New composition for treating spinal muscular atrophy

Abstract

Disclosed herein are pharmaceutical compositions and dosage forms comprising lisethopram, which are useful in the treatment of a subject suffering from SMA. The present disclosure also provides methods for preparing these pharmaceutical compositions and dosage forms, as well as methods of treating subjects with SMA using the pharmaceutical compositions and dosage forms provided herein.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480066817.0 (22) Application Date 2024.10.25 (30) Priority Data 23206351.1 2023.10.27 EP (85) PCT International Application Entering National Phase Date 2026.04.17 (86) PCT International Application Application Data PCT / EP2024 / 080163 2024.10.25 (87) PCT International Application Publication Data WO2025 / 088083 EN 2025.05.01 (71) Applicant: Hofmeister Roche Ltd. Address: Switzerland (72) Inventors: Reto Moellerselge Oberdorf, Stephanie Peter, Katrina Sengar (74) Patent Agency: China Patent & Trademark Agency Co., Ltd. 11021 Patent Attorneys: Liu Chunqi, Li Xinhong (51) Int.Cl. A61K 9 / 20 (2006.01) A61K 47 / 12 (2006.01) A61K 47 / 18 (2006.01) A61K 47 / 22 (2006.01) A61K 47 / 26 (2006.01) A61K 31 / 519 (2006.01) A61K 31 / 5025 (2006.01) A61P 21 / 00 (2006.01) (54) Title of Invention Novel Compositions for the Treatment of Spinal Muscular Atrophy (57) Abstract This disclosure discloses pharmaceutical compositions and dosage forms comprising lisciniforme, which may be used to treat subjects suffering from SMA. This disclosure also provides methods for preparing these pharmaceutical compositions and dosage forms, and methods for treating subjects suffering from SMA using the pharmaceutical compositions and dosage forms provided herein. Claims 10 pages Description 32 pages Drawings 4 pages CN 122055139 A 2026.05.15 CN 1 22 05 51 39 A 1. A pharmaceutical composition comprising: (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) crospovidone; and (c) an acidifying agent selected from tartaric acid, citric acid, or malic acid, more particularly tartaric acid. 2. The pharmaceutical composition of claim 1, comprising i) a tablet core (also known as a chip or first-layer tablet) comprising: (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) crospovidone; and (c) an acidifying agent selected from tartaric acid, citric acid, or malic acid, more particularly tartaric acid; and ii) at least one film coating. 3. The pharmaceutical composition of any one of claims 1 to 2,4. The pharmaceutical composition according to any one of claims 1 to 3, comprising a first film coating, wherein the first film coating directly coats the tablet core (also referred to as a chip or first-layer tablet (i)). 5. The pharmaceutical composition according to any one of claims 2 to 4, wherein at least one film coating, particularly wherein the first film coating is free of iron oxides, particularly wherein the film coating, particularly the first film coating, is a polyvinyl alcohol-based coating (PVA-based coating), particularly having 5 mg or less of PVA-based coating, more particularly having 3.0 mg of PVA-based coating, and most particularly having 2.5 mg of PVA-based coating. 6. The pharmaceutical composition according to any one of claims 3 to 4, wherein the first film coating is free of iron oxides, particularly wherein the film coating, particularly the first film coating, is a polyvinyl alcohol-based coating (PVA-based coating), particularly having 5 mg or less of PVA-based coating, and more particularly having 2.5 mg of PVA-based coating. 7. The pharmaceutical composition according to any one of claims 1 to 6, comprising a second film coating, wherein the second film coating coats the first film coating, particularly wherein the second film coating is a polyvinyl alcohol-based coating (PVA-based coating), particularly having 5 mg or less of PVA-based coating, more particularly having 2.5 mg of PVA-based coating. 8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the composition further comprises a filler selected from microcrystalline cellulose, cellulose powder, isomaltitol, lactose (specific examples of lactose may be spray-dried lactose, anhydrous lactose, or lactose monohydrate), maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugars (specific examples of sugars may be sucrose, glucose, or sugar alcohols), starches (specific examples of starches may be hydrolyzed starch, corn starch, or pregelatinized starch), polysaccharides, dicalcium phosphate, and calcium sulfate, and combinations thereof. 9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the composition further comprises a filler selected from lactose, starch (especially hydrolyzed starch), maltodextrin, isomaltitol, microcrystalline cellulose, mannitol, sorbitol, sucrose, glucose, calcium hydrogen phosphate, and calcium sulfate, and combinations thereof. 10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the composition further comprises microcrystalline cellulose and mannitol as fillers. 11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the composition does not contain disodium ethylenediaminetetraacetate. 12. The pharmaceutical composition according to any one of claims 1 to 11,The composition described herein does not contain sucralose. 13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the composition further comprises a lubricant selected from sodium stearoyl fumarate and magnesium stearate. 14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the composition further comprises a lubricant, wherein the lubricant is sodium stearoyl fumarate. 15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the composition further comprises a flow aid, wherein the flow aid is colloidal silica. 16. The pharmaceutical composition according to any one of claims 1 to 15, comprising: (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) crospovidone; (c) an acidifying agent selected from tartaric acid, citric acid, or malic acid, more particularly tartaric acid; and (d) at least one filler selected from microcrystalline cellulose, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, sugar alcohol, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dicalcium phosphate, and calcium sulfate, and combinations thereof, particularly selected from lactose, starch, hydrolyzed starch, maltodextrin, isomaltitol, microcrystalline cellulose, mannitol, sorbitol, sucrose, glucose, dicalcium phosphate, and calcium sulfate, and combinations thereof, more particularly combinations of microcrystalline cellulose and mannitol. Claims 2 / 10 pages 3 CN 122055139 A 17. A pharmaceutical composition according to any one of claims 1 to 16, comprising: (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) crospovidone; (c) an acidifying agent selected from tartaric acid, citric acid, or malic acid, more particularly tartaric acid; (d) at least one filler selected from microcrystalline cellulose, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, sugar alcohol, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dicalcium phosphate, and calcium sulfate, and combinations thereof, particularly selected from lactose, starch, hydrolyzed starch, maltodextrin, isomaltitol, microcrystalline cellulose, mannitol, sorbitol, sucrose, Glucose, calcium hydrogen phosphate, and calcium sulfate, and combinations thereof, particularly combinations of microcrystalline cellulose and mannitol; and (e) a lubricant selected from sodium stearoyl fumarate and magnesium stearate, particularly sodium stearoyl fumarate. 18. The pharmaceutical composition according to any one of claims 1 to 17, comprising: (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) crospovidone; (c) an acidifying agent selected from tartaric acid, citric acid, or malic acid.More particularly, tartaric acid; (d) at least one filler selected from microcrystalline cellulose, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, sugar alcohol, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dicalcium phosphate and calcium sulfate, and combinations thereof, particularly selected from lactose, starch, hydrolyzed starch, maltodextrin, isomaltitol, microcrystalline cellulose, mannitol, sorbitol, sucrose, glucose, dicalcium phosphate and calcium sulfate, and combinations thereof, more particularly combinations of microcrystalline cellulose and mannitol; (e) a lubricant selected from sodium stearoyl fumarate and magnesium stearate, particularly sodium stearoyl fumarate; and (f) a flow aid, wherein the flow aid is colloidal silica; Claims 3 / 10 pages 4 CN 122055139 A The prerequisite is that the pharmaceutical composition does not contain disodium EDTA. 19. The pharmaceutical composition according to any one of claims 1 to 17, comprising: (a) about 5 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) crospovidone; (c) an acidifier selected from tartaric acid, citric acid, or malic acid, more particularly tartaric acid; (d) at least one filler selected from microcrystalline cellulose, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, sugar alcohol, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharide, dicalcium phosphate, and calcium sulfate, and combinations thereof, particularly selected from lactose, starch, hydrolyzed starch, maltodextrin, isomaltitol, microcrystalline cellulose, mannitol, sorbitol, sucrose, glucose, dicalcium phosphate, and calcium sulfate, and combinations thereof, more particularly combinations of microcrystalline cellulose and mannitol; (e) a lubricant selected from sodium stearoyl fumarate and magnesium stearate, particularly sodium stearoyl fumarate; and (f) a flow aid, wherein the flow aid is derived from colloidal silica; provided that the pharmaceutical composition does not contain disodium ethylenediaminetetraacetate. 20. The pharmaceutical composition according to any one of claims 1 to 19, comprising 0.5% to 30% by weight of lisporanic acid, particularly 1% to 15% by weight of lisporanic acid, more particularly 2% to 8% by weight of lisporanic acid, and most particularly 4% ± 2% by weight of lisporanic acid (particularly wherein the weight is the weight of the uncoated core). 21. The pharmaceutical composition according to any one of claims 1 to 20, comprising 2% to 80% by weight of mannitol, particularly 15% to 45% by weight of mannitol, more particularly 20% to 40% by weight of mannitol.Most particularly, 30% ± 5% mannitol by weight (especially wherein the weight is the weight of the uncoated core). 22. The pharmaceutical composition according to any one of claims 1 to 21, comprising colloidal silica between 0.2% and 5.0% by weight, more particularly between 1.0% and 3.0% by weight, and most particularly 2.0% ± 0.5% by weight (especially wherein the total weight is the weight of the uncoated core). 23. The pharmaceutical composition according to any one of claims 1 to 22, comprising sodium stearoyl fumarate between 0.2% and 5% by weight, more particularly between 2.0% and 4.0% by weight, and most particularly 3.0% ± 0.5% by weight (especially wherein the total weight is the weight of the uncoated core). 24. The pharmaceutical composition according to any one of claims 1 to 23, comprising microcrystalline cellulose at a weight of 5% to 90%, particularly at a weight of 20% to 60%, more particularly at a weight of 50.0% ± 5%, and most particularly at a weight of 50.0% ± 2% (particularly wherein the total weight is the weight of the uncoated core). 25. The pharmaceutical composition according to any one of claims 1 to 24, comprising tartaric acid at a weight of 0.2% to 12.0%, more particularly at a weight of 1.0% to 4.0%, and most particularly at a weight of 2.5% ± 0.5% (particularly wherein the total weight is the weight of the uncoated core). 26. The pharmaceutical composition according to any one of claims 1 to 25, comprising 0.5% to 12.0% crospovidone by weight, more particularly 4.0% to 8.0% crospovidone by weight, and most particularly 6.0% ± 1.0% crospovidone by weight (particularly wherein the total weight is the weight of the uncoated core). 27. The pharmaceutical composition according to any one of claims 1 to 26, comprising 0.5% to 30% liscinidin by weight, particularly 1% to 15% liscinidin by weight, and more particularly 2% to 8% liscinidin by weight.Most particularly, 4% ± 2% by weight of liscinidin (wherein the total weight is the weight of the coated tablet [core weight and coating weight]). 28. The pharmaceutical composition according to any one of claims 1 to 27, comprising between 2% and 80% by weight of mannitol, particularly between 15% and 45% by weight of mannitol, more particularly between 20% and 40% by weight of mannitol, and most particularly 30% ± 5% by weight of mannitol (wherein the total weight is the weight of the coated tablet [core weight and coating weight]). 29. The pharmaceutical composition according to any one of claims 1 to 28, comprising colloidal silica at a weight of 0.2% to 5.0%, more particularly at a weight of 1.0% to 3.0%, and most particularly at a weight of 1.90% ± 0.50% (wherein the total weight is the weight of the coated tablet [core weight and coating weight]). 30. The pharmaceutical composition according to any one of claims 1 to 29, comprising sodium stearoyl fumarate at a weight of 0.2% to 5%, more particularly at a weight of 2.0% to 4.0%, and most particularly at a weight of 2.90% ± 0.50% (wherein the total weight is the weight of the coated tablet [core weight and coating weight]). 31. The pharmaceutical composition according to any one of claims 1 to 30, comprising between 5% and 90% by weight microcrystalline cellulose, particularly between 20% and 60% by weight microcrystalline cellulose, more particularly 50.0% ± 5% by weight microcrystalline cellulose, and most particularly 48.90% ± 2.0% by weight microcrystalline cellulose (wherein the total weight is the weight of the coated tablet [core weight and coating weight]). 32. The pharmaceutical composition according to any one of claims 1 to 31, comprising between 0.2% and 12.0% by weight tartaric acid, more particularly between 1.0% and 4.0% by weight tartaric acid, and most particularly 2.30% ± 0.5% by weight tartaric acid (wherein the total weight is the weight of the coated tablet [core weight and coating weight]). 33. The pharmaceutical composition according to any one of claims 1 to 32, comprising crospovidone at a weight of 0.5% to 12.0%, more particularly at a weight of 4.0% to 8.0% crospovidone.Most notably, it contains 5.80% ± 1.0% crospovidone by weight (where the total weight is the weight of the coated tablet [core weight and coating weight]). 34. The pharmaceutical composition according to any one of claims 1 to 33, comprising: (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, in an amount of 0.5% to 30% by weight, particularly 1% to 15% by weight, more particularly 2% to 8% by weight, and most particularly 4% ± 2% by weight; (b) crospovidone, in an amount of 0.5% to 12.0% by weight, more particularly 4.0% to 8.0% by weight, and most particularly 6.0% ± 1.0% by weight; and (c) crospovidone, in an amount of 0.2% to 12.0% by weight, more particularly 1.0% to 4.0% by weight, and most particularly 2.5% ± 0.5% by weight. (d) An acidifying agent selected from tartaric acid, citric acid, or malic acid, more particularly tartaric acid; and (d) at least one filler selected from microcrystalline cellulose, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, sugar alcohol, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharide, dicalcium phosphate, and calcium sulfate, and combinations thereof, particularly selected from lactose, starch, hydrolyzed starch, maltodextrin, isomaltitol, microcrystalline cellulose, mannitol, sorbitol, sucrose, glucose, dicalcium phosphate, and calcium sulfate, and combinations thereof, more particularly combinations of microcrystalline cellulose and mannitol. (e) a lubricant comprising, by weight, between 0.2% and 5%, more particularly between 2.0% and 4.0%, and most particularly 3.0% ± 0.5%, of sodium stearoyl fumarate and magnesium stearate, particularly sodium stearoyl fumarate; and (f) a flow aid comprising, by weight, between 0.2% and 5.0%, more particularly between 1.0% and 3.0%, and most particularly 2.0% ± 0.5%, of colloidal silica; provided that the pharmaceutical composition does not contain disodium ethylenediaminetetraacetate; wherein the total amount of the components does not exceed 100% by weight. 35. The pharmaceutical composition according to any one of claims 1 to 34,It comprises: (a) a pharmaceutically acceptable salt of formula (I) in an amount of 0.5% to 30% by weight, particularly 1% to 15% by weight, more particularly 2% to 8% by weight, and most particularly 4% ± 2% by weight; (b) crospovidone in an amount of 0.5% to 12.0% by weight, more particularly 4.0% to 8.0% by weight, and most particularly 6.0% ± 1.0% by weight; and (c) crospovidone in an amount of 0.2% to 12.0% by weight, more particularly 1.0% to 4.0% by weight, and most particularly 2.5% ± 0.5% by weight. The acidifying agent is selected from tartaric acid, citric acid, or malic acid, more particularly tartaric acid; (d) microcrystalline cellulose at a weight of 5% to 90%, particularly at a weight of 20% to 60%, more particularly at a weight of 50.0% ± 5%, and most particularly at a weight of 50.0% ± 2%; (e) mannitol at a weight of 2% to 80%, particularly at a weight of 15% to 45%, more particularly at a weight of 20% to 40%, and most particularly at a weight of 30% ± 5%; (f) sodium stearoyl fumarate at a weight of 0.2% to 5%, more particularly at a weight of 2.0% to 4.0%, and most particularly at a weight of 3.0% ± 0.5%; and (g) sodium stearoyl fumarate at a weight of 0.2% to 5.0%. The pharmaceutical composition comprises, more particularly, 1.0% to 3.0% by weight, and most particularly 2.0% ± 0.5% by weight of colloidal silica; provided that the pharmaceutical composition does not contain disodium ethylenediaminetetraacetate; wherein the total amount of the components does not exceed 100% by weight (in particular, wherein the weight is the weight of the uncoated core). 36. The pharmaceutical composition according to any one of claims 1 to 35, comprising: i) a tablet core (also known as a chip or first-layer tablet) comprising: (a) a compound of formula (I) or a pharmaceutically acceptable salt by weight, comprising, between 0.5% and 30% by weight, particularly between 1% and 15% by weight, more particularly between 2% and 8% by weight, and most particularly 4% ± 2% by weight; (b) crospovidone by weight, comprising, between 0.5% and 12.0% by weight.More particularly, crospovidone at a weight of 4.0% to 8.0%, most particularly 6.0% ± 1.0% by weight; (c) an acidifying agent at a weight of 0.2% to 12.0%, more particularly 1.0% to 4.0%, most particularly 2.5% ± 0.5%, selected from tartaric acid, citric acid, or malic acid, more particularly tartaric acid; (d) microcrystalline cellulose at a weight of 5% to 90%, more particularly 20% to 60%, more particularly 50.0% ± 5%, most particularly 50.0% ± 2%; (e) microcrystalline cellulose at a weight of 2% to 80%, more particularly 15% by weight. (a) 0.2% to 45% by weight, more particularly 20% to 40% by weight, and most particularly 30% ± 5% by weight; (b) 0.2% to 5% by weight, more particularly 2.0% to 4.0% by weight, and most particularly 3.0% ± 0.5% by weight; and (c) 0.2% to 5.0% by weight, more particularly 1.0% to 3.0% by weight, and most particularly 2.0% ± 0.5% by weight; and (d) at least one film coating; provided that the pharmaceutical composition does not contain disodium ethylenediaminetetraacetate; wherein the total amount of the components does not exceed 100% by weight. 37. The pharmaceutical composition according to any one of claims 1 to 36, wherein sodium stearoyl fumarate has a saponification value of 142.2 to 146.0, particularly having a Dv50 of 13.6 µm, and more particularly, sodium stearoyl fumarate is Pruv®. 38. The pharmaceutical composition according to any one of claims 1 to 37, wherein the microcrystalline cellulose is CAS 9004-34-6, particularly having a Dv50 of 135 µm, and more particularly having a pH of 102. 39. The pharmaceutical composition according to any one of claims 1 to 38, comprising a single active pharmaceutical ingredient (API), more particularly wherein the single API is a compound of formula (I), also known as lisclan. 40. A tablet comprising the pharmaceutical composition according to any one of claims 1 to 39. 41. The tablet according to claim 40, wherein the tablet is dispersible in water within 5 minutes. 42. The tablet according to any one of claims 40 to 41,The tablets are dispersible in water with an HCl content of less than 1 mg / L, and more particularly in drinking water with an HCl content of less than 0.2 mg / L, especially mineral water. 43. The tablets according to any one of claims 40 to 42, having the shape shown in FIG2, and more particularly having a diameter of 6.50 ± 0.50 mm. 44. A kit comprising: a pharmaceutical composition according to any one of claims 1 to 39, in tablet form containing a therapeutically effective amount of liscovah's flavonoids; prescription information, also known as "instructions for use"; blister packs or bottles (HDPE or glass), particularly moisture-proof primary packaging, more particularly Alu / Alu blister packs or plastic bottles with desiccant; and a container, wherein the prescription information specifically includes recommendations for patients regarding the administration of the liscovah's flavonoids with food. 45. A method for producing a pharmaceutical composition according to any one of claims 1 to 39, the method comprising the following steps: i) blending the compound of formula (I), also known as liscovalin, with tartaric acid powder, mannitol, microcrystalline cellulose, colloidal silica, crospovidone, and strawberry flavoring in container 1; ii) sieving container 1; iii) sieving sodium stearoyl fumarate in container 2, particularly to 0.5 mm; iv) blending the mixture of container 1 and container 2; v) compressing the blend of iv) into a tablet core; and vi) suspending a first membrane coating system, particularly a membrane coating system free of iron oxides, and more particularly a membrane coating system of OPADRY II white (i.e., 85F18422), in purified water; and vii) spraying the membrane coating system vi) onto the tablet core. viii) suspending the membrane coating system, particularly a membrane coating system that does not contain iron oxides, and more particularly a membrane coating system that is OPADRY II Yellow (i.e., 85F220022), in purified water, and ix) spraying the membrane coating system (viii) onto the core of the coated tablet. 46. A pharmaceutical composition obtained by the method according to claim 45. 47. A pharmaceutical composition according to any one of claims 1 to 39, comprising lisclan administered to an individual at any suitable dose (e.g., to achieve a therapeutically effective amount), particularly at a suitable dose of about 5 mg of a therapeutically effective amount per day. 48. A pharmaceutical composition according to any one of claims 1 to 39,It is used for the treatment, prevention, delay of progression, and / or improvement of diseases caused by inactive mutations or deletions in the SMN1 gene and / or associated with loss or defect in SMN1 gene function, particularly for the treatment, prevention, delay of progression, and / or improvement of spinal muscular atrophy (SMA). 49. The pharmaceutical composition of claim 48, used for said treatment, wherein the patient's weight is greater than or equal to 20 kg. 50. The pharmaceutical composition of claim 48, used for said treatment, wherein the weight of the human subject is greater than or equal to 20 kg. 51. The invention as described above. Claims 10 / 10 pages 11 CN 122055139 A Novel Composition for the Treatment of Spinal Muscular Atrophy

