AT9490U1 - USE OF RARE EARTH COMPOUNDS FOR THE PREVENTION OF PRESERVATIVES - Google Patents

Abstract

The invention relates to the use of a non-toxic salt of a rare earth metal ion, optionally in hydrated form, for the manufacture of a medicament for the treatment or prevention of kidney stone diseases. The invention further relates to a pharmaceutical composition for the treatment or prevention of renal stone diseases, characterized in that it comprises at least one non-toxic salt of a rare earth metal ion, optionally in hydrated form.

Description

2 AT 009 490 U1

Cross-reference to related applications

The application claims according to 35 U.S.C. §119 (e) Priority of US Provisional Application 60 / 285,901 filed on April 23, 2001. The content of this application is incorporated herein by reference.

Area of Expertise

The invention relates to a method for the prevention or treatment of urolithiasis (kidney stone disease) by the administration of rare earth metal salts, for. Lanthanum salts to bind the oxalate from the diet and prevent its absorption into the gastrointestinal tract.

Background of the invention 15

Nephrolithiasis or urolithiasis is a common condition, such as kidney stone disease, which is defined as the development of stones in the urinary tract. This condition is a serious health problem. Depending on local conditions, between 1 and 14% of the population suffer from this condition. The economic damage of urolithiasis in the United States was estimated at $ 1.83 billion in 1993 (Grases, et al., International Urology and Nephrology, 31 (5) pp. 591-600 (1999)). The current prevention / treatment for urolithiasis, e.g. As potassium citrate tablets, is not easy to take and not very effective. Calcium oxalate is the predominant component in kidney stones. The amount of oxalate excreted in the urine has a significant impact on calcium oxalate supersaturation and kidney stone formation (R. Holmes, et al., Kidney International, 59, pp. 270-276 (2001)). It is also known that calcium oxalate is associated with arthritis (Reginato AJ, Kurnik BRC: " Calcium oxalate and other crystals associated with kidney disease 30 and arthritis ", Semin Arthritis Rheum 18: 198, 1989).

PCT publication WO 99/22744 suggests the use of aliphatic polyamines to reduce oxalate levels in the digestive tract. The publication suggests that the polyamines be administered orally, optionally in the presence of enzymes such as oxalate decarboxylase 35 or oxalate oxidase capable of degrading the oxalate. Various forms of oral dosing are described. The content of this publication is incorporated herein by reference.

In US 5,968,976 and WO 96/30029, hydrates of lanthanum carbonate [La 2 (C03) 3] are described for the treatment of hyperphosphatemia in patients with renal failure by removing elevated levels of phosphates. This treatment is particularly suitable for patients undergoing kidney dialysis. These compounds are particularly preferred.

There is a need for agents that bind oxalate and thereby inhibit or prevent kidney stone formation. The present invention addresses this need through the use of rare earth compounds to lower oxalate levels in animals, including humans.

The citation of the above documents should not be construed as an admission that the aforementioned belong to the relevant state of the art. All statements regarding the date or presentation of the content of these documents are based on the information available to the applicants and do not imply any acknowledgment as to the accuracy of the data or the content of these documents. Furthermore, all documents referred to in this application are hereby incorporated by reference herein in their entirety. 3 AT 009 490 U1

Disclosure of the invention

The invention relates to methods for the control, prevention or treatment of individuals at risk of oxalate deposits in the kidneys, i. Kidney stones, or the symptoms of oxalate deposits in the kidneys, i. Kidney stones, by the oral administration of rare earth salts, eg. Lanthanum salts which have high affinity oxalate binding properties.

Thus, in one embodiment, the invention relates to a method of inhibiting the formation of kidney stones in a subject, the method comprising administering to the subject's gastrointestinal tract an effective amount of a non-toxic rare earth metal salt, optionally in hydrated form. In typical embodiments, the rare earth metal salt has the formula [RE] a [X] bcH 2 O (1), where RE is a rare earth cation, X is a non-toxic anion, and a and b are each suitable values to form a neutral salt, and c has a value of 0 to 10.

