Method of treating chronic kidney disease

Abstract

To provide methods for treating a subject with chronic kidney disease.SOLUTION: The present invention discloses pharmaceutical-grade ferric organic compounds having enhanced dissolution rates. These ferric organic compounds, including but are not limited to ferric citrate, are useful for treating chronic kidney disease.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] This application claims priority to PCT / US2006 / 032585, filed Aug. 18, 2006, and U.S. Provisional Application No. 60 / 763,253, filed Jan. 30, 2006. The contents and entire disclosures of the prior applications are incorporated herein by reference.

[0002] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

[0003] Field of the Invention The present invention relates to the use of pharmaceutical grade ferric organic compounds for the treatment of chronic kidney disease. [Background technology]

[0004] 2. Background of the Invention Chronic kidney disease is characterized by a gradual and progressive loss of the kidney's ability to excrete waste products, concentrate urine, and conserve electrolytes. Unlike acute renal failure, which involves a sudden but reversible loss of kidney function, renal function in chronic kidney disease progresses and deteriorates irreversibly toward end-stage renal disease (ESRD). Patients with ESRD cannot survive without dialysis or a kidney transplant.

[0005] The US National Kidney Foundation defines chronic kidney disease according to the presence or absence of kidney damage and the level of kidney function, regardless of the type of kidney disease (clinical diagnosis). The main measure of kidney function is the glomerular filtration rate (GFR), which is often assessed as creatinine clearance from serum and urinary creatinine concentration. Chronic kidney disease or chronic renal failure is defined as having a glomerular filtration rate of less than 60 ml / min for a period of 3 months or more. The US National Kidney Foundation proposes a 5-stage classification of kidney damage based on glomerular filtration rate: JPEG2025016448000002.jpg145166 According to the US National Kidney Foundation, over 20 million US citizens, approximately 11 percent of the population, suffer from chronic kidney disease, and another 20 million are at high risk. The high prevalence of chronic kidney disease places a significant burden on the health care system. One of the most obvious economic costs associated with chronic kidney disease is the development of end-stage renal disease, which is estimated to have cost approximately US$23 billion in 2001 and increase to US$35 billion per year in 2010 in the United States alone. For patients with early chronic kidney disease, reviews have generally reported increased costs of US$14,000 to US$22,000 per patient per year compared to the age-matched general population.

[0006] The pathogenesis of progressive renal injury is complex and multifactorial, and current understanding is based mainly on experimental animal models. Chronic kidney disease often progresses by a "common pathway" mechanism, independent of the initiating insult. Early studies of renal dysfunction focused on functional and structural glomerular changes. Recently, there has been a strong interest in tubulointerstitial changes as a major determinant of progressive kidney injury, one of the key factors being the formation of calcium phosphate precipitates in the lumen and interstitium. Chronic kidney disease progression results from chronic tubulointerstitial inflammation resulting from an increase in the single nephron filtration load of phosphate, an increase in absolute tubular reabsorption of phosphate, an increase in the calcium-phosphorus product in the lumen of the tubules, and the precipitation of calcium phosphate in the tubules and interstitium, promoted by a decrease in the concentration of citrate in the tubular fluid (precipitation-calcification hypothesis).

[0007] The precipitation-calcification hypothesis is supported in experimental animals showing that a high-phosphate diet exacerbates chronic kidney disease, whereas a low-phosphate diet, administration of phosphate binders, and 3-phosphocitrate (an inhibitor of calcium phosphate precipitation) slow the progression of chronic kidney disease. Based on these results, reducing serum phosphate and calcium-phosphorus product levels and increasing serum citrate and 3-phosphocitrate levels may reduce nephron damage and then slow the progression of chronic kidney disease. It was reported that slowing the rate of progression of chronic kidney disease by 30% (defined as a 30% reduction in the rate of decline of glomerular filtration rate) between 2000 and 2010 would result in estimated potential cumulative direct medical cost savings of US$60.61 billion.

[0008] Hyperparathyroidism is one of the early manifestations of renal dysfunction, and subtle bone changes were found in patients with a glomerular filtration rate of 60 ml / min (chronic kidney disease stage 2-3). With the deterioration of the renal condition and phosphorus accumulation, the parathyroid gland continuously increases the release of parathyroid hormone (PTH), leading to the development of hyperparathyroidism. High PTH increases calcium release from bone to serum. As a result, serum concentrations of calcium and phosphorus become abnormal, leading to bone disease and extraskeletal calcification. Precipitation of calcium phosphate in renal tissue begins early. This may affect the rate of progression of renal disease and be closely related to hyperphosphatemia and calcium-phosphorus (CaxP) product.

[0009] Acid-base balance is normally maintained by renal excretion of the daily acid load. When renal function declines, acid-base balance is maintained by various compensatory mechanisms, of which increased ammonia synthesis by the proximal tubules is the most important. Impaired ammonia capture in the medulla places additional demand on the proximal tubules to increase ammonia synthesis, resulting in elevated concentrations of ammonia in the renal cortex. High concentrations of free base ammonia in the renal cortex can result in complement activation and interstitial inflammation. It has been reported to be one of the major determinants of progressive renal damage. Renal acidosis results in bone mineral loss, hyperparathyroidism, increased protein catabolism, insulin resistance, and growth failure. Recent observations suggest that acidosis causes inflammation and accelerates the progression of chronic kidney disease.

[0010] Chronic metabolic acidosis can lead to impaired protein metabolism and therefore increased excretion of uric acid and the formation of kidney stones. If untreated, kidney stones can lead to urinary obstruction, urinary tract infections, and, as a result, chronic kidney disease can develop.

[0011] To date, there is no cure for chronic renal failure once the renal degenerative process begins. Early preventive measures have been proposed to identify and treat underlying conditions such as urinary track infection, obstruction, kidney stones, or to stop taking drugs with nephrotoxic effects (i.e., NSAIDs) before chronic kidney disease can develop. Also, early changes in dietary plans (i.e., low protein diets) have been proposed. Furthermore, hypertension and diabetes have been identified as the most common risk factors for the disease. The benefits of using antihypertensive therapy against the progression of chronic kidney disease have been widely investigated. The use of angiotension converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) has been shown to be beneficial among patients with or without diabetes and those with or without proteinuria.

[0012] In practice, however, many physicians do not use these drug classes in patients with renal failure because these two classes of drugs may potentially increase the levels of serum creatinine (one sign of kidney damage) or potassium (the most common life-threatening emergency in patients with end-stage renal disease). It has been suggested that these drugs should not be used in patients with advanced renal failure, bilateral renal artery stenosis, and renal artery stenosis of a single kidney. Thus, these drugs are not likely to be used in general in patients who already have kidney disease, and these drugs are not expected to slow the progression of chronic kidney disease.

[0013] In addition to treating or preventing the progression of chronic kidney disease, other medications, such as iron and erythropoietin supplementation, are required to suppress anemia in patients with chronic kidney disease. NaHCO3 is used to improve one of the uremic syndromes, such as metabolic acidosis, which results in osteopenia and urinary excretion of calcium.

