WO2016159897A1 - Potassium citrate suspension - Google Patents

Potassium citrate suspension Download PDF

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Publication number
WO2016159897A1
WO2016159897A1 PCT/TR2015/000136 TR2015000136W WO2016159897A1 WO 2016159897 A1 WO2016159897 A1 WO 2016159897A1 TR 2015000136 W TR2015000136 W TR 2015000136W WO 2016159897 A1 WO2016159897 A1 WO 2016159897A1
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WO
WIPO (PCT)
Prior art keywords
suspension according
potassium citrate
pharmaceutical
pharmaceutical suspension
sodium
Prior art date
Application number
PCT/TR2015/000136
Other languages
French (fr)
Inventor
Doğan AY
Muharrem ÖLÇER
Aysel ÖLÇER
Original Assignee
Ay Doğan
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Ay Doğan filed Critical Ay Doğan
Priority to PCT/TR2015/000136 priority Critical patent/WO2016159897A1/en
Publication of WO2016159897A1 publication Critical patent/WO2016159897A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/194Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12Carboxylic acids; Salts or anhydrides thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/02Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers

Abstract

The present invention relates to the oral suspension comprising potassium citrate monohydrate between 540mg (5mEq) and 2160mg (20mEq) in 5ml for the treatment and prophylaxis of renal stones.

