WO2019092179A1 - Pharmaceutical compositions comprising zs-9 - Google Patents

Abstract

ZS-9 is an efficient new molecular sieve used in compositions for the treatment of hyperkalemia, chronic kidney disease, coronary vascular disease, diabetes mellitus, and transplant rejection. As rather large quantities of the product have to be ingested good agreeability is of high importance to guaranty patient compliance. It was found that fine particle size permits different formulations of improved taste and mouthfeel for the patient. The formulation can further comprise an absorption inhibitor which captures the fine particles in a swelling matrix, which on the one hand prevents absorption in the gastrointestinal tract and on the other hand protects the molecular sieves from the strong acidic environment in the stomach. Optionally a mucoadhesive excipient can be added to elongate the passage time in the intestinal tract and thereby increase the amount of bond potassium still further.

Description

Pharmaceutical compositions comprising ZS-9

Microporous zirconium silicates are a novel group of molecular sieves used in compositions to remove toxins, e.g. potassium ions or ammonium ions, from the gastrointestinal tract or dialysate solutions. From the 1 1 known zirconium silicates ZS-9 showed a high affinity to monovalent ions. The sodium zirconium silicate known as ZS-9 has the chemical formula Na2.19ZrSi3.01 O9.1 1 X2.71 H20. It is a preferred crystalline structure of the eleven known sodium zirconium silicates due to favorable physical qualities like non-solubility, high potassium exchange capacity (KEC) and affinity. The microporous structure is composed of Zr03 octahedral units and Si02 tetrahedral units arranged in a three-dimensional crystalline lattice, the pore sizes are crystallographically regular.

Hyperkalemia is a common electrolyte disorder associated with potentially fatal arrhythmias. It most frequently occurs in patients with chronic kidney disease, heart failure and diabetes mellitus. ZS-9 is a potassium absorbing drug used in the treatment of hyperkalaemia which can be a life-threatening condition without any preliminary clinical indicators. Traditional treatments include the use of organic polymers like Kayexalate® also known as Sodium polystyrene sulfonate (SPS) or Patiromer (Veltassa). Kayexalate® is viewed controversially concerning its safety and efficacy; as it has a low selectivity for potassium ions, is only known with sodium as counter ion and exhibits a tendency to cause severe constipation.

ZS-9 is an insoluble, non-systemic inorganic cation exchanger. It has a high affinity to potassium and entraps it effectively over other monovalent or divalent cations. This makes it ideal in the treatment of hyperkalemia (Pharmacotherapy 2016, 36(8), 923; Am. J. Kidney Dis. 2014, 63 (5), A1 15). The mode of action is ion-exchange: sodium ions in the structure of zirconium silicate are exchanged for potassium ions. Potassium ions preferably bind to the cyclic structure of zirconium silicate due to their more suitable ion diameter compared to sodium ions.

ZS-9 compositions known in the art are essentially insoluble in bodily fluids (at neutral or basic pH), they can be orally ingested in order to remove toxins in the gastrointestinal system. However, ZS-9 is unstable in concentrations of hydrochloric acid (HCI) exceeding 0.2 M at room temperature, and will undergo structural collapse after overnight exposure. While ZS-9 is slightly stable in 0.2 M HCI at room temperature, at 37°C the material rapidly loses crystallinity. Due to the fact that small particles, less than 3 microns in diameter, could potentially be absorbed into a patient's bloodstream resulting in undesirable effects such as the accumulation of particles in the urinary tract of the patient, and particularly in the patient's kidneys. Unfortunately this leaves the patient with high amounts of a coarse powder/suspension to swallow during treatment which may led to noncompliance, not taking the whole amount or avoiding treatment, due to an unpleasant mouthfeel.

This leaves ZS-9 as highly efficient molecular sieves which's ion exchange capacity is reduced by the instability in an acidic environment and additionally has the issue of potential toxicity due to absorption into the blood stream. Attempts to counteract the instability by coating or avoid toxicity with the use of a larger particle size gave only partially satisfying results. Furthermore, ZS-9 can have a very gritty texture in the mouth and does not easily form a suspension. Failure to form a stable suspension means that a significant amount of the API remains in the container after administration resulting in a risk of under dosing. Moreover, particularly high effective doses are required for use in the treatment of hyperkalaemia; 10 g is required as an initial dose with 5 g being administered once daily as a maintenance dose. This makes the use of traditional tablets impractical because a single tablet would be too large to swallow and taking multiple tablets can result in problems with patient compliance. In view of the above mentioned difficulties there was a need to find formulations that overcome the above problems and are both practical to administer and result in accurate dosing.

