about 20 to about 900mEq/L, preferably about 70 to about 150mEq/L, a therapeutically effective amount of iron, and sufficient physiologically acceptable cations to provide a neutral composition, wherein the composition has a pH of less than 4 and is free of any of acetate, bicarbonate, or lactate.

3. The composition of claim 1 or 2, wherein the concentration of the buffering anion is from about 0.01 to about 150mEq/L, preferably from about 0.3 to about 125 mEq/L.

4. The composition according to any one of claims 1 to 3, wherein the iron is present in the form of ferric iron, or ferrous iron, or an iron complex, preferably selected from iron dextran, iron saccharide, ferrous gluconate, ferric pyrophosphate or ferric citrate, or an iron salt, preferably an iron citrate salt.

5. The composition of any one of claims 1-4, further comprising one or more trace elements.

6. The composition of any one of claims 1-5, wherein the physiologically acceptable cation is selected from the group consisting of hydrogen, sodium, potassium, calcium, magnesium, and combinations thereof.

7. A method of forming the dialysate precursor composition of any one of claims 1-6 comprising mixing treated water, iron, chloride, citrate, at least one buffering anion selected from acetate in the form of acetate or lactate in the form of lactate, and at least one physiologically-acceptable cation to provide a composition having a chloride concentration of about 1000 to about 7000mEq/L, citrate concentration of about 20 to about 900mEq/L, preferably about 70 to about 150mEq/L, buffering anion concentration of about 0.01 to about 150mEq/L, and a therapeutically effective amount of iron.

8. The method of claim 7, wherein the citrate is in the form of at least one of citric acid and salts thereof selected from the group consisting of sodium dihydrogen citrate, disodium hydrogen citrate, trisodium citrate dihydrate, potassium dihydrogen citrate, dipotassium hydrogen citrate, calcium citrate, and magnesium citrate.

9. The method of claim 7 or 8, wherein the acetate salt is selected from the group consisting of sodium acetate, sodium acetate trihydrate, potassium acetate, calcium acetate monohydrate, magnesium acetate, and magnesium acetate tetrahydrate.

10. The method of any one of claims 7-9, wherein the lactate salt is selected from the group consisting of sodium lactate, potassium lactate, calcium lactate, and magnesium lactate trihydrate.