[0014] Ferric compounds containing ferric iron are useful in the treatment of many disorders, including but not limited to hyperphosphatemia and metabolic acidosis. See Hsu et al., New Phosphate Binding Agents: Ferric Compounds, J Am Soc Nephrol. 10:1274-1280 (1999). Previous studies and inventions have reported the use of ferric iron compounds to bind dietary phosphate and that such ferric iron compounds are potentially useful in treating hyperphosphatemia in patients with renal failure (US Patent No. 5,753,706; US Patent No. 6,903,235; CN 1315174; Yang et al., Nephrol. Dial. Transplant 17:265-270 (2002)). Increased amounts of phosphate in the blood can be removed by administering compounds such as ferric iron citrate. Once in solution, ferric iron binds phosphate and the ferric phosphate compound precipitates in the digestive tract, effectively removing dietary phosphate from the body. Also, absorbed citric acid from ferric citrate is converted to bicarbonate, which may correct metabolic acidosis, a common condition in patients with renal failure.

[0015] US Patent No. 5,753,706 discloses the use of ferric-containing compounds, including crystalline forms of ferric citrate and ferric acetate, in an orally effective 1 gram dosage form to bind soluble dietary phosphate, thus causing precipitation of the phosphate as ferric or ferrous phosphate in the digestive tract and preventing oral absorption of soluble phosphate from dietary sources. Because dissolution of orally administered ferric citrate is required for ferric ions to bind soluble phosphate in the digestive tract, and because the dissolution rate of crystalline ferric citrate is slow (up to 10-12 hours at 37°C), a substantially large amount of ferric citrate is required to be orally administered, 1 g. A related Chinese patent application (CN 1315174) also discloses a similar use of ferric citrate and related compounds in an oral solution dosage form to treat hyperphosphatemia in patients with renal failure.

[0016] Fe(III) is a Lewis acid and is chemically less soluble in the stomach, at a pH below 5, than in the intestine, which typically exceeds 7. However, the stomach is thought to be an important site of action for the dissolution of Fe(III) compounds. The stomach is thought to be an important site of action for mediating the action of Fe(III) in binding dietary phosphate, preventing it from reaching the intestine, and therefore reducing its absorption from the intestine.

[0017] In International Application PCT / US2004 / 004646 filed on February 18, 2004 (published under International Publication WO2004 / 074444 on September 2, 2004), a method for preparing novel ferric organic compounds is disclosed, including ferric citrate that has a large effective surface area and remains soluble over a wider range of pH than previously reported preparations. This publication also teaches the use of these novel ferric organic compounds in the treatment of various disorders, such as hyperphosphatemia and metabolic acidosis. Because they are more soluble, these novel forms of ferric organic compounds can be used to more effectively deliver ferric organic compounds to patients by oral administration route. However, this publication did not provide any data showing whether these novel forms of ferric organic compounds are useful for providing treatment for patients with chronic kidney disease. [Prior art documents] [Patent documents]

[0018] [Patent Document 1] U.S. Patent No. 5,753,706 [Patent Document 2] U.S. Patent No. 6,903,235 [Patent Document 3] Chinese Patent No. 1315174 [Patent Document 4] International Publication No. 2004 / 074444 [Non-patent literature]

[0019] [Non-Patent Document 1] Hsu et al., New Phosphate Binding Agents: Ferric Compounds, J Am Soc Nephrol. 10:1274-1280 (1999) [Non-Patent Document 2] Yang et al., Nephrol. Dial. Transplant 17:265-270 (2002) DISCLOSURE OF THEINVENTION [Problem to be solved by the invention]

[0020] The present invention discloses that these novel forms of ferric organic compounds have several properties that are beneficial in the treatment or amelioration of chronic kidney disease. [Means for solving the problem]

[0021] Summary of the Invention In accordance with the above and other objects of the present invention, a brief summary of the present invention is presented. The following summary may include some simplifications and omissions, which are intended to highlight and introduce some aspects of the present invention, but are not intended to limit its scope. Detailed descriptions of preferred exemplary embodiments adequate to enable those skilled in the art to implement and use the concepts of the present invention are presented in later sections.

[0022] The present invention provides a method of treating a subject with chronic kidney disease, comprising administering at least about 2 mg / cm 2 The method includes administering to the subject an effective amount of a ferric organic compound having a dissolution rate of about 2.5 mg / cm3 / min. An example of a ferric organic compound is ferric citrate. Exemplary dissolution rate ranges include, but are not limited to, about 2.5 mg / cm3 / min. 2 / min ~ approx. 3.0 mg / cm 2 / min, or approximately 3.0 mg / cm 2 / min ~ approx. 3.5 mg / cm 2 / min, or approximately 3.5 mg / cm 2 / min ~ approx. 4.0 mg / cm 2 / min included.

[0023] In one embodiment, the ferric organic compound is prepared according to a method comprising the steps of: (a) obtaining a ferric salt; (b) adding an alkali metal hydroxide to the ferric salt under conditions effective to produce a mixture comprising a polyiron oxide; (c) isolating a precipitate from the mixture; (d) adding an organic acid to the precipitate; (e) forming a ferric organic acid solution by heating the organic acid and the precipitate; and (f) precipitating the ferric organic compound from the ferric organic acid solution by adding an organic solvent to the solution.

[0024] Generally, the subject is a human or an animal. The subject may have any stage of chronic renal disease (e.g., end-stage renal disease) or undergo renal dialysis. The ferric organic compound may be administered by oral route or any other suitable route generally known in the art, and the ferric organic compound may be formulated into a number of dosage forms generally known in the art. Representative dosage forms include, but are not limited to, tablets, powders, suspensions, emulsions, capsules, lozenges, granules, troches, pills, liquids, spirits, or syrups.

[0025] In one embodiment, treatment with the ferric organic compound results in a decrease in serum creatinine and BUN levels in a subject, hi another embodiment, treatment with the ferric organic compound results in a decrease in serum phosphorus and calcium phosphorus product (CaxP) levels.

[0026] In one embodiment, treatment with the ferric organic compound prevents, reverses, maintains, or delays the progression of chronic kidney disease. In another embodiment, the onset of hyperparathyroidism, bone disorders, or cardiovascular disease in a subject is prevented, reversed, maintained, or delayed. In yet another embodiment, calcium phosphate precipitation in renal tissue of a subject is prevented, reversed, maintained, or delayed. In yet another embodiment, kidney stone formation is prevented, reversed, maintained, or delayed. In yet another embodiment, the onset of metabolic acidosis in a subject is prevented, reversed, maintained, or delayed.

[0027] The present invention also provides the use of a ferric organic compound as described herein for the manufacture of a medicament for the treatment of a subject with chronic kidney disease.

[0028] The present invention also provides a method of treating a subject with chronic kidney disease, comprising administering to the subject an effective amount of a ferric organic compound. An example of the ferric organic compound is ferric citrate. In one embodiment, the ferric organic compound is at least about 2 mg / cm 2 / min dissolution rate.

