Lanilanol formulations

Abstract

The present invention relates to a pharmaceutical composition for the treatment of hepatic fibrosis, said composition comprising from 55.0 wt% to 75.0 wt% of Lranilanol and from 25.0 wt% to 45.0 wt% of one or more excipients.

Description

Technical Field

[0001] This invention relates to pharmaceutical compositions comprising lanilanol and the use of said compositions in treatment, particularly for the treatment of liver fibrosis. Background Technology

[0002] Lanilano, or 1-(6-benzothiazolylsulfonyl)-5-chloro-1H-indole-2-butyric acid, is a pan-PPAR agonist currently in clinical development for the treatment of patients with non-alcoholic steatohepatitis (NASH), for which there is currently no approved treatment.

[0003] Lanilandol is described in Example 117 of WO 2007 / 026097, wherein it is obtained as a pale yellow powder having a melting point of 74°C-80°C and having the following structure:

[0004] .

[0005] The daily dose regimen of lanigenin used in the Phase II clinical trials was 800 mg or 1200 mg, administered once daily as two or three 400 mg tablets containing 44 wt% lanigenin, depending on the regimen under consideration. The upcoming Phase III clinical trials are expected to use the same daily dose regimen but with a formulation containing a higher lanigenin loading. While it is theoretically desirable to incorporate as much of the active ingredient as possible into the formulation, challenges exist, such as in manufacturing processes or patient acceptability (dosage form size). In particular, incorporating hydrophobic components (as is the case with lanigenin) into the formulation is not straightforward, let alone in large quantities, as this can negatively impact bioavailability.

[0006] The present invention was made in view of the above-mentioned problems. Summary of the Invention

[0007] On one hand, this disclosure relates to pharmaceutical compositions, which, based on the total weight of the composition, comprise:

[0008] Lanilandol, approximately 55.0 wt% to approximately 75.0 wt%; and

[0009] Pharmaceutically acceptable excipients, approximately 25.0 wt% to approximately 45.0 wt%.

[0010] Among them, lanilano has a particle size distribution such that D50≤30 μm and D90≤50 μm.

[0011] In some embodiments, pharmaceutically acceptable excipients include two or more of binders, disintegrants, fillers, flow aids, lubricants, and surfactants.

[0012] In some embodiments, the pharmaceutical composition is in a solid dosage form, such as capsules, sachets, lozenges, powders, pills, or tablets.

[0013] In some embodiments, the solid dosage form contains about 200 mg to about 1200 mg of lanilanol, for example, 200 mg, 400 mg, 600 mg, 800 mg, 1000 mg or 1200 mg of lanilanol.

[0014] In some implementations, lanilanol exists in crystalline form.

[0015] In some embodiments, such as when measured using a USP test apparatus 1 (basket 10 mesh) at a constant temperature of 37°C ± 0.5°C in 1000 mL of sodium phosphate buffer at pH 6.8, the dissolution of the pharmaceutical composition is at least 30% and not more than 60% after 15 minutes, and at least 80%, preferably at least 85%, after 45 minutes, and the sodium phosphate buffer contains about 0.7% to 1.7% tetradecyltrimethylammonium bromide.

[0016] On the other hand, this disclosure relates to a method for treating non-alcoholic fatty liver disease, the method comprising administering a pharmaceutical composition as defined above to a subject in need.

[0017] On the other hand, this disclosure relates to a method for treating a subject with cirrhosis who is at risk of progressing from a compensated to a decompensated stage, the method comprising administering to the subject a pharmaceutical composition as defined above.

[0018] The foregoing general description and the following detailed description are exemplary and explanatory, and are intended to further explain the invention as defined in the appended claims. Attached Figure Description

[0019] Figure 1 Dissolution characteristics of 600 mg lanylanoate tablets are shown.

[0020] Figure 2 Dissolution characteristics of 400 mg lanylanoate tablets are shown. Detailed Implementation

[0021] As used in this article, articles including “a” and “an” should be understood to refer to one or more of the claimed or described objects.

[0022] As used herein, the terms “including,” “comprising,” and “containing” are non-restrictive.

[0023] As used herein, the term "about xx" refers to a measurable value (e.g., a parameter, quantity, duration, etc.) that encompasses variations of the specified value and variations from the specified value as follows: + / - 10% or less, preferably + / - 5% or less, more preferably + / - 1% or less, even more preferably + / - 0.5% or less, more preferably + / - 0.05% or less, and even more preferably + / - 0.04% or less, + / - 0.03% or less, + / - 0.02% or less, + / - 0.01% or less, provided that such variations are suitable for implementation in the disclosed invention. However, it should be understood that the value referred to by "about" is itself specifically disclosed. In other words, the term "about xx" includes the value "xx".

[0024] It should be understood that, unless otherwise stated, the concentrations disclosed herein as weight percentages (wt%) are based on the total weight of the prepared pharmaceutical composition or formulation.

[0025] The embodiments described herein can be combined.

