Palatable liquid solutions containing high concentrations of megranrude

Abstract

The present invention relates to a stable and palatable formulation containing a high content of meglustat, which can be used in particular by children or persons with dysphagia. This highly concentrated formulation contains at least 150 mg / mL of megranurite, and as excipients sodium benzoate, tartaric acid, a sweetener, and optionally an acidic flavoring. This formulation can advantageously be administered with a therapeutic bienzyme activator to alleviate the intestinal side effects of Magrude.

Description

Technical Field

[0001] The present invention relates to a stable and palatable formulation containing a high content of miglustat, which is particularly suitable for use by children or individuals with swallowing difficulties. This highly concentrated formulation contains at least 150 mg / mL of miglustat, along with sodium benzoate, tartaric acid, a sweetener, and an optional acidic flavoring as excipients. This formulation can be advantageously administered with a therapeutic disaccharidase activator to mitigate the intestinal side effects of miglustat. Background Art

[0002] Miglustat (1,5-[butylimino]-1,5-dideoxy-D-glucitol) is a single stereoisomer synthetically derived from iminosugars extracted from plants and microorganisms. It has a molecular weight of 219 and is a white crystalline substance that is highly soluble in water (>1 g / mL at ambient temperature). It is used to treat mild to moderate Gaucher disease type 1 (GD1) and Niemann-Pick disease type C (NP-C), both inherited metabolic disorders, when enzyme replacement therapy is inadequate (Riahi et al, 2015). It has also recently been shown to be a promising drug candidate for the treatment of Batten disease (or JNCL or CLN3 disease) (WO 2022 / 023573).

[0003] The standard adult dose of migludec for GD1 is 100 mg three times a day. For NP-C, the standard dose for adults and adolescents is 200 mg three times a day. For younger patients under 12 years of age, the dose should be adjusted based on their body surface area.

[0004] However, Currently, only 100 mg capsules are available. These capsules are not suitable for children because i) they are highly loaded with active ingredients, which is not suitable for their body surface, and ii) the capsules are not easily swallowed by children or sick patients with dysphagia. In this context, there is a need to Reconstitute into a swallowable formulation, such as a liquid formulation, the volume of which depends on the patient's obesity level.

[0005] However, it has been reformulated for the purpose of administration by alternative routes (ie, as a liquid, orally, or via a nasogastric tube). The decision to reconstitute a different dosage strength is currently left to the discretion of the prescribing physician. The process should only be performed by experienced and qualified healthcare professionals to ensure the safe administration of the required dosage.

[0006] In this context, there is a need in the art to provide a A liquid preparation that can be easily obtained and swallowed by patients with dysphagia and / or patients (especially children) who require a specific dose of this molecule.

[0007] Although there is a great need for the handling of such liquid preparations, there are still many unresolved problems associated with such preparations.

[0008] Reformulation in a liquid solution The first problem that arises is that miglustat has a very bitter taste that is generally considered inedible. Due to this intolerable taste, miglustat cannot simply be added to purees or beverages, as these immediately become inedible once miglustat is added. Therefore, it is necessary to combine the molecule with flavoring agents and / or sweeteners that will mask this adverse taste and make the preparation palatable, especially for children.

[0009] The second problem is related to the well-known risk of gastrointestinal side effects that are generally associated with the ingestion of. In fact, when administered orally, miglustat reaches high concentrations in the intestinal lumen, where it inhibits disaccharidases and impairs carbohydrate breakdown, resulting in abnormal carbohydrate accumulation. This accumulation of undigested carbohydrates is associated with the osmotic influx of water, an increase in the fermentative activity of commensal bacteria, and the production of irritant metabolites in the intestinal lumen, which leads to the emergence of gastrointestinal intolerance (Amiri M. et al, J. Inherit Metab Dis (2012)). Given this problem, in treatments containing this molecule, it is not possible to use complex carbohydrates, especially sugars, sorbitol or mannitol, and milk (unless lactose-free). Therefore, it is necessary to identify an excipient that can effectively mask the bitterness of high-dose miglustat and make children willing to swallow the liquid preparation, and the excipient is not a complex carbohydrate.

[0010] The third problem is related to poor stability when formulated in a liquid suspension Indeed, it has been reported that a suspension of miglustat with a final concentration of 20 mg / mL turns brown even when stored in the refrigerated area, unless the pH of the suspension is maintained strongly acidic (Riahi et al, 2015). This is why it is only recommended to temporarily reformulate miglustat by dissolving it in water or pure unsweetened fruit juice immediately before administration, and the solution should not be stored (Janssen scientific affairs literature on synthetic miglustat). It is not possible for medical practitioners to do this every day.

[0011] Therefore, there is a need to handle the meglutol liquid solution that is stable for several months at room temperature so that it can be easily transported and administered at any time of the day, even at school. Additionally, the liquid solution should ideally remain microbiologically safe even when the bottle is opened several times a day over a period of more than 2 months.

[0012] The fourth problem is due to the fact that the solution should have a higher concentration of meglutol than the 20 mg / mL reported in the prior art, so that the volume administered to the patient can be smaller. In fact, a 250 mg / mL solution of 0.8 mL is easier to swallow than a 20 mg / mL solution of 10 mL. Since the liquid solution is dedicated to patients with dysphagia, the smaller the volume, the better the compliance. However, using a smaller volume does not solve the problem of bitterness, as the bitterness is the same in a 10 mg / mL solution and a 250 mg / mL solution and is strongly felt even in a 0.8 mL volume.

[0013] In summary, the technical problem proposed herein is therefore to provide a meglutol liquid solution that is suitable for patients (especially children) with dysphagia and / or in need of a specific dose of this molecule, the liquid solution containing at least 150 mg / mL meglutol, but at the same time i) being free of bitterness, ii) being microbiologically stable over time (at least one month in a non-refrigerated area), and iii) being free of carbohydrates (to avoid gastrointestinal side effects).

[0014] To the best knowledge of the present inventors, few liquid solutions containing meglutol have been proposed and studied in the art. In fact, so far, only two proposals for liquid formulations containing meglutol have been disclosed:

[0015] On the one hand, Riahi et al, 2015 described the stability of dissolved in a suspending agent, which is a liquid suspending excipient for formulating oral solutions and suspensions. The authors reported that Although was soluble in at all test concentrations, some excipients were insoluble. Initially, suspensions containing 20 mg / mL were studied. Subsequently, pH-adjusted suspensions of 20 mg / mL and unadjusted suspensions of 10 and 5 mg / mL were evaluated. All suspensions were stored under refrigerated conditions. Physicochemical and microbiological challenge tests were performed at 0 hours, 14 days, and 28 days. Degradation was evaluated by high-performance liquid chromatography, appearance was evaluated visually, and the pH was recorded. Additionally, the suspensions were inoculated with seven bacteria, yeasts, and molds, and growth was evaluated using membrane filtration. The 20 mg / mL suspension changed from yellow (0 hours) to brown (day 14 and day 28); the pH value was stable at 7.4 - 7.6. Pure (pH 4.6) remained yellow throughout the study. Pure adjusted to pH 7.5 showed a nearly brown discoloration after 9 days, and the 5 and 20 mg / mL suspensions adjusted to pH 6.5 and 4.4 respectively remained yellow on days 14 and 28. The 10 mg / mL suspension (pH 7.3) changed from yellow to brown on day 9. However, in these stable solutions, the concentration of miglustat was too low to be administered in small volumes, especially not to be swallowed by children and / or patients with dysphagia. In addition, the bitter taste of miglustat was neither tested nor masked. Therefore, this liquid solution does not solve the technical problem of the present invention.