[0001] The present invention provides pharmaceutical formulations comprising a compound as an SMN2 gene splicing regulator, particularly wherein the SMN2 gene splicing regulator is risdiplam, its manufacture, and its use for the treatment, delay of progression, or improvement of spinal muscular atrophy (SMA). This disclosure also provides methods for preparing these pharmaceutical formulations and dosage forms, and methods for treating SMA, delaying the progression of SMA, or improving SMA using the pharmaceutical formulations and dosage forms provided herein. The present invention generally relates to a more patient-friendly drug delivery system for a target population. Specifically, the present invention relates to a pharmaceutical composition in tablet form, more particularly film-coated tablets. In particular, the present invention provides compliance dosage forms especially for patients weighing 20 kg or more. Tablets can generally be swallowed whole or dispersed in a small amount of water before administration to provide a liquid form, especially in cases where swallowing is difficult or for pediatric populations.

[0002] In particular, the present invention relates to a pharmaceutical composition comprising:

[0003] (a) a compound of formula (I)

[0004]

[0005] or a pharmaceutically acceptable salt thereof;

[0006] (b) crospovidone; and

[0007] (c) an acidifying agent selected from tartaric acid, citric acid, or malic acid, more particularly tartaric acid.

[0008] Spinal muscular atrophy (SMA) describes, in its broadest sense, a range of hereditary and acquired central nervous system (CNS) diseases characterized by progressive loss of motor neurons in the spinal cord and brainstem leading to muscle weakness and atrophy. SMA is characterized by the degeneration of α motor neurons from the anterior horn of the spinal cord, leading to muscle atrophy and paralysis. Thus, this degeneration of α motor neurons substantially impairs the important prognosis of patients. In healthy subjects, these neurons transmit information from the brain to the muscles, thereby causing muscle contraction. Without this stimulation, the muscles atrophy. Subsequently,In addition to generalized muscle weakness and atrophy (especially in the trunk, upper arms, and thighs), these conditions can also be accompanied by severe respiratory problems.

[0009] Infantile SMA is the most severe form of this neurodegenerative disease. Symptoms include muscle weakness, poor muscle tone, weak crying, limping or a tendency to fall, difficulty sucking or swallowing, buildup of secretions in the lungs or throat, difficulty feeding, and increased susceptibility to respiratory infections. The legs are often weaker than the arms and fail to reach developmental milestones such as lifting the head or sitting up. Generally, the earlier symptoms appear, the shorter the lifespan. Symptoms appear soon after the deterioration of motor neurons. The severe forms of this disease are fatal, and there is no known cure for any form. The course of SMA is directly related to the rate of degeneration of motor neurons and the severity of the resulting weakness. Infants with severe forms of SMA often die from respiratory illnesses due to weakness of the muscles that support breathing. Children with milder forms of SMA survive much longer, although they may require extensive medical support, especially those at the more severe end of the symptom spectrum. SMA Manual 1 / 32 pages 12 CN 122055139 A The clinical presentation of the disease is divided into the following five groups:

[0010] 1. Type 0 SMA (Intrauterine SMA) is the most severe form of the disease and begins before birth. Typically, the first symptom of type 0 SMA is reduced fetal movement, which can be first observed between 30 and 36 weeks of gestation. After birth, these newborns are rarely active and have difficulty swallowing and breathing.

[0011] 2. Type I SMA (Infantile SMA or Warnick-Hoffman syndrome) presents with symptoms between 0 and 6 months of age; this form of SMA is very severe. Patients are unable to sit up and usually die within the first 2 years without ventilatory support.

[0012] 3. Type II SMA (Intermediate SMA) has an age of onset between 7 and 18 months of age. Patients can sit upright without support, but are never able to stand or walk independently. The prognosis for this group largely depends on the extent of respiratory involvement.

[0013] 4. Type III SMA (juvenile SMA or Kugelberg-Weyland disease) is usually diagnosed after 18 months. Individuals with type III SMA are able to walk independently at some point during the course of their disease, but usually begin to rely on a wheelchair in adolescence or adulthood.

[0014] 5. Type IV SMA (adult-onset SMA). Weakness usually begins in the tongue, hands, or feet in late adolescence and then spreads to other parts of the body. The course of adult SMA is much slower.And it has little or no impact on life expectancy.

[0015] All forms of spinal muscular atrophy are accompanied by progressive muscle weakness and atrophy following the degeneration of neurons in the anterior horn of the spinal cord. SMA is currently one of the most common causes of infant mortality. It affects girls and boys equally in all parts of the world, with a prevalence between 1 / 6000 and 1 / 10000.

[0016] The goal of any drug delivery system is to deliver a therapeutic dose of drug to the appropriate site in the body to achieve and maintain the desired drug concentration. Due to the characteristics of patients, lixithromycin was initially approved as a 0.75 mg / ml oral solution powder. The oral solution powder (PfOS) formulation was the first approved formulation, developed to provide flexible dosing based on patient weight for all patients from newborns to adults. Due to the disease spectrum of SMA as outlined above, treatment options for patients from birth to adulthood are necessary, and the ability to accurately administer medication across such a wide range of patient weights is crucial, especially for patients greater than 20 kg. Due to the specific requirements of reconstitution, PfOS reconstitution must be performed in a hospital pharmacy, and the bottles need to be refrigerated afterward, which is inconvenient for patients and requires a complex supply chain.

[0017] Oral solutions, especially when reconstituted in solution, may face some stability burdens under certain conditions. To ensure product quality over the expected usage time, reconstituted PfOS requires refrigerated storage. Notably, the present invention addresses these limitations.

[0018] To provide stable conventional film-coated tablets that do not require refrigerated storage, a formulation composition for film-coated tablets was selected.

[0019] Furthermore, the composition contains tartaric acid as an acidifier, which ensures complete dissolution of lisciphalan at elevated and variable gastric pH. Studies have found that the solubility of lisciphalan is affected by the pH of the solution. Therefore, by lowering the pH with tartaric acid, lisciphalan can be completely dissolved. Bioequivalence of the tablets compared to PfOS was confirmed. Both showed bioequivalence in both eaten and fasting states, with the tablets swallowed whole but also dispersed in small amounts of water.

[0020] According to the present invention, the chip formulation unexpectedly disintegrates rapidly. The presence of crospovidone is the cause of this rapid disintegration. Therefore, film-coated tablets can be dispersed in water so that they can be used by patients who have difficulty swallowing tablets.

[0021] Tablets are typically coated with film. Standard coatings used for film-coated tablets are generally used to reduce dust, for careful handling, for aesthetics, and for differentiation between dosage strengths. Iron oxides are widely used as colorants to maintain a homogeneous appearance. Surprisingly, lisciphagan is chemically incompatible with iron oxides. As further described in detail in the specification 2 / 32 pages 13 CN 122055139 A,The presence of iron oxides leads to significant and severe degradation of lisciphagus and extreme discoloration of the tablets. Therefore, the present invention must ensure that the tablets do not come into direct contact with the iron oxide coating. Thus, the present invention includes the use of a first coating free of iron oxides, thereby preventing interaction between lisciphagus and a second coating, which may contain iron oxides (such as a yellow coating) used to determine color.

[0022] Figure 1: Dissolution performance of lisciphagus at pH 4.5 in the presence of an acidifying agent, film-coated tablets 5 mg containing different levels of tartaric acid (TA), formulation 1 containing 0.00 mg TA, formulation 2 containing 2.00 mg TA, formulation 3 containing 3.00 mg TA, formulation 4 containing 4.00 mg TA, formulation 5 containing 6.00 mg TA, formulation 6 containing 6.0000 mg TA, and formulation 7 containing 7.53 mg TA.

[0023] Figure 2: Lisperidone tablets

[0024] Figure 3: Discoloration and decomposition of lisperidone in the presence of sucralose, a) Lisperidone + sucralose, at time 0, b) Lisperidone + sucralose (70°C / 75% RH), after 15 days, c) Sucralose without lisperidone (70°C / 75% RH), after 15 days.

[0025] Figure 4: Formulation 12 (uncoated) left open for two weeks at 70°C / 75% RH and 70°C / 5% RH.

[0026] Figure 5: a) Placebo tablets, after two weeks at 70°C / 5% RH, b) Placebo tablets, after two weeks at 70°C / 75% RH.

[0027] Figure 6: a) Tablet of Formulation 14 at time t0, b) Tablet of Formulation 14 after two weeks at 70°C / 5% relative humidity, c) Tablet of Formulation 14 after two weeks at 70°C / 75% relative humidity, d) Tablet of Formulation 15 at time t0, e) Tablet of Formulation 15 after two weeks at 70°C / 5% relative humidity, f) Tablet of Formulation 15 after two weeks at 70°C / 75% relative humidity.

[0028] All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference in their entirety.

[0029] Unless otherwise indicated, the nomenclature used in this application is based on the IUPAC system nomenclature.

[0030] Various features and embodiments of the invention have been disclosed herein; however, other features, modifications and equivalents of the invention will be apparent to those skilled in the art based on the teachings provided. The invention described herein is not limited to the examples and embodiments provided.Those skilled in the art will recognize various alternative equivalents. As used herein, the singular forms “an,” “a,” and “the” include the plural unless the context clearly specifies otherwise. For example, “an” individual will also include “a plurality of individuals.”

[0031] Unless otherwise stated, the following terms used in the specification and claims have the following meanings:

[0032] “about” or “approximately” means a value falling within a range of 5% greater or less than the specified reference value.

[0033] The “individual” or “subject” used interchangeably refers to mammals. Mammals include, but are not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the individual or subject is a human. In a particular embodiment of the invention, the subject is a person suffering from spinal muscular atrophy (SMA). In another specific implementation, the subject is a person with SMA, wherein SMA is caused by an inactivating mutation or deletion in the SMN1 gene on two chromosomes (which results in loss of function of the SMN1 gene).