It was an object of the present invention to provide a ZS-9 composition for oral administration

• which avoids at the same time absorption into the system to prevent possible side effects for the patient and an unpleasant mouthfeel for the patient, additionally stabilizes the molecular sieves in the acidic environment to retain its excellent potassium exchange capacity (KEC);

• in which ZS-9 is protected from pH mediated degradation, in particular under the acidic

environment of the stomach;

• which shows after administration in mammals, particular humans, a reduced toxicity by reduced absorption of ZS-9 into the blood stream;

• which has a better mouthfeel;

• which is a homogenous ready to use formulation;

• which is an easy to redisperse formulation; and/or

• which is stable at low pH ranges, e.g. at pH 2 and below, shows a reduced toxicity and has a better mouthfeel.

Detailed description:

In order to overcome the problems as described above as well as the drawbacks of known ZS-9 formulations and to solve the objectives mentioned above, the present invention provides novel ZS-9 compositions.

It was found that fine particle size permits different formulations of improved taste and mouthfeel for the patient. The present invention relates to pharmaceutical compositions of sodium zirconium cyclosilicate ZS- 9 with fine particle sizes, methods of preparing them and to the use of said novel formulations in the treatment of hyperkalemia. The formulations of the invention show improved stability in acidic environment and elongated passage time to maximize potassium exchange. The formulation can further comprise an absorption inhibitor which captures the fine particles in a swelling matrix, which on the one hand prevents absorption in the gastrointestinal tract and on the other hand protects the molecular sieves from the strong acidic environment in the stomach.

These formulations preserve the integrity of the crystalline material and with it the KEC. The microporous structure of ZS-9, contained in the composition of the invention, is composed of Zr03 octahedral units and Si02 tetrahedral units arranged in a three-dimensional crystalline lattice, as described in WO 2012/109590, the pore sizes are crystallographically regular. The addition of an absorption inhibitor embeds ZS-9 in a swelling matrix and protects against the acidic environment from the stomach. Furthermore the incorporation of fine ZS-9 particles into the swelling matrix prevent the absorption of particles of a fine size into the body. Optionally, a mucoadhesive excipient, e.g. Poloxamer 188, can be added to elongate the passage time in the intestinal tract and thereby increase the amount of bound potassium. Herein, the terms "sodium zirconium cyclosilicate" and "ZS-9" are used interchangeably.

This invention refers to a pharmaceutical composition for oral administration comprising ZS-9 with fine particle sizes, wherein the composition optionally further comprise an absorption inhibitor. Surprisingly, in compositions of the present invention the integrity of the crystalline structure and thus its high KEC are stabilized by the absorption inhibitor in particular under conditions of a pH between 1 and 2.

Particle size:

The use of fine particle size in the composition improves the taste and mouthfeel and thereby increases the patient compliance during the therapy. The particle size of the ZS-9 used in the compositions described within can be characterized by a particle size distribution of D(0.9) not greater than 40 μιη.

The use of a finer ZS-9 particle size in the compositions of the present invention lead to better patient compliance and by adding an absorption inhibitor absorption into the body and possible toxic side effects are prevented. The particle size of sodium zirconium cyclosilicate is measured according to methods known in the art. For example, laser diffraction (Malvern, Mastersizer 2000®) utilising a wet dispersion cell comprising demineralised water with one drop of Tween® 80, 2500 RPM, 2 minutes, obscuration: 10-20%.

In certain embodiments of the present invention, the pharmaceutical compositions of the present invention comprise ZS-9 having a D(0.9) particle size distribution:

• of not greater than about 40 μιη.

• of from, at a lower end, any of the values 1.0 μιη, 3.0 μιη, 5.0 μιη or 6.0 μιη to, at an upper end, any of the values 7.0 μιη, 10 μιη, 13 μιη, 20 μιη, 30 μιη, or 40 μιη;

• of about 1.0 μιη to about 7.0 μιη, 10 μιη, 13 μιη, 20 μιη, 30 μιη, or 40 μιη;

• of about 3.0 μιη to about 7.0 μιη, 10 μιη, 13 μιη, 20 μιη, 30 μιη, or 40 μιη;

• of about 5.0 μιη to about 7.0 μιη, 10 μιη, 13 μιη, 20 μιη, 30 μιη, or 40 μιη;

• of about 1.0 μιη, 3.0 μιη, 5.0 μιη or 6.0 μιη to about 7.0 μιη; • of about 1.0 μιη, 3.0 μιη, 5.0 μιη or 6.0 μιη to about 10 μιη;

• of about 1.0 μιη, 3.0 μιη, 5.0 μιη or 6.0 μιη to about 13 μιη;

• of about 1.0 μιη, 3.0 μιη, 5.0 μιη or 6.0 μιη to about 20 μιη;

• of about 1.0 μιη, 3.0 μιη, 5.0 μιη or 6.0 μιη to about 30 μιη; or

• of about 1.0 μιη, 3.0 μιη, 5.0 μιη or 6.0 μιη to about 40 μιη.