[0029] The present invention also provides a treatment regimen for treating a subject with chronic kidney disease; the treatment regimen comprises administering to a subject an acceptable carrier and at least 2 mg / cm 2 The present invention also includes a pharmaceutical composition comprising an effective amount of a ferric organic compound having a dissolution rate of 1 / min, wherein the pharmaceutical composition is administered in a single or multiple dose regimen.

[0030] The present invention also provides a pharmaceutical composition for treating a subject with chronic kidney disease, comprising at least about 2 mg / cm 2 The present invention provides a pharmaceutical composition comprising an effective amount of a ferric organic compound having a dissolution rate of 1 / min.

[0031] The invention also provides the use of the pharmaceutical composition in the manufacture of a medicament for treating a subject with chronic kidney disease.

[0032] Detailed Description of the Drawings The drawings illustrate specific embodiments of the invention but are not to be construed as limiting the spirit or scope of the invention in any way. [Brief description of the drawings]

[0033] [Figure 1] FIG. 1 is a schematic diagram outlining a method for producing a novel form of ferric organic compound according to the present invention. [Diagram 2] Figure 2 compares the safety profiles of chemical grade and pharmaceutical grade ferric citrate. [Diagram 3] Figure 3 compares the potency profiles of chemical grade and pharmaceutical grade ferric citrate. [Figure 4] FIG. 4 shows a bar graph of the association between dialysis patient mortality and rate of hyperphosphatemia. [Diagram 5] FIG. 5 shows the serum creatinine levels of a patient treated with 6 g / day of ferric citrate (patient code: 2-01-1-029). [Figure 6] FIG. 6 shows the serum creatinine levels of a patient treated with 6 g / day of ferric citrate (patient code: 2-01-1-032). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] Detailed Description of the Invention The drawings illustrate certain embodiments of the invention, which are not to be construed as limiting the scope of the invention or are described in detail to avoid unnecessarily obscuring the invention. Accordingly, the specification and drawings are to be regarded in an illustrative rather than a restrictive sense.

[0035] Results presented below show that treatment with ferric citrate, an exemplary ferric organic compound produced according to the methods described herein, reduces serum levels of creatinine, phosphorus, and calcium-phosphorus product (CaxP) in patients with chronic kidney disease. Thus, the ferric organic compounds of the present invention, including but not limited to ferric citrate, can be used to alleviate the progression of chronic kidney disease (CKD) in a subject; e.g., prevent, reverse, maintain, or slow the progression of CKD.

[0036] The present invention is not limited to the use of the ferric citrate disclosed herein. Other ferric citrate compounds, or salts, derivatives, analogs, metabolites, or preparations thereof, suitable for use in the methods of the present invention will be apparent to those of skill in the art following the teachings of this application. Furthermore, the methods of the present invention also encompass the use of other ferric organic compounds synthesized according to the methods described herein. These ferric organic compounds preferably have or include the following properties: High affinity for phosphorous binding; Solubility over a wide range of pH; Fast binding, independent of pH; High solubility; Low absorption throughout the body; Non-toxic; Orally available; and / or Cheap to manufacture.

[0037] In view of the data described herein, one of skill in the art will also readily appreciate that the present invention is not limited to the use of ferric organic compounds produced according to the methods disclosed herein. Thus, it will be apparent to one of skill in the art that the present invention encompasses methods of using ferric organic compounds to treat chronic kidney disease, where the ferric organic compounds have the specific properties described herein.

[0038] In one embodiment, the ferric organic compounds produced according to the methods described herein are useful for treating hyperphosphatemia, metabolic acidosis, and any other disorders that respond to ferric organic compound therapy. Because the ferric organic compounds of the present invention are more soluble than commercially available ferric organic compounds, small amounts of the ferric organic compounds of the present invention can be used to effectively treat patients suffering from such disorders.

[0039] In one embodiment of the present invention, the ferric citrate of the present invention has a significantly higher water solubility than commercially available forms of ferric citrate under physiological conditions, and therefore the ferric citrate of the present invention is believed to provide a significant improvement in the use of low-dose, orally effective ferric citrate. By reducing the orally effective amount of ferric citrate, the ferric citrate of the present invention is believed to result in a reduced incidence of ulcerative gastrointestinal side effects associated with commercially available ferric citrate compounds. Furthermore, the high dissolution rate of the ferric citrate of the present invention is believed to result in a faster onset of action to bind dietary phosphate. Furthermore, the ferric organic compounds of the present invention are more soluble over a wider pH range than commercially available ferric organic compounds; therefore, the ferric organic compounds of the present invention may be more effective by being soluble in the small intestine.

[0040] The ferric organic compounds of the present invention can be administered in many forms generally known in the art. Pharmaceutical compositions containing the ferric organic compounds of the present invention include, but are not limited to, solid, liquid, or semi-solid forms, such as gels, syrups, chewables, or pastes. The ferric organic compounds of the present invention can be administered alone or in combination with a pharma- ceutical acceptable carrier. Orally administrable forms include, but are not limited to, tablets, powders, suspensions, emulsions, capsules, granules, lozenges, pills, liquids, spirits, or syrups. The compositions can be administered to humans or other animals suffering from diseases that respond to ferric organic compound treatment.

[0041] An effective amount of pharmaceutical grade ferric citrate can be readily determined by one of skill in the art. For example, an effective amount may range from 2 to 100 grams per day, preferably 2 to 60 grams per day. Alternatively, an effective amount per day may be 2, 4, 6, or 8 grams.

[0042] The pharmaceutical grade ferric organic compound of the present invention, such as ferric citrate, is suitable for treating hyperphosphatemia or other disorders characterized by high serum phosphate levels. Thus, the present invention encompasses treating subjects or patients with various renal diseases, such as end-stage renal disease (ESRD), chronic kidney disease (CKD) or other related renal diseases, or subjects and patients undergoing dialysis, but not limited to hemodialysis.

[0043] In one embodiment, compositions containing the pharmaceutical grade ferric organic compounds of the present invention, such as ferric citrate, can be used to treat subjects or patients with metabolic acidosis. Other disorders that can be ameliorated by the conversion of citrate to bicarbonate are also encompassed by the invention.

[0044] In one embodiment, the method of using the pharmaceutical composition includes treating a human or non-human subject or patient with chronic kidney disease. There are generally five clinical stages of chronic kidney disease, numbered 1 to 5, with stage 1 being the least severe and stage 5 being the most severe. In the early stages, such as stages 1 and 2, dialysis is not required. Once chronic kidney disease progresses to stage 5, the patient may require dialysis treatment three times a week. Of note, high phosphate levels are observed in all stages of chronic kidney disease. Thus, an embodiment of the present invention is a method of treating a subject or human with early or mid-stage chronic kidney disease with a composition comprising pharmaceutical grade ferric citrate to achieve low serum phosphate levels.

