ANTI-KIDNEY COMPOSITION

Description

1 ANTI-LITHIASIS COMPOSITION Technical Field The present invention relates to the treatment of lithiasis causing kidney stones via the administration of citrate salts in a composition protected from gastric acid. 5 Prior Art Kidney stones (urinary lithiasis) result from the formation of hard deposits of minerals and salts in the kidneys. The formation of these stones is mainly due to the excessive concentration of certain ions in the urine, such as calcium, magnesium, oxalate, and uric acid. These ions can reach levels of supersaturation, which promotes precipitation and the formation of microcrystals. These microcrystals serve as nuclei, which leads to accelerated crystallization and the formation of larger crystals by agglomeration. As the crystals grow, they risk becoming large enough to be retained in the kidney, which causes an obstruction and significant painful symptoms.The process of lithogenesis is influenced by several factors, including ion concentration, urine pH, and the presence of substances that inhibit or promote crystallization. For example, inhibitors such as citrate and magnesium play a crucial role in preventing the formation of stones by binding to calcium and reducing the formation of insoluble complexes. Diet and lifestyle are essential elements in the prevention or aggravation of urinary stones. Adequate hydration is the main factor in reducing urinary supersaturation, particularly by diluting oxalate and calcium concentrations. In addition, the consumption of low-oxalate diets, the reduction of animal protein, and controlled sodium intake have proven effective in reducing the risk of stone formation. Obesity management is also essential, as an unbalanced diet and a lack of physical activity are associated with an increased risk of kidney stones, often due to high urinary calcium levels.Furthermore, genetic predispositions and certain metabolic conditions, such as calcium metabolism disorders or recurrent urinary tract infections, contribute to susceptibility to stone formation. These multifactorial causes mean that the prevention and treatment of kidney stones often require a multifactorial approach. Citrate salts, such as potassium citrate or magnesium citrate, are commonly used for kidney stone prevention. Their mechanism relies on two main actions: first, citrate binds to calcium ions in the urine, thus reducing the formation of calcium oxalate crystals; however, it increases the pH of the urine, thus increasing the solubility of oxalate. In addition, the use of citrate salts is often limited by 15 gastrointestinal side effects, including diarrhea and abdominal pain.These adverse effects are exacerbated by the rapid absorption of salts, which leads to sudden fluctuations in plasma and possibly urinary citrate levels, potentially also causing metabolic alkalosis or hypocalcituria. These limitations necessitate the development of better-tolerated formulations offering optimized release. Aceteffet, patent EP2640365B1 describes a solution aimed at improving the tolerability and efficacy of potassium citrate by implementing a more controlled-release formulation. This document discloses a micro-25 tablet containing between 50 and 70% by weight of potassium citrate, encapsulated in an ethyl-cellulose polymer to ensure a slow and controlled release of potassium citrate. This release occurs both in the highly acidic environments of the stomach (pH 1.3) and at neutral pH levels, allowing for gradual and uniform absorption of the citrate.30 2024 / 5972 BE2024 / 5972 3 This formulation is designed to prevent metabolic alkalosis by limiting the rapid and localized absorption of citrate, a problem frequently encountered with traditional non-encapsulated forms of potassium citrate. This controlled-release approach also improves gastrointestinal tolerance, thus allowing for better therapeutic adherence in patients. Besides the aforementioned problems of gastrointestinal disturbances and blood alkalosis, the inventors noted that the administration of citrate salts encounters several obstacles, particularly that of avoiding the concomitant administration of decations (e.g., sodium, potassium) in excessively high concentrations.10 For example, the recommended daily intake of potassium is approximately 3500 to 4700 mg for an adult. For calcium, the recommended intake is approximately 800 to 1000 mg, and for magnesium, 300 to 420 mg. Magnesium citrate is used as an inhibitor of stone formation.However, due to the laxative properties of magnesium citrate, its administration to lithiasic subjects who do not require this laxative effect is delicate. Indeed, the risk of dehydration can lead to excessive urine concentration, thus