[0016] On the other hand, the AMICUS patent application WO2014 / 110270 discloses a parenteral formulation comprising 1-DNJ (in particular miglustat) or a salt or derivative thereof suspended in a buffer selected from sodium citrate, sodium acetate, and sodium phosphate. In this formulation, the concentration of miglustat in the formulation is relatively low (in the range of about 10 mg / ml to about 100 mg / ml, or about 20 mg / mg to about 50 mg / ml, or about 20 mg / ml to about 35 mg / ml). This formulation can be used for intravenous injection or subcutaneous injection. Therefore, this liquid solution does not solve the technical problem of the present invention. Detailed Description

[0017] The formulation consists of the active product ingredient miglustat, which is known for its competitive inhibitory effect on glucosylceramide synthase and its inhibitory effect on disaccharidases suspected of inducing gastrointestinal adverse effects.

[0018] In order to determine the criteria for selecting the components of the product of the present invention, different objectives were set:

[0019] - Dosage form and route of administration: The recommended drug product label is specifically for children after birth or patients with dysphagia. Therefore, an oral liquid formulation is more suitable for precise dosing (per mg / m2 body surface area or mg / kg body weight)

[0020] - Dosage strength: The intake volume of high-concentration miglustat for children can be reduced, and if necessary, high-concentration miglustat can be easily mixed with fruit juice

[0021] - Palatability: Oral pediatric solutions need to be easy to swallow and have a taste acceptable to children,

[0022] - Stability: Since the pharmaceutical product will be administered several times a day, the formulation must have antimicrobial activity that allows for long-term storage, even if the drug container is opened several times a day.

[0023] Characterization of the target dose of miglustat by the e-tongue system indicated that the taste of miglustat may be close to salty and bitter. Considering the above objectives, special attention must be paid to masking the well-known bitter taste of miglustat to provide a pharmaceutical product acceptable to pediatric patients.

[0024] Multiple-dose administration of the planned oral solution requires maintaining the antibacterial effect. For this purpose, two preservatives (sodium benzoate and sodium metabisulfite) were tested in combination with miglustat. The color change of the sodium metabisulfite formulation under different storage conditions could be interpreted as a lack of stability or compatibility between the tested preservative and miglustat. In addition, the evaluation of related impurities showed that the total amount of impurities in the sodium metabisulfite formulation increased after different storage conditions, which may imply a risk to the stability of the formulation. After the storage conditions relatively similar to the initial measurement, the formulation containing the combination of sodium benzoate and miglustat remained clear, colorless and contained a certain amount of related impurities.

[0025] Therefore, further product development was carried out with sodium benzoate, which requires a specific pH value of the solution between 3 and 5 to exhibit its preservative effect in this formulation.

[0026] To ensure the efficacy of sodium benzoate, it is necessary to maintain the pH value of the solution between 3 and 5. In addition, according to the miglustat characteristics of the e-tongue experiment, miglustat seems to be highly bitter; the sour taste of the additive can offset the bitter taste of its taste.

[0027] For this purpose, the compatibility of miglustat with several acids was tested. Although ascorbic acid and / or ascorbate are commonly used for this purpose, unexpected unknown impurities appeared in all three formulations at 60 °C (1 week) and 40 °C (2 weeks). In addition, under all tested storage conditions (60 °C, 40 °C / 75% RH and 25 °C / 60% RH, up to 4 weeks), the combination of sodium ascorbate, ascorbic acid or both with miglustat would cause the solution to change color. Surprisingly, the combination of tartaric acid and miglustat did not show degradation of the solution or a particular change in the content of related impurities under any storage conditions.

[0028] Based on the compatibility results, tartaric acid was selected to maintain an acidic pH of 3 to 5 for the purpose of preservative efficacy. In addition, adding an acidic buffer helps to mask the bitter taste of the solution.

[0029] According to the miglustat characteristics analyzed by the e-tongue, adding sugar can reduce the bitter taste, thereby increasing the acceptability of miglustat. However, taking more than 80% Gastrointestinal adverse events were observed in patients, mainly diarrhea. The hypothesized mechanism of action is that miglustat inhibits intestinal disaccharidases as a sucrase-isomaltase, thereby reducing the absorption of disaccharides. Clinical practice has shown that GI events respond to a reduction in sucrose, lactose, and other carbohydrate intake, and otherwise the dose may have to be temporarily reduced (Zavesca SmPC).

[0030] Therefore, complex sugars such as sucrose or polyols cannot be used to enhance the sweetness of the formulation to avoid an increase in GI effects. Therefore, the drug compatibility of aspartame and acesulfame potassium with miglustat was tested. Under the tested storage conditions, the solution containing aspartame was clear, but the solution containing acesulfame potassium was pale yellow. In addition, the content of related impurities in the aspartame + miglustat formulation increased significantly compared to the initial measurement, while the related impurities of acesulfame potassium + miglustat were difficult to identify and no suitable analytical method was developed. Therefore, acesulfame potassium was selected for the next step. If it fails, a mixture of glycerol and ammonium glycyrrhizinate in a ratio of 10 / 1 will be added to the list of sweeteners for testing.

[0031] Surprisingly, during the product development study, precipitation was observed in the formulation containing acesulfame potassium. Precipitation occurred when the concentration of the acidic buffer was adjusted to obtain a pH below 5, so the adjustment of pH was suspected. No such precipitation was observed when using a mixture of glycerol and ammonium glycyrrhizinate without acesulfame potassium. Therefore, a mixture of glycerol and ammonium glycyrrhizinate was selected as the sweetener.

[0032] In the formulation according to the invention, despite the above challenges, the bitter and sweet taste of miglustat is controlled by increasing the proportion of sweetness and sourness (see Figure 4 ).

[0033] In a first aspect, the object of the present invention is an acidic liquid formulation for oral administration, the formulation containing at least 150 mg / mL of miglustat, and the liquid formulation containing:

[0034] - sodium benzoate as a preservative,

[0035] - tartaric acid to maintain the pH of the formulation between 3 and 5,

[0036] - a sweetener, and

[0037] - an optional flavoring agent, preferably an acidic flavoring agent.

[0038] Properties of the ingredients

[0039] The preparation of the present invention contains miglustat at least 150 mg / mL, preferably at least 200 mg / mL, more preferably at least 250 mg / mL, and even more preferably between 250 mg / mL and 300 mg / mL (inclusive).

[0040] The term "miglustat" refers to the compound N-butyl-deoxynojirimycin (N-butyl-DNJ), also known as 1,5-(butylimino)-1,5-dideoxy-D-glucitol, N-butyl-deoxynojirimycin or (2R,3R,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol, and any other forms such as salts, polymorphs, enantiomers, stereoisomers, conformational isomers, solvates, esters, amides, prodrugs, analogs, derivatives, etc., provided that the salts, enantiomers, stereoisomers, conformational isomers, solvate esters, amides, prodrugs, analogs or derivatives are capable of effectively inhibiting glucosylceramide synthase.

[0041] Sodium benzoate (CAS 532-32-1) is the sodium salt of benzoic acid. It is widely used as a food preservative (E number E211) and an impregnating agent. It is a white crystalline chemical substance with the molecular formula C6H5COONa. Benzoic acid (E210) can also be used in the compositions of the present invention.

