US20070077314A1 - Powder mix of potassium calcium citrate for the treatment of kidney stones and osteoporosis - Google Patents

Powder mix of potassium calcium citrate for the treatment of kidney stones and osteoporosis Download PDF

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US20070077314A1
US20070077314A1 US11/183,140 US18314005A US2007077314A1 US 20070077314 A1 US20070077314 A1 US 20070077314A1 US 18314005 A US18314005 A US 18314005A US 2007077314 A1 US2007077314 A1 US 2007077314A1
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calcium
citrate
potassium
meq
composition
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Charles Y.C. Pak
Khashayar Sakhaee
Neill Walsdorf
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University of Texas System
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Assigned to MISSION PHARMACAL CO. reassignment MISSION PHARMACAL CO. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WALSDORF, SR., NEILL B., SAKHAEE, KHASHAYAR, PAK, CHARLES Y.C.
Priority to AU2006270162A priority patent/AU2006270162B2/en
Priority to JP2008521643A priority patent/JP2009514786A/ja
Priority to EP06787322A priority patent/EP1922064A4/en
Priority to PCT/US2006/027398 priority patent/WO2007011740A2/en
Publication of US20070077314A1 publication Critical patent/US20070077314A1/en
Assigned to THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM reassignment THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PAK, CHARLES Y.C., SAKHAEE, KHASHAYAR
Assigned to MISSION PHARMACAL CO. reassignment MISSION PHARMACAL CO. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WALSDORF, NEILL B., SR.
Priority to US12/784,305 priority patent/US8216614B2/en
Assigned to THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM reassignment THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MISSION PHARMACAL COMPANY
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/08—Oxides; Hydroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • Mineral compositions are commonly taken as dietary aids, either as therapeutic preparations directed to a specific medical problem or as general nutritional supplements.
  • useful dietary supplements are dosage units of calcium citrate, orally administered in solid or liquid form (U.S. Pat. Nos. 4,772,467, 4,814,177, and 4,851,221; each patent herein incorporated by reference).
  • Oral administration of calcium citrate as a nutritional supplement both modestly increases levels of urinary citrate and provides bioavailable calcium. By modestly increasing levels of urinary citrate, administration of calcium citrate counters calcium nephrolithiasis (i.e., formation of calcium-containing kidney stones).
  • calcium is more readily absorbed when administered as calcium citrate than as calcium carbonate, i.e., the administration of calcium citrate provides calcium that is more bioavailable. Improved absorption of calcium allows more effective treatment of calcium-deficiency conditions like osteoporosis.
  • Potassium citrate is widely used for the prevention of kidney stone formation. It has been shown to be effective in increasing urinary citrate, which is well known to retard the formation of calcium-containing kidney stones. Thus, this citrate salt of potassium has regulatory approval for the prevention of kidney stones containing calcium oxalate, the most common constituent of stones (Pak et al., 1985, J. Urol. 134:11-19). Potassium citrate is also an effective alkalinizing agent (Sakhaee et al., 1991, J. Clin. Endo. Metab. 72:396-400). By increasing the pH of urine, this treatment also prevents uric acid stones that have a tendency to form in relatively acidic urine.
  • potassium citrate may protect against bone loss.
  • Potassium citrate treatment has been shown to prevent calcium loss into urine (Sakhaee et al., 1991, J. Clin. Endo. Metab. 72:396-400) and to increase bone density (Pak et al., 2001, J. Urol. 168:31-34).
  • a typical dose of potassium citrate is 20 mEq (20 mmol) twice daily.
  • Calcium supplementation is also widely recognized to be a linchpin for countering bone loss that occurs following menopause. It works by increasing the level of calcium in the blood by providing sufficient calcium to be absorbed from the bowel. This rise in blood calcium then suppresses the secretion of parathyroid hormone that cause bone destruction, preventing bone loss.
  • Calcium citrate and calcium carbonate are two widely used calcium supplements for this purpose. Calcium citrate is believed to be preferable, because it is generally better absorbed (Heller et al., 2000, J. Clin. Pharmacol. 40:1237-1244). Moreover, calcium citrate supplementation modestly increases urinary citrate, an inhibitor of kidney stone formation; thus, the risk of stone formation that might rise from calcium supplementation is thought to be low from this supplementation.