[0026] On one hand, this disclosure relates to pharmaceutical compositions, which, based on the total weight of the composition, comprise:

[0027] Lanilandol, approximately 55.0 wt% to approximately 75.0 wt%; and

[0028] Pharmaceutically acceptable excipients, approximately 25.0 wt% to approximately 45.0 wt%.

[0029] Among them, lanilano has a particle size distribution such that D50≤30 μm and D90≤50 μm.

[0030] As used herein, D50 and D90 (sometimes also referred to as D(v; 0.5) and D(v; 0.9) respectively) are points in the size distribution below which up to 50% and 90% of the total volume of material in the sample is “contained”, respectively. For example, D90 ≤ 50 μm means that 90% of the sample has a size of 50 μm or more. D50 and D90 are measured using a laser diffraction / scattering particle size distribution analyzer (e.g., available from Malvern).

[0031] In some embodiments, the particle size distribution of lanilanol is such that it has D50 ≤ 10 μm and D90 ≤ 30 μm, and advantageously, lanilanol has D90 ≤ 15 μm.

[0032] In some implementations, the particle size distribution of the lanilanol is such that both its D90 and D50 are ≤5 μm, for example, the values ​​of D90 and D50 are both in the range of about 200 nm to about 2000 nm.

[0033] As used herein, “lanilanol” refers to the lanilanol referred to in CAS No. 927961-18-0 (also known as IVA337) or as described in Example 117 of WO 2007 / 026097. In some embodiments, the term “lanilanol” also includes deuterated derivatives of lanilanol. In some embodiments, lanilanol is in crystalline form. Examples of crystalline forms of lanilanol have been described in WO 2023 / 194339, WO 2023 / 016319, WO 2022 / 122014, WO 2022 / 261410 or WO 2022 / 258060, all of which are incorporated herein by reference.

[0034] In some embodiments, the deuterated derivatives of lanilanol are compounds of formula (I):

[0035]

[0036] (I)

[0037] Wherein, as described in WO 2020 / 021215, at least one of groups R1 to R7 is a deuterium (D) atom, and the other groups R1 to R7 are hydrogen (H) atoms. In some aspects, at least group R1 is D. In some aspects, at least one of groups R2 to R7 is D, particularly at least one of groups R2 and R3, and / or at least one of groups R4 and R5, and / or at least one of groups R6 and R7 is D. In a preferred aspect, each of R2, R3, R4, R5, R6, and R7 is D. Preferably, the compounds of formula (I) include 4-(1-(2-deuterated-1,3-benzothiazol-6-yl)sulfonyl)-5-chloro-1H-indol-2-yl)butyric acid and 4-[1-(1,3-benzothiazol-6-ylsulfonyl)-5-chloro-indol-2-yl]-2,2,3,3,4,4-hexadeuterated butyric acid.

[0038] In some embodiments, lanilanol or its deuterated derivatives are in one of their pharmaceutically acceptable salts or solvates. The term "solvate" is used herein to describe a molecular complex comprising lanilanol or its deuterated derivatives and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is used. Pharmaceutically acceptable salts of lanilanol or its deuterated derivatives include their base addition salts. Base addition salts can be prepared from inorganic and organic bases. Examples of inorganic bases include sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide. Examples of organic bases include amines, amino alcohols, basic amino acids (e.g., lysine or arginine), and quaternary ammonium compounds (e.g., betaine or choline).