In some preferred embodiments of the present invention, the pharmaceutical compositions of the present invention comprise sodium zirconium cyclosilicate ZS-9 having a D(0.9) particle size distribution of

• 1.0 μιη to 30 μιη;

• 3.0 μιη to 20 μιη;

• 5.0 μιη to 10 μιη;

• 1.0 μιη to 7.0 μιη; or

• 3.0 μιη to 13 μιη.

Absorption inhibitor:

The pharmaceutical composition according to the present invention can further comprise an absorption inhibitor. An absorption inhibitor according to the present invention is an excipient/additive characterized in that its addition to an oral composition prevents the absorption of small particles, smaller than 3 microns, through the gastrointestinal (Gl) tract into the blood stream. The addition of an absorption inhibitor affects the viscosity of the oral composition in the way that it forms a matrix in the formulation by swelling and increases the viscosity of the formulation.

Suitable absorption inhibitor according to the present invention are in aqueous systems oligo or polysaccharides, synthetic or semi-synthetic macromolecular additives, inorganic additives; examples include but are not limited to oligo or polysaccharides, e.g., Tragacanth, xanthan gum, gum arabic, guar galactomannan, modified starch, alginic acid; synthetic or semi-synthetic macromolecular additives, e.g., polyvinyl alcohol, pectin, poly(acrylic acid) (PAA or Carbomer), carboxy methyl cellulose (CMC), hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), methyl hydroxypropyl cellulose, polyvinylpyrrolidone (PVP), carrageenan, methyl cellulose, povidone, gelatin; and in oily systems, e.g. triglycerides, corn oil, can be ethyl acrylate (Eudragit R, Eudragit S), bentonite, silica dioxide and mixtures thereof.

In another embodiment, the absorption inhibitor of the composition as described above preferably is selected from xanthan gum, pectin, carboxy methyl cellulose (CMC), polyvinylpyrrolidone, carrageen, bentonite, carbomer, methyl cellulose, povidone and gelatine for aqueous systems, preferably xanthan gum and carboxy methyl cellulose; and ethyl acrylate (Eudragit® R, Eudragit® S), silica dioxide, lecithin, for oiliy systems, e.g. triglycerides, corn oil, and mixtures thereof. Preferred absorption inhibitors are xanthan gum and CMC.

In an embodiment of the present invention, ZS-9 and the absorption inhibitor are used in a weight ratio of 13: 1 to 150:1 , preferably in a weight ratio of 25: 1 to 120: 1 , most preferably a weight ratio of 50:1 to 100: 1.

The composition of the present invention can be a liquid to semi-solid composition comprising ZS-9 and an absorption inhibitor, preferably a suspension or paste, wherein ZS-9 and the absorption inhibitor are ideally combined in a weight ratio of 13:1 to 150:1 , preferably in a weight ratio of 25: 1 to 120: 1 , most preferably a weight ratio of 50: 1 to 100: 1.

Additional additives:

a) Tensides

As described above beside ZS-9 and at least one absorption inhibitor the compositions of the present invention optionally include further components.

Tensides are commonly used to stabilize formulations with respect to separation or agglomeration. Tensides can are surface active agents which include emulsifiers, wetting agents, dispersants and so forth. Tensides in this invention include but are not limited to Tween 20 or Polysorbate 20, which is a polyoxyethene sorbitan fatty acid ester, and Poloxamer 188. Further tensides are sodium dodecylsulfate, sodium cetyl stearyl sulfate, sodium dioctylsulfosuccinate, lecithin, cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, cholesterol, sorbitan fatty acids, polyoxyethylene fatty acid glycerides, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, lignosulfonates, Poloxamer 188, Poloxamer 407.

One embodiment of this invention refers to a composition according to the previous embodiments, further comprising a tenside.

The tenside is preferably selected from sodium dodecylsulfate, sodium cetyl stearyl sulfate, sodium dioctylsulfosuccinate, lecithin, cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, cholesterol, sorbitan fatty acids, polyoxyethene sorbitan fatty acid ester, polyoxyethylene fatty acid glycerides, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, lignosulfonates, Poloxamer 188, Poloxamer 407, Tween 20, and mixtures thereof.

In a preferred aspect of the previous embodiments of the invention the tenside is selected from Tween 20 and/or Poloxamer 188.

In yet another preferred aspect of the previous embodiments the tenside is Tween 20. Another embodiment refers to a homogeneous composition according to the previous embodiments comprising ZS-9 in 20-45% w/w, preferably 25-40% ZS-9 w/w, most preferably 30-38% ZS-9 w/w, an absorption inhibitor, which is xanthan gum and/or CMC and a tenside.

