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Methods and compositions for selectively removing potassium ion from the gastrointestinal tract of a mammal

a technology of gastrointestinal tract and composition, applied in drug compositions, synthetic polymeric active ingredients, metabolic disorders, etc., can solve the problems of high risk of hyperkalemia in certain groups, high risk of patients at the extreme of life, and limited current treatment options for hyperkalemia

Inactive Publication Date: 2013-10-03
RELYPSA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0029]In the various embodiments of the first and second aspects of the invention, the selectivity (e.g., permselectivity) of the pharmaceutical composition (such as core-shell particles) of the invention is sufficiently persistent to have a beneficial effect, such as a beneficial prophylactic or a beneficial therapeutic effect. In particular, in applications involving the gastrointestinal environment, the compositions (and core-shell particles) of the invention can remove a greater amount of potassium ion than sodium ion from the gastrointestinal tract (within a potassium-binding period representative of the transit time for the lower colon), and can have a persistent selectivity for potassium ion over one or more divalent ions, e.g., magnesium ion, calcium ion (over a divalent ion-binding period representative of the transit time through the gastrointestinal tract or a relevant portion there of (e.g., through the small intestine and the colon)).
[0053]Advantageously, the compositions and methods of the invention provide substantial advantages for removing monovalent ions from an environment, such as from a gastrointestinal tract of a mammal. In particular, the compositions and methods of the invention provide improved selectivity for binding monovalent ions preferentially over competing solutes, particularly over divalent cations such as magnesium ion and / or calcium ion present in the environment. The compositions and methods of the invention also provide improved retention of monovalent ions, even in the presence of substantial concentrations of competing solutes such as divalent cations, and even over long periods of time. The improvements in performance characteristics realized by the compositions and methods of the invention translate to substantial benefits for treatment of ion balance disorders in humans and other mammals. In particular, for example, the compositions and methods of the invention offer improved approaches (compositions and methods) for (prophylactic or therapeutic) treatment of hyperkalemia and other indications related to potassium ion homeostasis, and for treatment of hypertension and other indicates related to sodium ion homeostasis. Notably, such prophylactic and / or therapeutic benefits can be realized using the compositions and methods of the invention, while also reducing the risk of potential off-target effects (e.g., the risk of hypocalcemia and hypomagnesemia).

Problems solved by technology

However, certain groups definitely exhibit a higher incidence of hyperkalemia.
Patients at the extremes of life, either premature or elderly, are at high risk.
Most of the current treatment options for hyperkalemia are limited to use in hospitals.
For example, exchange resins, such as Kayexalate, are not suitable for outpatient or chronic treatment, due to the large doses necessary that leads to very low patient compliance, severe GI side effects and significant introduction of sodium (potentially causing hypernatremia and related fluid retention and hypertension).
Diuretics that can remove sodium and potassium from patients via the kidneys are often limited in their efficacy due to underlying kidney disease and frequently related diuretic resistance.

Method used

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  • Methods and compositions for selectively removing potassium ion from the gastrointestinal tract of a mammal
  • Methods and compositions for selectively removing potassium ion from the gastrointestinal tract of a mammal
  • Methods and compositions for selectively removing potassium ion from the gastrointestinal tract of a mammal

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Core-Shell Particles Having Crosslinked Polyvinylamine Shell (2 gm / 100 ml Scale) (Reference ID #253)

[0314]This example illustrates the preparation of a core-shell particle comprising a core component comprising polystyrenesulfonate and a shell component comprising a crosslinked polyvinylamine, using a multiphase in situ crosslinking process with 2 gm core polymer and epichlorhydrin crosslinker in a 100 ml scale reactor.

[0315]Shell Polymer

[0316]Polyvinylamine (Mw, 340,000; >90% hydrolyzed) was provided by BASF under trade name, lupamin9095 (20˜22 wt % in aqueous solution). As described herein, more than 90% of the polyvinylformamide was hydrolyzed (or deprotected) to produce polyvinylamine, but the balance of the polymer contained formamide groups, thus, a copolymer of polyvinylamine and polyvinylamide was used. In each example where the polymer was described as 90% hydrolyzed, this copolymer was generally the starting material. The solution was diluted with nanopure w...

example 2

Preparation of Core-Shell Particles Having Crosslinked Polyvinylamine Shell (100 gm / 1 Liter Scale) (Reference ID #293)

[0330]This example illustrates the preparation of a core-shell particle comprising a core component comprising polystyrenesulfonate and a shell component comprising a crosslinked polyvinylamine, using a multiphase in situ crosslinking process with 100 gm core polymer and epichlorhydrine crosslinker in a 1 liter scale reactor.