promoting the formation of kidney stones. In other words, the formulation of dietary supplements based on citrate salts poses several challenges, notably the risk of excessive administration of certain minerals such as sodium, potassium, calcium, or magnesium, each of which is associated with potential side effects. In particular, high consumption of these salts can promote the precipitation of calcium oxalate, thus contributing to the formation of kidney stones. Furthermore, research suggests that a higher dietary intake of magnesium is associated with a reduced risk of kidney stone formation. Magnesium administered in the form of citrate can increase urinary concentrations of magnesium and citrate, while reducing the urinary availability of oxalate.This helps to reduce the risk of 2024 / 5972 BE2024 / 5972 4 formation of insoluble complexes with calcium. However, some studies indicate that the protective effect of magnesium may be less significant than expected, potentially due to complex interactions with citrate. The administration of zinc, however, raises concerns due to its potential association with an increased risk of kidney stone formation. Some studies show higher zinc consumption among people suffering from kidney stones (Tange et al., 2012; Cohanim & Yendt, 1975), although others are more nuanced. Zinc is also implicated in the formation of Randall's plaques, which serve as nuclei for stone formation (Carpentier et al., 2011). Thus, several problems remain to be overcome for the development of a citrate-based formulation capable of reducing kidney stones without causing other problems for the patient.Brief summary of the invention A first aspect of the present invention relates to an unmanageable pharmaceutical composition comprising an active principle surrounded by a protective layer from gastric acidity, said active principle being substantially constituted of one or more citrate(3-) sulphates, chosen from the group consisting of sodium citrate, potassium citrate, magnesium citrate, zinc citrate, lithium citrate, lanthanum citrate, and calcium citrate, all said citrate sulphates comprising either potassium citrate, magnesium citrate or calcium citrate.Preferably, this composition (comprising calcium citrate, or potassium citrate, or magnesium citrate) comprises in addition to zinc citrate and / or lithium citrate and / or lanthanum citrate, preferably between 0.1 and 5%, preferably between 0.5 and 2% (weight of zinc citrate: sum of all the weights of the saline citrates) and / or between 0.1 and 5%, preferably between 0.5 and 2% (weight of lithium citrate: sum of all the weights of the saline citrates) and / or between 1 and 25% (weight of lanthanum citrate: sum of all the weights of the saline citrates) of lanthanum citrate (valence 3), preferably between 5% and 20%, preferably between 10% and 15%.Preferably, this composition (comprising calcium citrate, or potassium citrate and magnesium citrate) comprises 5 in addition to lithium carbonate and / or lanthanum carbonate, preferably the overall lithium content (lithium carbonate and lithium citrate) is between 0.1 and 5% (weight of citrate and / or lithium carbonate: sum of all the weight of the anhydrous citrates), and / or overall lanthanum regulator (lanthanum carbonate (III) and lanthanum citrates (III)) is between 1 and 10 25% (weight of the citrate and / or lanthanum carbonate: sum of all the weight of the anhydrous citrates), preferably between 5 and 20%, preferably between 10 and 15%. This composition is advantageous for the treatment or prevention of urinary lithiasis.15 A preferred alternative to the composition includes calcium citrate (hemitrized calcium), preferably at least 30% by weight of calcium citrate (weight of hemitricized calcium: total weight of anhydrous citrates).Preferably, this unmanageable composition is for administration substantially concomitant with a meal, preferably a meal containing a high amount of oxalate, fats and / or proteins. This preferred composition advantageously also includes tripotassium citrate, preferably between 20 and 40% by weight of potassium citrate (weight of anhydrous tripotassium citrate: total weight of anhydrous citrates). Another preferred composition, according to the other branch of the alternative, comprises potassium citrate (tripotassium citrate) and magnesium citrate (magnesium hemitricitrate), preferably at least 15% by weight of magnesium citrate:weight of magnesium citrate (anhydrous magnesium hemitricitrate:sum of all anhydrous citrate salts), preferably at least 20% by weight, preferably at least 40% by weight, and / or between 20 and 50% by weight of potassium citrate (anhydrous tripotassium citrate:sum of all anhydrous citrate