Another embodiment refers to a homogeneous composition according to the previous embodiments comprising ZS-9 in 20-45% w/w, preferably 25-40% ZS-9 w/w, most preferably 30-38% ZS-9 w/w, an absorption inhibitor, which is xanthan gum and/or CMC and a tenside, which is Tween 20.

One embodiment of this invention refers to a composition comprising 20-45% w/w ZS-9, preferably 25-40% w/w ZS-9, most preferably 30-38% w/w ZS-9, and 0.3-1.5% absorption inhibitor; preferably 0.4-1.0% w/w absorption inhibitor, most preferably 0.5-0.8% w/w absorption inhibitor, and 0-10% w/w tensides, preferably 2-5% w/w tenside, most preferably 3-4% w/w tenside, preferred tenside is Tween 20.

One embodiment of this invention refers to a composition in form of ZS-9 comprising 20-45% w/w ZS-9, preferably 25-40% w/w ZS-9, most preferably 30-38% w/w ZS-9, and 0.3-1.5% w/w absorption inhibitor; preferably 0.4-1.0% w/w absorption inhibitor, most preferably 0.5-0.8% w/w absorption inhibitor, and 0-10% w/w Tween 20, most preferably 2-4% w/w Tween 20.

A preferred ready made composition of the invention contains ZS-9 in 45% w/w, the absorption inhibitor is 0.8% w/w xanthan gum and the tenside is 4% w/w Tween 20.

A preferred composition of the invention contains ZS-9 in 37.5% w/w, the absorption inhibitor is 0.5% w/w xanthan gum and tenside is 2% w/w Tween 20.

Another preferred composition of the invention contains ZS-9 in 30% w/w, the absorption inhibitor is 0.8% w/w xanthan gum and tenside is 4% w/w Tween 20.

Another preferred composition of the invention contains ZS-9 in 25%, the absorption inhibitor is carboxy methyl cellulose, and the tenside is Tween 20.

A preferred composition of the invention contains ZS-9 in 25% w/w, the absorption inhibitor is 5.5% w/w carboxy methyl cellulose, and the tenside is 4% w/w Tween 20.

b) Mucoadhesive excipients

Certain tensides also exhibit mucoadhesive properties and as such can be used either in their dual function or added to a mixture already comprising a tenside.

Bioadhesion is achieved by interaction of a synthetic or polymeric material and the mucous membrane of the Gl tract, thus prolonging the residence time and with it the action time of the active ingredients. Therefore mucoadhesives are optionally added to increase the contact time with ZS-9. One embodiment of this invention refers to a composition according to the previous embodiments, further comprising a mucoadhesive excipient.

Mucoadhesives in this invention include but are not limited to the groups of Poloxamers which are polyethylene-polypropyleneoxide triblock copolymers. Poloxamers can be Poloxamer 188 or Poloxamer 407. Further mucoadhesive polymers include but are not limited to: alignate, caromer, hyaluronic acid, carboxy methyl cellulose, pectine, polycarbophil, chitosan, polylysine, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyethylene oxide, polyvinyl alcohol, polyvinyl pyrrolidone, and mixtures thereof. [Schafer-Korting M., Drug Delivery, 2010, Springer-Verlag Berlin Heidelberg]

In a preferred aspect of the previous embodiments of the invention the mucoadhesive excipient is selected from polyethylene-polypropyleneoxide triblock copolymers, preferably the mucoadhersive excipient is selected from Poloxamer 188 and Poloxamer 407, most preferably Poloxamer 188.

One embodiment of this invention refers to a composition comprising 20-45% w/w ZS-9, preferably 25-40% w/w ZS-9, most preferably 30-38% w/w ZS-9, and an absorption inhibitor selected from xanthan gum and/or CMC, and a mucoadhesive excipient. A prefered mucoadhesive excipients in this embodiment is Poloxamer 188.

One embodiment of this invention refers to a composition comprising 37.5% w/w ZS-9, xanthan gum and Poloxamer 188.

A preferred composition of the invention contains 37.5% w/w ZS-9, and 0.4% w/w xanthan gum and 10% w/w Poloxamer 188.

A w/w 37.5% w/w ZS-9, and 0.75% w/w xanthan gum and 5% w/w Poloxamer 188.

Another embodiment of this invention refers to a composition comprising 20-45% w/w ZS-9, preferably 25- 40% w/w ZS-9, most preferably 30-38% w/w ZS-9, CMC and a mucoadhesive excipient.

One embodiment of this invention refers to a composition comprising 20-45% w/w ZS-9, preferably 25-40% w/w ZS-9, most preferably 30-38% w/w ZS-9, and 0.3-1.5% w/w absorption inhibitor; preferably 0.4-1.0% w/w absorption inhibitor, most preferably 0.5-0.8% w/w absorption inhibitor, including Tween 20 as a tenside, and further including 2-8% w/w mucoadhesive excipient, preferably 4-6% w/w mucoadhesive excipient.