[0039] In some embodiments, lanilanol comprises about 55.0 wt% to about 75.0 wt%, for example, about 55.0 wt% to about 70.0 wt%, for example, about 55.0 wt% to about 65.0 wt%, for example, about 55.0 wt% to about 60.0 wt%. In some embodiments, lanilanol comprises, for example, about 57.0 wt% to about 75.0 wt%, for example, about 57.0 wt% to about 70.0 wt%, for example, about 57.0 wt% to about 65.0 wt%, for example, about 57.0 wt% to about 60.0 wt%. In some embodiments, lanilanol comprises approximately 55.0 wt%, approximately 55.1 wt%, approximately 55.2 wt%, approximately 55.3 wt%, approximately 55.4 wt%, approximately 55.5 wt%, approximately 55.6 wt%, approximately 55.7 wt%, approximately 55.8 wt%, approximately 55.9 wt%, approximately 56.0 wt%, approximately 56.1 wt%, approximately 56.2 wt%, approximately 56.3 wt%, approximately 56.4 wt%, approximately 56.5 wt%, approximately 56.6 wt%, approximately 56.7 wt%, and approximately 56. 8 wt%, approximately 56.9 wt%, approximately 57.0 wt%, approximately 57.1 wt%, approximately 57.2 wt%, approximately 57.3 wt%, approximately 57.4 wt%, approximately 57.5 wt%, approximately 57.6 wt%, approximately 57.7 wt%, approximately 57.8 wt%, approximately 57.9 wt%, approximately 58.0 wt%, approximately 58.1 wt%, approximately 58.2 wt%, approximately 58.3 wt%, approximately 58.4 wt%, approximately 58.5 wt%, approximately 58.6 wt%, approximately 58.7 wt%, approximately 58. 8 wt%, approximately 58.9 wt%, approximately 59.0 wt%, approximately 59.1 wt%, approximately 59.2 wt%, approximately 59.3 wt%, approximately 59.4 wt%, approximately 59.5 wt%, approximately 59.6 wt%, approximately 59.7 wt%, approximately 59.8 wt%, approximately 59.9 wt%, approximately 60.0 wt%, approximately 60.1 wt%, approximately 60.2 wt%, approximately 60.3 wt%, approximately 60.4 wt%, approximately 60.5 wt%, approximately 60.6 wt%, approximately 60.7 wt%, approximately 60. 8 wt%, approximately 60.9 wt%, approximately 61.0 wt%, approximately 61.1 wt%, approximately 61.2 wt%, approximately 61.3 wt%, approximately 61.4 wt%, approximately 61.5 wt%, approximately 61.6 wt%, approximately 61.7 wt%, approximately 61.8 wt%, approximately 61.9 wt%, approximately 62.0 wt%, approximately 62.1 wt%, approximately 62.2 wt%, approximately 62.3 wt%, approximately 62.4 wt%, approximately 62.5 wt%, approximately 62.6 wt%, approximately 62.7 wt%, approximately 62.8wt%, approximately 62.9wt%, approximately 63.0wt%, approximately 63.1wt%, approximately 63.2wt%, approximately 63.3wt%, approximately 63.4wt%, approximately 63.5wt%, approximately 63.6wt%, approximately 63.7wt%, approximately 63.8wt%, approximately 63.9wt%, approximately 64.0wt%, approximately 64.1wt%, approximately 64.2wt%, approximately 64.3wt%, approximately 64.4wt%, approximately 64.5wt%, approximately 64.6wt%, approximately 64.7wt%, approximately 64.8wt%, approximately 64.9wt%, approximately 65.0wt%, approximately 65.1wt%, approximately 65.2wt%, approximately 65.3wt%, approximately 65.4wt%, approximately 65.5wt%, approximately 65.6 wt%, approximately 65.7 wt%, approximately 65.8 wt%, approximately 65.9 wt%, approximately 66.0 wt%, approximately 66.1 wt%, approximately 66.2 wt%, approximately 66.3 wt%, approximately 66.4 wt%, approximately 66.5 wt%, approximately 66.6 wt%, approximately 66.7 wt%, approximately 66.8 wt%, approximately 66.9 wt%, approximately 67.0 wt%, approximately 67.1 wt%, approximately 67.2 wt%, approximately 67.3 wt%, approximately 67.4 wt%, approximately 67.5 wt%, approximately 67.6 wt%, approximately 67.7 wt%, approximately 67.8 wt%, approximately 67.9 wt%, approximately 68.0 wt%, approximately 68.1 wt%, approximately 68.2 wt%, approximately 68.3 wt% Approximately 68.4 wt%, approximately 68.5 wt%, approximately 68.6 wt%, approximately 68.7 wt%, approximately 68.8 wt%, approximately 68.9 wt%, approximately 69.0 wt%, approximately 69.1 wt%, approximately 69.2 wt%, approximately 69.3 wt%, approximately 69.4 wt%, approximately 69.5 wt%, approximately 69.6 wt%, approximately 69.7 wt%, approximately 69.8 wt%, approximately 69.9 wt%, approximately 70.0 wt%, approximately 70.1 wt%, approximately 70.2 wt%, approximately 70.3 wt%, approximately 70.4 wt%, approximately 70.5 wt%, approximately 70.6 wt%, approximately 70.7 wt%, approximately 70.8 wt%, approximately 70.9 wt%, approximately 71.0 wt%, approximately 71.1 wt%. t%, approximately 71.2wt%, approximately 71.3wt%, approximately 71.4wt%, approximately 71.5wt%, approximately 71.6wt%, approximately 71.7wt%, approximately 71.8wt%, approximately 71.9wt%, approximately 72.0wt%, approximately 72.1wt%, approximately 72.2wt%, approximately 72.3wt%, approximately 72.4wt%, approximately 72.5wt%, approximately 72.6wt%, approximately 72.7wt%, approximately 72.8wt%, approximately 72.9wt%, approximately 73.0wt%, approximately 73.1wt%, approximately 73.2wt%, approximately 73.3wt%, approximately 73.4wt%, approximately 73.5wt%, approximately 73.6wt%, approximately 73.7wt%, approximately 73.8wt%, approximately 73.9 wt%, approximately 74.0 wt%, approximately 74.1 wt%, approximately 74.2 wt%, approximately 74.3 wt%, approximately 74.4 wt%, approximately 74.5 wt%, approximately 74.6 wt%, approximately 74.7 wt%, approximately 74.8 wt%, approximately 74.9 wt%, approximately 75.0 wt%.

[0040] The inventors have unexpectedly demonstrated that a specific distribution of lanilanol (as the active ingredient) and pharmaceutically acceptable excipients enables the production of stable and readily compressible immediate-release pharmaceutical compositions with good dissolution characteristics and good overall tolerability.