  • Calcium citrate may be helpful by binding oxalate and preventing its absorption.
  • a typical dose of calcium citrate for the prevention of bone loss is 400-500 mg calcium given twice daily (Ruml et al., 1999, Am. J. Therap. 3:13-331).
  • liquid oral compositions comprising a calcium compound and an acidulant are disclosed.
  • the '490, '963, and '909 patents deal with adding calcium salt to acidic beverage to prevent erosion of teeth.
  • the product contains no potassium, an essential ingredient to achieve the benefits of the present invention.
  • the pH range disclosed in the patents is 3.5-4.5, whereas that of the present invention is higher; ⁇ 4.5 to ⁇ 6.
  • the teachings of this patent family do not provide an alkali load to the extent that the composition of the present invention does so.
  • U.S. Pat. No. 6,680,305 teaches physiologically acceptable aqueous solutions and methods for their use.
  • the '305 patent deals with making a parenteral solution that has electrolytes and buffer into which drugs to fight cancer and nutrients (hydroxyethyl starch) can be added.
  • the present invention is orally administered.
  • U.S. Pat. Nos. 4,871,554 and 4,722,847 disclose methods of adding calcium salt to citrus-containing fruit juices for calcium fortification of juices.
  • An important ingredient in one patent is malic acid, and that in another is phosphate.
  • the patents mention calcium bioavailability, but nothing of alkali load, rise in urinary citrate or stone prevention, which are the focus of our patent. No importance to the K:Ca:citrate ratio is made.
  • a composition comprising a mixture of potassium citrate, citric acid and a component selected from the group consisting of calcium carbonate, calcium hydroxide, calcium oxide and any combination thereof.
  • the mixture is a powder mixture.
  • the potassium citrate is at a level of from about 10 mEq to about 40 mEq
  • the calcium carbonate is at a level of from about 10 mEq to about 40 mEq
  • citric acid is at a level of from about 20 mEq to about 100 mEq.
  • the composition comprises about 20 mEq potassium citrate, about 20 mEq calcium carbonate, and about 20 mEq citric acid.
  • the composition further comprises an additional 0.17-1.34 mEq of citrate in the form of citric acid.
  • the composition may further comprises a sweetener. Where a sweetener is used, the sweetener may be an artificial sweetener.
  • the composition is in the form of a solution. In cases where the composition is in the form of a solution, the solution may be an aqueous solution. Other forms are possible, for example, the composition may be in the form of a suspension.
  • a powder mixture comprising potassium citrate, calcium carbonate and citric acid which when dissolved in water yields an aqueous solution of potassium, calcium and citrate at a molar ratio of potassium:calcium:citrate in a range of 2:1:1.33 to 2:1:2.67.
  • the potassium citrate is at a level of from about 10 mEq to about 40 mEq
  • the calcium carbonate is at a level of from about 10 mEq to about 40 mEq
  • citric acid is at a level of from about 20 mEq to about 100 mEq.
  • the powder mixture comprises about 20 mEq potassium citrate, about 20 mEq calcium carbonate, and about 20 mEq citric acid.
  • the composition comprises an additional 0.17-1.34 mEq of citrate in the form of citric acid.
  • the powder mixture has a molar ratio of potassium:calcium:citrate of 2:1:1.33.
  • a method of treating or preventing osteoporosis or kidney stones or both in an animal comprising the administration of a composition comprising a mixture of potassium citrate, citric acid and a component selected from the group consisting of calcium carbonate, calcium hydroxide, calcium oxide and any combination thereof, said composition having a molar ratio of potassium:calcium:citrate ranging from 2:1:1.33 to 2:1:2.67.
  • the animal to which the composition is administered is human.
  • the human is preferably a postmenopausal woman.
  • the administration comprises oral administration.
  • the animal to which the composition is administered has chronic diarrheal syndrome.
  • the composition has a molar ratio of potassium:calcium:citrate of 2:1:1.33.
  • a method of treating or preventing osteoporosis or kidney stones or both in an animal comprising the administration of a composition comprising a mixture of potassium citrate and calcium citrate having a molar ratio of potassium:calcium:citrate ranging from 2:1:1.33 to 2:1:2.67.