One embodiment of this invention refers to a composition of ZS-9 according to the previous embodiments comprising 20-45% w/w ZS-9, preferably 25-40% w/w ZS-9, most preferably 30-38% w/w ZS-9, xanthan gum, Tween 20, Poloxamer 188.

One embodiment of this invention refers to a composition according to the previous embodiments comprising 37.5% w/w ZS-9, xanthan gum, Tween 20, and Poloxamer 188. A preferred composition of the invention contains 37.5% ZS-9 w/w, 0.65% w/w xanthan gum, 2% w/w Tween 20, and 7% w/w Poloxamer 188.

Dosage forms and further excipients:

As the intake of the molecular sieves is needed in a rather big quantity, 5-15g daily as reported by Linder et al. (Pharmacotherapy 2016, 36(8), 923), a suitable dosage form is very important.

In an embodiment of this invention the composition comprising ZS-9 and an absorption inhibitor is in the form of an oral suspension, which can be drunk. A homogeneous and easy to re-disperse composition in form of a ready-made solution comprising ZS-9, an absorption inhibitor and optionally further additives can be used directly from the bottle. In another embodiment the composition of this invention is in the form of a paste e.g. packet in a sachet or tube, which can be directly eaten from the packet.

In another embodiment the dosage form of this invention is solid for example in form of a slice or bar. Preferably the composition of this invention is in the form of a homogeneous mixture in form of a ready- made solid of ZS-9 is described, which can be eaten directly from the package. A homogenous composition according to the present invention is uniform in composition or character, no particles or precipitate are visible.

As mentioned above, in one embodiment the dosage form of the invention refers to a liquid to semi-solid composition comprising ZS-9 and an absorption inhibitor, preferably a suspension or paste. In one aspect of said embodiment the composition of the invention is a homogeneous and easy to re-disperse composition in form of a ready-made suspension or paste comprising 20-45% w/w ZS-9, preferably 25-40% w/w ZS-9, most preferably 30-38% w/w ZS-9. In yet another preferred aspect of said embodiment the composition of the invention refers to a homogeneous or easy to re-disperse composition in form of a ready- made suspension or paste of ZS-9 comprising 0.3-1.5% w/w absorption inhibitor; preferably 0.4-1.0% w/w absorption inhibitor, most preferably 0.5-0.8% w/w absorption inhibitor.

One embodiment of this invention refers to a homogeneous and easy to re-disperse composition in form of a ready-made suspension or paste of ZS-9 comprising 20-45% w/w ZS-9, preferably 25-40% w/w ZS-9, most preferably 30-38% w/w ZS-9, and 0.3-1.5% absorption inhibitor; preferably 0.4-1.0% w/w absorption inhibitor, most preferably 0.5-0.8% w/w absorption inhibitor, optionally including 0-10% w/w tensides, preferably 2-5% w/w tenside, most preferably 3-4% w/w tenside, and further optionally including 0-10% w/w mucoadhesive excipient, preferably 2-8% w/w mucoadhesive excipient, most preferably 4-6% w/w mucoadhesive excipient.

As mentioned above in one embodiment of this invention the composition is a solid composition in the form of a ready made solid form, e.g. a slice or bar. In one aspect of said embodiment the composition of the invention is a homogeneous composition in form of a ready-made solid comprising 10-45% w/w ZS-9, preferably 20-40% w/w ZS-9, most preferably 25-38% w/w ZS-9, and the absorption inhibitor is carboxy methyl cellulose (CMC).

In a preferred aspect of said embodiment of the invention ZS-9 is present in the composition in 25% w/w and the absorption inhibitor is CMC.

In yet another preferred aspect of said embodiment the composition of the invention refers to a homogeneous composition in form of a ready-made solid comprising 3-10% w/w of CMC as absorption inhibitor; preferably 4-8% w/w CMC, most preferably 5-7% w/w CMC.

A preferred ready made solid composition of the invention contains 25% w/w ZS-9 and 5.5% w/w or 7% w/w CMC.

As mentioned above in another embodiment of this invention refers to a solid composition comprising ZS- 9 and CMC as absorption inhibitor, preferably a slice or bar, wherein ZS-9 and the absorption inhibitor are used in a weight ratio of 1 : 1 to 15: 1 , preferably in a weight ratio of 2.5:1 to 10: 1 , most preferably a weight ratio of 3.5:1 to 7.6: 1.

As mentioned above in one embodiment of this invention the composition is a solid composition in the form of a ready made solid form, e.g. a slice or bar. In one aspect of said embodiment the composition of the invention is a homogeneous composition in form of a ready-made solid comprising 5-40% w/w ZS-9, preferably 7-30% w/w ZS-9, most preferably 10-20% w/w ZS-9, and the absorption inhibitor is xanthan gum.