[0041] In some embodiments, pharmaceutically acceptable excipients include two or more of binders, disintegrants, fillers, flow aids, lubricants, and surfactants.

[0042] filler

[0043] In some embodiments, the pharmaceutically acceptable excipient includes a filler, and the filler comprises about 10.0 wt% to about 35.0 wt% of the total weight of the composition, for example, about 11.0 wt% to about 35.0 wt%, for example, about 12.0 wt% to about 35.0 wt%, for example, about 13.0 wt% to about 35.0 wt%, for example, about 14.0 wt% to about 35.0 wt%, for example, about 15.0 wt% to about 35.0 wt%, for example, about 16.0 wt% to about 35.0 wt%, for example, about 17.0 wt% to about 35.0 wt%, for example, about 18.0 wt% to about 35.0 wt%, for example, about 19.0 wt% to about 35.0 wt%, for example, about 20.0 wt% to About 35.0 wt%, for example, about 21.0 wt% to about 35.0 wt%, for example, about 22.0 wt% to about 35.0 wt%, for example, about 23.0 wt% to about 35.0 wt%, for example, about 24.0 wt% to about 35.0 wt%, for example, about 25.0 wt% to about 35.0 wt%, for example, about 26.0 wt% to about 35.0 wt%, for example, about 27.0 wt% to about 35.0 wt%, for example, about 28.0 wt% to about 35.0 wt%, for example, about 29.0 wt% to about 35.0 wt%, for example, about 30.0 wt% to about 35.0 wt%, for example, about 31.0 wt% to about 35.0 wt%, for example, about 32.0 wt% to about 35.0 wt%. For example, about 33.0 wt% to about 35.0 wt%, about 34.0 wt% to about 35.0 wt%, about 10.0 wt% to about 34.0 wt%, about 11.0 wt% to about 34.0 wt%, about 12.0 wt% to about 34.0 wt%, about 13.0 wt% to about 34.0 wt%, about 14.0 wt% to about 34.0 wt%, about 15.0 wt% to about 34.0 wt%, about 16.0 wt% to about 34.0 wt%, about 17.0 wt% to about 34.0 wt%, about 18.0 wt% to about 34.0 wt%, about 19.0 wt% to about 34.0 wt%, and about 20.0 wt%. From wt% to about 34.0 wt%, for example, from about 21.0 wt% to about 34.0 wt%, for example, from about 22.0 wt% to about 34.0 wt%, for example, from about 23.0 wt% to about 34.0 wt%, for example, from about 24.0 wt% to about 34.0 wt%, for example, from about 25.0 wt% to about 34.0 wt%, for example, from about 26.0 wt% to about 34.0 wt%, for example, from about 27.0 wt% to about 34.0 wt%, for example, from about 28.0 wt% to about 34.0 wt%, for example, from about 29.0 wt% to about 34.0 wt%, for example, from about 30.0 wt% to about 34.0 wt%, for example, from about 31.0 wt% to about 34.0 wt%, for example, from about 32.0 wt% to about 34.0 wt%.0 wt%, for example, about 33.0 wt% to about 34.0 wt%, for example, about 10.0 wt% to about 33.0 wt%, for example, about 11.0 wt% to about 33.0 wt%, for example, about 12.0 wt% to about 33.0 wt%, for example, about 13.0 wt% to about 33.0 wt%, for example, about 14.0 wt% to about 33.0 wt%, for example, about 15.0 wt% to about 33.0 wt%, for example, about 16.0 wt% to about 33.0 wt%, for example, about 17.0 wt% to about 33.0 wt%, for example, about 18.0 wt% to about 33.0 wt%, for example, about 19.0 wt% to about 33.0 wt%, for example, about 20.0 wt% to about 33.0 wt%, for example, about 21 wt%. 0.0 wt% to about 33.0 wt%, for example about 22.0 wt% to about 33.0 wt%, for example about 23.0 wt% to about 33.0 wt%, for example about 24.0 wt% to about 33.0 wt%, for example about 25.0 wt% to about 33.0 wt%, for example about 26.0 wt% to about 33.0 wt%, for example about 27.0 wt% to about 33.0 wt%, for example about 28.0 wt% to about 33.0 wt%, for example about 29.0 wt% to about 33.0 wt%, for example about 30.0 wt% to about 33.0 wt%, for example about 31.0 wt% to about 33.0 wt%, for example about 32.0 wt% to about 33.0 wt%, for example about 10.0 wt% to about 32.0 wt%. 