[0034] The term “spinal muscular atrophy” (or SMA) refers to a disease caused by an inactivating mutation or deletion in the SMN1 gene on two chromosomes (which results in loss of function of the SMN1 gene). Symptoms of SMA (depending on the type of SMA) include: muscle weakness, poor muscle tone, weak crying, weak cough, limping or tendency to fall, difficulty sucking or swallowing, difficulty breathing, secretions accumulating in the lungs or throat, sweaty hands and clenched fists, tongue flapping / trembling, head often tilted to one side (even when lying down), legs often weaker than arms, legs frequently exhibiting a "frog leg" posture, difficulty eating, increased susceptibility to respiratory infections, bowel / bladder weakness, below-normal weight, inability to sit without support, inability to walk, inability to crawl, and decreased muscle tone, lack of reflexes.And congenital multiple contractures (joint contractures) associated with anterior horn cell loss.

[0035] "Treatment of spinal muscular atrophy (SMA)" or "treatment for spinal muscular atrophy (SMA)" means one or more of the following effects: (i) reducing or improving the severity of SMA; (ii) delaying the onset of SMA; (iii) inhibiting the progression of SMA; (iv) reducing the number of hospitalizations of the subject; (v) shortening the length of hospital stay of the subject; (vi) increasing the survival rate of the subject; (vii) improving the quality of life of the subject; (viii) reducing the number of symptoms associated with SMA; (ix) reducing or improving the severity of one or more symptoms associated with SMA; (x) shortening the duration of symptoms associated with SMA; (xi) preventing the recurrence of symptoms associated with SMA; (xii) inhibiting the development or onset of SMA symptoms; and / or (xiii) inhibiting the progression of symptoms associated with SMA. More specifically, “treatment of SMA” means one or more of the following beneficial effects: (i) reduced muscle strength loss; (ii) increased muscle strength; (iii) reduced muscle atrophy; (iv) reduced motor function loss; (v) increased motor neurons; (vii) reduced motor neuron loss; (viii) protection of SMN-deficient motor neurons from degeneration; (ix) increased motor function; (x) increased lung function; and / or (xi) reduced lung function loss. More particularly, “treatment of SMA” produces or helps maintain the following functional abilities: for human children or adults, to sit independently; or for human children or adults, to stand independently, walk independently, run independently, breathe independently, turn over independently during sleep, or swallow independently.

[0036] “Patients” or “patients” means a person (such as a man or woman) diagnosed with SMA.

[0037] “Active pharmaceutical ingredient” (or “API”) means a compound or molecule in a pharmaceutical composition that has a specific biological activity. More specifically, the term "API" refers to the active substance licorice as described in the present invention.

[0038] "Pharmaceutical-acceptable excipient," "pharmaceutical-acceptable carrier," and "therapeutic inert excipient" are used interchangeably and refer to any pharmaceutically acceptable component in a pharmaceutical composition that is not therapeutically active and is non-toxic to the subject to which it is administered, such as disintegrants, binders, fillers, solvents, buffer systems, tension agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants used in the formulation of pharmaceutical products.

[0039] "Pharmaceutical composition" and "pharmaceutical formulation" (or "formulation") refer to a form in which the active ingredient permitted to be contained is biologically effective.And the formulation does not contain any additional components that would have unacceptable toxicity to the subject to whom the composition will be administered. The term “pharmaceutical” means that a substance that can be used to prepare a pharmaceutical composition has the following properties: generally safe, non-toxic, neither biologically nor otherwise undesirable, and acceptable for veterinary and human pharmaceutical use.

[0040] “Fill” refers to an excipient that fills the volume of a tablet or capsule, thereby facilitating the manufacture of the tablet or capsule and making it convenient for the consumer to use. Suitable fillers include, for example, pharmaceutically acceptable fillers such as microcrystalline cellulose (e.g., Avicel®), cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, sugar alcohol, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dicalcium phosphate, calcium sulfate, and combinations thereof.

[0041] As used herein, the term “acidifier” refers to an excipient added to a pharmaceutical formulation to lower the pH of a solution or mixture. Acidifying agents are used to create an acidic environment, which can enhance the stability, solubility, and bioavailability of active pharmaceutical ingredients (APIs). Examples of acidifying agents can be "organic acidifying agents" or "inorganic acidifying agents." As used herein, the term "organic acidifying agent" means an acidifying agent whose chemical composition contains carbon. As used herein, the term "inorganic acidifying agent" means an acidifying agent whose composition does not contain carbon. In particular, the acidifying agent according to the invention is selected from tartaric acid, malic acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. More particularly, the acidifying agent is tartaric acid, citric acid, or malic acid. Even more particularly, the acidifying agent is tartaric acid. Further and more particularly, the acidifying agent is (D) or (L) tartaric acid or a combination thereof, more particularly (L) tartaric acid. Furthermore, and most notably, tartaric acid was found to specifically lower the pH near lisciphagus, rather than simply lowering the overall pH of the solution. By creating a localized acidic environment, the acidifier enhances the solubility of lisciphagus, thus ensuring its optimal performance. This targeted pH adjustment also occurs under elevated pH conditions. Therefore, it helps maintain the efficacy of lisciphagus throughout the product's shelf life. Incorporating tartaric acid into the formulation to achieve this localized pH reduction improves the overall therapeutic efficacy of the drug. Other acidifiers have not shown an advantage over tartaric acid.

[0042] "Pharmaceutically acceptable carrier" refers to a component of the pharmaceutical composition that is non-toxic to the subject, other than the active ingredient. Pharmaceutically acceptable carriers include, but are not limited to, buffers or acidifiers, excipients, stabilizers, or preservatives.

[0043] As used herein,The term “administration / administering” refers to the delivery of a bioactive composition or formulation to a subject via a route of administration, including but not limited to oral, intravenous, intra-arterial, intramuscular, intraperitoneal, subcutaneous, intramuscular, local, or combinations thereof. In some embodiments, the route of administration to the subject is oral.

[0044] “Cmax” (expressed in pg / mL) refers to the peak concentration of the compound achieved in the plasma of the subject after administration of the compound or a pharmaceutical composition containing the compound. In some embodiments, the compound or a pharmaceutical composition containing the compound is administered orally to the subject to achieve a specific Cmax.

[0045] “Tmax” (expressed in hours, or as the median number of hours for Tmax in a study population) refers to the time it takes for the compound to reach a peak concentration in the plasma of the subject after administration of the compound or a pharmaceutical composition containing the compound. If it occurs at multiple time points, Tmax is defined as the first time point with this value.

[0046] “Moisture” refers to the presence of water, including trace amounts of water, vapor, humidity, and liquid water.

[0047] "OPADRY II White" refers to an iron oxide-free film coating comprising polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, and talc; more particularly for 2.5 g of the film coating according to the invention, the film coating comprises 1.000 mg of polyvinyl alcohol, 0.625 mg of titanium dioxide, 0.505 mg of polyethylene glycol 3350, and 0.370 mg of talc.

[0048] "OPADRY II Yellow" refers to a film coating comprising polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, and iron oxide yellow; more particularly for 2.5 g of the film coating according to the invention, the film coating comprises 1.000 mg of polyvinyl alcohol, 0.608 mg of titanium dioxide, 0.505 mg of polyethylene glycol 3350, 0.370 mg of talc, and 0.017 mg of iron oxide yellow.

[0049] In the context of any excipient and / or liximab, “x% by weight” or “x% ± y% by weight” means “x% ± y% by weight” of the total weight of the tablet core (chip) (this total weight is the weight of the pharmaceutical composition excluding the film coating). For example, for 5 mg of liximab in a 125 mg tablet core (chip), liximab is said to account for 4% by weight of the total core weight.

[0050] In the context of any coating agent, colorant, plasticizer, and / or anti-adhesive, “x% by weight” or “x% ± y% by weight” means “x% ± y% by weight” of the total film coating weight. For example,For 0.61 mg of titanium dioxide in a 2.5 mg tablet coating, it is stated that it accounts for 24.4% by weight of the total weight of “film coating,” “film coating system,” “film coating,” or “coating system.”

[0051] In the context of any of the excipients and / or lisciphagen, “x% by weight” or “x% ± y% by weight” means “x% ± y% by weight” of the coated tablet (core + film coating). For example, for 0.61 mg of titanium dioxide in a 2.5 mg tablet coating, it is stated that it accounts for 24.4% by weight of the total weight of “film coating,” “film coating system,” “film coating,” or “coating instructions 5 / 32 page 16 CN 122055139 A system.”

[0052] Unless otherwise expressly indicated, terms such as “% w / w” mean the weight percentage of a component relative to the total weight of the composition.

[0053] The term “core” or “tablet core” (also referred to as “chip formulation” or “first-layer tablet”) refers to the core composition of a pharmaceutical formulation, excluding any outer coating or layer. The core contains the active pharmaceutical ingredient, particularly lisclan, along with any excipients that are integral to the core structure of the formulation. These excipients may include, but are not limited to, the excipients mentioned herein. The core is designed to efficiently deliver the API, and its composition is optimized for stability, solubility, and bioavailability.

[0054] As used herein, the term “flowability” means and includes the ability of a material to move smoothly from one location to another without the application of excessive force, particularly in the case of powders. The flowability of loose materials, particularly powders, can be determined by their flow factor coefficient (FFC). FFC values ​​are known to those skilled in the art and are also described, for example, in Dietmar Schulze's article "On the Flying of the Flow of Flow – Definition and Flow" published in the journal *Chemie Ingenieur Technik*, Volume 67, Issue 1, 1995, pp. 60-68, published in Wiley VCH, and in Dietmar Schulze's *Powders and Bulk Solids – Behavior, Characterization, Storage and Flow*, published by Springer-Verlag Berlin Heidelberg in 2008. FFC values ​​can be obtained from http: / / www.uspbpep.com / usp29 / v29240 / usp29nf24s0_c1174.html.This method is the USP method and the Pheur method. For example, the FFC value can be determined by a uniaxial compression test. In a uniaxial compression test, the loose material to be studied, especially powder, is typically filled into a hollow cylinder (ideally with frictionless walls); and in the first step, a stress σ1 (consolidation stress) is applied in the vertical direction. Subsequently, the consolidation stress σ1 applied to the specimen is released, and the hollow cylinder is removed. Then, an increasing vertical compressive stress is applied to the consolidated cylindrical loose material specimen (especially the consolidated powder specimen) until the stress σc at which the cylindrical specimen breaks (or fails) is reached. The stress σc can be referred to as compressive strength or unconfined yield strength. When stress σc is applied, the breakage of the consolidated cylindrical specimen indicates that the consolidated loose material (especially the consolidated powder) has just begun to flow. The FFC value can then be determined as the ratio FFC = σc / σ1.

[0055] The term "direct compression" refers to the process of directly blending the components and then compacting them without using a granulation step involving heat and solvents. Preferably, direct compression will be performed at a temperature of about ambient temperature to about 45°C, more preferably at a temperature of about 20°C to about 30°C.

[0056] As used herein, the term “particle size distribution” or “PSD” refers to the relative proportion of particles of a compound having a given particle size. While the particle size of a spherical object can be defined clearly and quantitatively by its diameter, the shape of particles containing an active pharmaceutical ingredient or excipient may be non-spherical and irregular. Those skilled in the art can measure and express the size of non-spherical and irregular particles by a variety of methods, such as measuring the size of such particles using a laser diffractometer, and expressing the size of such particles based on replacing a given particle with an imaginary sphere having one of the many properties of that particle. Such properties may be selected from, for example, but not limited to: the diameter of an imaginary sphere having the same volume as the particle being tested (volume-based particle size), the diameter of an imaginary sphere having the same weight as the particle being tested (weight-based particle size), and the diameter of an imaginary sphere having the same surface area as the particle being tested (area-based particle size). Those skilled in the art are familiar with such methods and the ways in which the results of such methods are expressed, and such methods can be applied to the embodiments disclosed herein without excessive experimentation. Particle size distribution can be represented, for example, graphically as a graph. A common type of graph is a cumulative undersize graph, which represents the proportion (e.g., by number, volume, or mass) of particles smaller than a specified particle size. According to the invention, PSD is measured by laser diffraction.

[0057] As used herein, parameters Dv10, Dv50, and Dv90 represent the particle size of the undersize particle size distribution at 10%, 50%, and 90% of the cumulative number or volume. Therefore,A material's "Dv10" indicates that 10% of the material, by quantity or volume, consists of particles with a particle size equal to or smaller than the Dv10 value. A material's "Dv50" indicates that 50% of the material, by quantity or volume, consists of particles with a particle size equal to or smaller than the Dv50 value. A material's "Dv90" indicates that 90% of the material, by quantity or volume, consists of particles with a particle size equal to or smaller than the Dv90 value.

[0058] “7-(4,7-diazaspiro[2.5]oct-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one” refers to the compound of formula (I),

[0059]

[0060] also known as lisperan, 7-(4,7-diazaspiro[2.5]oct-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-(4,7-diazaspiro[2.5]oct-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrimidin-4H-[1 [2-a]pyrimidin-4-one, RG7916, RO7034067 or CAS number 1825352-65-5. Methods for preparing and using the compound are described in EP3143025 A1. In this document, the names or references of compounds of formula (I) are used interchangeably. In a particular embodiment of the invention, lisciniform is presented as crystalline polymorph A as disclosed in WO2020079203.

[0061] WO2017080967 discloses a pharmaceutical composition comprising lisciniform in powder form for oral aqueous solution.

[0062] The present invention prevents stability problems and / or minimizes the risk of exposure to toxicity for the patient's caregivers. Lisciniform is known to be a highly potent compound. For example, regulatory agencies at the EU and national levels classify it as 1.0 to 10 micrograms / m³ (10EL). IEOL (Occupational Exposure Limit) is a regulatory value indicating the level of exposure to chemicals in the air of the workplace that is considered safe (health-based). Film-coated tablets make it easier and safer for caregivers to handle medications because (1) it is in tablet form, rather than a powder that may be more difficult to handle and more easily exposed to caregivers; and (2) the tablet coating prevents dust exposure.

[0063] This invention enables the rapid dispersion of formulations, particularly in 5 ml of water, more particularly in drinking water with an HCl content of less than 1 mg / L, and even more particularly in drinking water with an HCl content of less than 0.2 mg / L.Most notably, the drinking water used is mineral water. This ability is crucial for administering tablets to subjects with limited swallowing ability and / or those with physical impairments of the swallowing system, including those caused by SMA. Many individuals with SMA use feeding tubes (e.g., nasogastric tubes) in their care, including adults who may require a 5 mg dose but are unable to swallow tablets. Therefore, the dispersion of the formulation is a key component of certain embodiments of this disclosure.

[0064] To develop rapid dispersion, many different disintegrants were evaluated. Furthermore, it was surprisingly found that the integration of crospovidone ensured rapid disintegration of the tablets, while other super-disintegrants such as crospovidone sodium carboxymethyl cellulose resulted in incomplete dissolution due to complexation and / or salt formation with lisciphagen.

[0065] Surprisingly, the present invention has overcome the limited stability of lisciphagen in contact with certain excipients, particularly tartaric acid, in high humidity environments. Surprisingly, it was found that the stability of lisciphagus was greatly reduced in the presence of iron oxides or in contact with iron oxides, resulting in a dark brown color. The tablets may even turn black, as shown in Figure 6. This color change is mainly attributed to the chemical reaction of lisciphagus. The present invention solves these stability problems of lisciphagus. Notably, this problem is solved by using at least one iron oxide-free film coating.

[0066] Surprisingly, it was found that, for example, lisciphagus is incompatible with the presence of sucralose when exposed to humidity, as sucralose promotes decomposition and discoloration, as shown in Figure 3. Therefore, in a particular embodiment of the invention, the composition as described herein does not contain sucralose.

[0067] All embodiments of the invention can be combined.

[0068] According to the invention described herein, more specific embodiments of the invention are described below:

[0069] Example 1. A pharmaceutical composition comprising:

[0070] (a) a compound of formula (I)

[0071]

[0072] or a pharmaceutically acceptable salt thereof;

[0073] (b) crospovidone; and

[0074] (c) an acidifier selected from tartaric acid, citric acid, or malic acid, more particularly tartaric acid.