In another embodiment, the invention relates to a method for modulating the absorption of oxalate from the gastrointestinal tract of an individual, the method comprising administering the compounds of formula (I) to an individual in need of such treatment.

In a further embodiment, the invention relates to the use of an optionally hydrated non-toxic rare earth metal salt for the manufacture of a medicament for the treatment of individuals at risk for or exhibiting the risk of oxalate-based kidney stones.

Brief description of the drawings

Figures 1A and 1B show the oxalate removal by 0.1 M lanthanum carbonate hydrates, d. H. Lanthanum carbonate tetrahydrate (La2 (C03) 3-4H20) (Figure 1A) and lanthanum pentahydrate (La2 (C03) 3-5H20) (Figure 1B) at pH 7 using an oxalate solution containing 0.01M sodium oxalate and 8, 5 g / l sodium chloride.

Figure 2 shows a comparison of the binding of oxalate by lanthanum carbonate tetrahydrate at pH 3 to pH 7.

Figures 3A and 3B show competitive binding of a 0.01 M oxalate and 0.1 M phosphate solution using 0.1 M lanthanum carbonate at pH 3 (Figure 3A) and pH 7 (Figure 3B).

Figures 4A and 4B show the binding of oxalate by yttrium carbonate [Y2 (C03) 3-3H20] (Figure 4A) and cercarbonate [Ce2 (C03) 3xH20] (Figure 4B) (ex Aldrich) at pH 3 and pH7 ,

Fig. 5 shows the oxalate removal by lanthanum chloride at pH 7.

Figure 6 shows the removal of oxalate and phosphate by lanthanum carbonate as the pH changes from pH 3 to pH 7. Possibilities for carrying out the invention

The invention provides pharmaceutical compositions using non-toxic salts of rare earth metal elements, optionally in hydrated form. The rare earth cations are typically trivalent anions from the lanthanide series, including, but not limited to, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Y and Sc , preferably La, Y and Ce. The cation is neutralized by negatively charged counterions or mixtures of counterions selected from carbonate, chloride, formate and acetate, preferably carbonate. Subscripts a and b in the above formula (1) are dependent on the nature of the counter ion and are selected so that a neutral salt is obtained. Hydrate water may be present and, if present, may include as many as up to 10 hydrate water molecules, preferably less than 8, more preferably less than 7.

Preferred rare earth metal salts are those of yttrium, lanthanum and cerium. These rare earth metal salts may be neutralized by counterions, such as acetates, chlorides or carbonates, as counterions, the carbonates being particularly preferred. Also preferred are the hydrated forms of these salts, in particular the hydrates with water of hydration of less than 7 water molecules per mole of salt, preferably 3 to 5 water of hydration.

The compositions of the invention are designed to remove oxalates from the gastrointestinal tract. The administration of these compositions is preferably to the upper digestive tract, more conveniently by oral administration. The compounds are effective in a pH range encountered at these sites, ranging from pH 2 in the stomach to pH 7 in the regions downstream thereof. At high pH, the compositions of the invention are not subject to degradation, and thus it is unnecessary to take special precautions, such as the provision of enteric coatings for oral administration.

It is believed that the conditions characterized by kidney stones are related to a malabsorption of oxalate from the intestinal tract; the inhibition of such absorption is apparently apt to bring this condition under control. While not wishing to be bound by theory, Applicants specifically include kidney stones in the conditions affected by excessive oxalate absorption from the gastrointestinal tract. In addition, a malabsorption of oxalate from the gastrointestinal tract is per se a condition requiring medication. The consequences of such a false absorption include the symptoms of kidney stones, however, other oxalate deposits may also form in other organs or oxalate levels in the bloodstream may be disadvantageous in themselves. Thus, any individual showing blood or serum oxalate levels higher than a normal level is also a candidate for treatment by the method of the invention. Method for the determination of oxalate levels in the diet and in the bloodstream or serum known in the art.