  • the animal to which the composition is administered is human.
  • the human is preferably a postmenopausal woman.
  • the administration comprises oral administration.
  • the animal has chronic diarrheal syndrome.
  • FIG. 1 graphically illustrates the delivery of alkali load; (A) net GI alkali absorption, (B) urinary ammonium, for various compositions, including that of the present invention.
  • FIG. 2 graphically illustrates (A) urinary pH and (B) urinary citrate levels for various compositions, including that of the present invention.
  • FIG. 3 graphically illustrates (A) urinary calcium and (B) urinary oxalate levels for various compositions, including that of the present invention.
  • FIG. 4 graphically illustrates (A) undissociated uric acid and (B) relative saturation ratio levels for various compositions, including that of the present invention.
  • FIG. 5 graphically illustrates (A) serum calcium and (B) serum parathyroid hormone for various compositions, including that of the present invention.
  • FIG. 6 graphically illustrates the percent change from placebo of (A) urinary hydroxyproline, (B) urinary N-telopeptide, and (C) type I collagen telopeptide for various compositions, including that of the present invention.
  • FIG. 7 graphically illustrates the trends in (A) urinary NTX and (B) serum CTX indicative of the trends in bone resorption as the treatment changed from placebo to potassium citrate to calcium citrate to combined treatment.
  • animal includes both human animal and non-human animals.
  • preventing as the term is associated with a medical condition, disease state or symptom is defined as delaying onset or averting onset of the medical condition, disease state or symptom.
  • treating means improving at least one symptom or condition.
  • the present invention teaches a modification of potassium calcium citrate (PCC) therapy which removes disadvantages of tablet formulations of potassium calcium citrate.
  • PCC potassium calcium citrate
  • the modification promotes the use of a powder mixture of potassium citrate and calcium citrate that dissolves rapidly and fully, permitting ingestion as a liquid. Some patients prefer to drink a liquid preparation rather than swallow tablets. The rapidity with which the powder formulations dissolved overcomes the problem of somewhat poor solubility of tablet formulations of potassium calcium citrate.
  • composition is administered orally as an aqueous solution; however, other forms of administration and other forms of the composition known to those skilled in the art (e.g., suspensions, or solid dosage forms such as tablets, etc.) are also part of the present invention.
  • Urinary pH a measure of urinary alkalinity, increased marginally with calcium citrate, significantly and substantially rose with potassium citrate, and even more so when both salts were given ( FIG. 2 ). Urinary citrate also increased in the same direction. These changes were due to, or represent response of the kidneys to, alkali load.
  • Urinary calcium increased during calcium citrate treatment (owing to absorption of calcium from the bowel), but decreased with potassium citrate treatment (due to the kidney's response to the alkali load) ( FIG. 3 ). It was also increased during combined treatment (with a slightly lower mean value from calcium citrate alone). Urinary oxalate decreased significantly with calcium citrate and marginally with combined treatment, as a result of the binding of oxalate by calcium in the bowel. It was unaffected by potassium citrate.
  • Urinary content of undissociated (non-ionized) uric acid decreased progressively with treatment, with the most prominent decline occurring with combined treatment ( FIG. 4 ).
  • This form of uric acid is sparingly soluble in urine, accounting for uric acid stone formation.
  • the above changes were largely due to the rise in urinary pH that increased the dissociation of uric acid to an ionized form, making uric acid more soluble and thereby rendering less likely the formation of uric acid stones.
  • Urinary saturation of calcium oxalate declined with potassium citrate, due to a reduction in urinary calcium and rise in citrate (which reduced ionized calcium by complexing calcium).
  • the combined treatment confers more alkali load than either component alone, and thereby produces the largest rise in urinary pH and citrate.
  • the combined treatment increases urinary calcium but decreases urinary oxalate, resembling the action of calcium oxalate, and is most effective in preventing uric acid stone formation. Additionally, it does not alter the saturation of calcium oxalate, the most common constituent of kidney stones, and probably confers inhibition against formation of calcium-containing kidney stones, by increasing urinary citrate, an “inhibitor” of stone formation.