[0075] Example 2. A pharmaceutical composition according to Example 1 comprising

[0076] i) a tablet core (also known as a chip or first-layer tablet) comprising:

[0077] (a) a compound of formula (I)

[0078]

[0079] or a pharmaceutically acceptable salt thereof;

[0080] (b) crospovidone; and

[0081] (c) an acidifier selected from tartaric acid, citric acid, or malic acid,More particularly tartaric acid; and

[0082] ii) at least one film coating.

[0083] Example 3. A pharmaceutical composition according to any one of Examples 1 to 2, comprising a first film coating.

[0084] Example 4. A pharmaceutical composition according to any one of Examples 1 to 3, comprising a first film coating, wherein the first film coating directly coats the tablet core (also referred to as a chip or first-layer tablet (i)).

[0085] Example 5. A pharmaceutical composition according to any one of Examples 2 to 4, wherein at least one film coating, particularly wherein the first film coating is free of iron oxides, particularly wherein the film coating, particularly the first film coating, is a polyvinyl alcohol-based coating (PVA-based coating), particularly having 5 mg or less of PVA-based coating, more particularly having 3.0 mg of PVA-based coating, and most particularly having 2.5 mg of PVA-based coating.

[0086] Example 6. A pharmaceutical composition according to any one of Examples 3 to 4, wherein the first film coating is free of iron oxides, and in particular wherein the film coating, and especially the first film coating, is a polyvinyl alcohol-based coating (PVA-based coating), particularly having 5 mg or less of PVA-based coating, more particularly having 3.0 mg of PVA-based coating, and most particularly having 2.5 mg of PVA-based coating.

[0087] Example 7. A pharmaceutical composition according to any one of Examples 1 to 6, comprising a second film coating, wherein the second film coating coats the first film coating, and in particular wherein the second film coating is a polyvinyl alcohol-based coating (PVA-based coating), particularly having 5 mg or less of PVA-based coating, more particularly having 3.0 mg of PVA-based coating, and most particularly having 2.5 mg of PVA-based coating.

[0088] Example 8. A pharmaceutical composition according to any one of Examples 1 to 7, wherein the composition further comprises a filler selected from microcrystalline cellulose, cellulose powder, isomaltitol, lactose (specific examples of lactose may be spray-dried lactose, anhydrous lactose or lactose monohydrate), maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar (specific examples of sugar may be sucrose, glucose or sugar alcohol), starch (specific examples of starch may be hydrolyzed starch, corn starch or pregelatinized starch), polysaccharides, dicalcium phosphate and calcium sulfate, and combinations thereof.

[0089] Example 9. A pharmaceutical composition according to any one of Examples 1 to 8, wherein the composition further comprises a filler,The filler is selected from lactose, starch (especially hydrolyzed starch), maltodextrin, isomaltitol, microcrystalline cellulose, mannitol, sorbitol, sucrose, glucose, dicalcium phosphate and calcium sulfate, and combinations thereof.

[0090] Example 10. A pharmaceutical composition according to any one of Examples 1 to 9, wherein the composition further comprises microcrystalline cellulose and mannitol as fillers.

[0091] Example 11. A pharmaceutical composition according to any one of Examples 1 to 10, wherein the composition comprises less than 1% by weight, less than 0.1% by weight, less than 0.05% by weight, less than 0.01% by weight, less than 0.005% by weight, or less than 0.001% by weight of disodium ethylenediaminetetraacetate, most particularly not containing disodium ethylenediaminetetraacetate.

[0092] Example 12. A pharmaceutical composition according to any one of Examples 1 to 11, wherein the composition comprises less than 0.1%, less than 0.05%, less than 0.01%, less than 0.005%, or less than 0.001% by weight of sucralose, most particularly sucralose-free.

[0093] Example 13. A pharmaceutical composition according to any one of Examples 1 to 12, wherein the composition further comprises a lubricant selected from sodium stearoyl fumarate and magnesium stearate.

[0094] Example 14. A pharmaceutical composition according to any one of Examples 1 to 13, wherein the composition further comprises a lubricant, wherein the lubricant is sodium stearoyl fumarate.

[0095] Example 15. A pharmaceutical composition according to any one of Examples 1 to 14, wherein the composition further comprises a flow aid, wherein the flow aid is colloidal silica.

[0096] Example 16. A pharmaceutical composition according to any one of Examples 1 to 15, comprising:

[0097] (a) Formula (I) Compound Specification 9 / 32 pages 20 CN 122055139 A

[0098]

[0099] or a pharmaceutically acceptable salt thereof;

[0100] (b) crospovidone;

[0101] (c) an acidifier selected from tartaric acid, citric acid or malic acid, more particularly tartaric acid; and

[0102] (d) at least one filler selected from microcrystalline cellulose, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, sugar alcohol, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dicalcium phosphate and calcium sulfate and combinations thereof.In particular, it is selected from lactose, starch, hydrolyzed starch, maltodextrin, isomaltitol, microcrystalline cellulose, mannitol, sorbitol, sucrose, glucose, dicalcium phosphate and calcium sulfate, and combinations thereof; more particularly, combinations of microcrystalline cellulose and mannitol.

[0103] Example 17. A pharmaceutical composition according to any one of Examples 1 to 16, comprising:

[0104] (a) a compound of formula (I)

[0105]

[0106] or a pharmaceutically acceptable salt thereof;

[0107] (b) crospovidone;

[0108] (c) an acidifier selected from tartaric acid, citric acid and malic acid, more particularly tartaric acid;

[0109] (d) at least one filler selected from microcrystalline cellulose, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, Sugar alcohols, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dicalcium phosphate and calcium sulfate and combinations thereof, particularly selected from lactose, starch, hydrolyzed starch, maltodextrin, isomaltitol, microcrystalline cellulose, mannitol, sorbitol, sucrose, glucose, dicalcium phosphate and calcium sulfate and combinations thereof, more particularly combinations of microcrystalline cellulose and mannitol; and

[0110] (e) lubricants selected from sodium stearoyl fumarate and magnesium stearate, particularly sodium stearoyl fumarate.

[0111] Example 18. A pharmaceutical composition according to any one of Examples 1 to 17, comprising:

[0112] (a) Formula (I) Compound Specification 10 / 32 Page 21 CN 122055139 A

[0113]

[0114] or a pharmaceutically acceptable salt thereof;

[0115] (b) crospovidone;

[0116] (c) an acidifying agent selected from tartaric acid, citric acid or malic acid, more particularly tartaric acid;

[0117] (d) at least one filler selected from microcrystalline cellulose, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, Sugar alcohols, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dicalcium phosphate and calcium sulfate, and combinations thereof, particularly selected from lactose, starch, hydrolyzed starch, maltodextrin, isomaltitol, microcrystalline cellulose, mannitol, sorbitol, sucrose, glucose, dicalcium phosphate and calcium sulfate, and combinations thereof, more particularly combinations of microcrystalline cellulose and mannitol;

[0118] (e) a lubricant selected from sodium stearoyl fumarate; and magnesium stearate, particularly sodium stearoyl fumarate; and

[0119] (f) a flow aid, wherein the flow aid is colloidal silica.

[0120] Example 19. A pharmaceutical composition according to any one of Examples 1 to 18,It comprises:

[0121] (a) a compound of formula (I)

[0122]

[0123] or a pharmaceutically acceptable salt thereof;

[0124] (b) crospovidone;

[0125] (c) an acidifier selected from tartaric acid, citric acid or malic acid, more particularly tartaric acid;

[0126] (d) at least one filler selected from microcrystalline cellulose, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, sugar alcohol, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharide, dicalcium phosphate and calcium sulfate and combinations thereof, particularly selected from lactose, starch, hydrolyzed starch, maltodextrin, isomaltitol, microcrystalline cellulose, mannitol, sorbitol, sucrose, glucose, dicalcium phosphate and calcium sulfate and combinations thereof, more particularly combinations of microcrystalline cellulose and mannitol;

[0127] (e) a lubricant selected from sodium stearoyl fumarate and magnesium stearate, particularly sodium stearoyl fumarate; and

[0128] (f) a flow aid, wherein the flow aid is colloidal silica;

[0129] provided that the pharmaceutical composition does not contain disodium ethylenediaminetetraacetate. Instructions for Use, Page 11 / 32, 22 CN 122055139 A

[0130] Example 20. A pharmaceutical composition according to any one of Examples 1 to 19, comprising:

[0131] (a) about 5 mg of a compound of formula (I)

[0132]

[0133] or a pharmaceutically acceptable salt thereof;

[0134] (b) crospovidone;

[0135] (c) an acidifying agent selected from tartaric acid, citric acid or malic acid, more particularly tartaric acid;

[0136] (d) at least one filler selected from microcrystalline cellulose, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, Sugar alcohols, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dicalcium phosphate and calcium sulfate, and combinations thereof, particularly selected from lactose, starch, hydrolyzed starch, maltodextrin, isomaltitol, microcrystalline cellulose, mannitol, sorbitol, sucrose, glucose, dicalcium phosphate and calcium sulfate, and combinations thereof, more particularly combinations of microcrystalline cellulose and mannitol;

[0137] (e) a lubricant selected from sodium stearoyl fumarate and magnesium stearate, particularly sodium stearoyl fumarate; and

[0138] (f) a flow aid, wherein the flow aid is colloidal silica;

[0139] provided that the pharmaceutical composition does not contain disodium ethylenediaminetetraacetate.

[0140] Example 21. A pharmaceutical composition according to any one of Examples 1 to 20, comprising between 0.5% and 30% by weight of lisclan,In particular, 1% to 15% by weight of lichepidium, more particularly 2% to 8% by weight of lichepidium, and most particularly 4% ± 2% by weight of lichepidium (in particular, the weight of which is the weight of the uncoated core).

[0141] Example 22. A pharmaceutical composition according to any one of Examples 1 to 21, comprising 2% to 80% by weight of mannitol, in particular 15% to 45% by weight of mannitol, more particularly 20% to 40% by weight of mannitol, and most particularly 30% ± 5% by weight of mannitol (in particular, the weight of which is the weight of the uncoated core).

[0142] Example 23. A pharmaceutical composition according to any one of Examples 1 to 22, comprising between 0.2% and 5.0% by weight of colloidal silica, more particularly between 1.0% and 3.0% by weight of colloidal silica, and most particularly 2.0% ± 0.5% by weight of colloidal silica (particularly wherein the total weight is the weight of the uncoated core).

[0143] Example 24. A pharmaceutical composition according to any one of Examples 1 to 23, comprising between 0.2% and 5% by weight of sodium stearoyl fumarate, more particularly between 2.0% and 4.0% by weight of sodium stearoyl fumarate, and most particularly 3.0% ± 0.5% by weight of sodium stearoyl fumarate (particularly wherein the total weight is the weight of the uncoated core).

[0144] Example 25. A pharmaceutical composition according to any one of Examples 1 to 24, comprising between 5% and 90% by weight of microcrystalline cellulose, particularly between 20% and 60% by weight of microcrystalline cellulose, more specifically 50.0% ± 5% by weight of microcrystalline cellulose, and most particularly 50.0% ± 2% by weight of microcrystalline cellulose (particularly wherein the total weight is the weight of the uncoated core).

[0145] Example 26. A pharmaceutical composition according to any one of Examples 1 to 25, comprising between 0.2% and 12.0% by weight of tartaric acid, more particularly between 1.0% and 4.0% by weight of tartaric acid, and most particularly 2.5% ± 0.5% by weight of tartaric acid (particularly wherein the total weight is the weight of the uncoated core).

[0146] Example 27. The pharmaceutical composition according to any one of Examples 1 to 26,It contains between 0.5% and 12.0% crospovidone by weight, more particularly between 4.0% and 8.0% crospovidone by weight, and most particularly 6.0% ± 1.0% crospovidone by weight (particularly wherein the total weight is the weight of the uncoated core).

[0147] Example 28. A pharmaceutical composition according to any one of Examples 1 to 27, comprising between 0.5% and 30% liscovah's tablets by weight, particularly between 1% and 15% liscovah's tablets by weight, more particularly between 2% and 8% liscovah's tablets by weight, and most particularly 4% ± 2% liscovah's tablets by weight (particularly wherein the total weight is the weight of the coated tablets [the weight of the core tablets [the weight of the core and the weight of the coating]).

[0148] Example 29. A pharmaceutical composition according to any one of Examples 1 to 28, comprising between 2% and 80% mannitol by weight, particularly between 15% and 45% mannitol by weight, more particularly between 20% and 40% mannitol by weight, and most particularly 30% ± 5% mannitol by weight (wherein the total weight is the weight of the coated tablet [core weight and coating weight]).

[0149] Example 30. A pharmaceutical composition according to any one of Examples 1 to 29, comprising between 0.2% and 5.0% colloidal silica by weight, more particularly between 1.0% and 3.0% colloidal silica by weight, and most particularly 1.90% ± 0.50% colloidal silica by weight (wherein the total weight is the weight of the coated tablet [core weight and coating weight]).

[0150] Example 31. A pharmaceutical composition according to any one of Examples 1 to 30, comprising sodium stearoyl fumarate at a weight of 0.2% to 5%, more particularly at a weight of 2.0% to 4.0%, and most particularly at a weight of 2.90% ± 0.50% (wherein the total weight is the weight of the coated tablet [core weight and coating weight]).

[0151] Example 32. A pharmaceutical composition according to any one of Examples 1 to 31, comprising microcrystalline cellulose at a weight of 5% to 90%, more particularly at a weight of 20% to 60%, and more particularly at a weight of 50.0% ± 5%.Most notably, 48.90% ± 2.0% by weight of microcrystalline cellulose (wherein the total weight is the weight of the coated tablet [core weight and coating weight]).

[0152] Example 33. A pharmaceutical composition according to any one of Examples 1 to 32, comprising tartaric acid at a weight of 0.2% to 12.0%, more particularly at a weight of 1.0% to 4.0%, and most particularly at a weight of 2.30% ± 0.5% (wherein the total weight is the weight of the coated tablet [core weight and coating weight]).

[0153] Example 34. A pharmaceutical composition according to any one of Examples 1 to 33, comprising between 0.5% and 12.0% by weight of crospovidone, more particularly between 4.0% and 8.0% by weight of crospovidone, and most particularly 5.80% ± 1.0% by weight of crospovidone (wherein the total weight is the weight of the coated tablet [core weight and coating weight]).

[0154] Example 35. A pharmaceutical composition according to any one of Examples 1 to 34, comprising:

[0155] (a) a compound of formula (I) in an amount of 0.5% to 30% by weight, particularly in an amount of 1% to 15% by weight, and more particularly in an amount of 2% to 8% by weight, and most particularly in an amount of 4% ± 2% by weight

[0156]

[0157] or a pharmaceutically acceptable salt thereof;

[0158] (b) crospovidone in an amount of 0.5% to 12.0% by weight, more particularly in an amount of 4.0% to 8.0% by weight, and most particularly in an amount of 6.0% ± 1.0% by weight;

[0159] (c) crospovidone in an amount of 0.2% to 12.0% by weight. The acidifier is selected from tartaric acid, citric acid, or malic acid, more particularly tartaric acid;

[0160] (d) the filler is selected from 30% to 90% by weight, more particularly 40% to 90% by weight, more particularly 70% to 90% by weight, and most particularly 80% to 5% by weight.The filler comprises at least one selected from the following: microcrystalline cellulose, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, sugar alcohol, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dicalcium phosphate and calcium sulfate, and combinations thereof, particularly selected from lactose, starch, hydrolyzed starch, maltodextrin, isomaltitol, microcrystalline cellulose, mannitol, sorbitol, sucrose, glucose, dicalcium phosphate and calcium sulfate, and combinations thereof, more particularly combinations of microcrystalline cellulose and mannitol;

[0161] (e) between 0.2% and 5% by weight, more particularly between 2.0% and 4.0% by weight, and most particularly 3.0% ± 0.5% by weight. The lubricant is selected from sodium stearoyl fumarate and magnesium stearate, especially sodium stearoyl fumarate; and

[0162] (f) a flow aid in the amount of 0.2% to 5.0% by weight, more particularly in the amount of 1.0% to 3.0% by weight, and most particularly in the amount of 2.0% ± 0.5% by weight, wherein the flow aid is colloidal silica;

[0163] provided that the pharmaceutical composition does not contain disodium ethylenediaminetetraacetate;

[0164] wherein the total amount of the components does not exceed 100% by weight (in particular, wherein the weight is the weight of the uncoated core).