[0042] Tartaric acid (CAS 87-69-4, 2,3-dihydroxybutanedioic acid) is an α-hydroxy carboxylic acid that is diprotic and aldaric in terms of its acid properties and is a dihydroxy derivative of succinic acid. It has two enantiomers: (2R,3R)-tartaric acid (L-(+)-tartaric acid), and (2S,3S)-tartaric acid (D-(-)-tartaric acid). Both of them can be used in the compositions of the present invention. Tartrates can also be used.

[0043] The preparation of the present invention may contain any sweetener that does not increase the viscosity of the preparation, does not restore its bitterness, and does not affect its acidity. In a preferred embodiment, the sweetener contains only glycerol. In a more preferred embodiment, the sweetener of the present invention is a mixture of glycerol and ammonium glycyrrhizinate, and the ratio of glycerol to ammonium glycyrrhizinate ranges from 10 / 1 to 100 / 1, preferably from 10 / 1 to 70 / 1, more preferably from 10 / 1 to 65 / 1, even more preferably from 10 / 1 to 50 / 1. For example, it may be a sweetener called "Magnasweet MM110". Preferably, the sweetener is formulated as a liquid solution. Whether it is Magnasweet MM110 or not, the sweetener of the present invention is preferably used in an amount of 0.01% to 10% by weight (weight / weight), preferably 1% to 10% by weight, more preferably 1% to 8% by weight, more preferably 2% to 7% by weight, even more preferably 3% to 7% by weight.

[0044] The liquid preparation of the present invention may contain a "flavoring agent". Flavoring agents used in the pharmaceutical industry refer to natural or artificial flavors, which may include fragrances and colors. In particular, flavoring agents can be used in orally ingested products such as syrups, chewable tablets, suspensions, or chewing gums to make the bitterness of the drug more palatable.

[0045] The preparation of the present invention may contain any flavoring agent that is palatable to the patient receiving treatment. For example, the flavoring agent may be selected from the group consisting of pineapple, fennel, apple, apricot, banana, blackberry, blueberry, caramel, cherry, chocolate, cocoa, coconut, coffee, cola, cranberry, blackcurrant, redcurrant, grape, grapefruit, pomegranate syrup, lemon, maple, mint, orange, walnut, passion fruit, peach, pear, pineapple, plum, prune, raspberry, strawberry, citrus, tutti frutti, vanilla, etc.

[0046] In a preferred embodiment, the flavoring agent used in the preparation of the present invention is redcurrant or orange.

[0047] The preparation of the present invention also contains a "pharmaceutically acceptable carrier" or "excipient" or "solution", which is any type of non-toxic liquid filler, diluent, or preparation aid. In a preferred embodiment, the preparation of the present invention is an aqueous preparation and thus contains water as a pharmaceutically acceptable excipient (usually about 50% to 90% water).

[0048] Dosage

[0049] In a preferred embodiment, the liquid preparation of the present invention contains 0.5 to 100 mg / mL, preferably 1 to 80 mg / mL, more preferably 1 to 50 mg / mL, even more preferably 1 to 10 mg / mL of sodium benzoate.

[0050] In a preferred embodiment, the liquid preparation of the present invention contains 50 to 200 mg / mL, preferably 50 to 180 mg / mL, more preferably 100 to 175 mg / mL of tartaric acid.

[0051] In a preferred embodiment, the liquid preparation of the present invention contains 0.1% to 10% by weight, preferably 1% to 8% by weight, more preferably 2% to 7% by weight, even more preferably 3% to 7% by weight of a sweetening agent, which is preferably a mixture of glycerol and ammonium glycyrrhizinate, and the proportion ranges from 10 (glycerol) / 1 (ammonium glycyrrhizinate) to 100 (glycerol) / 1 (ammonium glycyrrhizinate), 10 / 1 to 70 / 1, 10 / 1 to 65 / 1 or 10 / 1 to 50 / 1.

[0052] In a preferred embodiment, the liquid preparation of the present invention contains 0.1% to 10% of an acidic flavoring agent.

[0053] In summary, the preparation of the present invention preferably contains

[0054] - at least 150 mg / mL of miglustat,

[0055] - 0.5 to 100 mg / mL of sodium benzoate,

[0056] - 50 to 200 mg / mL of tartaric acid, such that the final pH of the preparation is included in 3 to 5,

[0057] - 0.1% to 10% of a mixture of glycerol and ammonium glycyrrhizinate, and the proportion ranges from 10 (glycerol) / 1 (ammonium glycyrrhizinate) to 100 (glycerol) / 1 (ammonium glycyrrhizinate), preferably 10 (glycerol) / 1 (ammonium glycyrrhizinate) to 70 (glycerol) / 1 (ammonium glycyrrhizinate), more preferably 10 (glycerol) / 1 (ammonium glycyrrhizinate) to 65 (glycerol) / 1 (ammonium glycyrrhizinate), even more preferably 10 (glycerol) / 1 (ammonium glycyrrhizinate) to 50 (glycerol) / 1 (ammonium glycyrrhizinate), and

[0058] - 0.1% to 10% of a redcurrant or orange flavoring agent.

[0059] It should be noted that the preparation of the present invention should not contain any carbohydrates, because the known active ingredient miglustat has a competitive inhibitory effect on intestinal disaccharidase, which can cause adverse gastrointestinal effects.

[0060] In addition, it is not recommended to add any flavor enhancers to the preparation, because this may increase the bitterness of miglustat, thus making the preparation more bitter and less palatable.

[0061] Viscosity

[0062] When measured under "standard conditions" (20 °C, 1 atm.), the preparation of the present invention is preferably a liquid solution having a low viscosity of from 1 to 20 mPa·s -1 and is a low-viscosity liquid solution.

[0063] It may also be somewhat viscous and thus have a higher viscosity of from 20 to 60 mPa·s when measured using a viscometer under "standard conditions" (20 °C, 1 atm.). -1 between.

[0064] Stability

[0065] The preparation of the present invention should be stable enough to be used for several weeks after the container is opened, preferably at room temperature.

[0066] In a preferred embodiment, when the product is stored before sale, the preparation of the present invention remains unchanged (taste, color and microbial composition) at room temperature for several months and is stored at room temperature for at least two weeks, preferably three weeks, more preferably one month.

[0067] The inventors have demonstrated in the following examples that the preparation of the present invention is indeed capable of remaining unchanged for at least 12 weeks under conditions of high humidity (up to 75% RH) and high temperature (up to 40 °C) (Tables 9-16).

[0068] Therapeutic use

[0069] In a second aspect, the present invention relates to a liquid preparation as described above for use as a medicament. The present invention also aims at the use of the above liquid preparation for the manufacture of a medicament.

[0070] Such a medicament or liquid preparation of the present invention can be used to treat all diseases known to benefit from high concentrations of miglustat, in particular lysosomal storage diseases.