0 wt%, for example, about 11.0 wt% to about 32.0 wt%, for example, about 12.0 wt% to about 32.0 wt%, for example, about 13.0 wt% to about 32.0 wt%, for example, about 14.0 wt% to about 32.0 wt%, for example, about 15.0 wt% to about 32.0 wt%, for example, about 16.0 wt% to about 32.0 wt%, for example, about 17.0 wt% to about 32.0 wt%, for example, about 18.0 wt% to about 32.0 wt%, for example, about 19.0 wt% to about 32.0 wt%, for example, about 20.0 wt% to about 32.0 wt%, for example, about 21.0 wt% to about 32.0 wt%, for example, about 22.0 wt% to about 32.0 wt%, for example, about 23 wt%. 0.0 wt% to about 32.0 wt%, for example about 24.0 wt% to about 32.0 wt%, for example about 25.0 wt% to about 32.0 wt%, for example about 26.0 wt% to about 32.0 wt%, for example about 27.0 wt% to about 32.0 wt%, for example about 28.0 wt% to about 32.0 wt%, for example about 29.0 wt% to about 32.0 wt%, for example about 30.0 wt% to about 32.0 wt%, for example about 31.0 wt% to about 32.0 wt%, for example about 10.0 wt% to about 31.0 wt%, for example about 11.0 wt% to about 31.0 wt%, for example about 12.0 wt% to about 31.0 wt%, for example about 13.0 wt% to about 31.0 wt%.0 wt%, for example, about 14.0 wt% to about 31.0 wt%, for example, about 15.0 wt% to about 31.0 wt%, for example, about 16.0 wt% to about 31.0 wt%, for example, about 17.0 wt% to about 31.0 wt%, for example, about 18.0 wt% to about 31.0 wt%, for example, about 19.0 wt% to about 31.0 wt%, for example, about 20.0 wt% to about 31.0 wt%, for example, about 21.0 wt% to about 31.0 wt%, for example, about 22.0 wt% to about 31.0 wt%, for example, about 23.0 wt% to about 31.0 wt%, for example, about 24.0 wt% to about 31.0 wt%, for example, about 25.0 wt% to about 31.0 wt%, for example, about 26 wt%. 0.0 wt% to about 31.0 wt%, for example about 27.0 wt% to about 31.0 wt%, for example about 28.0 wt% to about 31.0 wt%, for example about 29.0 wt% to about 31.0 wt%, for example about 30.0 wt% to about 31.0 wt%, for example about 10.0 wt% to about 30.0 wt%, for example about 11.0 wt% to about 30.0 wt%, for example about 12.0 wt% to about 30.0 wt%, for example about 13.0 wt% to about 30.0 wt%, for example about 14.0 wt% to about 30.0 wt%, for example about 15.0 wt% to about 30.0 wt%, for example about 16.0 wt% to about 30.0 wt%, for example about 17.0 wt% to about 30.0 wt%. 0 wt%, for example, about 18.0 wt% to about 30.0 wt%, for example, about 19.0 wt% to about 30.0 wt%, for example, about 20.0 wt% to about 30.0 wt%, for example, about 21.0 wt% to about 30.0 wt%, for example, about 22.0 wt% to about 30.0 wt%, for example, about 23.0 wt% to about 30.0 wt%, for example, about 24.0 wt% to about 30.0 wt%, for example, about 25.0 wt% to about 30.0 wt%, for example, about 26.0 wt% to about 30.0 wt%, for example, about 27.0 wt% to about 30.0 wt%, for example, about 28.0 wt% to about 30.0 wt%, for example, about 29.0 wt% to about 30.0 wt%, for example, about 10 0.0 wt% to about 29.0 wt%, for example about 11.0 wt% to about 29.0 wt%, for example about 12.0 wt% to about 29.0 wt%, for example about 13.0 wt% to about 29.0 wt%, for example about 14.0 wt% to about 29.0 wt%, for example about 15.0 wt% to about 29.0 wt%, for example about 16.0 wt% to about 29.0 wt%, for example about 17.0 wt% to about 29.0 wt%, for example about 18.0 wt% to about 29.0 wt%, for example about 19.0 wt% to about 29.0 wt%, for example about 20.0 wt% to about 29.0 wt%, for example about 21.0 wt% to about 29.0 wt%, for example about 22.0 wt% to about 29.0 wt%.0 wt%, for example, about 23.0 wt% to about 29.0 wt%, for example, about 24.0 wt% to about 29.0 wt%, for example, about 25.0 wt% to about 29.0 wt%, for example, about 26.0 wt% to about 29.0 wt%, for example, about 27.0 wt% to about 29.0 wt%, for example, about 28.0 wt% to about 29.0 wt%, for example, about 10.0 wt% to about 28.0 wt%, for example, about 11.0 wt% to about 28.0 wt%, for example, about 12.0 wt% to about 28.0 wt%, for example, about 13.0 wt% to about 28.0 wt%, for example, about 14.0 wt% to about 28.0 wt%, for example, about 15.0 wt% to about 28.0 wt%, for example, about 16 wt%. 