salts).Preferably, this unmanageable composition is for administration before bedtime. One aspect of the present invention relates to an assembly comprising a plurality of the unmanageable composition (including calcium citrate) of the first preferred composition, and a plurality of the unmanageable composition (including magnesium citrate) of the second preferred composition. Detailed description of an embodiment of the invention: The inventors have succeeded in formulating citrate salts in concentrations allowing effective action against kidney stones while avoiding the generation of metabolic disorders, for example, caused by excessive administration of alkaline or bivalent cations. This has been achieved by formulating the citrate salts, often in a mixture. To develop a food supplement based on citrate salts that is effective in preventing kidney stones while minimizing undesirable effects, the inventors noted that several elements must be taken into consideration: 25 1.Balance between citrate salts: Ensure a balanced dosage of calcium, magnesium, potassium, and even sodium in citrate form to prevent the precipitation of calcium oxalate. For example, the inventors noted that calcium should be taken in moderate amounts and preferably with meals to minimize risks. 2. Precautions concerning zinc, or lanthanum, if present: Limit the amount of zinc and lanthanum (if present) in the formulation or combine it with other minerals to compensate for potential effects on kidney stone formation or the drop in blood phosphate levels. 3. Synergistic approach: highlighting synergistic combinations, particularly those which promote the reduction of urinary oxalate and the increase of urinary citrate levels without causing adverse effects on bone or anterenal mineralization.10 Thus, the inventors have demonstrated that an optimized formulation of food supplements based on citrate salts (protected from gastric acidity) offers an effective solution for preventing the formation of kidney stones, while taking into account the needs for bone mineralization and the other physiological effects of the minerals involved. 15 Thus, a first aspect of the present invention relates to an unmanageable pharmaceutical composition comprising an active principle surrounded by a protective layer from gastric acidity, said active principle being substantially constituted of one or more citrate salts (3-), preferably either at least potassium citrate with magnesium citrate (without excluding the presence of other citrate salts), or calcium citrate (without excluding the presence of other citrate salts). In the context of the present invention, the protective layer of 25 gastric acid is not limited.The inventors have successfully tested hydroxypropyl-methylcelluloses, but other compositions are known and could therefore be used, such as structures based on fatty acids, fats, waxes, acrylate-methacrylate copolymers, and alginate. 2024 / 5972 BE2024 / 5972 8 In the context of the present invention, "substantially consisting of one or more citrate(3-) salts" preferably means that there are no other active ingredients. However, additives, such as silicon dioxide or fatty acid salts, may be present, typically in contents between 1 and 10% by weight (sum of the weights of the additives / 5 weights of all the citrate salts (anhydrous)). This is in addition to the protective layer. An exception concerns the advantageous presence of lithium carbonate and / or lanthanum(III) carbonate, preferably as a substitute for lithium citrate and / or lanthanum citrate(III), if present.A weight content of 0.1 to 5% of lithium carbonate and / or a weight content of 1 to 25% of lanthanum(III) carbonate, preferably 5 to 20%, preferably 10 to 15%, is preferred (weight of lithium carbonate or lanthanum: sum of the weights of the anhydrous citrates present in the composition). The inventors have noted that the addition of these lithium salts and / or lanthanum (carbonate and / or citrate), in small amounts, provides a synergistic effect with the citrate salts present in higher concentrations (calcium, potassium, and / or magnesium citrate). The composition of the present invention is preferably in the form of a capsule. Such a capsule shall preferably comprise between 500 mg and 1 g of the gastric acid-protecting layer (for example, hydroxypropyl-methylcellulose). The composition according to the present invention preferably contains between 500 mg and 2 g of citrate, preferably between 600 mg and 1.2 g, preferably between 950 mg and 1.1 g of citrate (total weight of citrate (anhydrous)).The composition may also include excipients, preferably excipients acting on the release of citrate after ingestion or excipients having a beneficial effect