In a preferred aspect of said embodiment of the invention ZS-9 is present in the composition in 10% w/w, and the absorption inhibitor is xanthan gum.

In yet another preferred aspect of said embodiment the composition of the invention refers to a homogeneous composition in form of a ready-made solid 5-25% w/w of xanthan gum as absorption inhibitor; preferably 10-22% w/w xanthan gum, most preferably 16-20% w/w xanthan gum.

A preferred ready made solid composition of the invention contains 10% w/w ZS-9 and 18% w/w xanthan gum.

As mentioned above in another embodiment of this invention refers to a solid composition comprising ZS- 9 and CMC as absorption inhibitor, preferably a slice or bar, wherein ZS-9 and the absorption inhibitor are used in a weight ratio of 0.2:1 to 8: 1 , preferably in a weight ratio of 0.3:1 to 3: 1 , most preferably a weight ratio of 0.5:1 to 1.3: 1.

The solid composition described herein optionally contains 0-10% w/w tensides, preferably 0-5% w/w tenside, most preferably 0-3% w/w tenside, and further optionally including 0-10% w/w mucoadhesive excipient, preferably 0-5% w/w mucoadhesive excipient, most preferably 0-3% w/w mucoadhesive excipient. In another embodiment of the present invention, the pharmaceutical compositions of the invention are in the form of an effervescent powder; effervescent tablet or chewable tablet.

A particular advantage of effervescent formulations is that they require a minimum amount of, or even no, mixing. The effervescent formulations use in situ carbon dioxide formation as a mechanism for granule disintegration and provide a mixing mechanism within the suspension. The chewable tablets of the invention have the further advantage that they can be administered without water and can be larger in size enabling them to accommodate the high effective dose of sodium zirconium cyclosilicate. Furthermore, the small particle size of the sodium zirconium cyclosilicate improves mouthfeel which, in combination with the effective dose being in a single tablet, leads to improved patient compliance.

The pharmaceutical composition according to the invention can further comprise at least one excipient selected from a sweetening agent, a filler, a binder, a disintegrant and a flavour modifier.

In such an embodiment, the at least one excipient preferably has a water solubility of greater than 33.3 mg/mL at room temperature. The filler is preferably selected from: sucrose, glucose anhydrous, dextrose (glucose monohydrate), polydextrose, mannitol, sorbitol, xylitol and lactose. The binder is preferably selected from povidone, low viscosity hydroxypropyl cellulose, and low viscosity hydroxypropoxy methyl cellulose. In particular, suitable binders may be selected from povidone (K25, K30); low viscosity hydroxypropyl cellulose (e.g. Klucel® ELF, Klucel® EF, Nisso® HPC-SL, Nisso® HPC-SSL); and low viscosity HPMC (e.g. Pharmacoat® 603 or 606). The disintegrant preferably comprises a source of carbonate selected from calcium carbonate, sodium bicarbonate, and sodium carbonate and a source of acid selected from citric acid and fu marie acid.

In a preferred embodiment, the composition consists of ZS-9 and excipients with a water solubility of greater than 33.3 mg/mL at room temperature. The water soluble excipients may include, but are not limited to, binders, fillers, disintegrants, sweetening agents and flavour modifiers (as defined above).

The effervescent pharmaceutical dosage forms of the invention preferably comprise a source of carbonate and an organic acid. The small particle size of the sodium zirconium cyclosilicate; the water soluble excipients and the effervescent nature of the solution combine to rapidly form a stable suspension that remains homogenous for 5 minutes, preferably 10 minutes and even more preferably 15 minutes after suspension preparation. This reduces the likelihood of sedimentation, thus reducing the risk of under dosing. The source of carbonate may be selected from calcium carbonate, sodium bicarbonate or sodium carbonate and the organic acid may be selected from citric acid or fumaric acid.

The compositions described above show improved performance by improving compliance of the patient during treatment due to unpleasant mouthfeel and taste; minimizing the absorption of ZS-9, improving stability of ZS-9 in acid environment; and thus protection again stomach acid and finally increasing potassium elimination due to a longer passage time of the formulation in the body. Medical use:

Another embodiment of this invention refers a composition according to the previous embodiments for use in a method of treatment of the human or animal body.

A composition according to the previous embodiments for use in the treatment or prevention of hyperkalemia. Other medical uses include the use of the composition in the treatment or prevention of chronic kidney disease, coronary vascular disease, diabetes mellitus, and transplant rejection.

Pharmaceutical compositions of the present invention are described, but not limited to, the following examples.

Examples:

Example A:

47.7 g NaOH were dissolved stepwise in 621.2 g water under stirring (solution heated up to 35-40°C) and 363.8 g Na20.Si02 were added to the solution after about 5 min stirring.