[0071] Non-limiting examples of lysosomal storage diseases and disorders characterized by lysosomal dysfunction that can be treated using the liquid preparation of the present invention include: juvenile neuronal ceroid lipofuscinosis (JNCL, juvenile Batten disease or CLN3 disease), aspartylglucosaminuria, cystinosis, Fabry disease, SanFilippo disease, Gaucher disease types I, II and III, glycogen storage disease type II (Pompe disease), GM2-gangliosidosis type I (Tay-Sachs disease), GM2-gangliosidosis type II (Sandhoff disease), metachromatic leukodystrophy, mucolipidosis types I, II / III and IV, mucopolysaccharidosis, Niemann-Pick disease types A / B, C1 and C2, Schilder disease types I and II, CLN1 disease, CLN2 disease, CLN4 disease, CLN5 disease, CLN6 disease, CLN7 disease, CLN8 disease, CLN10 disease, CLN11 disease, CLN12 disease, CLN13 disease and CLN14 disease.

[0072] Mucopolysaccharidoses are preferably selected from: Hurler syndrome (MPS IH), Hurler–Scheie syndrome (MPS IH / S), Scheie syndrome (MPS IS; mucopolysaccharidosis type V), Hunter syndrome (MPS II), Sanfilippo syndrome A (MPS IIIA), Sanfilippo syndrome C (MPS IIIC), Sanfilippo syndrome D (MPS IIID), Morquio type A, Morquio type B, Maroteaux-Lamy (MPS VI), Sly disease (MPS VII), and Natowicz syndrome (MPS IX).

[0073] In a preferred embodiment, the formulation of the present invention is capable of treating juvenile neuronal ceroid lipofuscinosis (JNCL, juvenile Batten disease or CLN3 disease), aspartylglucosaminuria, cystinosis, SanFilippo disease, glycogen storage disease type II (Pompe disease), metachromatic leukodystrophy, mucolipidosis types I, II / III, and IV, mucopolysaccharidosis, Niemann-Pick disease types A / B, C1, and C2, Hallervorden-Spatz disease types I and II, CLN1 disease, CLN2 disease, CLN4 disease, CLN5 disease, CLN6 disease, CLN7 disease, CLN8 disease, CLN10 disease, CLN12 disease, CLN13 disease, and CLN14 disease.

[0074] In a preferred embodiment, the formulation of the present invention is capable of treating neuronal ceroid lipofuscinosis (CLN disease), particularly CLN1 disease, CLN2 disease, CLN3 disease, CLN4 disease, CLN5 disease, CLN6 disease, CLN7 disease, CLN8 disease, CLN10 disease, CLN11 disease, CLN12 disease, CLN13 disease, or CLN14 disease.

[0075] In a most preferred embodiment, the formulation of the present invention is capable of treating juvenile neuronal ceroid lipofuscinosis (JNCL, or Batten disease, or the CLN3 form of Batten disease). Although it shares some common patterns with other CLN diseases, this disease remains poorly understood because the primary function of CLN3 remains unknown and because the protein has multiple interacting partners (Getty A.L. and Pearce D.A., 2011).

[0076] JNCL is the most common neurodegenerative disorder in childhood. A hallmark of JNCL is the accumulation of ceroid lipofuscin within lysosomes in the vast majority of nerve cells and various extra - cerebral tissues, indicating impairment of the autophagy - lysosome pathway. JNCL presents with visual failure and hearing loss and progresses to include seizures, motor dysfunction, and dementia. JNCL patients experience continuous physical and cognitive decline, leading to death in the third decade of life. Thus, treating JNCL with the formulations of the present invention will prevent the lysosomal accumulation of ceroid lipofuscin in the nerve cells and various brain and extra - cerebral tissues of subjects with JNCL, or will reduce or eliminate the lysosomal accumulation of ceroid lipofuscin. In addition, treating JNCL with the formulations of the present invention will prevent, reverse, or arrest the cognitive decline of the subject. Methods for determining cognitive decline caused by JNCL in a subject are known in the art. For example, treating JNCL with the formulations of the present invention can prevent, reverse, or arrest visual failure. Treating JNCL with the formulations of the present invention can also prevent, reverse, or arrest hearing loss. Treating JNCL with the formulations of the present invention can also reduce the severity and / or intensity of seizures. In addition, treating JNCL with the formulations of the present invention can improve or prevent motor dysfunction. Treating JNCL with the formulations of the present invention can also improve or prevent dementia.

[0077] In another embodiment, the formulations of the present invention are capable of treating patients suffering from neurodegenerative disorders known to be associated with lysosomal disorders, especially when they experience dysphagia.

[0078] In a preferred embodiment, the formulations of the present invention are administered to human patients who have difficulty swallowing tablets or pills. It is particularly suitable for patients presenting with dysphagia or, conversely, for children weighing less than 30 kg.

[0079] In a preferred embodiment, the liquid formulations of the present invention are administered to human patients suffering from lysosomal storage diseases, preferably to patients suffering from dysphagia or patients suffering from Batten disease.

[0080] As used herein, the term "treatment" can be used to describe the prevention, amelioration, prevention, or cure of lysosomal storage diseases and disorders characterized by lysosomal dysfunction and / or one or more of their associated symptoms. For example, treatment of existing lysosomal storage diseases and disorders characterized by lysosomal dysfunction can alleviate, improve, or completely eliminate the disorder, or prevent its progression. Preventive treatment can reduce the risk of the disorder developing and / or mitigate its severity if the disorder later develops.

[0081] Kit containing a therapeutic disaccharidase

[0082] Treatment with miglustat usually results in gastrointestinal side effects similar to those of carbohydrate malabsorption, such as diarrhea, abdominal distension, vomiting, and abdominal colic. These side effects have been shown to be due to miglustat interfering with carbohydrate digestion in the intestinal lumen, particularly by reversibly inhibiting disaccharidases that cleave carbohydrates linked by α-glycosidic bonds (Amiri M. et al, J. Inherit Metab Dis (2012)). In addition, it has recently been shown that miglustat interferes with the N-glycosylation of sucrase-isomaltase in the endoplasmic reticulum, thus delaying its intracellular trafficking and apical targeting (Amiri M. et al, J. Inherit Metab Dis (2014)).

[0083] Intestinal disaccharidases are membrane-integrated glycoproteins located in the brush border membrane of intestinal epithelial cells. Prominent members of this hydrolase family are: sucrase-isomaltase (SI), lactase-phlorizin hydrolase (LPH), and maltase-glucoamylase (MGA). These enzymes digest carbohydrates in the intestinal lumen and show a preferential affinity for the cleavage of α-glycosidic or β-glycosidic bonds. For example, the sucrase and isomaltase activities of SI and the maltase and glucoamylase activities of MGA can hydrolyze the α-glycosidic bonds of major dietary carbohydrates such as starch, glycogen, sucrose, and maltose. The resulting monosaccharides are ultimately transported across the brush border membrane of epithelial cells into the cell interior.

[0084] When administered orally, miglustat reaches high concentrations in the intestinal lumen, where it inhibits disaccharidases and impairs carbohydrate breakdown, so that carbohydrates accumulate abnormally. This accumulation of undigested carbohydrates is associated with an osmotic influx of water, an increase in the fermentative activity of commensal bacteria, and the production of irritant metabolites in the intestinal lumen, which leads to the appearance of gastrointestinal intolerance (Amiri M. et al, J. Inherit Metab Dis (2012).

[0085] The daily diet usually consists of large amounts of starch, confectionery, and soft drinks rich in α-glycosidic bond sugars. Therefore, patients receiving miglustat treatment are generally advised to avoid consuming carbohydrate-containing foods for several hours after taking miglustat to prevent these carbohydrates from being present in the intestinal lumen simultaneously with miglustat (Belmatoug N et al, J. InheritMetab Dis 2011).