[0045] In another embodiment, a method is provided for treating a human or non-human subject or patient with late stage chronic renal disease undergoing hemodialysis by administering a composition comprising pharmaceutical grade ferric citrate of the present invention. It is generally known that hemodialysis is not fully effective in reducing serum phosphate levels. The treatment of a subject or human with late stage renal disease is applicable regardless of whether the subject or human is currently undergoing hemodialysis treatment.

[0046] An additional embodiment of the present invention is a method of treating a subject or human having chronic kidney disease and undergoing peritoneal dialysis with a pharmaceutical grade ferric citrate-containing composition as described herein, which is known to be ineffective in reducing serum phosphate levels.

[0047] The present invention provides a method of treating a subject with chronic kidney disease. Generally, the subject is a human or an animal. The subject may have end stage renal disease or may be undergoing kidney dialysis. The method includes administering at least about 2 mg / cm 2 The method includes administering to the subject an effective amount of a ferric organic compound having a dissolution rate of about 2.5 mg / cm3 / min. Exemplary dissolution rate ranges include, but are not limited to, about 2.5 mg / cm3 / min. 2 / min ~ approx. 3.0 mg / cm 2 / min, or approximately 3.0 mg / cm 2 / min ~ approx. 3.5 mg / cm 2 / min, or approximately 3.5 mg / cm 2 / min ~ approx. 4.0 mg / cm 2 / min included.

[0048] In one embodiment, the ferric organic compound is produced according to a method comprising the steps of: (a) producing a ferric salt; (b) adding an alkali metal hydroxide to the ferric salt under conditions effective to obtain a mixture comprising polyiron oxide; (c) isolating a precipitate from the mixture; (d) adding an organic acid to the precipitate; (e) forming a ferric organic acid solution by heating the organic acid and the precipitate; and (f) precipitating the ferric organic compound from the ferric organic acid solution by adding an organic solvent to the solution.

[0049] In one embodiment, the alkali metal hydroxide is sodium hydroxide, the ferric salt is ferric chloride hexahydrate, and the organic acid is crystalline citric acid.

[0050] Typically, an alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide) is added at a rate of less than 20 ml / min, preferably in the range of about 10 ml / min to about 20 ml / min, and the alkali metal hydroxide is added to the ferric salt at a temperature of less than 40° C., preferably in the range of about 10° C. to about 40° C. The organic acid and precipitate is heated to a temperature in the range of about 80° C. to about 90° C. Precipitating the ferric organic compound from the ferric organic acid solution with an organic solvent includes cooling the ferric organic acid solution to less than 30° C., preferably to a temperature in the range of about 10° C. to about 30° C., prior to adding the organic solvent.

[0051] In the method of synthesizing the ferric organic compounds, several organic acids can be used, such as citric acid, acetic acid, isocitric acid, succinic acid, fumaric acid, and tartaric acid. In one embodiment, the organic acid is in crystalline form. Furthermore, several organic solvents can be used in the synthesis of the ferric organic compounds described herein, such as ethanol, methanol, butanol, isopropyl alcohol, acetone, and tetrahydrofuran.

[0052] The ferric organic compound can be administered in an effective amount, for example, 2-20 gm / day, as determined by one of skill in the art. The ferric organic compound can be administered orally or by any other suitable route, as can be readily determined by one of skill in the art. In general, the ferric organic compound can be formulated as a tablet, powder, suspension, emulsion, capsule, lozenge, granule, troche, pill, liquid, spirit, or syrup.

[0053] In one embodiment, treatment with the ferric organic compound results in a decrease in serum creatinine and BUN levels in a subject, hi another embodiment, treatment with the ferric organic compound results in a decrease in serum phosphorus, calcium phosphorus product (CaxP) levels.

[0054] In one embodiment, treatment with the ferric organic compound prevents, ameliorates, maintains, or delays the progression of chronic kidney disease. In another embodiment, the onset of hyperparathyroidism, bone disorders, or cardiovascular disease in a subject is prevented, ameliorates, maintains, or delays. In yet another embodiment, calcium phosphate precipitation in renal tissue of a subject is prevented, ameliorates, maintains, or delays. In yet another embodiment, kidney stone formation is prevented, ameliorates, maintains, or delays. In yet another embodiment, the onset of metabolic acidosis in a subject is prevented, ameliorates, maintains, or delays.

[0055] The present invention also provides a method of treating a subject with chronic kidney disease comprising administering to the subject an effective amount of a ferric organic compound, wherein the ferric organic compound is produced according to a method comprising the steps of: (a) obtaining a ferric salt; (b) adding an alkali metal hydroxide to the ferric salt under conditions effective to obtain a mixture comprising polyiron oxide; (c) isolating a precipitate from the mixture; (d) adding an organic acid to the precipitate; (e) forming a ferric organic acid solution by heating the organic acid and the precipitate; and (f) precipitating the ferric organic compound from the ferric organic acid solution with an organic solvent. This synthesis method provides a high dissolution rate (e.g., at least about 2 mg / cm2 The present invention relates to a method for producing a ferric organic compound (e.g., ferric citrate) having a dissolution rate of 100 mg / kg / min. This method of treatment provides the therapeutic effect described above.

[0056] The present invention also provides a method of treating a subject with chronic kidney disease, comprising administering to the subject an effective amount of a ferric organic compound. Examples of ferric organic compounds include, but are not limited to, ferric citrate. Generally, the subject is a human or an animal. The subject may have end stage renal disease or may be undergoing kidney dialysis. In one embodiment, the ferric organic compound is at least about 2 mg / cm. 2 / min dissolution rate.

[0057] The present invention also provides a treatment regimen for treating a subject with chronic kidney disease, the treatment regimen comprising an acceptable carrier and at least 2 mg / cm 2 The present invention also includes pharmaceutical compositions comprising an effective amount of a ferric organic compound having a dissolution rate of at least 2 mg / cm3 / min, where the pharmaceutical composition is administered in a single or multiple dose regimen. An example of a ferric organic compound is ferric citrate. 2 Ferric organic compounds having a dissolution rate of about 2.5 mg / cm3 / min, such as ferric citrate, are useful in the present method. For example, the dissolution rate of the ferric organic compound may be about 2.5 mg / cm3 / min. 2 / min ~ approx. 3.0 mg / cm 2 / min, or approximately 3.0 mg / cm 2 / min ~ approx. 3.5 mg / cm 2 / min, or approximately 3.5 mg / cm 2 / min ~ approx. 4.0 mg / cm 2 / min. Generally, at least a portion of the pharmaceutical composition is administered orally. In one embodiment, the subject may have end stage renal disease, and the method may optionally include kidney dialysis or peritoneal dialysis.

[0058] The present invention also provides a pharmaceutical composition for treating a subject with chronic kidney disease, comprising at least about 2 mg / cm 2The present invention provides a composition comprising an effective amount of a ferric organic compound (e.g., ferric citrate) having a dissolution rate of about 2 mg / cm3 / min. In one embodiment, the dissolution rate is about 2 mg / cm3 / min. 2 / min ~ approx. 4 mg / cm 2 Generally, the composition is in a form suitable for oral administration, such as tablets, powders, suspensions, emulsions, capsules, lozenges, granules, troches, pills, liquids, spirits, or syrups.

