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    • 专利摘要:

    公开号:DK200600251U1
    申请号:DK200600251U
    申请日:2006-09-26
    公开日:2007-01-12
    发明作者:Michael J Abrams；Gary J Bridger；Simon P Fricker；Stefan R Idzan
    申请人:Anormed Inc；
    IPC主号:
    专利说明:

    DK 2006 00251 U4
    Use of lanthanum carbonate for the prevention of kidney stone disease. Cross reference to related applications
    This application requires priority from Provisional Application US 60/285901, filed April 23, 2001, according to U.S.C. § 119 (e).
    Technical area
    This provision relates to the prevention or treatment of urolithiasis (kidney stones) by administration of lanthanum carbonate to the binding of oxalate from the diet and the prevention of absorption thereof in the gastrointestinal tract.
    The background of the creation
    Nephrolithiasis or urolithiasis is a common disorder characterized by the development of stones in the urinary tract, such as kidney stone disease. This disorder poses a serious health problem. Between 1 and 14% of the population suffer from this disease, depending on local conditions. The economic impact of urolithiasis in the United States in 1993 was estimated to be $ 1.83 billion (Grases, et al., International Urology and Nephrology, 31 (5) pp. 591-600 (1999)). The current prevention / treatment of urolithiasis is not easy to ingest and is not very effective, for example potassium citrate loss.
    Calcium oxalate is the major component of kidney stones. The amount of oxalate which is excreted through the urine has a significant effect on the saturation of calcium oxalate and the formation of kidney stones. (R. Holmes, et al., Kidney International, 59, pp. 270-276 (2001)). In addition, calcium oxalate is also known to be associated with arthritis (Reginato AJ, Kurnik BRC: "Calcium oxalate and other crystals associated with kidney disease and arthritis," Semin Arthritis Rheum 18: 198, 1989).
    2 DK 2006 00251 U4 PCT publication WO 99/22744 proposes the use of aliphatic polyamines for reducing oxalate levels in the gastrointestinal tract. This publication suggests that the polyamines may be administered orally, optionally with enzymes, such as oxalate decarboxylase or oxalate oxidase, which can degrade oxalate. Various forms of oral dosages are described.
    U.S. Patent No. 5,968,976 and WO 96/30029 disclose lanthanum carbonate hydrates [La2 (CO3) 3] for the treatment of hyperphosphataemia in renal failure patients by removing elevated phosphate levels. This treatment is particularly suitable for patients undergoing renal dialysis. These compounds are highly preferred.
    There is a need for agents that bind oxalate and thus inhibit or prevent stone formation in the kidneys. The present invention addresses this need through the use of lanthanum carbonate to lower oxalate levels in animals, including humans.
    Description of the production
    The invention relates to methods for controlling, preventing or treating patients at risk of exhibiting the symptomology of oxalate deposits in the kidneys - that is, kidney stones, through oral administration of lanthanum carbonate with high affinity binding properties for oxalate.
    More specifically, the production in a first aspect relates to the use of the non-toxic salt, lanthanum carbonate, which salt is optionally hydrated, for the manufacture of a medicament for treating or preventing a kidney stone disorder.
    In another aspect, the preparation relates to a pharmaceutical composition for treating a kidney stone disorder which comprises lanthanum carbonate, optionally in hydrated form, and a pharmaceutically acceptable binder.
    3 DK 2006 00251 U4
    Brief description of the drawings
    Figures 1A and 1B show the removal of oxalate with 0.1 M lanthanum carbonate hydrates, i.e., lanthanum carbonate tetrahydrate (La2 (CO3) 3-4H20) (Fig. 1A) and lanthanum pentahydrate (La2 (CO3) 3-5H20) (Fig. 1B). pH 7 using an oxalate solution containing 0.01 M sodium oxalate and 8.5 g / L sodium chloride.
    Figure 2 shows a comparison between lanthanum carbonate tetrahydrate oxalate bond at pH 3 and at pH 7.
    Figures 3A and 3B show competitive binding of a solution of 0.01 M oxalate and 0.1 M phosphate using 0.1 M lanthanum carbonate at pH 3 (Figs.