[0086] In patients with congenital sucrase-isomaltase deficiency (CSID) or in patients treated with miglustat, alternative treatments have been proposed to counteract the negative intestinal effects of intestinal hydrolase impairment:

[0087] - Administer compounds that slow intestinal transit, such as loperamide or trimebutine (Lyseng-Williamson K.A. et al, Drugs 2014; Belmatoug N et al, J. Inherit Metab Dis 2011).

[0088] - Administer replacement disaccharidases by "enzyme replacement therapy" (ERT). These replacement enzymes can be, for example, sucrase (EC 3.2.1.26), sucrase-isomaltase (SI, EC 3.2.1.48 and EC 3.2.1.10 respectively), β-galactosidase (EC 3.2.1.21), lactase-phlorizin hydrolase (LPH, EC 3.2.1.108), sacrosidase (such as ), amylase (EC 3.2.1.1) and / or amyloglucosidase (EC 3.2.1.3), which contribute to the digestion of sucrose and / or starch.

[0089] - Administer bacterial probiotics that highly express at least one of these disaccharidases, or enzymes that stimulate endogenous disaccharidases (Belmatoug N et al, J. Inherit Metab Dis 2011, Remenova et al, Journal of rare diseases, 2015).

[0090] - Administer yeast cells, such as freeze-dried Saccharomyces cerevisiae (LSC) or Saccharomyces boulardii cells, which express a large amount of at least one of these disaccharidases, or enzymes that stimulate endogenous disaccharidases.

[0091] For example, the intestinal side effects of miglustat can be counteracted by administering yeast sucrase (Treem W.R. et al, 1993), especially baker's yeast sucrase (sucrase from Saccharomyces cerevisiae).

[0092] Purified enzymes from Saccharomyces cerevisiae can also be administered, such as invertase (EC 3.2.1.26) commercialized by Sigma-Aldrich (I4504).

[0093] All these enzyme replacement therapies have been proposed for the treatment of patients suffering from congenital sucrase-isomaltase deficiency (CSID), who are known to experience the same intestinal disorders as patients treated with miglustat. Therefore, these treatments are considered to relieve the intestinal symptoms of patients treated with high doses of miglustat (Belmatoug N et al, J. Inherit. Metab. Dis 2011, Remenova et al, Journal of rare diseases, 2015).

[0094] In the present invention, there is provided a combination product which, on the one hand, comprises a preparation of the present invention and, on the other hand, an activator of enterodisaccharidase for simultaneous, separate or staggered use for the treatment of the above-mentioned disorders.

[0095] The present invention also discloses a method for treating or alleviating lysosomal storage diseases or disorders characterized by lysosomal dysfunction or at least one symptom associated therewith in a human subject in need thereof, said method comprising administering a preparation of the present invention and at least one enterodisaccharidase activator, preferably orally.

[0096] Non-limiting examples of lysosomal storage diseases and disorders characterized by lysosomal dysfunction that can be treated with such a combination product include: juvenile neuronal ceroid lipofuscinosis (JNCL, juvenile Batten disease or CLN3 disease), aspartylglucosaminuria, cystinosis, Fabry disease, SanFilippo disease, Gaucher disease types I, II and III, glycogen storage disease type II (Pompe disease), GM2-gangliosidosis type I (Tay-Sachs disease), GM2-gangliosidosis type II (Sandhoff disease), metachromatic leukodystrophy, mucolipidosis types I, II / III and IV, mucopolysaccharidosis, Niemann-Pick disease types A / B, C1 and C2, Schilder disease types I and II, CLN1 disease, CLN2 disease, CLN4 disease, CLN5 disease, CLN6 disease, CLN7 disease, CLN8 disease, CLN10 disease, CLN11 disease, CLN12 disease, CLN13 disease and CLN14 disease.

[0097] Preferably, the mucopolysaccharidosis is selected from: Hurler syndrome (MPS IH), Hurler–Scheie syndrome (MPS IH / S), Scheie syndrome (MPS IS; mucopolysaccharidosis type V), Hunter syndrome (MPS II), Sanfilippo syndrome A (MPS IIIA), Sanfilippo syndrome C (MPS IIIC), Sanfilippo syndrome D (MPS IIID), Morquio A type, Morquio B type, Maroteaux-Lamy (MPS VI), Sly disease (MPS VII), and Natowicz syndrome (MPS IX).

[0098] In a preferred embodiment, the combination product of the present invention is capable of treating juvenile neuronal ceroid lipofuscinosis (JNCL, juvenile Batten disease or CLN3 disease), aspartylglucosaminuria, cystinosis, SanFilippo disease, glycogen storage disease type II (Pompe disease), metachromatic leukodystrophy, mucolipidosis I, II / III and IV, mucopolysaccharidosis, Niemann-Pick disease types A / B, C1 and C2, Krabbe disease types I and II, CLN1 disease, CLN2 disease, CLN4 disease, CLN5 disease, CLN6 disease, CLN7 disease, CLN8 disease, CLN10 disease, CLN12 disease, CLN13 disease, and CLN14 disease. In a preferred embodiment, the combination product of the present invention is capable of treating neuronal ceroid lipofuscinosis (CLN disease), particularly CLN1 disease, CLN2 disease, CLN3 disease, CLN4 disease, CLN5 disease, CLN6 disease, CLN7 disease, CLN8 disease, CLN10 disease, CLN11 disease, CLN12 disease, CLN13 disease, or CLN14 disease. In a most preferred embodiment, the combination product of the present invention is capable of treating juvenile neuronal ceroid lipofuscinosis (JNCL, or Batten disease, or the CLN3 form of Batten disease).

[0099] The term "activator of intestinal disaccharidase" as used herein refers to any molecule (e.g., a small compound or an enzyme protein) or organism (e.g., a bacterium or a yeast cell) that can enhance the activity and / or expression level of at least one intestinal disaccharidase, said intestinal disaccharidase being selected from: invertase (EC 3.2.1.26), maltase (EC 3.2.1.20), trehalase (EC 3.2.1.18), sucrase-isomaltase (SI, EC 3.2.1.48 and EC 3.2.1.10 respectively), β-galactosidase (EC 3.2.1.21), lactase-phlorizin hydrolase (LPH, EC 3.2.1.108), saccharozyme (such as ) Amylase (EC 3.2.1.1) and amyloglucosidase (EC 3.2.1.3).

[0100] In a preferred embodiment, these activators are the enzymes themselves obtained by purification or recombinant production. In one embodiment, only one type of enzyme is administered. In another embodiment, a combination of different types of enzymes (e.g., two or three alternative enzymes) is administered. All these enzymes should still be active once they reach the patient's intestine.

[0101] In another preferred embodiment, these activators are bacterial probiotics or yeast cells, which are known to express large amounts of at least one of these intestinal hydrolases.

[0102] In a more preferred embodiment, these activators are provided by oral administration of a mixture or of baker's yeast Saccharomyces cerevisiae or Saccharomyces boulardii.

[0103] In a particular embodiment, in the combination products of the present invention, the activator of the intestinal enzyme is administered a few hours (usually 1 - 3 hours) before the administration of the formulation of the present invention. Description of the Drawings

[0104] Figure 1 A: Distance between each test formulation and miglustat at 250 mg / mL (Principal Component Analysis, PCA). B: PCA aromatic characteristics of miglustat at 10 mg / mL, miglustat at 250 mg / mL, and formulation 12.