[0165] Example 36. A pharmaceutical composition according to any one of Examples 1 to 35, comprising:

[0166] (a) between 0.5% and 30% by weight, particularly between 1% and 15% by weight, more particularly between 2% and 8% by weight, and most particularly between 4% ± 2% by weight of compound (I)

[0167]

[0168] or a pharmaceutically acceptable salt;

[0169] (b) between 0.5% and 12.0% by weight of crospovidone, more particularly between 4.0% and 8.0% by weight, and most particularly between 6.0% ± 1.0% by weight of crospovidone;

[0170] (c) between 0.2% and 12.0% by weight of crospovidone. The acidifying agent is selected from tartaric acid, citric acid, or malic acid, and is present in amounts between 1.0% and 4.0% by weight, and most particularly between 2.5% ± 0.5% by weight.More particularly tartaric acid;

[0171] (d) microcrystalline cellulose in the range of 5% to 90% by weight, particularly in the range of 20% to 60% by weight, more particularly in the range of 50.0% ± 5% by weight, and most particularly in the range of 50.0% ± 2% by weight;

[0172] (e) mannitol in the range of 2% to 80% by weight, particularly in the range of 15% to 45% by weight, more particularly in the range of 20% to 40% by weight, and most particularly in the range of 30% ± 5% by weight;

[0173] (f) sodium stearoyl fumarate in the range of 0.2% to 5% by weight, more particularly in the range of 2.0% to 4.0% by weight, and most particularly in the range of 3.0% ± 0.5% by weight; and

[0174] (g) in the range of 0.2% to 5.0% by weight. The pharmaceutical composition contains, more particularly, 1.0% to 3.0% by weight, and most particularly 2.0% ± 0.5% by weight of colloidal silica;

[0175] provided that the pharmaceutical composition does not contain disodium ethylenediaminetetraacetate;

[0176] wherein the total amount of the components does not exceed 100% by weight (in particular, wherein the weight is the weight of the uncoated core).

[0177] Example 37. A pharmaceutical composition according to any one of Examples 1 to 36, comprising:

[0178] i) a tablet core (also known as a chip or first-layer tablet) comprising:

[0179] (a) a compound of formula (I) in an amount of 0.5% to 30% by weight, particularly in an amount of 1% to 15% by weight, more particularly in an amount of 2% to 8% by weight, and most particularly in an amount of 4% ± 2% by weight

[0180]

[0181] or a pharmaceutically acceptable salt;

[0182] (b) crospovidone in an amount of 0.5% to 12.0% by weight, more particularly in an amount of 4.0% to 8.0% by weight, and most particularly in an amount of 5.8% ± 1.0% by weight;

[0183] (c) An acidifying agent comprising, by weight, between 0.2% and 12.0%, more particularly between 1.0% and 4.0% by weight, and most particularly between 2.3% ± 0.5% by weight, said acidifying agent being selected from tartaric acid, citric acid, or malic acid.More particularly tartaric acid;

[0184] (d) microcrystalline cellulose in the range of 5% to 90% by weight, particularly in the range of 20% to 60% by weight, more particularly in the range of 50.0% ± 5% by weight, and most particularly in the range of 48.9% ± 2% by weight;

[0185] (e) mannitol in the range of 2% to 80% by weight, particularly in the range of 15% to 45% by weight, more particularly in the range of 20% to 40% by weight, and most particularly in the range of 30% ± 5% by weight;

[0186] (f) sodium stearoyl fumarate in the range of 0.2% to 5% by weight, more particularly in the range of 2.0% to 4.0% by weight, and most particularly in the range of 2.9% ± 0.5% by weight; and

[0187] (g) in the range of 0.2% to 5.0% by weight. The pharmaceutical composition contains, more particularly, 1.0% to 3.0% by weight, and most particularly 1.9% ± 0.5% by weight of colloidal silica; and

[0188] ii) at least one film coating;

[0189] provided that the pharmaceutical composition does not contain disodium ethylenediaminetetraacetate;

[0190] wherein the total amount of the components does not exceed 100% by weight.

[0191] Example 38. A pharmaceutical composition according to any one of Examples 1 to 37, comprising:

[0192] i) a tablet core (also known as a chip or first-layer tablet) comprising:

[0193] (a) a compound of formula (I) in an amount of 0.5% to 30% by weight, particularly in an amount of 1% to 15% by weight, more particularly in an amount of 2% to 8% by weight, and most particularly in an amount of 4% ± 2% by weight

[0194]

[0195] or a pharmaceutically acceptable salt;

[0196] (b) crospovidone in an amount of 0.5% to 12.0% by weight, more particularly in an amount of 4.0% to 8.0% by weight, and most particularly in an amount of 5.8% ± 1.0% by weight;

[0197] (c) crospovidone in an amount of 0.2% to 12.0% by weight The acidifying agent is selected from tartaric acid, citric acid, or malic acid, and is present in amounts between 1.0% and 4.0% by weight, and most particularly between 2.3% ± 0.5% by weight.More particularly tartaric acid;

[0198] (d) microcrystalline cellulose in the amount of 5% to 90% by weight, particularly in the amount of 20% to 60% by weight, more particularly in the amount of 50.0% ± 5% by weight, and most particularly in the amount of 48.9% ± 2.0% by weight;

[0199] (e) mannitol in the amount of 2% to 80% by weight, particularly in the amount of 15% to 45% by weight, more particularly in the amount of 20% to 40% by weight, and most particularly in the amount of 30% ± 5% by weight;

[0200] (f) sodium stearoyl fumarate in the amount of 0.2% to 5% by weight, more particularly in the amount of 2.0% to 4.0% by weight, and most particularly in the amount of 2.9% ± 0.50% by weight; and specification 16 / 32 pages 27 CN 122055139 A

[0201] (g) Colloidal silica in the amount of 0.2% to 5.0% by weight, more particularly in the amount of 1.0% to 3.0% by weight, and most particularly in the amount of 1.9% ± 0.50% by weight; and

[0202] (ii) a first film coating, wherein the first film coating directly coats the chip agent (i), and a second film coating coats the first film coating;

[0203] provided that the pharmaceutical composition does not contain disodium ethylenediaminetetraacetate

[0204] wherein the total amount of the components does not exceed 100% by weight.

[0205] Example 39. A pharmaceutical composition according to any one of Examples 1 to 38, wherein sodium stearoyl fumarate has a saponification value of 142.2 to 146.0, particularly having a Dv50 of 13.6 µm, and more particularly, sodium stearoyl fumarate is Pruv®.

[0206] Example 40. A pharmaceutical composition according to any one of Examples 1 to 39, wherein the microcrystalline cellulose is CAS 9004-34-6, particularly having a Dv50 of 135 µm, and more particularly having a pH of 102.

[0207] Example 41. A pharmaceutical composition according to any one of Examples 1 to 40, comprising a single active pharmaceutical ingredient (API), and more particularly wherein the single API is a compound of formula (I)

[0208] ,

[0209] also known as lisclan.

[0210] Example 42. A tablet comprising a pharmaceutical composition according to any one of Examples 1 to 41.

[0211] Example 43. A tablet according to Example 42, wherein the tablet is dispersible in water within 5 minutes.

[0212] Example 44. A tablet according to any one of Examples 42 to 43,The tablets are dispersible in water with an HCl content of less than 1 mg / L, and even more particularly in drinking water with an HCl content of less than 0.2 mg / L, especially in mineral water.

[0213] Example 45. A tablet according to any one of Examples 42 to 44, having the shape shown in FIG2, and more particularly having a diameter of 6.50 ± 0.50 mm.

[0214] Example 46. A kit comprising: a pharmaceutical composition according to any one of Examples 1 to 41, in tablet form containing a therapeutically effective amount of liscini; prescription information, also known as “instructions for use”; blister packs or bottles (HDPE or glass), particularly moisture-proof primary packaging, more particularly Alu / Alu blister packs or plastic bottles with desiccant; and a container, wherein the prescription information specifically includes recommendations for patients regarding the administration of the liscini with food.

[0215] Example 47. A method for producing a pharmaceutical composition according to any one of Examples 1 to 41, comprising the following steps:

[0216] i) mixing the compound of formula (I) (page 17 / 32, CN 122055139 A)

[0217] ,

[0218] also known as lisciphagen, with tartaric acid (especially fine powder), mannitol, microcrystalline cellulose, colloidal silica, crospovidone and strawberry flavoring in container 1;

[0219] ii) sieving container 1;

[0220] iii) sieving sodium stearoyl fumarate in container 2, especially sieving to 0.5 mm;

[0221] iv) blending the mixture of container 1 and container 2;

[0222] v) compressing the blend of iv) into tablet cores;

[0223] vi) Spraying a first membrane coating system onto the tablet core to form a first membrane coating, wherein the first membrane coating system comprises a suspension of OPADRY II white in purified water, wherein the first membrane comprising a system substantially free of iron oxides; and

[0224] vii) Spraying a second membrane coating system onto the first membrane coating to form a second membrane coating, wherein the second membrane coating system comprises a suspension of OPADRY II yellow in purified water.

[0225] Example 48. A method for producing a pharmaceutical composition according to any one of Examples 1 to 41, comprising the following steps:

[0226] viii) Applying the compound of formula (I)

[0227] ,

[0228] also known as liscinidin,The mixture is blended with tartaric acid powder, mannitol, microcrystalline cellulose, colloidal silica, crospovidone and strawberry flavoring in container 1;

[0229] ix) sieve container 1,

[0230] x) sieve sodium stearoyl fumarate in container 2, particularly sieve to 0.5 mm,

[0231] xi) blend the mixture of container 1 and container 2;

[0232] xii) compress the blend of iv) into tablet cores; and

[0233] xiii) suspend the first membrane coating system, particularly the membrane coating system that is free of iron oxides, and more particularly the membrane coating system that is OPADRY II white (i.e. 85F18422), in purified water, and the specification page 18 / 32 29 CN 122055139 A

[0234] xiv) spray the membrane coating system vi) onto the tablet cores,

[0235] xv) Suspending the membrane coating system, particularly a membrane coating system that does not contain iron oxides, and more particularly a membrane coating system that is OPADRY II Yellow (i.e., 85F220022), in purified water, and

[0236] xvi) Spraying the membrane coating system viii) onto the core of the coated tablet.

[0237] Example 49. A pharmaceutical composition obtained by the method according to Example 47 or 48.

[0238] Example 50. A pharmaceutical composition according to any one of Examples 1 to 41, comprising lisclan administered to an individual at any suitable dose (e.g., to achieve a therapeutically effective dose), particularly at a suitable dose of about 5 mg of a therapeutically effective dose per day.

[0239] Example 51. Use of a pharmaceutical composition according to any one of Examples 1 to 41 for the treatment, prevention, delay of progression, and / or improvement of diseases caused by inactive mutations or deletions in the SMN1 gene and / or associated with loss or defect in SMN1 gene function, particularly for the treatment, prevention, delay of progression, and / or improvement of spinal muscular atrophy (SMA), especially in human subjects in need of such treatment.

[0240] Example 52. Use of a pharmaceutical composition according to any one of Examples 1 to 41 for the preparation of a medicament for the treatment, prevention, delay of progression, and / or improvement of diseases caused by inactive mutations or deletions in the SMN1 gene and / or associated with loss or defect in SMN1 gene function, particularly for the treatment, prevention, delay of progression, and / or improvement of spinal muscular atrophy (SMA).Especially in human subjects in need.

[0241] Example 53. A pharmaceutical composition according to any one of Examples 1 to 41, for the treatment, prevention, delay of progression and / or improvement of diseases caused by inactive mutations or deletions in the SMN1 gene and / or associated with loss or defect of SMN1 gene function, particularly for the treatment, prevention, delay of progression and / or improvement of spinal muscular atrophy (SMA), especially in human subjects in need.

[0242] Example 54. A pharmaceutical composition according to Example 53, for said treatment, wherein the patient's weight is greater than or equal to 20 kg.

[0243] Example 55. A pharmaceutical composition according to Example 53, for said treatment, wherein the weight of the human subject is greater than or equal to 20 kg.

[0244] In a more specific embodiment, the present invention relates to a rapidly disintegrating film-coated tablet that promotes complete dissolution of lisclan when the tablet is dispersed in a small amount of water (e.g., 5 ml) based on the presence of a specific amount of tartaric acid as an acidifier.

[0245] In some embodiments, the tablet comprises a filler. In a particular embodiment of the invention, the filler is a combination of mannitol (particularly D-mannitol suitable for direct compression, such as Parteck® M100) and microcrystalline cellulose (particularly type 102) to promote good flowability and homogeneous distribution of the API used in the direct compression process.

[0246] In a particular embodiment of the invention, crospovidone comprises low amounts of nitrite (less than 100 ppm by weight, particularly less than 50 ppm by weight, more particularly less than 35 ppm by weight, and most particularly less than 0.1 ppm by weight).

[0247] In some embodiments, this document provides a pharmaceutical formulation comprising a tablet core, wherein the tablet core comprises lispiratum, an acidifier, and crospovidone. In some embodiments of the tablets provided herein, lisciniform is present in amounts between 2% and 6% w / w, between 3% and 5% w / w, between 3% and 4% w / w, between 3.5% and 4% w / w, or about 4% w / w. The amount of lisciniform present can be, for example, relative to the tablet core, or relative to the entire tablet formulation (e.g., if the formulation contains additional components). Therefore, in some embodiments, relative to the tablet core,Lisi-Philanthole, page 19 / 32, CN 122055139 A, is present in amounts between 2% and 6% w / w, between 3% and 5% w / w, between 3% and 4% w / w, between 3.5% and 4% w / w, or about 4% w / w, relative to the whole tablet formulation. In some embodiments, lisi-Philanthole is present in amounts between 2% and 6% w / w, between 3% and 5% w / w, between 3% and 4% w / w, between 3.5% and 4% w / w, or about 3.85% w / w, relative to the whole tablet formulation. In some embodiments, the acidifier is an organic acid. In some embodiments, the acidifier is selected from tartaric acid, maleic acid, and citric acid. In some embodiments, the acidifier is tartaric acid. The acidifier may be present, for example, at a ratio of about 2:1 to 1:4, or about 1:1 to 1:3, or about 1:1 to 1:2, or about 1:1.5 to about 1:2, or about 3:5 relative to lecithin. In some embodiments, the acidifier is present by weight between 0.5% and 8% w / w, or between 1% and 7% w / w, or between 1% and 5% w / w, or between 1% and 4% w / w, or between 2% and 3% w / w, or about 2.4% w / w, or about 2.3% w / w. The amount of acidifier present may be, for example, relative to the tablet core, or relative to the entire tablet formulation (e.g., if the formulation contains additional components). Therefore, in some embodiments, the acidifier is present by weight at a concentration between 0.5% and 5% w / w, or between 1% and 4% w / w, or between 2% and 3% w / w, or about 2.4% w / w, relative to the tablet core. In other embodiments, the acidifier is present by weight at a concentration between 0.5% and 5% w / w, or between 1% and 4% w / w, or between 2% and 3% w / w, or about 2.3% w / w, relative to the entire tablet formulation. The tablet further comprises crospovidone. In some embodiments, crospovidone is present at a ratio of about 4:1 to 1:6, or about 3:1 to 1:3, or about 3:1 to 1:1, or about 3:2, relative to lispiratum. In some embodiments, crospovidone is present at a weight of 1% to 10% w / w, or 2% to 8% w / w, or 4% to 8% w / w, or about 6% w / w, or about 5.7% w / w. The amount of crospovidone present can be, for example, relative to the tablet core, or relative to the entire tablet formulation (e.g., if the formulation contains additional components). Thus, in some embodiments,The crosslinked povidone is present by weight, relative to the tablet core, in amounts between 1% and 10% w / w, or between 2% and 8% w / w, or between 4% and 8% w / w, or about 6% w / w. In other embodiments, the crosslinked povidone is present by weight, relative to the entire tablet formulation, in amounts between 1% and 10% w / w, or between 2% and 8% w / w, or between 4% and 8% w / w, or about 5.7% w / w.