    3A) and at pH 7 (Fig. 3B).
    Figure 5 shows the removal of oxalate with lanthanum chloride at pH 7.
    Figure 6 shows the removal of oxalate and phosphate with lanthanum carbonate during a pH change from pH 3 to pH 7.
    Embodiments of the invention
    With the preparation, pharmaceutical compositions are provided using non-toxic carbonate salts of lanthanum, optionally in hydrated form. The cation is offset by negatively charged carbonate ions. Crystal water may be present and in this case they may comprise as many as 10 moles of crystal water, preferably less than 8 and more preferably less than 7, preferably 3-5 moles of crystal water.
    The compositions of the invention are designed to remove oxalate from the gastrointestinal tract. These compounds are preferably administered to the upper digestive tract, most preferably by oral administration. The compounds are effective within a pH range, which is present at these sites, which vary from pH 2 in the stomach to pH 7 in the subsequent regions. The compositions according to the preparation are not degraded at high pH and therefore no special measures are necessary, such as the preparation of enteric coatings for oral administration.
    The kidney stones characteristic are thought to be related to an inappropriate absorption of oxalate in the intestinal tract; inhibition of such absorption is considered useful in controlling this disorder. Applicants specifically include kidney stones among the disorders that are affected by excessive oxalate absorption in the gastrointestinal tract without intending to be bound by any theory. In addition, an inappropriate oxalate absorption in the gastrointestinal tract is itself a disorder that requires remediation. The sequelae of such inappropriate abortion include the symptomology of kidney stones, but also in other organs other oxalate deposits may occur or the levels of oxalate in the blood can be harmful in themselves. This means that any patient who has oxalate levels in blood or serum higher than a normal level is also a candidate for treatment with lanthanum carbonate or a hydrated form. Methods for determining oxalate levels in the diet and in the blood or serum are known in the art.
    Pharmaceutical compositions of the invention for oral administration may be formulated and prepared using methods known in the art. Suitable diluents, carriers, binders and other ingredients are also known. It may be desirable for the compositions to be in a dosable form to provide a once daily dose, or a number of doses per day. day. Traditional pharmacological methods can be used to find suitable dose levels. Suitable formulations suitable for all forms of administration are known in the art and could be found, for example, in Reminqton's Pharmaceutical Sciences, most recently, Mack Publishing Co., Easton, PA. Suitable forms for oral administration 5 include solid forms for oral administration, including solid forms such as tablets, capsules and dragees, as well as liquid forms such as suspensions and oral solutions. In addition to diluents and carriers, it is customary to add non-active ingredients, such as thickeners, flavor enhancers and colorants in the formulation of oral preparations. The compound of the pharmaceutical composition may also be coated or treated to provide depot release forms. Preferably, the daily dose is given in tablet form, for example in the form of chewable tablets.
    "To treat" is to be understood as either ameliorating a pre-existing disorder or preventing a disorder from occurring or further aggravating a condition which does not yet exist or exists in a form with the risk of developing into more severe, unwanted levels. Therefore, "treating" or "treating" includes both therapeutic and prophylactic uses.
    Individuals who can be treated with the lanthanum carbonates of the invention include those who show the symptomology of kidney stones who have a confirmed diagnosis of kidney stones or where it may be presumed due to other symptoms of this disorder. Patients also suitable for the preparation of lanthanum carbonates are those who would benefit from a general removal of oxalate from the digestive system; individuals with, for example, a high level of oxalate uptake through the diet could also be included. Further, those individuals would benefit if family history indicates a risk of inappropriate oxalate absorption in the gastrointestinal tract. Based on the diagnostic tools available in the art, the treating physician would be able to identify those individuals who could benefit from a change in the gastrointestinal tract oxala loss.
    The compositions to be administered may include additional active ingredients, such as, for example, the aliphatic polyamines described above described in WO99 / 22744 and any other medication compatible with the salts of rare earths which may be intended for the treatment of other disorders also experienced by the patient. Without wishing to be bound by any theory, it is believed that the lanthanum carbonates according to the invention form insoluble substances with the oxalate from the diet and influence the excretion of insoluble oxalate from the patient without giving the oxalate an opportunity to enter the urinary tract.