0.0 wt% to about 28.0 wt%, for example, about 17.0 wt% to about 28.0 wt%, for example, about 18.0 wt% to about 28.0 wt%, for example, about 19.0 wt% to about 28.0 wt%, for example, about 20.0 wt% to about 28.0 wt%, for example, about 21.0 wt% to about 28.0 wt%, for example, about 22.0 wt% to about 28.0 wt%, for example, about 23.0 wt% to about 28.0 wt%, for example, about 24.0 wt% to about 28.0 wt%, for example, about 25.0 wt% to about 28.0 wt%, for example, about 26.0 wt% to about 28.0 wt%, for example, about 27.0 wt% to about 28.0 wt%, for example, about 10.0 wt% to about 27.0 wt%. 0 wt%, for example, about 11.0 wt% to about 27.0 wt%, for example, about 12.0 wt% to about 27.0 wt%, for example, about 13.0 wt% to about 27.0 wt%, for example, about 14.0 wt% to about 27.0 wt%, for example, about 15.0 wt% to about 27.0 wt%, for example, about 16.0 wt% to about 27.0 wt%, for example, about 17.0 wt% to about 27.0 wt%, for example, about 18.0 wt% to about 27.0 wt%, for example, about 19.0 wt% to about 27.0 wt%, for example, about 20.0 wt% to about 27.0 wt%, for example, about 21.0 wt% to about 27.0 wt%, for example, about 22.0 wt% to about 27.0 wt%, for example, about 23 wt%. 0.0 wt% to about 27.0 wt%, for example about 24.0 wt% to about 27.0 wt%, for example about 25.0 wt% to about 27.0 wt%, for example about 26.0 wt% to about 27.0 wt%, for example about 10.0 wt% to about 26.0 wt%, for example about 11.0 wt% to about 26.0 wt%, for example about 12.0 wt% to about 26.0 wt%, for example about 13.0 wt% to about 26.0 wt%, for example about 14.0 wt% to about 26.0 wt%, for example about 15.0 wt% to about 26.0 wt%, for example about 16.0 wt% to about 26.0 wt%, for example about 17.0 wt% to about 26.0 wt%, for example about 18.0 wt% to about 26.0 wt%.0 wt%, for example, about 19.0 wt% to about 26.0 wt%, for example, about 20.0 wt% to about 26.0 wt%, for example, about 21.0 wt% to about 26.0 wt%, for example, about 22.0 wt% to about 26.0 wt%, for example, about 23.0 wt% to about 26.0 wt%, for example, about 24.0 wt% to about 26.0 wt%, for example, about 25.0 wt% to about 26.0 wt%, for example, about 10.0 wt% to about 25.0 wt%, for example, about 11.0 wt% to about 25.0 wt%, for example, about 12.0 wt% to about 25.0 wt%, for example, about 13.0 wt% to about 25.0 wt%, for example, about 14.0 wt% to about 25.0 wt%, for example, about 15 wt%. 0.0 wt% to about 25.0 wt%, for example about 16.0 wt% to about 25.0 wt%, for example about 17.0 wt% to about 25.0 wt%, for example about 18.0 wt% to about 25.0 wt%, for example about 19.0 wt% to about 25.0 wt%, for example about 20.0 wt% to about 25.0 wt%, for example about 21.0 wt% to about 25.0 wt%, for example about 22.0 wt% to about 25.0 wt%, for example about 23.0 wt% to about 25.0 wt%, for example about 24.0 wt% to about 25.0 wt%, for example about 10.0 wt% to about 24.0 wt%, for example about 11.0 wt% to about 24.0 wt%, for example about 12.0 wt% to about 24.0 wt%. 0 wt%, for example, about 13.0 wt% to about 24.0 wt%, for example, about 14.0 wt% to about 24.0 wt%, for example, about 15.0 wt% to about 24.0 wt%, for example, about 16.0 wt% to about 24.0 wt%, for example, about 17.0 wt% to about 24.0 wt%, for example, about 18.0 wt% to about 24.0 wt%, for example, about 19.0 wt% to about 24.0 wt%, for example, about 20.0 wt% to about 24.0 wt%, for example, about 21.0 wt% to about 24.0 wt%, for example, about 22.0 wt% to about 24.0 wt%, for example, about 23.0 wt% to about 24.0 wt%, for example, about 10.0 wt% to about 23.0 wt%, for example, about 11 wt%. 