Nutritional Compositions for the Management of Hyponatremia - Patent application

Abstract

The present invention relates to novel oral urea compositions useful for the treatment or management of hyponatremia. Novel methods for making the urea compositions are also disclosed.

Description

[Technical Field]

[0001] The present invention relates to novel urea compositions for oral administration useful for treating or managing hyponatremia. Novel methods for making the urea compositions are also disclosed. [Background technology]

[0002] Hyponatremia is an electrolyte abnormality that can result in significant morbidity and mortality. This condition occurs when a person exhibits a positive water balance with or without a sodium deficit and is recognized when plasma sodium falls below a level of 135 mmol / L. Hyponatremia can occur alone in individuals who are consuming too much water. However, more frequently, hyponatremia results from a complication of medication or other underlying medical conditions that lead to decreased water excretion.

[0003] Hyponatremia can lead to water intoxication. Water intoxication occurs due to excessive water retention, causing the normal osmotic pressure (tension) of extracellular fluid to fall below safe limits. This can lead to potentially fatal impairment of brain function. Typical symptoms of water intoxication include nausea, vomiting, headache, and fatigue. Nausea can also release antidiuretic hormone (ADH), which causes water retention, which can create a positive feedback loop that further worsens the symptoms of hyponatremia. As the condition worsens, patients may experience decreased reflexes, convulsions, stupor, coma, or death.

[0004] One method of treating hyponatremia is to administer urea to patients. See, for example, the 2014 European Society of Endocrinology, European Society of Intensive Care, and European Renal Association-EDTA. While the benefits of oral urea administration are well known, challenges exist in developing oral urea formulations acceptable to patients. Issues include delivering a clinically beneficial amount of urea and the undesirable organoleptic properties of urea compositions. Attempts to reduce the bitterness have been made, such as using citric acid. One such composition contains 10 g of urea, 2 g of NaHCO3, 1.5 g of citric acid, and 200 mg of sucrose, dissolved in 50–100 mL of water. However, the resulting solution was found to be less palatable. Furthermore, this composition deteriorates significantly when exposed to moisture due to the reaction between sodium bicarbonate and citric acid.

[0005] One product currently on the market that addresses some of these issues is a powdered form of urea sold under the trade name Ure-Na™. This product contained a 15g dose of urea. The composition included 15g of urea, 1.19g of maltodextrin, and a natural flavor, e.g., cherry or lemon-lime. The inventors discovered that the original version of Ure-Na had problems with clumping and sticking during packaging. The product also tended to solidify after a period of storage. Summary of the Invention [Problem to be solved by the invention]

[0006] The present inventors have identified a need for improved urea compositions that are easier to manufacture while maintaining desirable properties for use in treating hyponatremia. [Means for solving the problem]

[0007] In one embodiment, the present invention relates to a powder composition that can be used to treat hypernatremia. The powder composition comprises urea in an amount effective for treating hyponatremia, a polysaccharide having a dextrose equivalent (DE) of 3 to 20, and calcium silicate, the polysaccharide having a particle size in the range of 3 to 7 microns (3-7 μm), with less than 10% of the particles by weight having a diameter less than 3 microns (3 μm) or greater than 7 microns (7 μm). The polysaccharide is preferably maltodextrin. The composition of the present invention is useful for delivering urea to patients suffering from hyponatremia in a form useful for oral administration.

[0008] In one aspect, the present invention relates to a powder composition comprising: (a) 60-80% by weight urea; (b) 4-15% by weight maltodextrin; and (c) 2-10% by weight calcium silicate having a particle size in the range of 3-7 microns (3-7 μm), with less than 10% by weight of the particles having a diameter less than 3 microns (3 μm) or greater than 7 microns (7 μm).

[0009] In another aspect, the present invention relates to a method for treating hyponatremia by oral administration of these urea compositions, which may involve dispersing or dissolving the product in water and then ingesting it. Alternatively, the powder may be added to food or pre-packaged food products. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention can be broadly categorized as a more stable powder composition containing urea in an amount effective for treating hyponatremia. It may also involve treating individuals suffering from or at risk of developing hyponatremia with the urea composition of the present invention. The composition may be dispersed in water or other liquid before ingestion by a patient, or may be added to food. Alternatively, the composition may be added to food and packaged until ready for use.