[0059] The invention also provides the use of the pharmaceutical composition in the manufacture of a medicament for treating a subject with chronic kidney disease, in one embodiment, the subject has end stage renal disease or is undergoing kidney dialysis.

[0060] The following examples are intended to illustrate embodiments of the present invention and are not intended to limit the scope of the invention. EXAMPLES

[0061] Example 1 A general method for the synthesis of pharmaceutical grade ferric organic compounds General methods for synthesizing ferric organic compounds are disclosed in PCT / US2006 / 032585, and U.S. Provisional Application No. 60 / 763,253, which are incorporated herein by reference. Representative ferric organic compounds include, but are not limited to, ferric citrate.

[0062] Referring to FIG. 1, flow chart 10 is a general process for synthesizing ferric organic compounds or ferric citrate compounds in a form that can be used in the present invention. The starting material, as described in box 20, includes a soluble ferric salt. The soluble ferric salt can include ferric chloride hexahydrate (FeCl36H2O), as described in box 21, or any other suitable soluble ferric salt. An alkali metal hydroxide (box 30) is then added to the soluble ferric salt at a specific rate and temperature. Upon addition of the alkali metal hydroxide at a specific rate, preferably in the range of about 10 ml / min to about 20 ml / min, and at a specific temperature range, preferably below 40° C., a homogenous polyiron oxocolloid suspension is formed. The alkali metal hydroxide can include sodium hydroxide, potassium hydroxide, or any other suitable alkali metal hydroxide, as described in box 31.

[0063] The colloidal suspension precipitate is collected and rinsed with distilled water (box 40) to remove any soluble impurities. After rinsing, the precipitate is resuspended and a crystalline organic acid is added to the precipitate and heated to a specific temperature range, preferably about 80°C to about 90°C, as described in box 50. The organic acid can include any suitable organic acid. Box 51 lists several possible organic acids that can be used, including but not limited to citric acid, acetic acid, isocitric acid, succinic acid, fumaric acid, and tartaric acid. The organic acid is added to allow the acid to form a complex with the precipitate in solution. In box 60, the ferric organic compound is precipitated from the solution using an organic solvent to form a novel form of the ferric organic compound (box 70). A variety of organic solvents can be used, including but not limited to those described in box 61, such as ethanol, methanol, butanol, acetone, isopropyl alcohol, tetrahydrofuran, or any other suitable organic solvent.

[0064] Synthesis of Ferric Citrate In one embodiment of the present invention, the organic ferric compound is ferric citrate. The starting material for producing ferric citrate comprises a 1.85M solution of ferric chloride hexahydrate (FeCl36H2O). The volume of 5M sodium hydroxide required to achieve a 1:3 ratio of ferric to hydroxide ions is added to the ferric chloride hexahydrate solution at a rate of less than 20 ml / min, preferably in the range of about 10 ml / min to about 20 ml / min. Sodium hydroxide is added while maintaining the temperature of the mixture below 40°C, preferably in the range of about 10°C to about 40°C, to form a polyiron oxide colloidal suspension of ferric hydroxide. Sodium hydroxide is added while measuring the pH of the suspension. Once the pH is greater than 7.0, the suspension is cooled to less than 30°C, preferably in the range of about 10°C to about 30°C. The suspension is then filtered through a 1 mm pore filter to disperse aggregates and remove large particle ferric hydroxide precipitates. The filtered ferric hydroxide suspension is then centrifuged. The supernatant is discarded and the precipitated ferric hydroxide is centrifuged again to remove any remaining supernatant. The ferric hydroxide precipitate is then resuspended in distilled water. The centrifugation-resuspension step is repeated two more times to wash the ferric hydroxide precipitate and remove water-soluble impurities. The resulting ferric hydroxide precipitate is then homogenized.

[0065] Add the amount of citric acid needed to achieve a 1:1 ratio of ferric to citric acid to the precipitate. Heat the mixture in an oil bath to a range of about 80°C to about 90°C until the color of the mixture changes from orange-brown to clear black-brown or until all the ferric hydroxide precipitate has dissolved. Cool the reaction to below 30°C, preferably in the range of about 10°C to about 30°C, and measure the pH to determine it to be in the range of 0.8 to 1.5. Centrifuge the reaction and collect the supernatant. Precipitate the ferric citrate from the supernatant by adding 5 volumes of organic solvent.

[0066] A variety of organic solvents can be used, including ethanol, methanol, butanol, acetone, isopropyl alcohol, or tetrahydrofuran. Once the solvent is added, the mixture is stirred until a pale beige precipitate is formed. The suspension is centrifuged and the supernatant is discarded. The precipitate is washed and centrifuged two more times with the solvent. The precipitate is then dried in a vacuum oven at ambient temperature for 8-16 hours or by any other suitable industrial process, such as fluidized bed drying. The dried precipitate is crushed with a mortar and pestle and dried at ambient temperature for an additional 8-24 hours. The fine precipitate is again pulverized by grinding and sieved through a 45 mesh size (35 micron) sieve. The novel form of ferric citrate powder is again dried in a vacuum oven or in a fluidized bed dryer and dried at ambient temperature until a weight loss of less than 0.25% is achieved by drying for 1 hour.

[0067] Example 2 Solubility profile of the ferric organic compound according to the present invention The ferric organic compounds produced according to the above method are more soluble over a wider range of pH levels than commercially available ferric organic compounds. This increased solubility of the ferric organic compounds of the present invention is believed to be due to the uniquely large effective surface area of ​​the ferric organic compounds of the present invention. For example, at pH 8.0, the intrinsic dissolution rate of the ferric citrate of the present invention is 3.32 times higher than that of commercially available ferric citrate. See Table 1.

[0068] The intrinsic dissolution rates of commercially available ferric citrates were compared with the ferric citrate of the present invention. Intrinsic dissolution rate is defined as the dissolution rate of a pure substance under conditions of constant surface area. The dissolution rate and bioavailability of a drug substance are affected by its solid-state properties: crystallinity, amorphism, polymorphism, hydration, solvation, particle size and particle surface area. The measured intrinsic dissolution rate is dependent on these solid-state properties and is typically measured by exposing a constant surface area of ​​the substance to an appropriate dissolution medium while maintaining constant temperature, stirring speed and pH. The intrinsic dissolution rates are shown in Table 1. [Table 1]

[0069] The BET effective surface area of ​​the ferric citrate of the present invention is at least 16 times greater than commercially available ferric citrate. See Table 2.

[0070] The analysis of the effective surface area is based on the BET theory, which describes the phenomenon of mass and energy interactions and phase transitions during gas adsorption on solid surfaces and in interstitial spaces. BET effective surface area measurements determine the volume of a monolayer of gas, which allows the surface area of ​​a sample to be determined using the area occupied by a monolayer of adsorbed gas molecules. Table 2 compares the effective surface area of ​​the ferric citrate of the present invention compared to that of commercially available ferric citrate compounds. [Table 2]

[0071] Example 3 Methods for using and testing pharmaceutical grade ferric citrate in patients Handling and Formulation of Test Compositions Ferric citrate is provided in a 500 mg capsule, while a placebo is provided in a capsule of identical appearance (indistinguishable from the capsule containing the active drug), i.e., the placebo capsule contains sorbitol and coloring to match the powder color of the active capsule. The shell of the placebo capsule is identical to that of the active capsule.