[0248] In some embodiments, the tablet core further comprises a filler. In embodiments containing a filler, the filler may be present, for example, in amounts between 50% and 90% w / w, or between 60% and 90% w / w, or between 70% and 90% w / w, or between 75% and 85% w / w, relative to the tablet core or relative to the entire tablet formulation. In some embodiments, the filler is selected from microcrystalline cellulose, cellulose powder, isomaltitol, lactose (such as spray-dried lactose, anhydrous lactose, or lactose monohydrate), sugar (such as sucrose or glucose), sugar alcohol (such as mannitol or sorbitol), starch (such as hydrolyzed starch, corn starch, or pregelatinized starch), polysaccharide (such as maltodextrin), calcium hydrogen phosphate, and calcium sulfate, and any combination thereof. In some embodiments, the filler is cellulose and sugar alcohol. In some embodiments, the filler is microcrystalline cellulose and mannitol. In certain specific embodiments, the filler is D-mannitol suitable for direct compression, such as Parteck® M100; and microcrystalline cellulose, particularly type 102.

[0249] In some embodiments, the tablet core further comprises a lubricant. The lubricant may be present, for example, in the range of 1% to 5% w / w, or between 2% and 4% w / w, or between 2.5% and 3.5% w / w, or about 3% w / w or about 2.88% w / w, relative to the tablet core or the entire tablet formulation. In some embodiments, the lubricant is selected from sodium stearoyl fumarate and magnesium stearate. In some embodiments, the lubricant is sodium stearoyl fumarate.

[0250] In some embodiments, the tablet core further comprises a flow aid. The flow aid may be present, for example, in the range of 0.2% to 5% w / w, or between 0.5% and 4% w / w, or between 1% and 3% w / w, or between 1.5% and 2.5% w / w, or about 2% w / w or about 1.92% w / w, relative to the tablet core or the whole tablet formulation. In some embodiments, the flow aid is silica. In some embodiments, the flow aid is colloidal silica. Specification 20 / 32 pages 31 CN 122055139 A

[0251] In some embodiments,The tablet core further comprises a flavoring agent. Such a flavoring agent may be present in amounts such as 0.02% to 0.2% w / w or 0.05% to 0.15% w / w, such as about 0.1% w / w.

[0252] In some embodiments, the pharmaceutical composition is substantially free of disodium ethylenediaminetetraacetate (also known as disodium EDTA or disodium edetate). For example, in some embodiments, the pharmaceutical composition contains less than 1% w / w, less than 0.1% w / w, less than 0.05% w / w, less than 0.01% w / w, less than 0.005% w / w, or less than 0.001% w / w of disodium ethylenediaminetetraacetate relative to the entire tablet formulation. In some embodiments, the level of disodium ethylenediaminetetraacetate in the pharmaceutical composition is below the detection level.

[0253] In some embodiments, the pharmaceutical composition is substantially free of sucralose. For example, in some embodiments, the pharmaceutical composition contains less than 0.1% w / w, less than 0.05% w / w, less than 0.01% w / w, less than 0.005% w / w, or less than 0.001% w / w of sucralose relative to the entire tablet formulation. In some embodiments, the level of sucralose in the pharmaceutical composition is below a detection level.

[0254] In some embodiments, the pharmaceutical composition further comprises one or more layers coating a tablet core. In some embodiments, the pharmaceutical composition comprises at least one coating layer, which may also be referred to as a first film coating. In some embodiments, the first film coating is in direct contact with the tablet core. For example, the first film coating may be sprayed directly onto the tablet core. In some embodiments, the first film coating is substantially free of iron oxides. For example, the first film coating may contain less than 0.1% w / w, less than 0.05% w / w, less than 0.01% w / w, less than 0.005% w / w, or less than 0.001% w / w of iron oxides. In some embodiments, the level of iron oxides in the first film coating is below a detection level. In some embodiments, the first coating layer comprises polyvinyl alcohol (PVA), for example, comprising between 30% and 50% w / w or about 40% PVA. In some embodiments, the first coating layer further comprises polyethylene glycol (PEG), for example, comprising between 10% and 30% PEG, or about 20% PEG. In some embodiments, the first coating layer further comprises titanium dioxide or talc or a combination thereof. In some embodiments of pharmaceutical compositions comprising a first film coating as described herein,The tablet core is coated with a film coating in amounts of less than 5% w / w, less than 4% w / w, less than 3% w / w, about 2% w / w, between 0.5% and 5% w / w, between 0.5% and 4% w / w, or between 1% and 3% w / w of the uncoated tablet core. Thus, for example, a 125 mg tablet core coated with a 2.5 mg first film coating comprises 2% w / w of the uncoated tablet core. In some embodiments, the first film coating constitutes less than 5% w / w, less than 4% w / w, less than 3% w / w, about 2% w / w, between 0.5% and 5% w / w, between 0.5% and 4% w / w, or between 1% and 3% w / w, or between 1.5% and 2.5% w / w of the total weight of the coated tablet.

[0255] In some embodiments, the pharmaceutical composition comprises multiple coatings. For example, in some embodiments, the pharmaceutical composition comprises a first film coating and a second film coating, wherein the first film coating is in direct contact with the tablet core, and the second film coating coats the first film coating. In some embodiments, the second film coating is in direct contact with the first film coating. In other embodiments, one or more intermediate coatings are present between the first and second film coatings. In some embodiments, the second film coating comprises one or more iron oxides, such as yellow iron oxide. In some embodiments, the second film coating contains between 0.01% and 1% w / w of iron oxides, such as yellow iron oxide. In some embodiments, the second film coating comprises polyvinyl alcohol (PVA), for example, between 30% and 50% w / w or about 40% PVA. In some embodiments, the second film coating further comprises polyethylene glycol (PEG), for example, between 10% and 30% PEG, or about 20% PEG. In some embodiments, the second film coating further comprises titanium dioxide or talc, or a combination thereof. In some embodiments of pharmaceutical compositions comprising a second film coating as described herein, the tablet core is coated with a second coating (e.g., a first film coating also present) in amounts of less than 5% w / w, less than 4% w / w, less than 3% w / w, about 2% w / w, between 0.5% and 5% w / w, between 0.5% and 4% w / w, or between 1% and 3% w / w of the uncoated tablet core. Thus, for example, a 125 mg tablet core coated with a 2.5 mg second film coating comprises a 2% w / w coating of the uncoated tablet core. In some embodiments,The second film coating constitutes less than 5% w / w, less than 4% w / w, less than 3% w / w, about 2% w / w, between 0.5% and 5% w / w, between 0.5% and 4% w / w, or between 1% and 3% w / w, or between 1.5% and 2.5% w / w of the total weight of the coated tablet. In some embodiments, the amounts of the first and second film coatings are approximately the same, wherein the first film coating directly contacts the tablet core, and the second film coating coats the first film coating, for example, directly contacting the first film coating.

[0256] In some embodiments, this document provides a pharmaceutical formulation comprising a tablet core, wherein the tablet core comprises liximab, an acidifier, and crospovidone, wherein: relative to the tablet core, liximab is present in an amount between 2% and 6% w / w; the acidifier is present in an amount between 0.5% and 8% w / w; and crospovidone is present in an amount between 1% and 10% w / w. In some embodiments, the acidifier is present at a concentration between 1% and 7% w / w relative to the tablet core. In some embodiments, the acidifier is a carboxylic acid, such as a carboxylic acid selected from tartaric acid, maleic acid, and citric acid. In some embodiments, the acidifier is tartaric acid. In some embodiments, the tablet contains about 5 mg of lisclan. In some embodiments, the tablet core further comprises: a filler at a concentration between 70% and 90% w / w relative to the tablet core; a lubricant at a concentration between 1% and 5% w / w; and a flow aid at a concentration between 0.5% and 4% w / w. In some embodiments, the filler is cellulose and sugar alcohols, such as microcrystalline cellulose and mannitol, such as D-mannitol and type 102 microcrystalline cellulose. In some embodiments, the lubricant is selected from sodium stearoyl fumarate and magnesium stearate, such as sodium stearoyl fumarate. In some embodiments, the flow aid is silica, such as colloidal silica. In some embodiments, the pharmaceutical formulation further comprises a first film coating, wherein the first film coating directly contacts the tablet core and is substantially free of iron oxides. In some embodiments, the first film coating comprises PVA, for example, between 30% and 50% w / w. In some embodiments, the first film coating further comprises PEG, such as between 10% and 30% PEG. In some embodiments, the first film coating further comprises titanium dioxide or talc or a combination thereof. In some embodiments, the first film coating constitutes less than 5% w / w of the total weight of the coated tablet, such as between 1% and 3% w / w. In some embodiments, the pharmaceutical composition further comprises a second film coating containing iron oxide, wherein the second film coating coats the first film coating, for example, in direct contact with the first film coating. In some embodiments,The second film coating contains between 0.01% and 1% w / w of iron oxide, such as iron oxide yellow. In some embodiments, the second film coating contains PVA, for example, between 30% and 50% w / w. In some embodiments, the second film coating further contains PEG, such as between 10% and 30% PEG. In some embodiments, the second film coating further contains titanium dioxide or talc or a combination thereof. In some embodiments, the second film coating constitutes less than 5% w / w of the total weight of the coated tablet (including the first and second coatings), such as between 1% and 3% w / w.

[0257] The pharmaceutical compositions of the present invention containing lisciniforme have valuable pharmacological properties and have been found to enhance the inclusion of exon 7 of SMN1 and / or SMN2 into the mRNA transcribed from the SMN1 and / or SMN2 genes, thereby increasing the expression of SMN proteins in human subjects in need of this.

[0258] The pharmaceutical compositions of the present invention may be used alone or in combination with other pharmaceuticals for the treatment, prevention, delay of progression, and / or improvement of diseases caused by inactive mutations or deletions in the SMN1 gene and / or associated with loss or deficiency of SMN1 gene function. These diseases include, but are not limited to, spinal muscular atrophy (SMA).

[0259] A particular embodiment of the present invention relates to a pharmaceutical composition as defined herein for the treatment, prevention, delay of progression, and / or improvement of diseases caused by inactive mutations or deletions in the SMN1 gene and / or associated with loss or deficiency of SMN1 gene function, particularly for the treatment, prevention, delay of progression, and / or improvement of SMA.

[0260] A particular embodiment of the present invention relates to a pharmaceutical composition as defined herein, used as a therapeutically active substance, particularly for the treatment, prevention, delay of progression, and / or improvement of diseases caused by inactive mutations or deletions in the SMN1 gene and / or associated with loss or defect in SMN1 gene function, especially for the treatment, prevention, delay of progression, and / or improvement of spinal muscular atrophy (SMA).

[0261] A particular embodiment of the present invention relates to a pharmaceutical composition as defined herein, used for the treatment, prevention, delay of progression, and / or improvement of diseases caused by inactive mutations or deletions in the SMN1 gene and / or associated with loss or defect in SMN1 gene function, particularly for the treatment, prevention, delay of progression, and / or improvement of spinal muscular atrophy (SMA).

[0262] A particular embodiment of the present invention relates to a method,It is used for the treatment, prevention, delay of progression, and / or improvement of diseases caused by inactive mutations or deletions in the SMN1 gene and / or associated with loss or defect of SMN1 gene function, particularly for the treatment, prevention, delay of progression, and / or improvement of spinal muscular atrophy (SMA), the method comprising administering to a subject a pharmaceutical composition involving a pharmaceutical composition as described herein.

[0263] A particular embodiment of the invention relates to the use of a pharmaceutical composition involving a pharmaceutical composition as defined herein for the treatment, prevention, delay of progression, and / or improvement of diseases caused by inactive mutations or deletions in the SMN1 gene and / or associated with loss or defect of the SMN1 gene, particularly for the treatment, prevention, delay of progression, and / or improvement of spinal muscular atrophy (SMA).

[0264] A particular embodiment of the invention relates to the use of a pharmaceutical composition relating to a pharmaceutical composition as defined herein for the preparation of a medicament for the treatment, prevention, delay of progression, and / or improvement of a disease caused by and / or associated with loss or defect of SMN1 gene function due to inactivation mutations or deletions in the SMN1 gene, particularly for the treatment, prevention, delay of progression, and / or improvement of spinal muscular atrophy (SMA).

[0265] Generally, the nomenclature used in this application is based on AUTONOM™ 2000, a computerized system of the Beilstein Institute for generating IUPAC system nomenclature. The chemical structures shown herein were prepared using MDL ISIS™ 2.5 SP2. Any open valence appearing on carbon, oxygen, or nitrogen atoms in the structures herein indicates the presence of a hydrogen atom.

[0266] Examples

[0267] The invention will be more fully understood by reference to the following examples. However, they should not be construed as limiting the scope of the invention.

[0268] Example 1: Effect of acidifier concentration on the dissolution of lisciphagus

[0269] The formulations mentioned below were prepared according to the method described below by varying the amount of tartaric acid.

[0270] The tablets were then compressed using a Styl'One single-punch tablet press with a target main compression force between 4 and 4.65 kN by a subsequent manual screening, Turbula blending of all excipients except the lubricant, manual screening and addition of the lubricant, and a final Turbula blending process.Tablets were produced at a laboratory scale of 125 g.

[0271] Table 1: Composition of tablets used in Example 1, page 23 / 32, CN 122055139 A

[0272]

[0273] The tablets were dissolved in 500 ml of HCl (pH 4.5) at 5” 0 rpm. Three measurements were performed. The average of the measurements is disclosed in Table 2.

[0274] Tablets containing incremental amounts of acidifier (tartaric acid) were manufactured. The dissolution data clearly show that tablets without acidifier resulted in a slow and incomplete release of lisciniforme compared to tablets containing tartaric acid. The benefit of the acidifier was already present at the lowest tartaric acid concentration. Increasing the percentage of acidifier in the formulation resulted in a faster dissolution rate, with formulation 6 dissolving the fastest of all the formulations tested.

[0275] Table 2: Dissolution rate of tablets containing tartaric acid (lisciniforme % in solution)

[0276]

[0277] Example 2: Effect of the presence of iron in the coating on the stability of the drug

[0278] Two tablet formulations 7 and 8 as described in Table 3 were prepared according to the method described below.

[0279] Tablets were produced at a laboratory scale of 130 g by the following steps: a manual sieving step using a 0.9 mm sieve, followed by tumbling and mixing for 3 minutes. The lubricant was sieved through a 0.5 mm sieve and pre-mixed with one-tenth of the internal phase for 1 minute using a tumbling mixer. The pre-mix and the remainder of the internal phase were mixed using a tumbling mixer for 3 minutes. The final blend was compressed into tablets using a Styl'one single-punch press.