[0105] Figure 2 : Aromatic characteristics of miglustat alone (formulation F - 18) compared to sodium chloride, caffeine, sucrose, and citric acid.

[0106] Figure 3 : Aromatic characteristics of formulation F - 12 (formulation according to the present invention) compared to sodium chloride, caffeine, sucrose, and citric acid.

[0107] Figure 4 : PCA of formulation 12 and 18 (250 mg / mL miglustat) compared to 10 mg / mL NaCl, caffeine, sucrose, and citric acid. Formulation 12 is closer to sucrose and citric acid than formulation 18.

[0108] Examples

[0109] In order to develop a formulation suitable for the pediatric population, an oral formulation is more suitable for precise dosing according to each patient's weight and body size, and is also more suitable for better control of the therapeutic window. Therefore, it is easier to select a dose within the gap between the therapeutic effect and gastrointestinal effects. However, an oral pediatric solution requires a certain degree of palatability, i.e., the solution is easy to swallow and has an acceptable taste for the patient. This last point is very challenging because various sugars commonly used to sweeten the solution need to be avoided, as patients taking miglustat will suffer gastrointestinal effects due to the inhibition of disaccharidases.

[0110] The following examples show how it is possible to identify a formulation of the present invention that is pleasant to swallow and stable over time even when containing a high concentration of miglustat. In addition, it can be administered to Batten patients without increasing the risk of miglustat gastrointestinal side effects.

[0111] Materials and Methods

[0112] Preparation 1: Drug-excipient compatibility

[0113] This study aimed to evaluate the compatibility of miglustat with candidate excipients that could be used in liquid miglustat products. Each different excipient was manually stirred with miglustat and stored in amber glass bottles.

[0114] To achieve the desired aspects of a miglustat oral solution, a drug-excipient study was conducted with different excipients (inactive ingredients), including thickeners, preservatives, flavoring agents, sweeteners, colorants, etc.

[0115] Standard Preparation:

[0116] Accurately weigh 5 mg of miglustat standard and transfer it to a clean and dry 50 mL volumetric flask. Add 30 mL of diluent and dissolve it by sonication. Subsequently, further add diluent to the mark and mix well.

[0117] Sample Preparation Procedure:

[0118] Carefully transfer the contents of the sample bottle to a clean and dry 250 mL volumetric flask using a funnel. Rinse the vial and cap carefully with 5 mL of diluent 4 - 5 times and transfer all the washings to the volumetric flask. Add approximately 150 mL of diluent, then vortex for about 3 minutes, and then dilute to the mark with diluent and mix well.

[0119] Table 1: Composition of the test solution

[0120] Ingredient mg / ml g / 75ml Miglutol 300 22.5 Miglutol + Sodium Ascorbate 300+3.28 22.5+0.246 Miglutol + Ascorbic Acid 300+6.1 22.5+0.457 Miglutol + Sodium Ascorbate + Ascorbic Acid 300+3.28+6.1 22.5+0.246+0.457 Miglutol + Tartaric Acid 300+100 22.5+7.5 Miglutol + Sodium Metabisulfite 300+2 22.5+1.5 Miglutol + Aspartame 300+0.126 22.5+0.00945 Miglutol + Acesulfame Potassium 300+192 22.5+14.4 Miglutol + Sodium Benzoate 300+3 22.5+0.225 Miglutol + Red Currant 300+7.5 22.5+0.562 Miglutol + Black Currant 300+7.5 22.5+0.562

[0121] Storage Conditions:

[0122] The vials were stored in an artificial climate chamber with different environmental conditions: 25°C / 60% RH, 40°C / 75% RH, and 60°C in a closed container for up to 4 weeks. (RH = relative humidity)

[0123] Table 2: Storage conditions

[0124] 1 week 2 weeks 3 weeks 4 weeks 25°C / 60% RH D D,RS D D,RS 40°C / 75% RH D D,RS D D,RS 60℃ D,RS

[0125] D: Physical description

[0126] RS: Study of related substances

[0127] At each time point, the stored samples were analyzed for related substances and physically described.

[0128] Physical Description Method

[0129] After the specified storage time, the samples were removed from the artificial climate chamber. The operator observed the solution and described the appearance of the solution by visual inspection.

[0130] Analytical Method for Related Substances Analysis and Physical Description

[0131] Using the standard and sample preparation procedures, the drug excipient compatibility samples were analyzed using the Amino Chemicals API related substances method (QC-QCM-0778-01) of Apothecon Pharmaceuticals. All chromatographic conditions, mobile phase preparation, diluent, and blank preparation were taken from the related substances method of QC-QCM-0778-01.

[0132] Preparation 2: Taste evaluation by the experimenter

[0133] Preparation of Miglutol Solution

[0134] A small amount of purified water (Cooper) was poured into a 10-ml volumetric flask. Under a safety weighing cabinet (SAFETECH, APTYS550), 3 g of amino chemicals was weighed and added to the volumetric flask. Potassium acesulfame (Calenese) was weighed, and then aspartame (HSWT) was weighed and added (according to the formulation). After that, tastesense (Kerry) was weighed and added to the flask. According to the formula, the corresponding flavoring agents (raspberry, blackcurrant, redcurrant, grapefruit, cherry) were weighed and added (Firmenich or Givaudan). Finally, citric acid (according to the formulation) was added and sufficient (quantum satis) purified water was added. Each formulation was placed under magnetic stirring for about 1 hour.

[0135] Table 3: Formulation composition for taste evaluation

[0136]

[0137] Test Method

[0138] Thirty minutes before the start of the treatment course, the experimenters were not allowed to drink anything except water. According to the Latin square design, all the preparations were coded and blinded, and were randomized for each experimenter. The experimenters were required to taste each preparation and give an overall rating (0 - 20). After the test, the experimenters rinsed their mouths properly and were noted to have at least a 10 - minute interval between each preparation. The average of all the ratings was calculated by a third party.

[0139] Preparation 3: Turbidity evaluation and electronic tongue experiment

[0140] Preparation of Miglutol Solution

[0141] The preparations were made in batches of 30 - 100 mL according to the following composition:

[0142] Table 4: Composition of meglutol solution

[0143]

[0144] Table 5: Composition of reference solution - caffeine

[0145] Ingredient mg / mL Caffeine 10 Water q.s

[0146] Table 6: Composition of reference solution - citric acid

[0147] Ingredient mg / mL Citric Acid 10 Water q.s

[0148] Table 7: Composition of reference solution - sodium chloride

[0149] Ingredient mg / mL Sodium Chloride 10 Water q.s

[0150] Table 8: Composition of reference solution - sucrose

[0151] Ingredient mg / mL Sucrose 10 Water q.s

[0152] Appearance Analysis Procedure

[0153] The test for the appearance of the solution was a visual observation. After the final mixing, the operator evaluated the clarity and appearance of the solution after a visual inspection.

[0154] Electronic Tongue Procedure

[0155] To study the taste of each test formulation, an electronic tongue system (Astree, Alpha MOS) was used. 30 mL of samples were collected from the solution to be tested and transferred to test beakers. The set of sensor electrodes was immersed in each test solution for 3 minutes for analysis. The sensors were washed with water between each measurement. For each test solution, the sensors recorded a specific response (Alpha software, V12.0).