[0072] keep All study drug supplies must be stored under stability conditions and should not be used after the expiration date stamped on the study drug container. Study drug should be stored under controlled conditions (15-30°C; 59-86°F) in a closed container protected from light.

[0073] dose A recent pilot study compared ferric citrate (3 g / day) with calcium carbonate (3 g / day) for reducing serum P04 in patients with end-stage renal disease (ESRD). This dose of ferric citrate was associated with mild but tolerable GI symptoms.

[0074] The dose of ferric citrate selected for study or treatment may be 1-30 grams of ferric citrate per day. This dose may depend, in part, on the nature of the formulation provided. For example, ferric citrate capsules may be administered up to a daily dose of about 15 grams per day, while tablet form may be administered up to 30 grams per day. Thus, a very wide range of dosing regimens is encompassed by the present invention.

[0075] Titrate the optimal dose to the subject In the context of the present invention, the term "subject" refers to a human or non-human animal. The optimal dose for an individual subject or group of subjects can be determined as follows. A dose of about 1 or 2 grams / day is suggested merely as an exemplary starting dose. If necessary, the daily dose can be increased until the desired results are observed.

[0076] The present invention does not intend to limit the dose range used. Thus, depending on the subject(s), the daily dosage may be approximately 30, 40, 50, 60, 70, 80, 90, or 100 grams / day. The safety profile of pharmaceutical grade ferric citrate allows for a wide range of doses.

[0077] Furthermore, the present invention is not intended to be limited to oral formulations such as capsules and tablets, as it is known in the art that a wide variety of oral formulations will be suitable for use with the present invention.

[0078] Illustrative Examples of Dosage Regimens A non-limiting example of a dosing regimen is given below. This is not meant to limit the invention with respect to how to select the effective amount of ferric citrate, or the dosage form in which it is provided, or the frequency of administering the composition per day. The following is merely to describe how ferric citrate and placebo can be administered. For example, administered as 500 mg capsules of the same appearance. All patients receive 4 capsules (in a blinded manner) with each of the three meals every day for 28 days. Patients are instructed to take study drug within 10 minutes of finishing their meals (breakfast, lunch, and dinner).

[0079] The numbers of placebo and active capsules to be taken at each meal are as follows:

[0080] The placebo arm of the study Four placebo capsules with breakfast Four placebo capsules with lunch Four placebo capsules with dinner.

[0081] The ferric citrate 2 g / day treatment arm of this study 1 ferric citrate capsule and 3 placebo capsules with breakfast One ferric citrate capsule and three placebo capsules with lunch Two ferric citrate capsules and two placebo capsules with dinner.

[0082] Treatment group: 4 g / day ferric citrate Two ferric citrate capsules and two placebo capsules with breakfast Three ferric citrate capsules and one placebo capsule with lunch Three ferric citrate capsules and one placebo capsule with dinner.

[0083] Treatment group: ferric citrate 6 g / day 4 ferric citrate capsules with breakfast 4 ferric citrate capsules with lunch With dinner, four ferric citrate capsules.

[0084] Clinical Schedule and Evaluation Each patient's participation in the study will last for up to 8 weeks (a screening period (approximately 1-2 weeks), a 1-2 week washout period, and 4 weeks of treatment with study drug).

[0085] Screening Visit 1 (Study Days -30 to -15) The following procedures will be performed at the initial screening visit:

[0086] 1. Medical history (including concomitant medications).

[0087] 2. Demographic Data.

[0088] 3. Physical examination (including height, weight, and vital signs).

[0089] 4. Dietary questionnaires three times during the screening period (including one dialysis day, one non-dialysis day, and one weekend day) assessing dietary intake of calcium and phosphorus using a 24-hour recall method. Note: The dietary questionnaire may be partially or completely administered during the washout period.

[0090] 5. Laboratory evaluation: Hematology: Complete blood count (CBC) (with differential), platelets b. Chemicals: sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, glucose (random), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, total protein, albumin, serum calcium, serum phosphate, magnesium c. Total cholesterol and LDL cholesterol levels d. Serum (3-HCG for women of childbearing potential) e. Iron panel: serum iron, ferritin, transferrin saturation percentage, and total iron binding capacity.

[0091] 6. 12-lead ECG.

[0092] 7. Give patients instructions regarding the washout period (Study Days -14 to -1): a. Discontinue all phosphate binders on day -14 b. Discontinue all iron therapy (oral or intravenous) on day -14 c. Patients taking a stable dose of vitamin D or calcitriol for 1 month prior to enrollment will be instructed to maintain their current dose for the duration of the study. d. Advise patient to avoid changes in diet, calcium- or magnesium-containing antacids (and other medications).

[0093] Screening Visit 2 (Study Day -7 + / - 1) Laboratory evaluation of serum P04. Patients with a serum P04 ≥ 5.5 mg / dL and ≤ 10 mg / dL on day -7 may be randomized prior to completion of the 2-week washout. The day of randomization will automatically become day 0. Patients with phosphate levels ≥ 10 mg / dL on day -7 will be removed from the study and instructed to resume their pre-study medication.

[0094] Study Day 0 (Randomization and Dosing) 1. Physical examination (including weight and vital signs).

[0095] 2. Adverse events questions.

[0096] 3. Concomitant medication questions.

[0097] 4. Baseline Laboratory Assessment: a. Serum P04; b. Serum Ca; c. Iron Panel: serum iron, ferritin, percentage transferrin saturation, and total iron binding capacity. Baseline laboratory assessments can be performed up to 3 days prior to Day 0.

[0098] 5. Patients with P04 levels ≥ 0.5 mg / dL and ≤ 10 mg / dL will be randomized and receive a 15-day supply of study drug. Patients should be instructed to begin taking study drug on Day 0 within 10 minutes of the end of their next meal.

[0099] Research Day 14 (Interim Evaluation) Study Day The following procedures will be performed on Day 14 + / - 1.

[0100] 1. Physical examination (including weight and vital signs).

[0101] 2. Adverse events questions.

[0102] 3. Concomitant medication questions.

[0103] 4. Dispensing an additional 15-day supply of study medication. All returned capsules should be counted and recorded on the case report form.

[0104] 5. Laboratory evaluation: Hematology: CBC (with differential), platelets b. Chemicals: sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose (random), AST, ALT, ALP, total bilirubin, total protein, albumin, calcium, phosphate, magnesium c. Iron panel: serum iron, ferritin, transferrin saturation percentage, and total iron binding capacity d. Total cholesterol and LDL cholesterol levels.

[0105] NOTE: Patients with phosphate levels greater than 10 mg / dL on Day 14 will be removed from the study and instructed to resume their pre-study medication.