[0280] Table 3: Composition of tablets of Example 2 24 / 32 pages 35 CN 122055139 A

[0281]

[0282] a Contains iron oxide

[0283] b Does not contain iron oxide

[0284] Two tablet compositions (formulation 7) were manufactured. Formula 7 and Formulation 8 were stored for two weeks at 70°C / 5% RH or 70°C / 75% RH, respectively. Formula 7 contained an iron oxide-free coating, while Formula 8 contained an iron oxide coating. The concentration of lisciphalan was determined at the initial (t0) and after two weeks of storage. The results are shown in Table 4.

[0285] Table 4: Stability of Formulas 7 and 8 tablets

[0286]

[0287] a Total degradation corresponds to degradation products known at the time of analysis.

[0288] The experiments clearly show that decomposition is promoted under high humidity and especially in the presence of iron oxides, where the concentration of lisciphalan decreased significantly over time compared to the iron oxide-free tablets (Formulation 8). Formula 7, which does not contain iron oxides, showed that compared to low humidity (5% RH),Storage at high humidity (75% RH) for 2 weeks resulted in a degradation of more than 30% of lisciphalan. Compared to low humidity, the presence of iron oxides (formulation 8) under the same conditions led to a dramatic increase in degradation of more than 85% at high humidity. Therefore, the presence of iron oxides in lisciphalan tablet formulations causes significant instability of the API. Formulation 8 turned dark black after two weeks of storage at 70°C / 75% RH, as shown in Figure 7. Based on Table 4 of page 25 / 32 of the instruction manual (CN 122055139 A), less than 5.0% of lisciphalan can be recovered from formulation 8 coated with iron oxides. The decomposition includes the following degradation products:

[0289] a) 1-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl) ethyl ketone:

[0290]

[0291] b) 7-(2-diaminoethylamino)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one:

[0292]

[0293] c) 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-hydroxy-pyrido[1,2-a]pyrimidin-4-one:

[0294]

[0295] Example 3: Effect of Filler Composition on Manufacturing Process and Tablet Core Properties

[0296] A series of prototype placebo tablets containing different filler combinations were manufactured to identify compositions that promote good flowability of the powder blend, good tablet compressibility, and provide good tablet properties in terms of hardness, abrasion, and disintegration time. The tablets were compressed with increasing compression forces to evaluate the compressibility of a given composition and the resulting tablet properties. Other excipients, except for the fillers, were not changed as shown in Table 5. The tablets were manufactured as described below. The physical characteristics of each tablet were evaluated and summarized in Table 6.

[0297] Tablets were manufactured on a 1.5 kg laboratory scale by the following steps: a subsequent manual sieving step using a 1.2 mm sieve, followed by tumbling blending for 5 min. The lubricant was sieved through a 0.5 mm sieve and pre-mixed with one-tenth of the internal phase for 1 min using a tumbling blender. The pre-blended mixture and the remainder of the internal phase were blended using a tumbling blender for 5 min. The final blend was compressed into tablets using a Korsch XL-100 rotary tablet press. The main compression force was varied between 1.8 and 4.6 kN to study the compaction profile.

[0298] Table 5: Composition of placebo tablets. Instructions for use 26 / 32 pages 37 CN 122055139 A

[0299]

[0300] Table 6: Effect of filler composition Instructions for use 27 / 32 pages 38 CN 122055139 A

[0301]

[0302] Surprisingly,Formulation 10 is the optimal composition because it achieves sufficient flowability and low tablet core wear, demonstrating sufficient robustness for further processing (coating, packaging, and transportation) by still maintaining a rapid disintegration time.

[0303] Example 4: Effect of disintegrant level on disintegration time

[0304] Tablets mentioned in Table 7 were prepared according to the methods described herein. The effect of different coating types on the dissolution of the two formulations was then evaluated as summarized in Table 8.

[0305] Tablets were produced at a pilot scale of 12.4 kg by the following steps: a sieving step was performed using a ServoWitt conical mill with a 1.5 mm sieve, followed by tumbling blending (Servolift) at 15 rpm for 7 minutes. The lubricant was manually sieved through a 0.5 mm sieve and added to the internal phase. The final blend was blended using a Servolift at 15 rpm for 5 minutes. The final blend was compressed into tablets using a Fette 1090i rotary tablet press and a target main compression force between 3 and 5 kN. Aqueous film coating was performed using a Glatt roller coating machine.

[0306] Table 7: Composition of the tablets used in Example 4. Instructions for Use, Page 28 / 32, 39, CN 122055139 A

[0307]

[0308] Table 8: Effect of coating on the disintegration of lisciphagus

[0309]

[0310] a 1.000 mg polyvinyl alcohol, 0.625 mg titanium dioxide, 0.505 mg polyethylene glycol 3350 and 0.370 mg talc Instructions for Use, Page 29 / 32, 40, CN 122055139 A

[0311] b 1.000 mg polyvinyl alcohol, 0.608 mg titanium dioxide, 0.505 mg polyethylene glycol 3350, 0.370 mg talc and 0.017 mg iron oxide yellow

[0312] c polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc

[0313] For batch formulation 12 (high tartaric acid), the increased coating amount resulted in a significant increase in disintegration time. It was already at a low level, exceeding the target specification (< 3 minutes). Batch formulation 13 did not show such a significant effect and the disintegration time remained below 3 minutes.

[0314] Uncoated batch formulation 12 was used for accelerated stability assessment. The scale-up batch was incubated for two weeks at 70°C / 75% RH and 70°C / 5% RH.

[0315] When exposed to high humidity (75% RH), a sharp change in color was observed (see Figure 4), and severe discoloration was accompanied by a strong decrease in lisciphagus content. The discoloration was directly related to lisciphagus degradation.Because the placebo tablets did not exhibit any color change.

[0316] The discoloration can only be attributed to lixithiocyanate, as the placebo tablets (“placebos”) were also incubated under the same conditions: without coating, incubated for 2 weeks at 70°C / 5% RH (Fig. 5a) and for 2 weeks at 70°C / 75% RH (Fig. 5b). No color change was observed. The swelling and increased porosity in the placebo tablets stored under high humidity conditions were very noticeable. The placebo tablets stored under low humidity conditions were completely unaffected.

[0317] Example 6: Formulation A

[0318] A pharmaceutical composition comprising lixithiocyanate was prepared as described below.

[0319] Table 9: Composition of tablet formulation (A):

[0320]

[0321] a 1.000 mg polyvinyl alcohol, 0.625 mg titanium dioxide, 0.505 mg polyethylene glycol 3350 and 0.370 mg talc (Instructions for use, pages 30 / 32, CN 122055139 A)

[0322] b 1.000 mg polyvinyl alcohol, 0.608 mg titanium dioxide, 0.505 mg polyethylene glycol 3350, 0.370 mg talc and 0.017 mg iron oxide yellow

[0323] A 14.4 kg batch was produced. Lisperidone, L-tartaric acid, mannitol, microcrystalline cellulose, colloidal silica, crospovidone and strawberry flavoring were weighed and transferred to a suitable metal container and mixed at 15 rpm for 7 min. Then, the mixture was manually passed through a 1.5 mm sieve in container (A).

[0324] Sodium stearoyl fumarate was manually sieved through a 0.5 mm sieve and added to the powder mixture in container (A). It was then mixed at 15 rpm for 7 min.

[0325] Tableting was performed using a tableting tool on a standard tablet manufacturing machine.The target main compression force is between 4 and 4.65 kN. Aqueous film coating is performed using a Glatt roller coating machine.

[0326] Example 7: Formulation B

[0327] A pharmaceutical composition containing lisclan was prepared as described below.

[0328] Table 10: Composition of tablet formulation (B)

[0329]

[0330] a 1.000 mg polyvinyl alcohol, 0.625 mg titanium dioxide, 0.505 mg polyethylene glycol 3350 and 0.370 mg talc

[0331] b 1.000 mg polyvinyl alcohol, 0.608 mg titanium dioxide, 0.505 mg polyethylene glycol 3350, 0.370 mg talc and 0.017 mg iron oxide yellow

[0332] A 14.4 kg batch was produced. The following ingredients were weighed and transferred to a suitable metal container: liscinate, cellulose, L-tartaric acid, mannitol, microcrystalline cellulose, colloidal silica, crospovidone, and strawberry flavoring. The mixture was then manually passed through a 1.5 mm sieve in container (A).

[0333] Sodium stearoyl fumarate was manually sieved through a 0.5 mm sieve and added to the powder mixture in container (A). It was then co-mixed at 15 rpm for 7 min. (Instructions for use, pages 31 / 32, CN 122055139 A)

[0334] Tableting was performed using a tableting tool on a standard tablet manufacturing machine with a target main compression force between 4 and 4.65 kN. Aqueous film coating was performed using a Glatt roller coating machine.

[0335] Example 8: Comparison of croscarmellose sodium and croscarmellose

[0336] 60 mg of tartaric acid was dissolved in 100 ml of tap water (0.6 mg / ml) at room temperature and protected from light. Representative amounts of croscarmellose sodium or croscarmellose were added and dispersed. Then, 100 mg of lisciphagen was added, the suspension was stirred for 30 minutes, and the concentration was analyzed by UPLC (see Table 11).

[0337] Table 11: Effect of croscarmellose sodium and croscarmellose on the solubility of lisciphagen

[0338]

[0339] The concentration of lisciphagen was affected by croscarmellose sodium. It appears that croscarmellose sodium reduced the solubility of lisciphagen, most likely through complexation or salt formation.

[0340] Example 9: Effect of sucralose on lisciphagen

[0341] The effect of sucralose on the stability of lisciphagen was evaluated. The results are shown in Figure 3. Vial (a) contains only lecithin and is shown at time 0; vial (b) contains 25 mg lecithin and 475 mg sucralose.After 15 days at 70°C / 75% relative humidity; vial (c) contains sucralose without lisciphagus, after 15 days at 70°C / 75% relative humidity. Sucralose was found to cause discoloration and promote the decomposition of lisciphagus.

[0342] All references cited herein (including, but not limited to, published and unpublished applications, patents and documents) are incorporated herein by reference in their entirety and form part of this specification. To the extent that any publications and patents or patent applications incorporated herein by reference contradict the disclosures contained herein, this specification is intended to supersede and / or give precedence to any such contradictory material. Instruction manual, pages 32 / 32; 43 CN 122055139 A, Figure 1; Instruction manual, Figure 1 / 4 page; 44 CN 122055139 A, Figure 2; Figure 3; Instruction manual, Figure 2 / 4 page; 45 CN 122055139 A, Figure 4; Figure 5; Instruction manual, Figure 3 / 4 page; 46 CN 122055139 A, Figure 6; Instruction manual, Figure 4 / 4 page; 47 CN 122055139 A,

Claims

1. A pharmaceutical composition comprising: (a) Compound of formula (I) Or its pharmaceutically acceptable salt; (b) Cross-linked polyvinylpyrrolidone; and (c) An acidifying agent selected from tartaric acid, citric acid or malic acid, especially tartaric acid.

2. The pharmaceutical composition according to claim 1, comprising: i) The tablet core (also known as a chip tablet or first-layer tablet) contains: (a) Compound of formula (I) Or its pharmaceutically acceptable salt; (b) Cross-linked polyvinylpyrrolidone; and (c) An acidifying agent selected from tartaric acid, citric acid, or malic acid, with a particular emphasis on tartaric acid; and ii) At least one film coating.

3. The pharmaceutical composition according to any one of claims 1 to 2, comprising a first film coating.

4. The pharmaceutical composition according to any one of claims 1 to 3, comprising a first film coating, wherein the first film coating directly coats the tablet core (also referred to as a chip or first-layer tablet (i)).

5. The pharmaceutical composition according to any one of claims 2 to 4, wherein at least one film coating, particularly wherein the first film coating is free of iron oxide, particularly wherein the film coating, particularly the first film coating, is a polyvinyl alcohol-based coating (PVA-based coating), particularly having 5 mg or less of PVA-based coating, more particularly having 3.0 mg of PVA-based coating, and most particularly having 2.5 mg of PVA-based coating.

6. The pharmaceutical composition according to any one of claims 3 to 4, wherein the first film coating is free of iron oxide, and particularly wherein the film coating, particularly the first film coating, is a polyvinyl alcohol-based coating (PVA-based coating), particularly having 5 mg or less of PVA-based coating, and more particularly having 2.5 mg of PVA-based coating.

7. The pharmaceutical composition according to any one of claims 1 to 6, comprising a second film coating, wherein the second film coating coats the first film coating, particularly wherein the second film coating is a polyvinyl alcohol-based coating (PVA-based coating), particularly having 5 mg or less of PVA-based coating, more particularly having 2.5 mg of PVA-based coating.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the composition further comprises a filler selected from microcrystalline cellulose, cellulose powder, isomaltitol, lactose (specific examples of lactose may be spray-dried lactose, anhydrous lactose or lactose monohydrate), maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar (specific examples of sugar may be sucrose, glucose or sugar alcohol), starch (specific examples of starch may be hydrolyzed starch, corn starch or pregelatinized starch), polysaccharides, dicalcium phosphate and calcium sulfate, and combinations thereof.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the composition further comprises a filler selected from lactose, starch (especially hydrolyzed starch), maltodextrin, isomaltitol, microcrystalline cellulose, mannitol, sorbitol, sucrose, glucose, dicalcium phosphate and calcium sulfate, and combinations thereof.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the composition further comprises microcrystalline cellulose and mannitol as fillers.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the composition does not contain disodium ethylenediaminetetraacetate.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the composition does not contain sucralose.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the composition further comprises a lubricant selected from sodium stearoyl fumarate and magnesium stearate.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the composition further comprises a lubricant, wherein the lubricant is sodium stearoyl fumarate.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the composition further comprises a flow aid, wherein the flow aid is colloidal silica.

16. The pharmaceutical composition according to any one of claims 1 to 15, comprising: (a) Compound of formula (I) Or its pharmaceutically acceptable salt; (b) Crosslinked polyvinylpyrrolidone; (c) An acidifying agent selected from tartaric acid, citric acid, or malic acid, with a particular emphasis on tartaric acid; and (d) At least one filler selected from microcrystalline cellulose, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, sugar alcohol, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dicalcium phosphate and calcium sulfate, and combinations thereof, particularly selected from lactose, starch, hydrolyzed starch, maltodextrin, isomaltitol, microcrystalline cellulose, mannitol, sorbitol, sucrose, glucose, dicalcium phosphate and calcium sulfate, and combinations thereof, and more particularly combinations of microcrystalline cellulose and mannitol.

17. The pharmaceutical composition according to any one of claims 1 to 16, comprising: (a) Compound of formula (I) Or its pharmaceutically acceptable salt; (b) Crosslinked polyvinylpyrrolidone; (c) An acidifying agent selected from tartaric acid, citric acid or malic acid, especially tartaric acid; (d) At least one filler selected from microcrystalline cellulose, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, sugar alcohol, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dicalcium phosphate and calcium sulfate, and combinations thereof, particularly selected from lactose, starch, hydrolyzed starch, maltodextrin, isomaltitol, microcrystalline cellulose, mannitol, sorbitol, sucrose, glucose, dicalcium phosphate and calcium sulfate, and combinations thereof, more particularly combinations of microcrystalline cellulose and mannitol; and (e) A lubricant selected from sodium stearoyl fumarate and magnesium stearate, especially sodium stearoyl fumarate.