Description

POTASSIUM CITRATE SUSPENSION
DESCRIPTION
Potassium citrate alkalinizes the urine and reduces the formation of the two most common types of kidney stones: calcium oxalate and uric acid stones. The objective of treatment with Potassium Citrate is to restore normal urinary citrate (greater than 320 mg/day and as close to the normal mean of 640 mg/day as possible), and to increase urinary pH to a level of 6 or 7.
Also, potassium citrate helps relieve symptoms of cystitis and other mild urinary infections. It works by making urine less acidic and this helps relieve the discomfort caused by the infection.
The citrate moiety, which is largely oxidized, is absorbed while the K ion remains, leaving an alkali load. The alkali load increases urinary citrate and urinary pH. As a result, it decreases urinary saturation of calcium oxalate and inhibits both calcium oxalate and its crystallization.
Pharmaceuticals comprising potassium citrate is indicated for the management of renal tubuiar acidosis (RTA) with calcium stones, hypocitraturic calcium oxalate nephrolithiasis of any etiology, and uric acid lithiasis with or without calcium stones.
Potassium citrate is a potassium salt of citric acid with the molecular formula C6H5K3O7. Molecular weight is 306,39 g/mol.
Figure imgf000002_0001
Potassium citrate monohydrate is white crystals, granules or powder. One gram dissolves in 0.65 ml water. The pH of aqueous solution is about 8.5.
5 mEq equals 540mg of potassium citrate monohydrate. Also potassium citrate 10 mEq equals 1080mg and 15mEq equals 1620mg of potassium citrate monohydrate.
US4888182 and US4966776 relate to methods and compositions for the treatment and prophylaxis of calcium renal stones by administering the patient a daily oral dosage of a composition consisting essentially of potassium citrate. The daily oral dosage of potassium citrate is between about 30 meq and about 120 meq. A typical dosage scheme involves administering about 30 to 120 meq potassium citrate per day in divided doses. Such treatments are effective in dissolving existing calcium stones and preventing formation of new calcium stones. Moreover, the potassium citrate is superior to sodium citrate in the treatment of uric acid lithiasis. Potassium citrate therapy averts calcium renal stone formation, a complication which is often associated with sodium citrate or sodium bicarbonate alkalinization therapy.
CYTRA-3 Syrup contains Potassium Citrate Monohydrate 550 mg, Sodium Citrate Dihydrate 500 mg and Citric Acid Monohydrate 334 mg in each teaspoonful (5 ml_). Each 5 ml_ contains 1 mEq potassium ion and 1 mEq sodium ion and is equivalent to 2 mEq bicarbonate (HC03). This product alkalinizes the urine.
Mission Pharmacal (San Antonio, TX, USA) sells an extended-release potassium citrate tablet, Urocit-K, in three strengths: 5 -mEq, 10-meq, and 15- mEq tablets. The daily dose of Urocit-K is 30-60 mEq. Urocit-K is a wax matrix tablet containing potassium citrate, carnauba wax as extended-release agent, and magnesium stearate as lubricant.
US 4,904,478 teaches an extended-release wax matrix tablet of a highly water-soluble drug, sodium fluoride, wherein the carnauba wax, present at 35-70% w/w of the tablet weight, is dry mixed with the drug and other inactive ingredients prior to compression. In the case of potassium citrate, because the drug dosage is high, the inactive ingredients including the extended-release agent(s) must be kept below 25% w/w to keep the tablet size acceptable for swallowing. If carnauba wax is used at less than 25% w/w, Example 1 of US 2008/0131504 A! discloses that the drug and carnauba wax should be heated until the carnauba wax liquefies, to give an acceptable extended-release profile and abrasion.
WO 2014051443 relates to the extended-release potassium citrate tablets containing carnauba wax can be produced without melting the wax.
SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical oral suspension composition comprising potassium citrate for the treatment and prophylaxis of calcium renal stones in persons susceptible to such stone formations. (The terms of potassium citrate and potassium citrate monohydrate describes same compound.)
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to manufacture a pharmaceutical oral suspension form of high dosage potassium citrate having improved physico-chemical properties so that their use by patients. The pharmaceutical oral suspension comprises potassium citrate monohydrate between 540mg (5mEq) and 2160mg (20mEq) in 5ml, preferably 216Gmg (20mEq) in 5ml.
According to the present invention, a stable and easily pourable pharmaceutical composition prepares in the form of a suspension comprising potassium citrate.
The suspensions suitable for oral administration are aqueous-based. When an organic co- solvent is employed it is preferred that it is used in amounts of 0.5 to 10% (g/ml) of the total composition. Suitable solvents are those water-miscible solvents commonly used in the art, e. g., glycerol, propylene glycol (1 ,2-propane dio!), polyethylene glycol 300, polyethylene glycol 400 and ethanol. Preferably, glycerol is selected as co-solvent in the composition.
Oral suspensions according to the invention may contain other exctpients commonly employed in oral suspensions in order to provide the required stability and therapeutic efficacy.
Suspending agents can be any convenient agents known in the art for this purpose. The composition comprises at least one compound selected from the group consisting of xanthan gum, guar gum, hydroxypropylmethyl cellulose, hydroxypropyi cellulose, methylceilulose, hydroxyethylcellulose, polyvinyl pyrrolidone, alginates, acacia, tragacanth, carboxylmethylcellulose and sodium carboxylmethyice!lu!ose (Na CMC). Suspending agents may be employed in an amount within the range from about 0 to about 20% by weight of the powder formulation, and from about 0 to about 10% by weight of the oral suspension.
Sweeteners for use in the formulations of the invention may be any convenient agents known in the art for this purpose and may be selected from any compatible sweetener groups such as natural sweeteners like sucrose, fructose, dextrose, maltose, mannose, galactose, xylitol, sorbitol, or mannitol, glycerin as well as artificial sweeteners such as sodium cyclamate, sodium saccharin aspartame, acesulfam K and sucraiose. The composition comprises at least one sweetener. Preferably, sucraiose is used as sweetener.
Flavors and flavor modifiers or taste modifiers can also be used to further improve the taste and can be any convenient agents known in the art for this purpose and include, but are not limited to, orange flavor, vanilla flavor, licorice flavor, orange vanilla flavor, creme de mint, cherry flavor, cherry vanilla flavor, berry mix flavor, mandarin orange flavor and tutti-frutti- flavor, and combinations thereof. The composition comprises at least one flavoring or taste modifier. Preferably, orange flavor is used.
Preservatives can be any convenient agents known in the art for this purpose such as methy!paraben and propylparaben, benzoic acid, sodium benzoate, potassium sorbate. The composition comprises at least one preservative. Preferably, preservative agent used is mixture of methylparaben sodium and propylparaben sodium. Also wetting agents can be used in the composition such as polyethylene glycol stearates, (polyethylene glycol 400 monostearate), Poloxamer, Polysorbates.
Glidants can also optionally be used such as silicon dioxide, talc and titanium dioxide..
Methylparaben sodium, propylparaben sodium, potassium citrate, sucralose and Xanthan gum are dissolved in deionized water for preparing a palatable suspension with drug concentration of 20mEq/5 ml of potassium citrate. Glycerol and orange oil are added. Then the volume is completed with water and it is filled into glass or plastic (HDPE) 250 ml bottles for desired fill weight.
Example 1:
Figure imgf000005_0001

Claims

1. A pharmaceutical oral suspension comprising potassium citrate wherein the amount of potassium citrate monohydrate in 5ml is between 540mg (5mEq) and 2160mg (20mEq).
2. A pharmaceutical oral suspension according to claim 1 wherein the amount of potassium citrate monohydrate in 5ml is 2160mg (20mEq).
3. A pharmaceutical suspension according to claim 1-2 wherein it comprises at least one compound selected from the group consisting of xanthan gum, guar gum, hydroxypropylmethyi cellulose, hydroxypropyi cellulose, methylcellulose, hydroxyethylcellulose, polyvinyl pyrroiidone, alginates, Acacia, Tragacanth, carboxylmethy!cel!u!ose and sodium carboxylmethylcellulose (Na CMC) as suspending agents.
4. A pharmaceutical suspension according to claim 3 wherein suspending agent is xanthan gum.
5. A pharmaceutical suspension according to claim 4 wherein the amount of xanthan gum is from 0.05 to 2 grams in 100 ml of suspension.
6. A pharmaceutical suspension according to claims 1-5 wherein it comprises at least one co-solvent.
7. A pharmaceutical suspension according to claim 6 wherein co-solvent is glycerol.
8. A pharmaceutical suspension according to claims 1-7 wherein it comprises at least one sweetening agent.
9. A pharmaceutical suspension according to claim 8 wherein sweeting agent is sucralose.
10. A pharmaceutical suspension according to claims 1-9 wherein it comprises at least one preservative agent.
11. A pharmaceutical suspension according to claim 10 wherein preservative agent is mixture of methylparaben sodium and propylparaben sodium.
12. A pharmaceutical suspension according to previous claims wherein it uses for the treatment and preventing the formation of the kidney stones.
PCT/TR2015/000136 2015-04-01 2015-04-01 Potassium citrate suspension WO2016159897A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/TR2015/000136 WO2016159897A1 (en) 2015-04-01 2015-04-01 Potassium citrate suspension