[0106] Study Day 28 (End of Study Evaluation) Study Days The following procedures will be performed on Day 28 + / - 1 or on the day of early termination.

[0107] 1. Physical examination (including weight and vital signs).

[0108] 2. Adverse events questions.

[0109] 3. Concomitant medication questions.

[0110] 4. Laboratory evaluation: Hematology: CBC (with differential), platelets b. Chemicals: sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose (random), AST, ALT, ALP, total bilirubin, total protein, albumin, calcium, phosphate, magnesium c. Total cholesterol and LDL cholesterol levels d. Iron panel: serum iron, ferritin, transferrin saturation percentage, and total iron binding capacity.

[0111] 5. 12-lead ECG.

[0112] 6. After completion of the study, patients will be instructed to resume their pre-study medication.

[0113] Data Management and Analysis GloboMax is the primary data management, monitoring, and coordinating center. A Case Report Form (CRF) will be prepared for each subject. Subjects will not be identified by name or initials on the CRF. CRFs will be monitored at the clinical sites and collected by GloboMax's study monitors. Validated CRFs will be used to generate electronic data files.

[0114] The three main categories of endpoints reflect the biochemical and clinical questions that are being addressed from the outset. Additional clinical and biochemical questions will be addressed as they arise. Thus, the endpoints are not intended to limit the totality of relevant findings and measurements that will be collected in these or future studies.

[0115] Primary endpoint Changes in serum P04 concentrations from baseline on days 14 and 28.

[0116] Secondary endpoints Change in serum calcium concentration from baseline at days 14 and 28.

[0117] Changes from baseline in iron, ferritin, percentage transferrin saturation, and total iron binding capacity on days 14 and 28.

[0118] Change in Ca·PO4 product from baseline on days 14 and 28.

[0119] Safety evaluation items Safety is monitored by recording adverse events and the results of physical examinations, vital signs, and laboratory tests at each study visit.

[0120] In addition, specific rules regarding withdrawal from the study are established based on laboratory data and to ensure patient safety. Non-limiting examples of such criteria are illustrated by the following statements: If a patient's serum phosphate level increases to 10 mg / dL or greater at any time during the study, the patient will be withdrawn from the study.

[0121] Example 4 A randomized, double-blind, placebo-controlled, dose-ranging study of the effect of ferric citrate on serum phosphate in patients with end-stage renal disease (ESRD). OBJECTIVES: (1) To determine the effect of ferric citrate at doses of 2, 4, and 6 g / day administered TID (3 times / day) for 28 days on serum phosphate (PO4) levels in patients with end-stage renal disease (ESRD). (2) To evaluate the safety of ferric citrate at doses of 2, 4, and 6 g / day administered TID for 28 days in patients with ESRD.

[0122] Study Drug: Ferric citrate as disclosed in US 11 / 206,981 and WO 2004 / 07444.

[0123] STUDY DESIGN: A randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the effect of ferric citrate on serum phosphate concentrations in ESRD patients undergoing hemodialysis. Patients will be evaluated on study days 14 and 28 for efficacy as measured by serum phosphate concentrations. Additionally, patients receiving one or more doses of study drug will be evaluated for safety.

[0124] Study duration: 8 weeks (including screening period, 2 weeks washout, and 4 weeks treatment).

[0125] Results show a decrease in serum PO4 and CaxPO4 at 0, 2, 4 and 6 gm / day (administered TID immediately after a meal, i.e., within 10 minutes). Ferric citrate is administered orally, given 3 times / day evenly.

[0126] The ability of ferric citrate to reduce serum phosphate levels in ESRD patients was demonstrated. No significant changes in serum calcium levels were observed for placebo, 2, 4, and 6 gm / day over a 28-day period. However, Ca×PO4 levels were reduced and were statistically significant for the 6 gm / day dose at both 14 and 28 days. The results further indicate that calcification can be reversed or stabilized following treatment with ferric citrate. The following table summarizes the data from this study: [Table 3] [Table 4] [Table 5] [Table 6] [Table 7]

[0127] Treatment using pharmaceutical grade ferric citrate offers several advantages over chemical grade ferric citrate, as shown in Figures 2 and 3. In general, pharmaceutical grade ferric citrate exhibits roughly equivalent efficacy to chemical grade ferric citrate, but pharmaceutical grade ferric citrate achieves this result with fewer adverse side effects than chemical grade ferric citrate.

[0128] Figure 2 also shows that the adverse side effects associated with administration of pharmaceutical grade ferric citrate were not statistically different from those associated with placebo. The advantage of this safety profile is that individual patients can receive pharmaceutical grade ferric citrate titrated over a wide range of doses with less concern about side effects. In this way, a patient's individual treatment can be tailored to their specific needs and tolerance.

[0129] Decreased serum creatinine levels Glomerular filtration rate (GFR) levels correlate with structural kidney damage and are therefore used as the gold standard for measuring kidney function. GFR can be estimated by serum creatinine, a biomarker. As renal function deteriorates, the kidneys lose their ability to efficiently excrete creatinine, resulting in the retention of creatinine in the body. Thus, an increase in serum creatinine indicates a decline in GFR, which is an important sign of kidney deterioration.

[0130] In an open-label extension study of the Phase II clinical study: "A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of the Effect of Ferric Citrate on Serum Phosphate in Patients with End-Stage Renal Disease (ESRD)," some patients were given 2-6 g / day of ferric citrate and their serum creatinine levels were monitored to assess renal function. Patients who received 6 g / day of ferric citrate appeared to have a trend toward decreased serum creatinine levels, meaning that ferric citrate improves, delays, and arrests or prevents the progression of chronic kidney disease. Results from two patients are shown in Figures 5-6.

Claims

1. 1. A method of treating a subject with chronic kidney disease, comprising administering at least about 2 mg / cm 2 The method comprises administering to the subject an effective amount of a ferric organic compound having a dissolution rate of 1 / min.

2. The dissolution rate of the ferric organic compound is approximately 2.5 mg / cm 2 / min ~ approx. 3.0 mg / cm 2 10. The method of claim 1, wherein the heating rate is 100 / min.

3. The dissolution rate of the ferric organic compound is approximately 3.0 mg / cm 2 / min ~ approx. 3.5 mg / cm 2 10. The method of claim 1, wherein the heating rate is 100 / min.

4. The dissolution rate of the ferric organic compound is approximately 3.5 mg / cm 2 / min ~ approx. 4.0 mg / cm 2 10. The method of claim 1, wherein the heating rate is 100 / min.

5. The ferric organic compound is subjected to the following steps: a) obtaining a ferric salt; b) adding an alkali metal hydroxide to the ferric salt under conditions suitable to produce a mixture comprising polyiron oxide; c) isolating the precipitate from the mixture; d) adding an organic acid to the precipitate; e) heating the organic acid and the precipitate, thereby forming a ferric organic acid solution; and f) Precipitating the ferric organic compound from the ferric organic acid solution with an organic solvent The method according to any one of claims 1 to 4, wherein the composition is produced according to a process comprising:

6. 6. The method of claim 5, wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide.