on metabolism. Preferred excipients are chosen from the group consisting of silicon dioxide, acacia (arabic) gum, clays, preferably phyllosilicates such as bentonite, stearate, such as magnesium stearate, microcrystalline cellulose, carob extracts or carob seed flour, cellulose derivatives such as microcrystalline cellulose and hydroxypropyl cellulose. Preferably, the excipients are present in mass proportions of between 1 / 100 and 1 / 1, preferably between 1 / 20 and 1 / 2. Preferably between 1 / 10 and 1 / 3, or even between 1 / 5 and 1 / 4, relative to the citrate (weight of excipients / weight of citrate3-). Preferably, for this calculation, only the citrate is taken into consideration, not the weight of the cations (potassium, magnesium, zinc, calcium) and not the possible weight of water hydrating the citrate salts.The inventors noted that such excipients, although they "dilute" the administrable amount of citrate, offer other advantages such as a benefit to the pancreas (insulin), the intestine (diarrhea), or urinary pH, so that the synergy with the citrate outweighs the dilutive effect.15 Thus, the total weight of the capsule remains reasonable, typically about 2 grams or even less. Advantageously, this composition includes zinc citrate, in addition to calcium citrate, potassium citrate, and magnesium citrate.20 The inventors noted that the presence of zinc citrate was beneficial to patients. Similarly, the inventors noted that the presence of lithium citrate and / or lanthanum(III) citrate was beneficial to patients; these citrate salts can advantageously be substituted25 partially or totally by the corresponding carbonates.When it contains zinc and / or lithium and / or ulanthane(III), this composition preferably comprises between 0.1% and 10% by weight of zinc citrate (weight of zinc citrate: sum of the weights of the citrates considered in anhydrous form), preferably between 0.1% and 5% by weight of zinc citrate, preferably between 0.5% and 2% by weight and / or between 0.1% and 10% by weight of lithium citrate (weight of lithium citrate: sum of the total weights of the citrates considered in anhydrous form), preferably between 0.1% and 5% by weight of lithium citrate, preferably between 0.5% and 2% by weight, and / or between 15% by weight. and 25% by weight of lanthanum(III) citrate (weight of lanthanum citrate: sum of the weights of the citrates considered in anhydrous form). Zinc is considered a trace element. It is therefore, a priori, difficult to consider administering zinc via zinc citrate. Moreover, as written above, zinc citrate is associated with 10 risks related to kidney stones. Conversely, lithium can have deleterious effects on thyroid or kidney function, which is, a priori, to be avoided.The lanthanum, if present, is preferably incorporated into the formulation comprising calcium citrate and is advantageously administered substantially concomitantly with a meal (see below). In the context of the present invention, "citrate" preferably means non-protonated citrate, therefore having a triple negative charge; this citrate is present in the form of salts. Thus, "citrate" in the context of the present invention means, preferably, potassium citrate (monohydrate), and / or magnesium citrate, or calcium citrate, and / or zinc citrate, lithium citrate, and / or lanthanum citrate. In the context of the present invention, preferably, the weight contents of the different citrate salts are calculated by considering them as anhydrous, even if they only exist in hydrated form. Thus, if a citrate salt can exist, or be incorporated, in hydrated form, in the context of the present invention, its weight content will advantageously be calculated by deducting the hydration.2024 / 5972 BE2024 / 5972 11 Preferably, in the context of the present invention, the citrate salts incorporated in the composition contain only one type of decation, advantageously potassium, calcium, magnesium, lithium, lanthanum or zinc. However, the composition advantageously comprises mixtures of salts, for example tripotassium citrate (potentially also lithium citrate or lanthanum(III) citrate), mixed with zinc hemitricitrate (sesquicitrate), and / or magnesium or calcium. Thus, in the context of the present invention, preferably, the bivalent cation citrates shall be hemitri(sesqui)citrates(citrate3-)2(Me2+)3, where Me2+ signifies a bivalent cation, zinc, and / or magnesium or calcium.10 According to an advantageous alternative of the present invention, the composition comprising one or more citrates includes calcium citrate (calcium hemitricitrate).Although calcium is strongly implicated in the formation of oxalate crystals, leading to lithiasis (kidney stones), the inventors have