  • Example 2 In the same study involving the identical subjects described in Example 1, the effect on bone metabolism of potassium citrate, calcium citrate, and combination of the two was examined. During the last two days of each two-week phase, serum and 24-hour urine samples were collected for assessment of calcium metabolism, alkali load, and bone turnover markers.
  • Serum Calcium and Parathyroid Hormone Serum Calcium and Parathyroid Hormone.
  • Serum calcium and parathyroid hormone did not change with potassium citrate treatment ( FIG. 5 ). Serum calcium increased slightly, and serum parathyroid hormone significantly decreased with calcium citrate. The combined treatment (resembling potassium calcium citrate) significantly increased serum calcium and marginally decreased serum parathyroid hormone.
  • the effect of treatment on bone resorption was evaluated from urinary hydroxyproline, urinary N-telopeptide, and serum type 1 collagen C-telopeptide. These bone-derived substances are called markers of bone resorption, since they are elevated in states of high bone destruction.
  • markers of bone resorption since they are elevated in states of high bone destruction.
  • FIG. 6 the changes in these markers from the placebo phase are displayed. The decline in the markers was generally least prominent for potassium citrate, intermediate for calcium citrate, and most marked for the combined treatment (resembling potassium calcium citrate).
  • the combined treatment with potassium citrate and calcium citrate suppresses parathyroid function, as does calcium citrate. However, unlike calcium citrate, the combined treatment confers alkali load, as does potassium citrate. The combined treatment suppresses bone resorption more effectively than either potassium citrate or calcium citrate alone.
  • the Atkins' diet was shown to produce a marked acid load, nearly double urinary calcium, and lower urinary pH (making urine more acid) and citrate (inhibitor of calcium stone formation) (Reddy et al., 2002, Amer. J. Kid. Dis., 40: 265-274).
  • the urine became more supersaturated with respect to stone-forming salts, making the formation of uric acid and calcium oxalate stones more likely.
  • the calcium balance turned more negative, because the intestinal calcium absorption was not changed even though urinary calcium increased.
  • a 24-hour urine sample was collected from above patients during their random (customary) diet and during restricted diet when they were instructed to avoid excess intake of calcium, salt and oxalate.
  • the samples were analyzed for constituents that are involved in stone formation (called stone risk factors) as shown in Table 2.
  • the data shows the stone risk factors and one standard deviation for the sample.
  • Urinary pH was low, due to loss of alkali in the diarrheal fluid and resulting acid load to the body. This undue acidity of urine increased the amount of uric acid in non-charged (undissociated, poorly soluble) form, accounted for uric acid stones.
  • Urinary oxalate was high normal, due to stimulation of oxalate absorption from the bowel known to occur in some bowel diseases.
  • Urinary citrate (a substance that inhibits formation of calcium oxalate stones) was low, from the response of the kidneys to the acid load. As a result, urine became more supersaturated with respect to calcium oxalate, accounting for calcium oxalate stones. Urinary calcium and magnesium tended to be low normal, consistent with the impairment in intestinal absorption of these divalent cations (doubly charged positive ions).
  • potassium calcium citrate in this invention, may be taken to provide alkali (to neutralize the acid load and prevent stone formation), as well as offer absorbable calcium (to help avert bone loss).
  • alkali to neutralize the acid load and prevent stone formation
  • absorbable calcium to help avert bone loss
  • potassium calcium citrate may be an ideal agent.
  • Preparation A contained just the amount of total citrate (40 mEq) to neutralize total amount of calcium and potassium cations (40 mEq).
  • the molar ratio of Preparation A was 2:1:1.33, since each dose in 250 cc yielded 20 mmol potassium, 10 mmol calcium, and 1.33 mmol citrate (40 mEq divided by a valence of 3).
  • the chemical composition of Preparation A was identical to a single dose of combined calcium citrate and potassium citrate treatment described in Examples 1 and 2.
  • Solutions B-F contained additional citric acid, with an excess of citrate over potassium and calcium of 5-40 mEq. Thus, while the molar ratio of potassium and calcium and potassium remained the same at 2:1, the citrate component of the molar ratio of potassium calcium citrate increased from 1.33 to 2.67. TABLE 3 Composition of 6 powder preparation of potassium calcium citrate Preparation A B C D E F Citric acid.
  • Preparation A was dissolved in 250 mL of water containing 100 mEq of hydrochloric acid.