7. 7. The method of claim 5 or 6, wherein the alkali metal hydroxide is added at a rate of less than 20 ml / min and the alkali metal hydroxide is added to the ferric salt at a temperature of less than 40°C.

8. 8. The method of any one of claims 5 to 7, wherein the steps of heating the organic acid and the precipitate to a temperature of about 80°C to about 90°C and precipitating the ferric organic compound from the ferric organic acid solution with an organic solvent comprises cooling the ferric organic acid solution to below 30°C before adding the organic solvent.

9. The method of any one of claims 5 to 8, wherein the organic acid is in crystalline form.

10. The method according to any one of claims 5 to 9, wherein the organic acid is selected from the group consisting of citric acid, acetic acid, isocitric acid, succinic acid, fumaric acid, and tartaric acid.

11. The method according to any one of claims 5 to 10, wherein the organic solvent is selected from the group consisting of ethanol, methanol, butanol, isopropyl alcohol, acetone, and tetrahydrofuran.

12. 12. The method according to any one of claims 5 to 11, wherein the ferric salt is ferric chloride hexahydrate, the alkali metal hydroxide is sodium hydroxide and the organic acid is crystalline citric acid.

13. The method according to any one of claims 1 to 12, wherein the subject is a human or an animal.

14. The method of any one of claims 1 to 13, wherein the chronic kidney disease includes any stage of chronic kidney disease and end stage renal disease.

15. The method of any one of claims 1 to 14, wherein the subject is undergoing renal dialysis.

16. 16. The method of any one of claims 1 to 15, wherein the ferric organic compound is administered in a dosage of about 2 to 20 gm / day.

17. The method according to any one of claims 1 to 16, wherein the ferric organic compound is administered orally or by any other suitable route.

18. 18. The method according to any one of claims 1 to 17, wherein the ferric organic compound is formulated as a tablet, powder, suspension, emulsion, capsule, lozenge, granule, troche, pill, liquid, spirit, or syrup.

19. 19. The method of any one of claims 1 to 18, wherein treatment with the ferric organic compound results in a decrease in the serum concentration of one or more substances in the subject, the substances being selected from the group consisting of creatinine, BUN, phosphorus, and calcium phosphorus product (CaxP).

20. 19. The method of any one of claims 1 to 18, wherein treatment with the ferric organic compound results in the prevention, amelioration, maintenance, or delay of one or more disease conditions in the subject, the disease conditions being selected from the group consisting of the progression of chronic kidney disease, the onset of hyperparathyroidism, the onset of bone disorders, the onset of cardiovascular disease, the precipitation of calcium phosphate in renal tissue, kidney stone formation, and the onset of metabolic acidosis.

21. 1. A method of treating a subject having chronic kidney disease, comprising administering to the subject an effective amount of a ferric organic compound.

22. 22. The method of claim 21 , wherein the ferric organic compound is administered orally.

23. 22. The method of claim 21, wherein the subject is a human or an animal.

24. 22. The method of claim 21, wherein the subject has any stage of chronic kidney disease or is undergoing kidney dialysis.

25. 22. The method of claim 21, wherein the ferric organic compound is formulated as a tablet, powder, suspension, emulsion, capsule, lozenge, granule, troche, pill, liquid, spirit, or syrup.

26. At least about 2 mg / cm of ferric organic compounds 2 The method of claim 21 having a dissolution rate of 1 / min.

27. 27. The method of any one of claims 21 to 26, wherein treatment with the ferric organic compound results in a decrease in the serum concentration of one or more substances in the subject, the substances being selected from the group consisting of creatinine, BUN, phosphorus, and calcium phosphorus product (CaxP).

28. 27. The method of any one of claims 21 to 26, wherein treatment with the ferric organic compound results in the prevention, amelioration, maintenance, or delay of one or more disease conditions in the subject, the disease conditions being selected from the group consisting of the progression of chronic kidney disease, the onset of hyperparathyroidism, the onset of bone disorders, the onset of cardiovascular disease, the precipitation of calcium phosphate in renal tissue, kidney stone formation, and the onset of metabolic acidosis.

29. A method according to any one of claims 21 to 28, wherein the ferric organic compound is ferric citrate.

30. 1. A treatment regimen for a subject with chronic kidney disease comprising administering to said subject an acceptable carrier and at least 2 mg / cm 2 The treatment regimen comprises a pharmaceutical composition comprising an effective amount of a ferric organic compound having a dissolution rate of 1 / min, wherein the pharmaceutical composition is administered in a single or multiple dose regimen.

31. The dissolution rate of the ferric organic compound is approximately 2.5 mg / cm 2 / min ~ approx. 3.0 mg / cm 2 31. The treatment regimen of claim 30, wherein the

32. The dissolution rate of the ferric organic compound is approximately 3.0 mg / cm 2 / min ~ approx. 3.5 mg / cm 2 31. The treatment regimen of claim 30, wherein the

33. The dissolution rate of the ferric organic compound is approximately 3.5 mg / cm 2 / min ~ approx. 4.0 mg / cm 2 31. The treatment regimen of claim 30, wherein the

34. The treatment regimen of any one of claims 30 to 33, wherein at least a portion of the pharmaceutical composition is administered orally.

35. 31. The treatment regimen of claim 30, wherein the chronic kidney disease includes any stage of chronic kidney disease and end stage renal disease.

36. 36. The treatment regimen of any one of claims 30 to 35, further comprising renal dialysis or peritoneal dialysis.

37. 37. The treatment regimen of any one of claims 30 to 36, wherein the ferric organic compound is formulated as a tablet, powder, suspension, emulsion, capsule, lozenge, granule, troche, pill, liquid, spirit, or syrup.

38. 38. The treatment regimen of any one of claims 30 to 37, wherein the ferric organic compound is ferric citrate.

39. 1. A pharmaceutical composition for treating a subject with chronic kidney disease, comprising at least about 2 mg / cm 2 A pharmaceutical composition comprising an effective amount of a ferric organic compound having a dissolution rate of 1 / min.

40. The dissolution rate of the ferric organic compound is approximately 2 mg / cm 2 / min ~ approx. 4 mg / cm 2 40. The pharmaceutical composition of claim 39, wherein the dosage is in increments of 100 mg / min.

41. 41. The pharmaceutical composition of claim 39 or 40, wherein the ferric organic compound is ferric citrate.

42. The pharmaceutical composition according to any one of claims 39 to 41, which is in a form suitable for oral administration.

43. 43. The pharmaceutical composition of claim 42, wherein the dosage form suitable for oral administration is a tablet, powder, suspension, emulsion, capsule, lozenge, granule, troche, pill, liquid, spirit, or syrup.

44. 44. Use of the pharmaceutical composition of any one of claims 39 to 43 in the manufacture of a medicament for treating a subject with chronic kidney disease.

45. 45. The use of claim 44, wherein the subject has any stage of chronic kidney disease or is undergoing kidney dialysis.

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