surprisingly observed that administering calcium citrate (protected from gastric acid) to the patient is beneficial, particularly when the calcium citrate is administered with a meal. The inventors deduce from this that the calcium will force the precipitation of oxalate in the intestine, which will therefore no longer be reabsorbed. Furthermore, the citrate remains available for intestinal absorption and urinary excretion. This composition preferably comprises between 30% and 90% by weight of calcium citrate (weight of calcium hemitricitrate: total weight of 'anhydrous' citrates), preferably between 50% and 75% by weight of calcium citrate, preferably between 60% and 70% by weight.25 This composition advantageously comprises in addition tripotassium citrate (monohydrate).However, preferably this composition does not include, or does not include too much, magnesium citrate, especially when administered in synergy 2024 / 5972 BE2024 / 5972 12 with the second advantageous composition, which includes magnesium (see below the second composition, and the combination of the two compositions). Thus, this composition comprising between 30 and 90% (e.g., between 60 and 70% by weight of calcium citrate) preferably comprises less than 10% by weight, preferably less than 5% by weight of magnesium citrate.5 This composition preferably comprises between 10% and 50% by weight of potassium citrate (tripotassium citrate (the weight is calculated as if it were anhydrous): total weight of anhydrous citrates), preferably between 20% and 45% by weight of potassium citrate, preferably between 30 and 40% by weight.10 The composition may also include a low content of lithium citrate, for example between 0.1 and 2%, preferably between 0.5 and 1.5% (weight of lithium citrate: total weight of citrate (anhydrous)) and / or lanthanum(III) citrate, preferably between 1 and 25% (weight of lanthanum(III) citrate: total weight of citrate (anhydrous)), preferably between 5 and 15%. Advantageously, lithium carbonate may be incorporated as a partial or complete substitute for lithium citrate, or lanthanum(III) carbonate may be incorporated as a partial or complete substitute for lanthanum(III) citrate. 20 Advantageously, the presence of all three, or even all four or five citrate salts (calcium, potassium, lithium, lanthanum and zinc; proportions see above) ensure a high citrate content while avoiding excesses of potassium, but also of lithium, lanthanum or zinc, whereas the significant presence of calcium, which could be considered problematic, is, surprisingly, beneficial in the present invention.This composition is advantageous for administration substantially concomitant with a meal, preferably a meal comprising a high amount of oxalate, fats and / or proteins. 2024 / 5972 BE2024 / 5972 13 Indeed, the inventors have observed that calcium administered in this manner, rather than causing an amplifying effect on lithiasis, when administered via the composition of the present invention and, preferably, at the same time as meals (substantially concomitant with meals), reduces the absorbable neurotransmitter of oxalate. 5 In the context of the present invention, by "substantially concomitant" is understood preferably that the composition is ingested a maximum of 30 minutes, preferably a maximum of 15 minutes before the meal and at the latest a maximum of 30 minutes, preferably a maximum of 15 minutes after the meal. 10 This composition is therefore advantageously administered several times a day to a patient, for example, once, twice or three times a day.According to the other branch of the alternative, the composition comprising several citrate salts advantageously includes potassium citrate (tripotassium citrate monohydrate) and magnesium citrate (magnesium hemitricitrate). This composition preferably comprises at least 15% by weight of magnesium citrate (magnesium citrate (anhydrous magnesium hemitricitrate: sum of all anhydrous citrate salts)), preferably at least 20% by weight, or even at least 30% or at least 40% by weight. This composition preferably comprises between 10% and 60% by weight of potassium citrate (tripotassium citrate: total weight of anhydrous citrates), preferably between 20% and 50% by weight of potassium citrate, preferably between 30% and 45% by weight. However, preferably, this composition does not include, or does not include too much, calcium citrate, especially when administered in synergy with the first advantageous composition, which includes calcium (see above the first composition, and below, the combination of the two compositions).Indeed, this composition containing magnesium is advantageous for administration between meals (see below), and the inventors noted that taking