150.0 g Zr(OAc)4 were added to the mixture and a white, well-miscible suspension is achieved. The suspension was stirred for 25 min at room temperature.

40 g water were used to wash the suspension into the Kiloclave pressure reactor.

Stirring velocity was set to 350 rpm and the well-sealed reactor was heated from 30°C to 230°C in 5 h. The temperature of 230°C was maintained for 8 h at a pressure of 24 bar. Afterwards, the mixture was cooled to 40°C in 3 h.

150 mL water were applied to flush the Kiloclave and transfer the white suspension into a 1 L G3 glass

Biichner funnel. 1500 mL water were used for washing. The wet filter cake was filled into a 1 L baffled round- bottom flask and dried for 2 h at 127°C and 40 mbar in a Rotavapor until no further change in weight is observed.

1 15 g NaZS-9 were obtained after drying. The particle size distribution of the material was D(0.1 ) 1.8μιη; D(0.5) 7.0μιη and D(0.9) 12.48μιη. Example B:

Ready-made suspension

Example B1 :

ZS-9 37.5%

Xanthan gum 0.5%

Tween 20 2%

Water 60.0%

Example B2:

ZS-9 37.5%

Xanthan gum 0.75%

Poloxamer 188 5%

Water 56.75%

Example B3:

ZS-9 45%

Xanthan gum 0.8%

Tween 20 4%

Water 50.2%

Example B4:

ZS-9 37.5%

Xanthan gum 0.4%

Poloxamer 188 10%

Water 52.1 %

Example B5:

ZS-9 30.0%

Xanthan gum 0.8%

Tween 20 4%

Water 65.2% Example B6:

ZS-9 37.5%

Xanthan gum 0.6%

Poloxamer 188 7%

Tween 20 2%

Water 52.9%

Ready-made solid

Example B7:

ZS-9 25%

CMC 5.5%

Water 83.5%

Example B8:

ZS-9 25%

CMC 7%

Water 68%

Example B9:

ZS-9 10%

Xanthan gum 18%

Water 72%

Example B10:

ZS-9 25%

CMC 5.5%

Tween 20 4%

Water 65.5% Example C: Acid stability of new formulations

Formulation B8 (solid formulation) Formulation B5 (suspension)

Aliquots of each formulation and unformulated powder were transferred into citrate buffer, which was set to pH 2. The concentrations correspond to a 10% suspension density of pure ZS-9 for all samples.

The suspensions were stored at 37°C for 5 days and subsequently filtrated from the solution and dried.

A 0.2 % suspension of each sample and an untreated reference sample was prepared in a standard potassium chloride solution and homogenized for 2 hours. The potassium content of the standard solution before and after the mixing with ZS-9 was determined by ion chromatography. Based on these results the potassium exchange capacity (KEC) of each sample was calculated.

The results are displayed in the table below. Each value represents a double-determination.

Example D: Effervescent granules

Composition:

Technological procedure:

Batch size: 140 g.

Sodium zirconium cyclosilicate with a D(0.9) of 12.8 μιη was mixed with sucralose, mannitol and sodium bicarbonate in a polyethylene bag and screened through a 1.0 mm sieve. Powders were placed in a fluid bed granulator MiniGlatt (top spray) and granulated using 3% povidone water solution. The inlet air temperature was 80 °C and the product temperature was kept at about 30 °C. Air flow was kept in the range 10-20 m³/h to maintain a turbulent fluidization pattern of the material. Granulation duration was approximately 50 minutes. Granules were dried until the product temperature reached 42 °C and the resulting dried granules had a water activity of 0.088.

Orange aroma and citric acid were added to the dry granules, mixed in a polyethylene bag and screened through a 1.0 mm sieve.

The prepared granules were readily dispersible in water with the granules disintegrating in within 30 seconds to form a white suspension. Example E: Effervescent tablets

Composition:

As in Example D

Technological procedure:

The granules produced in Example D were compressed into tablets on single stroke tablet press using round flat punches with a 25 mm diameter. Tablets with a 3.49 g mass were compressed using a 66 kN compression force which resulted in tablets with a thickness of 4.85 mm and a disintegration time of approximately 1 ,5 minutes in water at room temperature.

Example F: Chewable tablets

Composition:

Technological procedure:

Batch size: 72.1 g.

A granulation liguid was prepared by dissolving sucralose and citric acid in a 3.9% povidone water solution. Sodium zirconium cyclosilicate with a D(0.9) of 12.8 μιη and mannitol were mixed in a polyethylene bag and screened through a 1.0 mm sieve. The powder was placed in a fluid bed granulator MiniGlatt (top spray) and granulated using the granulation liguid. The inlet air temperature was 80 °C and the product temperature was kept at about 30 °C. Air flow was kept in the range 10-15 m³/h to maintain a turbulent fluidization pattern of the material. Granulation duration was approximately 60 minutes. The granules were dried until product temperature reached 41 °C and the resulting dried granules has a water activity of 0.141 . Orange aroma was added to the dry granules and mixed in polyethylene bag.