    Following this general description of the invention, the same will be better understood by reference to the following examples, which are provided by way of illustration.
    7 DK 2006 00251 U4
    EXAMPLES
    EXAMPLE 1 Oxalate Binding Test
    An oxalate bond test was developed to investigate the removal of oxalate from a stock solution using lanthanum carbonate. The test is based on a phosphate bond test developed previously to investigate the removal of phosphate from a stock solution using lanthanum carbonate (US Patent 5,968,976). The buffer conditions were further determined to mimic the conditions present in the stomach and small intestine. Briefly, 50 mL of a stock solution of sodium oxalate, containing 8.5 g / L sodium chloride, was adjusted to the desired pH using 5N HCl and a Mettler-Toledo DL58 autotitrator. Various combinations of oxalate and lanthanum carbonate concentrations were tested to find the one with the greatest iron oxalate. A 2 mL sample was taken as sample at time zero prior to the addition of the desired amount of lanthanum carbonate. The buffer volume was supplemented to 50 mL by returning 2 mL of the oxalate buffer stock solution to the pH adjusted buffer and the lanthanum carbonate was added. A stopwatch was started and 2 mL samples were taken at predetermined time intervals over a period of 20 minutes and filtered through a 0.02 μιτι syringe filter (Whatman Anotop 10 # 6809 1002). The filtered samples were analyzed for oxalate using a modified version of Sigma Diagnostics' Oxalate As-say Kit (Sigma # 591-D) and an oxalate standard curve. Changes to the oxalate test included analysis of only 25 µL instead of 50 µL of the properly diluted, filtered sample as well as use of only 0.5 mL of Oxalate Reagent A (Sigma # 591-10) and only 50 µL of Oxalate Reagent B (Sigma # 591-2). Further, the samples were analyzed at 590 nm in a Falcon 96-well microplate using a MolecularDevices Spectramax 190 plate reader.
    For this test, shown in Figure 1, the oxalate bond was most potent when 50 mL of oxalate buffer containing 0.01 M sodium oxalate and 8.5 g / L of sodium chloride was adjusted to pH 7 and lanthanum carbonate was added to a concentration of 0.1 M (2.74 g La2 (CO3) 3-4H2O (Figure 1A) or 2.65g La2 (CO3) 3-5H2O (Figure 1B)). In order to maximize the accuracy of the results, the filtered samples were analyzed at a dilution of 1/20. Figures 1A and 1B show that various hydrated forms of lanthanum carbonate, namely lanthanum carbonate tetrahydrate and lanthanum carbonate pentahydrate, manage to bind oxalate effectively at pH 7.0.
    The above-described instructions were repeated at various pHs in the range of 3-7. The results are shown in Figure 2. These results show that lanthanum tetrahydrate is capable of binding oxalate in this pH range (3-7) with a preferred bond at pH 6-7.
    EXAMPLE 2
    Competitive binding of oxalate and phosphate using lanthanum carbonate
    Competitive binding of oxalate and phosphate with lanthanum carbonate was also investigated after an appropriate concentration combination of oxalate and lanthanum was found. The competitive binding test was based on the phosphate binding test developed previously to investigate the removal of phosphate from a lanthanum carbonate stock solution (US Patent 5,968,9699), as well as from the current oxalate studies.