calcium citrate at this time is a risk factor for kidney stones. Thus, this composition, comprising at least 20% by weight of magnesium citrate and, advantageously, between 20% and 50% by weight of potassium citrate, preferably comprises less than 10% by weight, preferably less than 5% by weight of calcium citrate. Preferably, this composition, comprising magnesium citrate and, advantageously, potassium citrate but not (too much) calcium citrate, further comprises zinc citrate and / or lithium citrate and / or lanthanum citrate in the (low) levels described above, or even lithium carbonate and / or lanthanum carbonate in the (low) levels described above. This composition is advantageous for administration before bedtime or between meals.15 Indeed, the inventors have observed that this composition acts on the urine.Concomitant administration with meals is therefore not necessary. However, this composition, taken between meals (if they are spaced out and especially if the composition of the first branch of the alternative is administered) or before sleep, will provide the patient with a citrate intake, either complementary, for example in situations requiring a significant administration of citrate, and therefore synergistic with the composition of the first branch of the alternative, or sufficient, for example for patients not having a significant need for a citrate intake. One aspect of the present invention relates to an assembly comprising a plurality of the unmanageable composition according to the first branch of the alternative and a plurality of the unmanageable composition according to the second branch of the alternative.2024 / 5972 BE2024 / 5972 15 Thus, thanks to this combination, the levels of the administered differentations (potassium, lithium, lanthanum, zinc, magnesium, calcium) remain acceptable (are unlikely to cause any problems for the patient) while the intestinal absorption of oxalate and the urinary secretion of oxalate crystals are reduced. 5 Examples. - It is understood that the present invention is in no way limited to the embodiments described above and that many modifications can be made to it without departing from the scope of the attached claims. Example 1: 10 The inventors have combined 360 mg of tripotassium citrate monohydrate with 9.7 mg of zinc citrate and 710.9 mg of calcium citrate. This mixture has been enriched with two types of synthetic silicon dioxide (2*9.5 mg) compatible with oral administration, and magnesium stearate (19 mg).This mixture was packed and placed in a capsule containing two types of commercial hydroxypropylcellulose compatible with oral administration, one having a methoxide content slightly less than 25% and a hydroxypropyl content of approximately 8%, the first having a viscosity (mPas; 1% solution, 25°C, Brookfield viscometer) of approximately 15,000, the second having a viscosity (mPas) of approximately 4,300, 307 mg of commercial microcrystalline cellulose (MCC12) compatible with oral administration, and 76 mg of hydroxypropylcellulose (Klucel) compatible with oral administration, plus silicon dioxide and magnesium stearate in significantly smaller proportions. The capsule was enriched with a yellow food coloring.25 This composition, or a placebo of the same yellow color, both in the form of identical capsules, was administered confidentially directly by the inventors to a panel of people not affected by urinary stones, then to a panel of patients susceptible to kidney stones, during meals (3 times a day), and the inventors duly verified that the capsules were ingested. The people not affected by urinary stones showed very good digestive tolerance. Patients who ingested the composition according to the invention noticed an improvement in urinary function, more alkaline, as well as an increase in citraturia, and the inventors noted a reduction in the risk of urine supersaturation due to calcium oxalate, calcium phosphate and / or uric acid.The same capsule was produced, but this time substituting magnesium citrate for calcium citrate; approximately 55% by weight of magnesium citrate (relative to the sum of the weights of the citrate molecules present), approximately 44% by weight of tripotassium citrate (approximately 44% by weight), and approximately 1% by weight of dipotassium citrate. This capsule, or placebo, was administered under supervision to patients in the evening before sleep (i.e., one capsule per day).15 The treated patients also showed an improvement in symptoms or measured parameters. Subsequently, the inventors combined the two methods of administration, and the improvement noted was even greater, especially for patients with a more extensive history of kidney stones.20 2024 / 5972 BE2024 / 5972.