0.0 wt% to about 23.0 wt%, for example, about 12.0 wt% to about 23.0 wt%, for example, about 13.0 wt% to about 23.0 wt%, for example, about 14.0 wt% to about 23.0 wt%, for example, about 15.0 wt% to about 23.0 wt%, for example, about 16.0 wt% to about 23.0 wt%, for example, about 17.0 wt% to about 23.0 wt%, for example, about 18.0 wt% to about 23.0 wt%, for example, about 19.0 wt% to about 23.0 wt%, for example, about 20.0 wt% to about 23.0 wt%, for example, about 21.0 wt% to about 23.0 wt%, for example, about 22.0 wt% to about 23.0 wt%, for example, about 10.0 wt% to about 22.0 wt%.0 wt%, for example, about 11.0 wt% to about 22.0 wt%, for example, about 12.0 wt% to about 22.0 wt%, for example, about 13.0 wt% to about 22.0 wt%, for example, about 14.0 wt% to about 22.0 wt%, for example, about 15.0 wt% to about 22.0 wt%, for example, about 16.0 wt% to about 22.0 wt%, for example, about 17.0 wt% to about 22.0 wt%, for example, about 18.0 wt% to about 22.0 wt%, for example, about 19.0 wt% to about 22.0 wt%, for example, about 20.0 wt% to about 22.0 wt%, for example, about 21.0 wt% to about 22.0 wt%, for example, about 10.0 wt% to about 21.0 wt%, for example, about 11 0.0 wt% to about 21.0 wt%, for example, about 12.0 wt% to about 21.0 wt%, for example, about 13.0 wt% to about 21.0 wt%, for example, about 14.0 wt% to about 21.0 wt%, for example, about 15.0 wt% to about 21.0 wt%, for example, about 16.0 wt% to about 21.0 wt%, for example, about 17.0 wt% to about 21.0 wt%, for example, about 18.0 wt% to about 21.0 wt%, for example, about 19.0 wt% to about 21.0 wt%, for example, about 20.0 wt% to about 21.0 wt%, for example, about 10.0 wt% to about 20.0 wt%, for example, about 11.0 wt% to about 20.0 wt%, for example, about 12.0 wt% to about 20.0 wt%. 0 wt%, for example, about 13.0 wt% to about 20.0 wt%, for example, about 14.0 wt% to about 20.0 wt%, for example, about 15.0 wt% to about 20.0 wt%, for example, about 16.0 wt% to about 20.0 wt%, for example, about 17.0 wt% to about 20.0 wt%, for example, about 18.0 wt% to about 20.0 wt%, for example, about 19.0 wt% to about 20.0 wt%, for example, about 10.0 wt% to about 19.0 wt%, for example, about 11.0 wt% to about 19.0 wt%, for example, about 12.0 wt% to about 19.0 wt%, for example, about 13.0 wt% to about 19.0 wt%, for example, about 14.0 wt% to about 19.0 wt%, for example, about 15 wt%. From 0.0 wt% to about 19.0 wt%, for example, from about 16.0 wt% to about 19.0 wt%, for example, from about 17.0 wt% to about 19.0 wt%, for example, from about 18.0 wt% to about 19.0 wt%, for example, from about 10.0 wt% to about 18.0 wt%, for example, from about 11.0 wt% to about 18.0 wt%, for example, from about 12.0 wt% to about 18.0 wt%, for example, from about 13.0 wt% to about 18.0 wt%, for example, from about 14.0 wt% to about 18.0 wt%, for example, from about 15.0 wt% to about 18.0 wt%, for example, from about 16.0 wt% to about 18.0 wt%, for example, from about 17.0 wt% to about 18.0 wt%, for example, from about 10.0 wt% to about 17.0 wt%.0 wt%, for example, about 11.0 wt% to about 17.0 wt%, for example, about 12.0 wt% to about 17.0 wt%, for example, about 13.0 wt% to about 17.0 wt%, for example, about 14.0 wt% to about 17.0 wt%, for example, about 15.0 wt% to about 17.0 wt%, for example, about 16.0 wt% to about 17.0 wt%, for example, about 10.0 wt% to about 16.0 wt%, for example, about 11.0 wt% to about 16.0 wt%, for example, about 12.0 wt% to about 16.0 wt%, for example, about 13.0 wt% to about 16.0 wt%, for example, about 14.0 wt% to about 16.0 wt%, for example, about 15.0 wt% to about 16.0 wt%, for example, about 10.0 wt% to about 15.0 wt%, for example, about 11.0 wt%. From wt% to about 15.0 wt%, for example, from about 12.0 wt% to about 15.0 wt%, for example, from about 13.0 wt% to about 15.0 wt%, for example, from about 14.0 wt% to about 15.0 wt%, for example, from about 10.0 wt% to about 14.0 wt%, for example, from about 11.0 wt% to about 14.0 wt%, for example, from about 12.0 wt% to about 14.0 wt%, for example, from about 13.0 wt% to about 14.0 wt%, for example, from about 10.0 wt% to about 13.0 wt%, for example, from about 11.0 wt% to about 12.0 wt%, for example, from about 10.0 wt% to about 11.0 wt%.