[0331]Shell Polymer

[0332]A polyvinylmine solution (Mw, 45,000; >90% hydrolyzed) was provided by BASF under trade name, lupamin5095 (20˜22 wt % in aqueous solution). The solution was diluted with nanopure water to 2.5 wt %. The solution pH was adjust to pH8.5 by using 33.3 wt % NaOH before coating.

[0333]Core Polymer

[0334]The core polymer was a polystyrenesulfonate material, Dowex 50WX4-200, as described in connection with Example 1.

[0335]Crosslinking Agent

[0336]The crosslinking agent was epichlorohydrin (ECH). The ECH was provided in a toluene sol...

example 3

Preparation of Core-Shell Particles Having Crosslinked Polyvinylamine Shell (4 gm / 100 ml Scale) (Reference ID #291)

[0345]This example illustrates the preparation of a core-shell particle comprising a core component comprising polystyrenesulfonate and a shell component comprising a crosslinked polyvinylamine, using a multiphase in situ crosslinking process with 4 gm core polymer and N,N-diglycidylaniline crosslinker in a 100 ml scale reactor.

[0346]Shell Polymer

[0347]A polyvinylmine solution (Mw, 45,000; >90% hydrolyzed) was provided by BASF under trade name, lupamin5095 (20˜22 wt % in aqueous solution). The solution was diluted with nanopure water to 2.5 wt %. The solution pH was adjust to pH8.5 by using 33.3 wt % NaOH before coating.

[0348]Core Polymer

[0349]The core polymer was a polystyrenesulfonate material, Dowex 50WX4-200, as described in connection with Example 1.

[0350]Crosslinking Agent. N,N-diglycidylaniline (N,N-DGA) was used as received from Aldrich.

[0351]Reactor

[0352]100 ml...

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Abstract

The present invention provides methods and compositions for the treatment of ion imbalances using core-shell composites and compositions comprising such core-shell composites. In particular, the invention provides core-shell particles and compositions comprising potassium binding polymers, and core-shell particles and compositions comprising sodium binding polymers, and in each case, pharmaceutical compositions thereof. Methods of use of the polymeric and pharmaceutical compositions for therapeutic and / or prophylactic benefits are also disclosed. The compositions and methods of the invention offer improved approaches for treatment of hyperkalemia and other indications related to potassium ion homeostasis, and for treatment of hypertension and other indicates related to sodium ion homeostasis.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 12 / 088,625, filed Sep. 30, 2008, which is a U.S. PCT National of PCT / US2006 / 038602, filed Mar. 30, 2005, which claims the benefit of U.S. Provisional Application Ser. No. 60 / 723,073 which was filed Sep. 30, 2005. The entire content of these applications is incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]Potassium (K+) is the most abundant intracellular cation, comprising ˜35-40 mEq / kg in humans. See Agarwal, R, et al. (1994) Gastroenterology 107: 548-571; Mandal, A K (1997) Med Clin North Am 81: 611-639. Only 1.5-2.5% of this is extracellular. Potassium is obtained through the diet, mainly through vegetables, fruits, meats and dairy products, with certain food such as potatoes, beans, bananas, beef and turkey being especially rich in this element. See Hunt, C D and Meacham, S L (2001) J Am Diet Assoc 101: 1058-1060; Hazell, T (1985) World Rev Nutr Die...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/74
CPCA61K9/5026A61K31/75A61K33/06A61K31/74A61K31/785A61K31/795A61P1/00A61P3/12A61P13/12A61P43/00A61K9/16A61K9/50A61K9/0053A61K9/14A61K9/1694
Inventor COPE, MICHAEL J.MANSKY, PAULLIU, FUTIANCHANG, HAN-TINGCHARMOT, DOMINIQUECONNOR, ERICBIYANI, KALPESHLIU, MINGJUNMONG, TONY KWOK-KONGCHEN, YAN
Owner RELYPSA INC
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