Pharmaceutical compositions of the invention may be formulated and prepared using methods known in the art. Suitable diluents, carriers, excipients and other components are also known. The compositions may desirably be in a dosage form to provide a single daily dose or a number of daily divided doses. Conventional pharmacological methods can be used to determine appropriate dose levels. Suitable formulations suitable for any route of administration are known in the art and are found, for example, in Remington's Pharmaceutical Sciences, Newest Edition, Mack Publishing Co., Easton, PA. Suitable forms for oral administration include solid forms for oral administration, including solid forms such as tablets, capsules and dragees, and liquid forms such as suspensions or syrups. In addition to diluents and carriers, it is common in the formulation of oral formulations to incorporate non-active ingredients such as thickeners, taste-improving components, and colorants. The compound in the drug may also be coated or treated to provide sustained release forms. Preferably, the required daily dose is given in tablet form, e.g. B. 5 AT 009 490 U1 in chewable tablet form. &Quot; treating " means either to improve an already existing state, or to inhibit the acquisition of a state or the further increase of a state that does not yet exist or that exists in a form that potentially transitions to more undesirable levels. Thus, " treat " or " treatment " both therapeutic and prophylactic use.

Individuals who may be treated by the methods of the present invention include those who have the symptoms of kidney stones, have confirmed diagnoses of kidney stones, or who are suspected of having kidney stones due to alternative symptoms to that condition. Suitable individuals for the methods of the invention are also those in which the removal of oxalate from the intestine would generally be beneficial; For example, individuals whose diet has a high degree of oxalate intake would also be included. It would also benefit individuals whose family history indicates a risk of malabsorption of oxalate from the gut. The attending physician would be in a position to identify those individuals who would benefit from the modulation of oxalate absorption from the gastrointestinal tract, based on diagnostic tools available in the art.

The compositions to be administered may contain additional active ingredients, such as the aliphatic polyamines disclosed in WO 99/22744, as described above, and any other medications compatible with the rare earth metal salts and for the treatment of other conditions to which the subject is also subject, are intended to include. While not intending to be bound by theory, it is believed that the rare earth compounds of the invention form insoluble materials with the dietary oxalate and cause excretion of the insoluble oxalate from the individual without the possibility of the oxalate being incorporated into the protein Urine system passes.

Having now generally described the invention, it will now be understood more readily by reference to the following examples, which are provided for illustration. It is not intended that the examples, unless stated otherwise, limit the invention.

Examples

example 1

Oxalate binding assay

To evaluate the removal of oxalate from a stock solution by lanthanum carbonate, an oxalate binding assay was developed. The assay was based on the phosphate binding assay already described for evaluating the removal of phosphate from a stock solution by lanthanum carbonate (US Pat. No. 5,968,976). Furthermore, buffer conditions were designed to mimic the conditions present in the stomach and small intestine. Briefly, 50 ml of a sodium oxalate stock solution containing 8.5 g / L of sodium chloride was adjusted to the desired pH using 5N HCl and the Mettler-Toledo DL58 autotitrator. Various combinations of oxalate and lanthanum carbonate levels were tested to determine which would maximize oxalate removal. Prior to the addition of the desired amount of lanthanum carbonate, a 2 ml sample was taken to serve as a time zero sample. The buffer volume was readjusted to 50 ml by again adding 2 ml of oxalate stock buffer to the pH adjusted buffer, and the lanthanum carbonate was added. A stopwatch was started and 2 ml samples were withdrawn at fixed time intervals over 20 minutes and filtered through a 0.02 pm syringe filter (Whatman Anotop 10 # 6809 1002). The filtered samples were analyzed 6 AT 009 490 U1 using a modified version of the Oxalate Assay Kit from Sigma Diagnostic (Sigma # 591-D) and an oxalate standard curve for oxalate. The modifications of the oxalate assay included testing only 25 μΙ of appropriately diluted filtered sample instead of 50 μΙ, and using only 0.5 ml of Oxalate Reagent A (Sigma # 591-10) and only 50 μΙ of oxalate. Reagent B (Sigma No. 591-2). In addition, the samples were tested at 590 nm in a Falcon 96-well microtiter plate using the Molecular Devices Spectramax 190 plate reader.