[0011] The present invention also relates to a method for producing a urea composition that avoids manufacturing and packaging problems caused by the active ingredient, urea. The inventors have identified several difficulties in producing a stable urea composition due to the unique properties of urea, including its hygroscopicity. For example, processing of Ure-Na powder was complicated by the adhesion of the powder to various parts of the manufacturing and packaging machinery and the clumping of the product. This required frequent shutdowns of the manufacturing line and cleaning of processing equipment to maintain consistent product quality.

[0012] The inventors have also found that Ure-Na products can cake during storage, resulting in waste of the finished product. Because the typical method of administration is to pour the powder from a sachet into a cup and disperse it in water by stirring, the solidified product makes this difficult. As a result, the solidified product goes unused, resulting in unnecessary waste of the product.

[0013] Previous attempts to solve these problems have included adding calcium silicate in the production of Ure-Na. Calcium silicate is a known anti-caking agent. However, while this added calcium silicate has the advantage of improving the product, the inventors have discovered that further improvements in the composition are needed. The present invention relates to a urea composition in powder form that does not clump and has desirable organoleptic properties, suitable for use in the treatment of hyponatremia.

[0014] The inventors discovered that previous Ure-Na™ compositions often clumped during manufacturing and stuck to machinery even when humidity was controlled. This led to the product becoming clumped over time. The original Ure-Na™ composition contained 15 g of urea and 1.19 g of maltodextrin. This composition was modified to add 4.8 g of calcium silicate to prevent clumping. However, the inventors found that clumps still appeared in the final packaged product. The calcium stearate used in this composition had an average particle size of between 7 and 10 microns (μm).

[0015] The inventors have discovered two key factors for avoiding agglomeration. First, proper selection of calcium silicate is important. Some calcium silicates with larger particle sizes, with an average particle diameter greater than 7 microns (7 μm), appear to reduce agglomeration to a lesser extent than particles with a diameter of 5 microns (5 μm). Therefore, proper selection of a metal silicate, such as calcium silicate with an average diameter of 3.0 to 7 microns (3.0 to 7 μm), more preferably 4.0 to 6.0 microns (4.0 to 6.0 μm), is desirable. Particles larger than these cutoff values ​​take longer to disperse or dissolve in water, while particles smaller than these cutoff values ​​contribute to agglomeration in the powder state.

[0016] Additionally, the particle size distribution of the calcium silicate is important, and the presence of significant amounts of calcium silicate above or below the aforementioned upper and lower micron limits is undesirable. For example, the particle size distribution of the calcium silicate is desirably tailored to avoid significant amounts of particles less than 3.0 microns (3.0 μm) and greater than 7.0 microns (7.0 μm). Thus, it is preferred that the calcium silicate have an average particle size within the range of 3.0-7.0 microns (3.0-7.0 μm), with less than 10% by weight of the particles being less than 3.0 microns (3.0 μm) or greater than 7.0 microns (7.0 μm) in diameter. In another embodiment, the calcium silicate has an average particle size within the range of 4.0-6.0 microns (4.0-6.0 μm), desirably a median particle size of 5.0 microns, with less than 10% by weight of the particles being less than 4.0 microns (4.0 μm) and greater than 6.0 microns (6.0 μm) in diameter. While a threshold of 10% by weight of particles outside the target particle size range is acceptable, preferably lower amounts of non-target particles, such as 8%, 6%, 4%, or even 1%, are desirable. For example, a composition may be desirable that has an average particle size within the range of 4-6 microns (4-6 μm), with less than 1% by weight outside that range.

[0017] Second, the inventors have found that an increased level of maltodextrin of 9.7% is desirable to reduce clumps. Therefore, it is desirable to have a maltodextrin level greater than 7% by weight, more preferably 7-12% by weight, and most preferably 9.7%. In one particular embodiment, the invention may be characterized by higher levels of maltodextrin (9.7% vs. 6.7%), lower levels of calcium silicate (5% vs. 21%), and a controlled particle size distribution of the calcium silicate. Other embodiments are more broadly characterized by the ranges and amounts disclosed herein.