  • two tablets of Citracal calcium citrate, 200 mg calcium per tablet, Mission Pharmacal Co., San Antonio, Tex.
  • 2 tablets of Urocit-K potassium citrate, 10 mEq per tablet, Mission Pharmacal, San Antonio, Tex.
  • the solution was analyzed for potassium, calcium and citrate. Exactly the same amounts of potassium, calcium and citrate were found in the two solutions, with a variation being within experimental error.
  • the pH was identical between the two solutions.
  • Solution A When added to 250 mL of deionized water, Solution A left a slightly cloudy fluid after 3 minutes without any settling. When added to 500 mL water, Solution A dissolved fully in 3 minutes imparting a clear solution (Table 4).
  • Preparations B-F dissolved rapidly in 250 mL of deionized water with bubbling (Table 4). As the citrate content increased from Preparation B-F, the powder dissolved more rapidly, with a greater elaboration of carbon dioxide (bubbling). Moreover, the taste of the solution became more tart, and pH decreased. All solutions were clear and free of smell.
  • Preparation B was tested for tolerance in 9 subjects who drank a full dose (250 mL). There were no complaints of upper abdominal discomfort or gas. One subject noted that one bowel movement was soft. One felt the preparation tasted flat.
  • Preparations C and D a flavoring and artificial sweetener were added; they were enclosed in convenient dose packets. Subjects found the preparation easy to prepare (in 250 mL water) and palatable. Some subjects preferred Preparation C for its lack of tartness, while others liked Preparation D better for is slight tartness.
  • Calcium hydroxide or another suitable calcium salt may be substituted for calcium carbonate (to be used in combination with citric acid to form soluble calcium citrate), although calcium carbonate is preferred.
  • a powder mix of potassium citrate and calcium citrate can be used directly, with an excess of citric acid added to increase solubility.

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US11/183,140 US20070077314A1 (en) 2005-07-15 2005-07-15 Powder mix of potassium calcium citrate for the treatment of kidney stones and osteoporosis
AU2006270162A AU2006270162B2 (en) 2005-07-15 2006-07-13 A powder mix of potassium calcium citrate for the treatment of kidney stones and osteoporosis
JP2008521643A JP2009514786A (ja) 2005-07-15 2006-07-13 腎結石及び骨粗鬆症の処置のためのクエン酸カリウムカルシウムの粉末混合物
EP06787322A EP1922064A4 (en) 2005-07-15 2006-07-13 PULSE MIXTURE OF CALIUM CALCIUM CITRATE FOR THE TREATMENT OF KIDNEY STONES AND OSTEOPOROSIS
PCT/US2006/027398 WO2007011740A2 (en) 2005-07-15 2006-07-13 A powder mix of potassium calcium citrate for the treatment of kidney stones and osteoporosis
US12/784,305 US8216614B2 (en) 2005-07-15 2010-05-20 Powder mix of potassium calcium citrate for the treatment of kidney stones and osteoporosis

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WO2014152789A1 (en) * 2013-03-15 2014-09-25 New York University Citrate containing beverage
CN104069125A (zh) * 2014-07-16 2014-10-01 华南理工大学 一种用于泌尿系磷酸盐结石的溶石剂及其制备方法
WO2019035989A1 (en) * 2017-08-17 2019-02-21 The Board Of Regents Of The University Of Texas System PREVENTION OF CALCIUM OXALATE RENAL CALCULATIONS BY POTASSIUM HYDROXYCITRATE

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US9529465B2 (en) * 2013-12-02 2016-12-27 At&T Intellectual Property I, L.P. Secure interaction with input devices
US20150216825A1 (en) * 2014-02-06 2015-08-06 University Of Houston System Organic acids as growth inhibitors of pathological calcification and uses thereof
US10285961B2 (en) 2014-02-06 2019-05-14 University Of Houston System Organic acids as agents to dissolve calcium minerals in pathological calcification and uses thereof
WO2016159897A1 (en) * 2015-04-01 2016-10-06 Ay Doğan Potassium citrate suspension
IT202200021258A1 (it) * 2022-10-14 2024-04-14 Neilos S R L “Composizione nutraceutica o farmaceutica per il benessere renale”

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