With regard to this assay, shown in Figure 1, oxalate binding was strongest when 50 ml of oxalate buffer containing 0.01 M sodium oxalate and 8.5 g / L sodium chloride was adjusted to pH 7, and Lanthanum carbonate in a concentration of 0.1 M (2.74 g La2 (C03) 3-4H20 (Figure 1A) or 2.65 g La2 (C03) 3-5H20 (Figure 1B) was added to improve the accuracy of the results The filtered samples were tested at 1/20 dilution and Figures 1A and 1B show that various hydrated forms of lanthanum carbonate, lanthanum carbonate tetrahydrate, and lanthanum carbonate pentahydrate, can effectively bind oxalate at pH 7.0.

The procedure described above was repeated at various pH's in the range of 3 to 7. The results are shown in FIG. These results show that lanthanum tetrahydrate can bind oxalate in this pH range (3 to 7), with preferential binding at pH 6 to 7.

Example 2

Competitive binding of oxalate and phosphate using lanthanum carbonate

After finding an appropriate concentration combination of oxalate and lanthanum carbonate, the competitive binding of oxalate and phosphate by lanthanum carbonate was also investigated. The competitive binding assay was based on the previously developed phosphate binding assay to evaluate the removal of phosphate from a stock solution by lanthanum carbonate (US Patent 5,968,976) and the results from current studies using oxalate. Briefly, a stock solution containing 0.1 M anhydrous disodium phosphate, 0.01 M sodium oxalate, and 8.5 g / L sodium chloride was prepared. Subsequently, 50 ml of this stock solution was adjusted to either pH 3 or pH 7 using 5 N and a Mettler-Toledo DL58 autotitrator. Immediately prior to the addition of lanthanum carbonate, a 2 ml sample was taken to serve as a time zero sample. The buffer volume was readjusted to 50 ml by again adding 2 ml of oxalate / phosphate stock buffer to the pH adjusted buffer, and the lanthanum carbonate was added. Lanthanum carbonate was added so that a concentration of 0.1M was present in the 50 ml of either the pH 3 or pH 7 phosphate / oxalate buffer. A stopwatch was started and 2 ml samples were taken at predetermined time intervals over 20 minutes and filtered through a 0.02 pm syringe filter (Whatman Ano-top 10 No. 6809 1002). As shown in Figure 3, the filtered samples were subsequently analyzed for the removal of both oxalate and phosphate. The oxalate removal was assessed by testing 1/20 dilutions of each sample using a modified version of the Sigma Diagnostic Oxalate Assay Kit (Sigma # 591-D) and an oxalate standard curve. Modifications to the oxalate assay included testing only 25 μΙ of appropriately diluted, filtered sample instead of 50 μΙ and using only 0.5 ml of Oxalate Reagent A (Sigma # 591-10) and only 50 μΙ of oxalate. Reagent B (Sigma No. 591-2). In addition, samples were tested at 590 nm in a Falcon 96-well microplate using the Molecular Devices Spectramax 190 plate reader. The phosphate removal was evaluated by testing 1/500 dilutions of each sample using the Sigma Diagnostics inorganic phosphorus assay kit (Sigma # 670-C) and a standard inorganic phosphate curve. The phosphorus assay was performed as outlined in Sigma Method # 670. 7 AT 009 490 U1