[0156] Analytical methods for formulation comparison

[0157] To compare the test batches of meglutol formulations with individual meglutol, the meglutol formulations were prepared as described above. Each solution was analyzed in triplicate by electronic tongue. Using Alpha soft (version 12.0), the distance between the average sensor response of each solution and the average response of 250 mg / kg of individual meglutol was calculated by PCA.

[0158] Profiling method analysis

[0159] Solutions of the reference and meglutol formulations were prepared as described above. 30 mL of samples were analyzed by the electronic tongue system. Each solution was analyzed in triplicate by electronic tongue. The distance between the average sensor response of each reference and individual meglutol or the formulation to be characterized was calculated (Alpha software, V12.0).

[0160] Results

[0161] Drug excipient compatibility results

[0162] Physical Description

[0163] The physical standards (dissolution state, color) of individual 300 mg / ml meglutol or its solutions in combination with acidic buffer were evaluated. According to the results summarized in Table 9, all the tested formulations were solutions after 4 weeks in a sealed container at 40 °C / 75 RH or 25 °C / 60% RH. Only formulation F containing tartaric acid and formulation P containing hydrochloric acid showed no change in color.

[0164] Table 9: Physical description of active and inactive ingredient combinations (acidic buffer)

[0165]

[0166] *All samples marked with * (week 1 and week 3 samples) are the surface physical descriptions observed when the samples were in amber bottles. All samples were found to be only in solution form, but precipitation and gel formation were observed in a few samples. However, the color of the solution could not be seen because the bottles were amber.

[0167] The physical standards (dissolution state, color) of a solution of 300 mg / ml meglutol alone or in combination with a preservative were evaluated. According to the results summarized in Table 10, Preparation I containing sodium benzoate remained a clear solution after being placed in a sealed container at 40 °C / 75% RH or 25 °C / 60% RH for 4 weeks, and also remained clear after being placed at 60 °C for 1 week. Preparation H containing sodium metabisulfite showed a light yellow color under various storage conditions, even after being placed at 60 °C for 1 week.

[0168] Unexpectedly, ascorbic acid was observed to be incompatible with meglutol because the solution containing both did not remain clear, as shown in Table 13. Oxidation was suspected.

[0169] Table 10: Physical description of combinations of active and inactive ingredients (preservatives)

[0170]

[0171] The physical standards (dissolution state, color) of a solution of 300 mg / ml meglutol alone or in combination with a sweetener were evaluated. According to the results summarized in Table 11, Preparation K containing aspartame remained a clear solution under all storage conditions. Preparation L containing acesulfame potassium showed a light yellow color after being stored at 40 °C / 75% RH for 2 and 4 weeks.

[0172] Table 11: Physical description of combinations of active and inactive ingredients (sweeteners)

[0173]

[0174]

[0175] The physical standards (dissolution state, color) of a solution of 300 mg / ml meglutol alone or in combination with a flavoring agent were evaluated. According to the results summarized in Table 12, Preparation K containing red currant remained a clear solution under all storage conditions. Under all tested storage conditions, Preparation J containing black currant showed a light yellow or light brown color.

[0176] Table 12: Physical description of combinations of active and inactive ingredients (flavoring agents)

[0177]

[0178] The physical standards (dissolution state, color) of a solution of 300 mg / ml meglutol alone or in combination with a viscosity modifier were evaluated. According to the results summarized in Table 13, crystal formation occurred under all storage conditions after several weeks. Preparation N containing carbopol became a gel after 4 weeks at 25°C / 60% HR or a thick gel after 4 weeks at 40°C / 75% HR.

[0179] Table 13: Physical description of combinations of active and inactive ingredients (flavoring agents)

[0180]

[0181]

[0182] Impurity Study

[0183] The total amount of impurities in a solution of 300 mg / mL meglutol alone or in combination with each acidic buffer was measured. According to the results summarized in Table 13, Solutions B, C, and D showed an increase in impurity content after being placed in a sealed container at 40°C / 75% HR and 25°C / 60% HR for 4 weeks.

[0184] After 2 weeks or 4 weeks at 40°C / 75% HR or 25°C / 60% HR, the solution containing tartaric acid was stable and no additional impurities appeared. The peaks were not interfered with.

[0185] Table 13: Quantification of related substances in meglutol solution alone and in combination with acidic buffers

[0186]

[0187] #For these 3 solutions, since the unknown impurity peaks interfered with the DBU impurity peak (API impurity), the degraded impurity content was not recorded at 60°C and in the second week at 40°C / 75% HR.

[0188] The total amount of impurities in a solution of 300 mg / mL meglutol alone or in combination with each preservative was measured. According to the results in Table 14, Solution H containing sodium metabisulfite showed an increase in the amount of impurities at 40°C / 75% HR and 25°C / 60% HR in the second week and the fourth week.

[0189] For Solution I containing sodium benzoate, a small increase in impurities occurred in the fourth week at 40°C / 75% HR, but there was no significant change at 25°C / 60% HR.

[0190] Table 14: Quantification of related substances in meglutol solution alone and in combination with preservatives

[0191]

[0192] Measure the total amount of impurities in a separate solution of miglustat at 300 mg / mL or its combinations with each sweetener. Based on the results in Table 15, in solution K containing aspartame, a large amount of impurities was observed at each time point and under each environmental condition, even at the beginning of the study (initial).

[0193] For solution L containing acesulfame potassium, it was very difficult to measure the amount of impurities, and there was no reliable analytical method to quantify the amount of related substances. There are no available results for this scenario.

[0194] Table 15: Quantification of related substances in a separate miglustat solution and its combinations with sweeteners

[0195]

[0196]

[0197] Measure the total amount of impurities in a separate solution of miglustat at 300 mg / mL or its combinations with each flavoring agent. The results are shown in Table 16. For solution J containing blackcurrant, the results were not significant due to analytical problems. For solution S containing redcurrant, there were no analytical problems. No increase in impurities was observed at 40 °C / 75% HR or 25 °C / 60% HR. A slight increase was observed at 60 °C, which is expected at this temperature.

[0198] Table 16: Quantification of related substances in a separate miglustat solution and its combinations with flavoring agents

[0199]

[0200] Measure the total amount of impurities in a separate solution of miglustat at 300 mg / mL or its combinations with each flavoring agent. The results are shown in Table 16. For solution M containing PEG400, the results were not significant due to analytical problems. For solution N containing carbopol 971P, a very significant increase in impurities was observed at all storage conditions since the initial time.

[0201] Table 16: Quantification of related substances in a separate miglustat solution and its combinations with flavoring agents

[0202]

[0203]

[0204] Conclusion: Based on the DEC study, the proposed binary mixtures of excipients (such as tartaric acid, sodium benzoate, and red currant) with meglutol were found to be compatible for up to 4 weeks at 40 °C / 75% RH accelerated conditions, 25 °C / 60% RH RT conditions, and for 1 week at 60 °C.

[0205] However, incompatibility was found for PEG 400, hydrochloric acid, and acesulfame potassium, for the reasons described above.

[0206] Experimenter's Taste Evaluation

[0207] Each experimenter was allowed to taste 3 solutions and assign a rating to each, allowing for comparison of preferences between different formulations. As shown in Table 17, the best average rating was attributed to formulation 632, corresponding to the red currant flavor.

[0208] Table 13: Mean of the overall ratings for each formulation tested by the experimenters

[0209]

[0210] pH Value and Appearance Evaluation of the Preparation

[0211] The pH values of all solutions were below 5, which is necessary for sodium benzoate to be effective. Only solution F12 was clear. All solutions containing acesulfame potassium were hazy or turbid. Only solution F12 was clear.