[0018] The present inventors have discovered a novel urea composition that does not aggregate while providing properties suitable for oral urea compositions. The composition preferably contains 60-80% by weight, more preferably 65-75% by weight, and most preferably about 67% by weight of urea. The composition preferably contains 4-15% by weight, more preferably 7-12% by weight, and most preferably about 9.7% by weight of a polysaccharide having a dextrose equivalent (DE) of 3-20. Preferably, the polysaccharide is maltodextrin. The composition preferably contains 2-10% by weight, more preferably 3-8% by weight, and most preferably about 5% by weight of calcium silicate. Calcium silicate typically comprises 99% by weight of calcium silicate and 1% by weight of sodium sulfate. Therefore, sodium sulfate may be present in the urea powder composition. [Example]

[0019] Example 1 The following ingredients were added to a mixer to form a dry powder which was then added to the pouch in 15g quantities. [Table 1]

[0020] This composition is prepared by adding urea, maltodextrin, and calcium silicate to a mixer. The resulting powder is free-flowing and does not easily clump. This powder composition is preferably packaged in a pouch that can be sprinkled on food or mixed with a liquid such as water. When mixed with water, this composition forms a suspension, which allows for convenient ingestion. In this sense, this powder can be distributed and sold as a medical food. Alternatively, this powder can be incorporated into another medical food, such as a cookie or bar similar to a diet bar.

[0021] The product of Example 1 was packaged in a pouch using the same packaging used for previous Ure-Na™ products lacking calcium silicate. Previous Ure-Na™ products had a 1.4% consumer return rate due to clumps. The product of Example 1 had a 0.2% return rate. Therefore, the present invention resulted in a 7-fold reduction in returns due to clumps compared to conventional Ure-Na™ products.

[0022] Other embodiments and uses of the present invention will be apparent to those skilled in the art from consideration of the description and practice of the invention disclosed herein. All references cited herein, including all U.S. and foreign patents and patent applications, are specifically and entirely incorporated herein by reference. It is intended that the above description and examples be considered exemplary only, with the true scope and spirit of the invention being indicated by the appended claims.

Claims

1. (a) 60 to 80 wt. % urea; (b) 7 to 12% by weight of maltodextrin; (c) 3 to 7 wt. % calcium silicate; A powder composition for treating hyponatremia comprising:

2. The composition described in claim 1, wherein the particle size of the calcium silicate is in the range of 3 to 7 microns (3 to 7 μm), and less than 10% by weight of the particles have a diameter less than 3 microns (3 μm) or greater than 7 microns (7 μm).

3. The composition of claim 1 comprising approximately 9.7% by weight of maltodextrin.

4. The composition of claim 1, comprising 5% by weight of calcium silicate.

5. The composition of claim 1 further comprising a flavoring agent.

6. 10. The composition of claim 1, further comprising citric acid, sucralose, and a flavoring agent.

7. A method for treating hyponatremia, comprising administering the composition of claim 1 to a patient (excluding humans) suffering from hyponatremia.

8. 8. The method of claim 7, wherein the composition is administered by dispersing or dissolving the composition in water prior to ingestion.

9. 8. The method of claim 7, wherein the composition is administered by mixing the composition with food prior to ingestion.

10. (a) 60 to 80 wt. % urea; (b) 7 to 12% by weight of maltodextrin; (c) 5% by weight of calcium silicate; A powder composition for treating hyponatremia comprising:

11. A powder composition as described in claim 10, wherein the particle size of the calcium silicate is in the range of 3 to 7 microns (3 to 7 μm), and less than 10% by weight of the particles have a diameter less than 3 microns (3 μm) or greater than 7 microns (7 μm).

12. 11. The powder composition of claim 10, further comprising citric acid, sucralose, and a flavoring agent.

13. A method for treating hyponatremia, comprising administering the composition of claim 10 to a patient (excluding humans) suffering from hyponatremia.

14. 14. The method of claim 13, wherein the composition is administered by dispersing or dissolving the composition in water prior to ingestion.

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