Figures 3A and 3B show the results of the competitive binding assay for oxalate solutions compared to phosphate solutions. One of the major ingredients in food that could compete with oxalate is phosphate. The phosphate levels in the diet are about 10 times higher than oxalate. The phosphate intake from the diet is between 800 and 1500 mg / day and about 300 mg P / meal. Dietary oxalate intake is about 100 mg / day. The results in Figure 3 examine the potential competitive effect of phosphate on oxalate binding by lanthanum carbonate. In the presence of a 10-fold excess of phosphate, it has been demonstrated that lanthanum carbonate pentahydrate preferentially binds oxalate to phosphate at pH 7.0 (Figure 3B), the pH optimum at which lanthanum carbonate has been shown to bind oxalate (Figure 2). The preferred binding of phosphate was shown at pH 3.0 (Figure 3A). This result shows, therefore, that lanthanum carbonate can still bind oxalate effectively even in the presence of a 10-fold excess of phosphate, and the different pH optimaities for binding of phosphate and oxalate also show that phosphate does not interfere with the binding of oxalate.

Example 3

Oxalate binding by additional rare earth compounds

These data show that other lanthanide salts can effectively bind oxalate. Yttrium carbonate and cercarbonate were tested for the ability to bind oxalate as described in Example 1. As shown in Figure 4, both 0.1 M yttrium carbonate (Figure 4A) and 0.1 M cercarbonate (Figure 4B) were as potent in binding oxalate at pH 7 to 0.1 M lanthanum carbonate, but were at pH 3 less effective.

Lanthanum, yttrium and cerium rare earth chlorides and acetates were also tested at pH 7 for oxalate binding using the assay method of Example 1. The assay was similar to that set forth in Example 1, except that after the oxalate solution was adjusted to the desired pH using 5N HCl, the pH was maintained with 1N NaOH. This was necessary because both the chloride and the acetate compounds significantly lower the pH of the solution as it is added. As shown in Figure 5, lanthanum chloride binds oxalate quite rapidly at pH 7. Similar results were obtained for cerium chloride and for yttrium chloride. Rare earth metal acetates were also tested at both pH 3 and pH 7, but the results showed that none of the rare earth acetates bound oxalate well enough at either pH.

Example 4

Simulating the pH transition in the digestive tract

To simulate the passage of lanthanum oxalate through the digestive system, a final experiment was designed which examines both oxalate and phosphate removal as the pH changes from pH 3 (ie, gastric pH) to pH 7 (ie, approx Value in the intestine) changes. This experiment was conducted to determine the applicability of lanthanum carbonate as an oxalate binder in the gut, where there is both a high level of competitive phosphate and a pH transition from pH 3 in the stomach to pH 7 in the small intestine. Previous results had shown that (1) oxalate binding was optimal at about neutral pH, (2) lanthanum carbonate was able to successfully compete with phosphate at pH 7, and (3) the binding ability was lower at pH 3.

Initially, 0.1 M lanthanum carbonate was added to a solution containing 0.1 M phosphate and 0.01 M oxalate at pH 3. The removal of both oxalate and phosphate was monitored for 10 minutes. After 10 minutes, the pH was gradually increased to pH 7. Samples were taken at pH 4, 5, 6 and 7 to detect changes in the amount of oxalate and phosphorous.

Claims (3)

8 AT 009 490 U1 phat present in the solution. As shown in Fig. 6, the solution was observed upon reaching pH 7 for an additional 10 minutes. The results show that lanthanum carbonate can effectively bind oxalate in the presence of excess phosphate under the pH conditions encountered during the transition from the stomach to the small intestine. Claims: 1. Use of lanthanum carbonate, optionally in hydrated form, for the manufacture of a medicament for the treatment or prevention of renal stone disease. 2. Use according to claim 1, characterized in that the drug is an oral dosage form. A pharmaceutical composition for the treatment or prevention of renal stone disease, characterized in that it comprises lanthanum carbonate, optionally in hydrated form, and a pharmaceutically acceptable excipient. For this purpose 6 sheets of drawings