The granules were compressed into tablets on a single stroke tablet press using round flat punches with a 25 mm diameter. Tablets with 3.50 g mass were compressed using a 52 kN compression force which resulted in tablets with a thickness of 5.15 mm and disintegration time of approximately 5 minutes 37°C.

Claims

Claims:

1. A pharmaceutical composition for oral administration comprising sodium zirconium cyclosilicate ZS-9 having a particle size distribution D(0.9) of not greater than 40 μιη.

2. The pharmaceutical composition according to claim 1 wherein the D(0.9) is from, at a lower end, any of the values 1.0 μιη, 3.0 μιη, 5.0 μιη or 6.0 μιη to, at an upper end, any of the values 7.0 μιη, 10 μιη, 13 μιη, 20 μιη, 30 μιη, or 40 μιη.

3. The pharmaceutical composition according to any preceding claims, further comprising an

absorption inhibitor, optionally being selected from xanthan gum, pectin, carboxy methyl cellulose (CMC), polyvinylpyrrolidone, carrageen, bentonite, carbomer, methyl cellulose, povidone, gelatine, ethyl acrylate (Eudragit® R, Eudragit® S), silica dioxide, lecithin, triglycerides, corn oil, and mixtures thereof.

4. The pharmaceutical composition according to claim 3, containing ZS-9 and the absorption

inhibitor in a weight ratio of 13: 1 to 150:1 , preferably in a weight ratio of 25: 1 to 120: 1 , most preferably a weight ratio of 50: 1 to 100:1 .

5. The pharmaceutical composition according to claim 3, wherein the absorption inhibitor is carboxy methyl cellulose and the weight ratio of ZS-9: carboxy methyl cellulose preferably is between 1 : 1 to 15:1 , 2.5:1 to 10:1 , or 3.5: 1 to 7.6:1 , or wherein the absorption inhibitor is xanthan gum and wherein the weight ratio of ZS-9:xanthan gum preferably is between 0.2:1 to 8:1 , 0.3: 1 to 3: 1 , or 0.5: 1 to 1.3:1.

6. The pharmaceutical composition according to any one of the preceding claims, further comprising a mucoadhesive excipient, preferably Poloxamer 188.

7. The pharmaceutical composition according to any one of claims 1 to 6, further comprising a

tenside, optionally being selected from sodium dodecylsulfate, sodium cetyl stearyl sulfate, sodium dioctylsulfosuccinate, lecithin, cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, cholesterol, sorbitan fatty acids, polyoxyethene sorbitan fatty acid ester, polyoxyethylene fatty acid glycerides, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, lignosulfonates, Poloxamer 188, Poloxamer 407, Tween 20; and mixtures thereof.

8. The pharmaceutical composition according to claim 7, wherein the tenside is selected from

Tween 20 and Poloxamer 188, and mixtures thereof.

9. The pharmaceutical composition according to any one of claims 1 to 8, containing 37.5% (w/w) ZS-9,

0.65% (w/w) xanthan gum,

2% (w/w) Tween 20, and

7% (w/w) Poloxamer 188.

10. The pharmaceutical composition according to any one of claims 1 to 8, containing 25% (w/w) ZS- 9 and from 5.5% (w/w) to 7% (w/w) CMC.

1 1. The pharmaceutical composition according to any one of claims 1 to 6, further comprising at least one excipient selected from a sweetening agent, a filler, a binder, a disintegrant and a flavour modifier,

wherein the filler is preferably selected from: sucrose, glucose anhydrous, dextrose (glucose monohydrate), polydextrose, mannitol, sorbitol, xylitol and lactose,

wherein the binder is preferably selected from povidone, low viscosity hydroxypropyl cellulose, and low viscosity hydroxy propoxy methyl cellulose,

and wherein the disintegrant preferably comprises a source of carbonate selected from calcium carbonate, sodium bicarbonate, and sodium carbonate and a source of acid selected from citric acid and fumaric acid.

12. The pharmaceutical composition according to claim 1 1 , wherein the excipient has a water

solubility of greater than 33.3 mg/mL at room temperature.

13. The pharmaceutical composition according to any one of the preceding claims, wherein the

composition is in a dosage form selected from the group consisting of effervescent powder, effervescent tablet, chewable tablet, oral suspension, paste, slice and bar.

14. A pharmaceutical composition according to any one of the preceding claims for medical use.

15. A pharmaceutical composition according to any one of the preceding claims for use in the

treatment of hyperkalemia.