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Application Number Priority Date Filing Date Title
PCT/TR2015/000136 WO2016159897A1 (en) 2015-04-01 2015-04-01 Potassium citrate suspension

Publications (1)

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WO2016159897A1 true WO2016159897A1 (en) 2016-10-06

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11395931B2 (en) 2017-12-02 2022-07-26 Mighty Fire Breaker Llc Method of and system network for managing the application of fire and smoke inhibiting compositions on ground surfaces before the incidence of wild-fires, and also thereafter, upon smoldering ambers and ashes to reduce smoke and suppress fire re-ignition
US11400324B2 (en) 2017-12-02 2022-08-02 Mighty Fire Breaker Llc Method of protecting life, property, homes and businesses from wild fire by proactively applying environmentally-clean anti-fire (AF) chemical liquid spray in advance of wild fire arrival and managed using a wireless network with GPS-tracking

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4888182A (en) 1983-04-11 1989-12-19 Board Of Regents Of The University Of Texas System Compositions and methods of treating calcium renal stones
US4904478A (en) 1983-08-11 1990-02-27 Mission Pharmacal Company Slow-release sodium fluoride tablet and method for treatment of osteoporosis
US4966776A (en) 1983-04-11 1990-10-30 Board Of Regents, The University Of Texas System Compositions and methods of treating calcium renal stones
US5759579A (en) * 1996-12-05 1998-06-02 American Home Products Corporation Pharmaceutical suspension systems
WO2007011740A2 (en) * 2005-07-15 2007-01-25 Mission Pharmacal Co. A powder mix of potassium calcium citrate for the treatment of kidney stones and osteoporosis
US20080131504A1 (en) 2006-12-01 2008-06-05 Mission Pharmacal Co. Short Term Slow Release Drug Delivery System
WO2014051443A1 (en) 2012-09-27 2014-04-03 Mendoza Wendell G Method for producing extended-release potassium citrate wax matrix tablet
US20140271929A1 (en) * 2013-03-15 2014-09-18 New York University Citrate containing beverage

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4888182A (en) 1983-04-11 1989-12-19 Board Of Regents Of The University Of Texas System Compositions and methods of treating calcium renal stones
US4966776A (en) 1983-04-11 1990-10-30 Board Of Regents, The University Of Texas System Compositions and methods of treating calcium renal stones
US4904478A (en) 1983-08-11 1990-02-27 Mission Pharmacal Company Slow-release sodium fluoride tablet and method for treatment of osteoporosis
US5759579A (en) * 1996-12-05 1998-06-02 American Home Products Corporation Pharmaceutical suspension systems
WO2007011740A2 (en) * 2005-07-15 2007-01-25 Mission Pharmacal Co. A powder mix of potassium calcium citrate for the treatment of kidney stones and osteoporosis
US20080131504A1 (en) 2006-12-01 2008-06-05 Mission Pharmacal Co. Short Term Slow Release Drug Delivery System
WO2014051443A1 (en) 2012-09-27 2014-04-03 Mendoza Wendell G Method for producing extended-release potassium citrate wax matrix tablet
US20140271929A1 (en) * 2013-03-15 2014-09-18 New York University Citrate containing beverage

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "tricitrates", July 2012 (2012-07-01), XP002740483, Retrieved from the Internet <URL:http://www.drugs.com/pro/tricitrates.html> *
CHARLES Y C PAK ET AL: "Augmentation of RenalCitrateExcretionby OralPotassium CitrateAdministration: TimeCourse, DoseFrequency Schedule, and Dose-Response Relatiooship", THE JOURNAL OF CLINICAL PHARMACOLOGY, vol. 24, 7 March 2013 (2013-03-07), pages 19 - 26, XP055193525, ISSN: 0091-2700 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11395931B2 (en) 2017-12-02 2022-07-26 Mighty Fire Breaker Llc Method of and system network for managing the application of fire and smoke inhibiting compositions on ground surfaces before the incidence of wild-fires, and also thereafter, upon smoldering ambers and ashes to reduce smoke and suppress fire re-ignition
US11400324B2 (en) 2017-12-02 2022-08-02 Mighty Fire Breaker Llc Method of protecting life, property, homes and businesses from wild fire by proactively applying environmentally-clean anti-fire (AF) chemical liquid spray in advance of wild fire arrival and managed using a wireless network with GPS-tracking

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