[0212] Table 18: Appearance and pH value results for each formulation

[0213]

[0214] Comparison of the distance between the formulation batch tests and meglutol alone

[0215] Seven solutions containing meglutol were prepared (see Table 4 for the content of each solution). The E-tongue system measured the distance between the reference solution (F-18 = 250 mg / mL meglutol alone) and the test formulations.

[0216] As Figure 1 shown in

[0217] Furthermore, Figure 1B shows that the concentration of miglustat does not change its aromatic characteristics. However, the aromatic characteristics of formulation 12 are completely different, even though it contains a high content of miglustat (250 mg / mL).

[0218] Characterization of miglustat alone and selected formulations

[0219] Miglustat alone at 250 mg / mL (formulation F-18) was compared with solutions of sodium chloride, caffeine, sucrose, and citric acid at 10 mg / mL each to obtain its aromatic characteristics.

[0220] According to the distances analyzed by the e-tongue system described above, miglustat seems to be closer to sodium chloride and caffeine, and farther from sucrose and citric acid ( Figure 2 ).

[0221] According to the e-tongue results, formulation F-12 is the only clear solution and is the farthest from miglustat alone. This solution was compared with solutions of sodium chloride, caffeine, sucrose, and citric acid at 10 mg / mL each to understand its aromatic characteristics. According to Figure 3 the distances analyzed by the e-tongue system shown, formulation F-12 seems to be farther from sodium chloride and closer to citric acid, which is the opposite of miglustat alone.

[0222] Solution examples according to the present invention

[0223] Ingredient mg / mL % W / W Miglutol 250.00 57.21 Tartaric Acid 150.00 34.32 Sodium Benzoate 3.00 0.68 Magna sweet MM 110 28.00 6.41 Red Currant 6.0 1.37 Water q.s --

[0224] The microbial stability of this solution has been tested: the solution remained completely sterile when stored in a closed container at room temperature for three months.

[0225] References

[0226] Amiri M.et Naim H.Y.,Miglustat-induced intestinal carbohydratemalabsorption is due to the inhibition of-glucosidases,but not-galactosidasesJ.Inherit Metab Dis2012,35:949–954

[0227] Amiri M. and Naim N.Y. Long term differential consequences of miglustat therapy on intestinal disaccharidases J. Inherit Metab Dis 2014, 37:929–937 Belmatoug N et al, Gastrointestinal disturbances and their management in miglustat-treated patients. J. Inherit Metab Dis 2011, 34:991–1001 Getty A.L. and Pearce D.A., 2011 Interactions of the proteins of neuronal ceroid lipofuscinosis: clues to function. Cell Mol Life Sci. 2011 Feb;68(3):453-74

[0228] Lyseng-Williamson K.A. et al, Miglustat: A Review of Its Use in Niemann-Pick Disease Type C. Drugs 2014, 74:61–74

[0229] Remenova et al, A double-blind, randomized, placebo-controlled trial studying the effects of Saccharomyces boulardii on the gastrointestinal tolerability, safety, and pharmacokinetics of miglustat, Journal of rare diseases, 2015;10:81

[0230] Treem WR et al, Evaluation of liquid Yeast-derived sucrase enzyme replacement in patients with sucrase-isomaltase deficiency, Gastroenterology, 1993;105:1061-1068

Claims

1. An acidic liquid preparation for oral administration, the preparation containing at least 150 mg / mL of miglustat, and the liquid preparation containing: - Sodium benzoate as a preservative, - Tartaric acid to maintain the pH of the preparation between 3 and 5, - A sweetening agent, and - An optional flavoring agent.

2. The liquid preparation according to claim 1, wherein the sweetening agent is a mixture of glycerol and ammonium glycyrrhizinate.

3. The liquid preparation according to any one of claims 1 to 2, wherein the flavoring agent is selected from the group consisting of: pineapple, fennel, apple, apricot, banana, blackberry, blueberry, caramel, cherry, chocolate, coconut, coffee, cocoa, cola, cranberry, blackcurrant, redcurrant, grape, grapefruit, pomegranate syrup, lemon, maple, mint, orange, walnut, passion fruit, peach, pear, pineapple, plum, prune, raspberry, strawberry, citrus, mixed fruit flavor, vanilla.

4. The liquid preparation according to any one of claims 1 to 3, wherein the flavoring agent has an acidic flavor, usually redcurrant or orange.

5. The liquid preparation according to any one of claims 1 to 4, which contains 0.5 to 100 mg / mL of sodium benzoate.

6. The liquid preparation according to any one of claims 1 to 5, which contains 50 to 200 mg / mL of tartaric acid.

7. The liquid preparation according to any one of claims 1 to 6, which contains 0.1% to 10% by weight of the sweetening agent, preferably a mixture of glycerol and ammonium glycyrrhizinate in a ratio range of 10 (glycerol) / 1 (ammonium glycyrrhizinate) to 100 (glycerol) / 1 (ammonium glycyrrhizinate).

8. The liquid preparation according to any one of claims 1 to 7, which contains 0.01% to 10% of the flavoring agent.

9. The liquid preparation according to any one of claims 1 to 8, which contains: - At least 150 mg / mL of miglustat, - 0.5 to 100 mg / mL of sodium benzoate, - 50 to 200 mg / mL of tartaric acid such that the final pH of the preparation is between 3 and 5, - 0.01% to 10% by weight, preferably 1% to 10% by weight, of a mixture of glycerol and ammonium glycyrrhizinate in a ratio range of 10 (glycerol) / 1 (ammonium glycyrrhizinate) to 100 (glycerol) / 1 (ammonium glycyrrhizinate), and - 0.1% to 10% of a redcurrant or orange flavoring agent.

10. The liquid preparation according to any one of claims 1 - 9, wherein it contains no carbohydrates and no flavor enhancers.

11. The liquid preparation according to any one of claims 1 - 10, wherein it contains 250 mg / mL to 300 mg / mL of miglustat.

12. The liquid preparation according to any one of claims 1 - 11, which is used as a medicine.

13. The liquid preparation according to any one of claims 1 - 11, which is used for the treatment of lysosomal storage diseases, preferably for the treatment of neuronal ceroid lipofuscinosis (CLN1 to CLN14) or Niemann - Pick C disease or Gaucher's disease.

14. Use of the liquid preparation according to claim 13, wherein it is administered to a patient suffering from neuronal ceroid lipofuscinosis 3.

15. A combination product comprising the liquid preparation as defined in any one of claims 1-11, an activator of intestinal disaccharidase, for simultaneous, separate or staggered use in the treatment of lysosomal storage diseases, preferably in the treatment of Batten disease, said activator being preferably a heterologous small compound, an enzyme protein or a living organism capable of enhancing the activity or expression level of at least one intestinal disaccharidase, said intestinal disaccharidase being selected from: invertase (EC 3.2.1.26), maltase (EC 3.2.1.20), trehalase (EC 3.2.1.18), sucrase-isomaltase (SI, EC 3.2.1.48 and EC 3.2.1.10 respectively), β-galactosidase (EC 3.2.1.21), lactase-phlorizin hydrolase (LPH, EC 3.2.1.108), saccharozyme, amylase (EC 3.2.1.1) and amyloglucosidase (EC 3.2.1.3).

Images