18. The pharmaceutical composition according to any one of claims 1 to 17, comprising: (a) Compound of formula (I) Or its pharmaceutically acceptable salt; (b) Crosslinked polyvinylpyrrolidone; (c) An acidifying agent selected from tartaric acid, citric acid or malic acid, especially tartaric acid; (d) At least one filler selected from microcrystalline cellulose, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, sugar alcohol, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dicalcium phosphate and calcium sulfate, and combinations thereof, particularly selected from lactose, starch, hydrolyzed starch, maltodextrin, isomaltitol, microcrystalline cellulose, mannitol, sorbitol, sucrose, glucose, dicalcium phosphate and calcium sulfate, and combinations thereof, more particularly combinations of microcrystalline cellulose and mannitol; (e) a lubricant selected from sodium stearoyl fumarate and magnesium stearate, particularly sodium stearoyl fumarate; and (f) a flow aid, wherein the flow aid is colloidal silica; The prerequisite is that the pharmaceutical composition does not contain disodium EDTA.

19. The pharmaceutical composition according to any one of claims 1 to 17, comprising: (a) Approximately 5 mg of compound (I) Or its pharmaceutically acceptable salt; (b) Crosslinked polyvinylpyrrolidone; (c) An acidifying agent selected from tartaric acid, citric acid or malic acid, especially tartaric acid; (d) At least one filler selected from microcrystalline cellulose, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, sugar alcohol, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dicalcium phosphate and calcium sulfate, and combinations thereof, particularly selected from lactose, starch, hydrolyzed starch, maltodextrin, isomaltitol, microcrystalline cellulose, mannitol, sorbitol, sucrose, glucose, dicalcium phosphate and calcium sulfate, and combinations thereof, and more particularly combinations of microcrystalline cellulose and mannitol; (e) a lubricant selected from sodium stearoyl fumarate and magnesium stearate, particularly sodium stearoyl fumarate; and (f) a flow aid, wherein the flow aid is derived from colloidal silica; The prerequisite is that the pharmaceutical composition does not contain disodium EDTA.

20. The pharmaceutical composition according to any one of claims 1 to 19, comprising between 0.5% and 30% by weight of lichepoprane, particularly between 1% and 15% by weight of lichepoprane, more particularly between 2% and 8% by weight of lichepoprane, and most particularly 4% ± 2% by weight of lichepoprane (in particular, said weight is the weight of the uncoated core).

21. The pharmaceutical composition according to any one of claims 1 to 20, comprising between 2% and 80% mannitol by weight, particularly between 15% and 45% mannitol by weight, more particularly between 20% and 40% mannitol by weight, and most particularly 30% ± 5% mannitol by weight (in particular, said weight is the weight of the uncoated core).

22. The pharmaceutical composition according to any one of claims 1 to 21, comprising colloidal silica at a weight of 0.2% to 5.0%, more particularly at a weight of 1.0% to 3.0%, and most particularly at a weight of 2.0% ± 0.5% (in particular, wherein the total weight is the weight of the uncoated core).

23. The pharmaceutical composition according to any one of claims 1 to 22, comprising sodium stearoyl fumarate at a weight of 0.2% to 5%, more particularly at a weight of 2.0% to 4.0%, and most particularly at a weight of 3.0% ± 0.5% (in particular, wherein the total weight is the weight of the uncoated core).

24. The pharmaceutical composition according to any one of claims 1 to 23, comprising between 5% and 90% by weight of microcrystalline cellulose, particularly between 20% and 60% by weight of microcrystalline cellulose, more particularly 50.0% ± 5% by weight of microcrystalline cellulose, and most particularly 50.0% ± 2% by weight of microcrystalline cellulose (particularly wherein the total weight is the weight of the uncoated core).

25. The pharmaceutical composition according to any one of claims 1 to 24, comprising tartaric acid at a weight of 0.2% to 12.0%, more particularly at a weight of 1.0% to 4.0%, and most particularly at a weight of 2.5% ± 0.5% (in particular, wherein the total weight is the weight of the uncoated core).

26. The pharmaceutical composition according to any one of claims 1 to 25, comprising between 0.5% and 12.0% by weight of crospovidone, more particularly between 4.0% and 8.0% by weight of crospovidone, and most particularly 6.0% ± 1.0% by weight of crospovidone (particularly wherein the total weight is the weight of the core without coating).

27. The pharmaceutical composition according to any one of claims 1 to 26, comprising between 0.5% and 30% by weight of lichepoprane, particularly between 1% and 15% by weight of lichepoprane, more particularly between 2% and 8% by weight of lichepoprane, and most particularly 4% ± 2% by weight of lichepoprane (wherein the total weight is the weight of the coated tablet [core weight and coating weight]).

28. The pharmaceutical composition according to any one of claims 1 to 27, comprising between 2% and 80% mannitol by weight, particularly between 15% and 45% mannitol by weight, more particularly between 20% and 40% mannitol by weight, and most particularly 30% ± 5% mannitol by weight (wherein the total weight is the weight of the coated tablet [core weight and coating weight]).

29. The pharmaceutical composition according to any one of claims 1 to 28, comprising colloidal silica at a weight of 0.2% to 5.0%, more particularly at a weight of 1.0% to 3.0%, and most particularly at a weight of 1.90% ± 0.50% (wherein the total weight is the weight of the coated tablet [core weight and coating weight]).

30. The pharmaceutical composition according to any one of claims 1 to 29, comprising sodium stearoyl fumarate at a weight of 0.2% to 5%, more particularly at a weight of 2.0% to 4.0%, and most particularly at a weight of 2.90% ± 0.50% (wherein the total weight is the weight of the coated tablet [core weight and coating weight]).

31. The pharmaceutical composition according to any one of claims 1 to 30, comprising between 5% and 90% by weight of microcrystalline cellulose, particularly between 20% and 60% by weight of microcrystalline cellulose, more particularly 50.0% ± 5% by weight of microcrystalline cellulose, and most particularly 48.90% ± 2.0% by weight of microcrystalline cellulose (wherein the total weight is the weight of the coated tablet [core weight and coating weight]).

32. The pharmaceutical composition according to any one of claims 1 to 31, comprising tartaric acid at a weight of 0.2% to 12.0%, more particularly at a weight of 1.0% to 4.0%, and most particularly at a weight of 2.30% ± 0.5% (wherein the total weight is the weight of the coated tablet [core weight and coating weight]).

33. The pharmaceutical composition according to any one of claims 1 to 32, comprising between 0.5% and 12.0% by weight of crospovidone, more particularly between 4.0% and 8.0% by weight of crospovidone, and most particularly 5.80% ± 1.0% by weight of crospovidone (wherein the total weight is the weight of the coated tablet [core weight and coating weight]).

34. The pharmaceutical composition according to any one of claims 1 to 33, comprising: (a) Compound of formula (I) in amounts between 0.5% and 30% by weight, particularly between 1% and 15% by weight, even more particularly between 2% and 8% by weight, and most particularly between 4% ± 2% by weight. Or its pharmaceutically acceptable salt; (b) Cross-linked polyvinylpyrrolidone in the range of 0.5% to 12.0% by weight, more particularly in the range of 4.0% to 8.0% by weight, and most particularly in the range of 6.0% ± 1.0% by weight; (c) An acidifying agent in the range of 0.2% to 12.0% by weight, more particularly in the range of 1.0% to 4.0% by weight, and most particularly in the range of 2.5% ± 0.5% by weight, said acidifying agent being selected from tartaric acid, citric acid or malic acid, more particularly tartaric acid; (d) At least one filler comprising, by weight, between 30% and 90%, particularly between 40% and 90%, between 70% and 90%, and most particularly between 80% ± 5%, of microcrystalline cellulose, cellulose powder, isomaltitol, lactose, spray-dried lactose, anhydrous lactose, lactose monohydrate, maltodextrin, mannitol, dicalcium phosphate, sorbitol, sugar, sucrose, glucose, sugar alcohol, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dicalcium phosphate and calcium sulfate, and combinations thereof, particularly selected from lactose, starch, hydrolyzed starch, maltodextrin, isomaltitol, microcrystalline cellulose, mannitol, sorbitol, sucrose, glucose, dicalcium phosphate and calcium sulfate, and combinations thereof, more particularly combinations of microcrystalline cellulose and mannitol; (e) a lubricant comprising, by weight, between 0.2% and 5%, more particularly between 2.0% and 4.0%, and most particularly 3.0% ± 0.5%, of sodium stearoyl fumarate and magnesium stearate, particularly sodium stearoyl fumarate; and (f) a flow aid comprising, by weight, between 0.2% and 5.0%, more particularly between 1.0% and 3.0% by weight, and most particularly between 2.0% ± 0.5% by weight, said flow aid being selected from colloidal silica; The prerequisite is that the pharmaceutical composition does not contain disodium EDTA; The total amount of the ingredients does not exceed 100% by weight.

35. The pharmaceutical composition according to any one of claims 1 to 34, comprising: (a) Compound of formula (I) in amounts between 0.5% and 30% by weight, particularly between 1% and 15% by weight, even more particularly between 2% and 8% by weight, and most particularly between 4% ± 2% by weight. Or pharmaceutically acceptable salts; (b) Cross-linked polyvinylpyrrolidone in the range of 0.5% to 12.0% by weight, more particularly in the range of 4.0% to 8.0% by weight, and most particularly in the range of 6.0% ± 1.0% by weight; (c) An acidifying agent in the range of 0.2% to 12.0% by weight, more particularly in the range of 1.0% to 4.0% by weight, and most particularly in the range of 2.5% ± 0.5% by weight, said acidifying agent being selected from tartaric acid, citric acid or malic acid, more particularly tartaric acid; (d) Microcrystalline cellulose in the range of 5% to 90% by weight, particularly in the range of 20% to 60% by weight, even more particularly in the range of 50.0% ± 5% by weight, and most particularly in the range of 50.0% ± 2% by weight; (e) Mannitol in the range of 2% to 80% by weight, particularly between 15% and 45% by weight, even more particularly between 20% and 40% by weight, and most particularly between 30% ± 5% by weight; (f) Sodium stearoyl fumarate in amounts ranging from 0.2% to 5% by weight, more particularly from 2.0% to 4.0% by weight, and most particularly from 3.0% ± 0.5% by weight; and (g) Colloidal silica in the range of 0.2% to 5.0% by weight, more particularly in the range of 1.0% to 3.0% by weight, and most particularly in the range of 2.0% ± 0.5% by weight; The prerequisite is that the pharmaceutical composition does not contain disodium EDTA; The total amount of the components shall not exceed 100% by weight (in particular, the weight mentioned refers to the weight of the uncoated kernel).

36. The pharmaceutical composition according to any one of claims 1 to 35, comprising: i) The tablet core (also known as a chip tablet or first-layer tablet) contains: (a) Compound of formula (I) in amounts between 0.5% and 30% by weight, particularly between 1% and 15% by weight, even more particularly between 2% and 8% by weight, and most particularly between 4% ± 2% by weight. Or pharmaceutically acceptable salts; (b) Cross-linked polyvinylpyrrolidone in the range of 0.5% to 12.0% by weight, more particularly in the range of 4.0% to 8.0% by weight, and most particularly in the range of 6.0% ± 1.0% by weight; (c) An acidifying agent in the range of 0.2% to 12.0% by weight, more particularly in the range of 1.0% to 4.0% by weight, and most particularly in the range of 2.5% ± 0.5% by weight, said acidifying agent being selected from tartaric acid, citric acid or malic acid, more particularly tartaric acid; (d) Microcrystalline cellulose in the range of 5% to 90% by weight, particularly in the range of 20% to 60% by weight, even more particularly in the range of 50.0% ± 5% by weight, and most particularly in the range of 50.0% ± 2% by weight; (e) Between 2% and 80% by weight, particularly between 15% and 45% by weight, even more particularly between 20% and 40% by weight, and most particularly between 30% ± 5% by weight; (f) Sodium stearoyl fumarate in amounts ranging from 0.2% to 5% by weight, more particularly from 2.0% to 4.0% by weight, and most particularly from 3.0% ± 0.5% by weight; and (g) Colloidal silica in the range of 0.2% to 5.0% by weight, more particularly in the range of 1.0% to 3.0% by weight, and most particularly in the range of 2.0% ± 0.5% by weight; and iii) At least one film coating; The prerequisite is that the pharmaceutical composition does not contain disodium EDTA; The total amount of the ingredients does not exceed 100% by weight.

37. The pharmaceutical composition according to any one of claims 1 to 36, wherein sodium stearoyl fumarate has a saponification value of 142.2 to 146.0, particularly having a Dv50 of 13.6 µm, and more particularly, sodium stearoyl fumarate is Pruv®.

38. The pharmaceutical composition according to any one of claims 1 to 37, wherein the microcrystalline cellulose is CAS9004-34-6, particularly having a Dv50 of 135 µm, and more particularly having a pH of 102.

39. The pharmaceutical composition according to any one of claims 1 to 38, comprising a single active pharmaceutical ingredient (API), more particularly wherein the single API is a compound of formula (I). ， Also known as lisper.

40. A tablet comprising the pharmaceutical composition according to any one of claims 1 to 39.

41. The tablet of claim 40, wherein the tablet is dispersible in water within 5 minutes.

42. The tablet according to any one of claims 40 to 41, wherein the tablet is dispersible in water with an HCl content of less than 1 mg / L, or more particularly in drinking water with an HCl content of less than 0.2 mg / L, and most particularly wherein the drinking water is mineral water.

43. The tablet according to any one of claims 40 to 42, having the shape shown in FIG2, and more particularly wherein the tablet has a diameter of 6.50 ± 0.50 mm.

44. A reagent kit comprising: The pharmaceutical composition according to any one of claims 1 to 39 is in the form of a tablet containing a therapeutically effective amount of liscovah's flavonoids; prescription information, also known as "instructions for use"; blister pack or bottle (HDPE or glass), particularly moisture-proof primary packaging, more particularly Alu / Alu blister packs or plastic bottles with desiccant; and container, particularly wherein the prescription information specifically includes recommendations for the patient regarding the administration of the liscovah's flavonoids with food.

45. A method for producing a pharmaceutical composition according to any one of claims 1 to 39, the method comprising the following steps: i) The compound of formula (I) ， Also known as lisper, it is blended in container 1 with tartaric acid powder, mannitol, microcrystalline cellulose, colloidal silica, crospovidone and strawberry flavoring; ii) Sieve container 1. iii) Sift sodium stearoyl fumarate in container 2, especially sieve to 0.5 mm. iv) Blend the mixture from container 1 and container 2 together; v) Compressing the blend of iv) into tablet cores; and vi) Suspend the first membrane coating system, particularly a membrane coating system free of iron oxides, and more particularly a membrane coating system of OPADRY II white (i.e., 85F18422), in purified water, and vii) Spray the film coating system vi) onto the tablet core. viii) The membrane coating system, particularly a membrane coating system that does not contain iron oxides, and more particularly a membrane coating system that is OPADRY II Yellow (i.e., 85F220022), is suspended in purified water, and ix) Spray the film coating system (viii) onto the core of the coated tablet.

46. ​​A pharmaceutical composition obtained by the method according to claim 45.

47. The pharmaceutical composition according to any one of claims 1 to 39, comprising lisclan administered to an individual at any suitable dose (e.g., to achieve a therapeutically effective dose), particularly at a suitable dose of about 5 mg per day for a therapeutically effective dose.

48. The pharmaceutical composition according to any one of claims 1 to 39, for the treatment, prevention, delay of progression and / or improvement of diseases caused by inactive mutations or deletions in the SMN1 gene and / or associated with loss or defect of SMN1 gene function, particularly for the treatment, prevention, delay of progression and / or improvement of spinal muscular atrophy (SMA).

49. The pharmaceutical composition of claim 48, used for said treatment, wherein the patient's weight is greater than or equal to 20 kg.

50. The pharmaceutical composition of claim 48, used for said treatment, wherein the human subject weighs 20 kg or more.

51. The present invention as described above.

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