    Briefly, 50 mL of a stock solution was prepared containing 0.1 M disodium phosphate anhydride, 0.01 M sodium oxalate and 8.5 g / L sodium chloride. Subsequently, 50 ml of this stock solution was adjusted to either pH 3 or pH 7 using 5N HCl and a Mettler-Toledo DL58 autotitrator. Just before the addition of the lanthanum carbonate, a 2 mL sample was taken as sample at time zero. The buffer volume was supplemented with 50 mL by returning 2 mL of the oxalate / phosphate buffer stock solution to the pH adjusted buffer and lanthanum carbonate was added. Lanthane carbonate was added such that a concentration of 0.1 M was present in the 50 mL of the phosphate / oxalate buffer of either pH 3 or pH 7. A stopwatch was started and 2 mL samples were taken at predetermined time intervals. over a period of 20 minutes and filtered through a 0.02 µm syringe filter (Whatman Anotop 10 # 6809 1002). As shown in Figure 3, the filtered samples were subsequently analyzed for the removal of both oxalate and phosphate. The removal of oxalate was determined by testing 1/20 dilutions of each sample using a modified version of Sigma Diagnostics' Oxalate Assay Kit (Sigma # 591-D) and an oxalate standard curve. Changes to the oxalate test included analysis of only 25 µL instead of 50 µL of the properly diluted filtered sample, as well as use of only 0.5 ml of oxalate reagent A (Sigma # 591-10) and only 50 µL of oxalate. latent reagent B (Sigma # 591-2). Furthermore, the samples were analyzed at 590 nm in a Falcon 96 well microplate using a Molecular Devices Spectramax 190 plate reader. Phosphate removal was determined by testing 1/500 dilutions of each sample using Sigma Diagnostics' Inorganic Phosphorus Assay Kit (Sigma # 570-C) and an inorganic phosphorus standard curve. The phosphorus test was performed as described in Sigma Procedure # 670.
    Figures 3A and 3B show the results of the competitive binding test for oxalate solutions compared to phosphate solutions. Phosphate is one of the primary ingredients in the diet that could compete with oxalate. Phosphate levels in the diet are about 10 times higher than oxalate. Uptake of phosphate from the diet is between 800-1500 mg / day and approx. 300 mg P / meal. Uptake of oxalate from dietary erca. 100 mg / day. The results in Figure 3 investigate the potential competitive effect of phosphate bonding on oxalate bonding using lanthanum carbonate. It was shown in the presence of a ten-fold excess of phosphate that lanthanum carbonate pentahydrate preferably binds oxalate to phosphate at pH 7.0 (Figure 3B), which is the previously shown optimal pH for lanthanum carbonate binding to oxalate (Figure 2). Preferred phosphate binding was shown at pH 3.0 (Figure 3A). This result thus demonstrates that lanthanum carbonate can still effectively bind oxalate even in the presence of a ten-fold excess of phosphate and the different pH optima for phosphate and oxalate binding show that phosphate will not generate oxalatbinding.
    EXAMPLE 3
    Simulation of the pH transition in the gastrointestinal tract
    A final experiment was designed to mimic the passage of lanthanum oxalate through the digestive system, which would investigate the removal of both oxalate and phosphate during a pH change from pH 3 (i.e. gastric bag pH) to pH 7 (i.e., approximate pH of the intestine). ). This experiment was conducted to investigate the usefulness of lanthanum carbonate as an oxalate binder in the gastrointestinal system, where both high, competing phosphate levels exist and a pH change from pH 3 in the stomach to pH 7 in the small intestine. Previous results have shown that (1) the oxalate bond was optimal at about neutral pH, (2) that lanthanum carbonate can successfully compete with phosphate at pH 7, and (3) that the binding capacity was lower at pH 3.
    To start, 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 observed for ten minutes. After ten minutes, the pH was gradually raised to pH 7. Samples were taken at pH 4, 5, 6 and 7 to assess changes in the amount of oxalate and phosphate present in the solution. As shown in Figure 6, the solution was examined for a further ten minutes after reaching pH 7. The results show that lanthanum carbonate successfully manages to bind oxalate in the presence of a phosphate excess, at the pH conditions found at the transition from the stomach to the small intestine.
    权利要求:
    Claims (3)
    [1]
    Use of the salted lanthanum carbonate, which salt is optionally hydrated, for the manufacture of a medicament for treating or preventing a kidney stone disorder.
    [2]
    Use according to claim 1, wherein the administration is by oral administration.
    [3]
    A pharmaceutical composition for treating a kidney stone disorder, the composition of which comprises lanthanum carbonate, optionally in hydrated form, and a pharmaceutically acceptable binder.
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    法律状态:
    2012-05-11| UUP| Utility model expired|
    优先权:
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    US28590101P| true| 2001-04-23|2001-04-23|
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