[0044] In some embodiments, the filler comprises about 10.0 wt%, about 10.1 wt%, about 10.2 wt%, about 10.3 wt%, about 10.4 wt%, about 10.5 wt%, about 10.6 wt%, about 10.7 wt%, about 10.8 wt%, about 10.9 wt%, about 11.0 wt%, about 11.1 wt%, about 11.2 wt%, about 11.3 wt%, about 11.4 wt%, about 11.5 wt%, about 11.6 wt%, about 11.7 wt%, about 11.8 wt%, about 11.9 wt%, about 12.0 wt%, about 12.1 wt%, about 12.2 wt%, about 12.3 wt%, about 12.4 wt%, about 12.5 wt%, about 1 2.6 wt%, approximately 12.7 wt%, approximately 12.8 wt%, approximately 12.9 wt%, approximately 13.0 wt%, approximately 13.1 wt%, approximately 13.2 wt%, approximately 13.3 wt%, approximately 13.4 wt%, approximately 13.5 wt%, approximately 13.6 wt%, approximately 13.7 wt%, approximately 13.8 wt%, approximately 13.9 wt%, approximately 14.0 wt%, approximately 14.1 wt%, approximately 14.2 wt%, approximately 14.3 wt%, approximately 14.4 wt%, approximately 14.5 wt%, approximately 14.6 wt%, approximately 14.7 wt%, approximately 14.8 wt%, approximately 14.9 wt%, approximately 15.0 wt%, approximately 15.1 wt%, approximately 15.2 wt%, approximately 15.3 wt%. Approximately 15.4 wt%, approximately 15.5 wt%, approximately 15.6 wt%, approximately 15.7 wt%, approximately 15.8 wt%, approximately 15.9 wt%, approximately 16.0 wt%, approximately 16.1 wt%, approximately 16.2 wt%, approximately 16.3 wt%, approximately 16.4 wt%, approximately 16.5 wt%, approximately 16.6 wt%, approximately 16.7 wt%, approximately 16.8 wt%, approximately 16.9 wt%, approximately 17.0 wt%, approximately 17.1 wt%, approximately 17.2 wt%, approximately 17.3 wt%, approximately 17.4 wt%, approximately 17.5 wt%, approximately 17.6 wt%, approximately 17.7 wt%, approximately 17.8 wt%, approximately 17.9 wt%, approximately 18.0 wt%, approximately 18.1 wt% t%, approximately 18.2wt%, approximately 18.3wt%, approximately 18.4wt%, approximately 18.5wt%, approximately 18.6wt%, approximately 18.7wt%, approximately 18.8wt%, approximately 18.9wt%, approximately 19.0wt%, approximately 19.1wt%, approximately 19.2wt%, approximately 19.3wt%, approximately 19.4wt%, approximately 19.5wt%, approximately 19.6wt%, approximately 19.7wt%, approximately 19.8wt%, approximately 19.9wt%, approximately 20.0wt%, approximately 20.1wt%, approximately 20.2wt%, approximately 20.3wt%, approximately 20.4wt%, approximately 20.5wt%, approximately 20.6wt%, approximately 20.7wt%, approximately 20.8wt%, approximately 20.9wt%, approximately 21.0wt%, approximately 21.1wt%, approximately 21.2wt%, approximately 21.3wt%, approximately 21.4wt%, approximately 21.5wt%, approximately 21.6wt%, approximately 21.7wt%, approximately 21.8wt%, approximately 21.9wt%, approximately 22.0wt%, approximately 22.1wt%, approximately 22.2wt%, approximately 22.3wt%, approximately 22.4wt%, approximately 22.5wt%, approximately 22.6wt%, approximately 22.7wt%, approximately 22.8wt%, approximately 22.9wt%, approximately 23.0wt%, approximately 23.1wt%, approximately 23.2wt%, approximately 23.3wt%, approximately 23.4wt%, approximately 23.5wt%, approximately 23.6wt%, approximately 23.7wt%, approximately 23.8wt%, approximately 23.9wt%, approximately 24.0wt%, approximately 24.1wt%, approximately 24.2wt%, approximately 24.3wt%, approximately 24.4wt%, approximately 24.5wt%, approximately 24.6wt%, approximately 24.7wt%, approximately 24.8wt%, approximately 24.9wt%, approximately 25.0wt%, approximately 25.1wt%, approximately 25.2wt%, approximately 25.3wt%, approximately 25.4wt%, approximately 25.5wt%, approximately 25.6wt%, approximately 25.7wt%, approximately 25.8wt%, approximately 25.9wt%, approximately 26.0wt%, approximately 26.1wt%, approximately 26.2wt%, approximately 26.3wt%, approximately 26.4wt% Approximately 26.5 wt%, approximately 26.6 wt%, approximately 26.7 wt%, approximately 26.8 wt%, approximately 26.9 wt%, approximately 27.0 wt%, approximately 27.1 wt%, approximately 27.2 wt%, approximately 27.3 wt%, approximately 27.4 wt%, approximately 27.5 wt%, approximately 27.6 wt%, approximately 27.7 wt%, approximately 27.8 wt%, approximately 27.9 wt%, approximately 28.0 wt%, approximately 28.1 wt%, approximately 28.2 wt%, approximately 28.3 wt%, approximately 28.4 wt%, approximately 28.5 wt%, approximately 28.6 wt%, approximately 28.7 wt%, approximately 28.8 wt%, approximately 28.9 wt%, approximately 29.0 wt%, approximately 29.1 wt%, approximately 29.2 wt%. t%, approximately 29.3wt%, approximately 29.4wt%, approximately 29.5wt%, approximately 29.6wt%, approximately 29.7wt%, approximately 29.8wt%, approximately 29.9wt%, approximately 30.0wt%, approximately 30.1wt%, approximately 30.2wt%, approximately 30.3wt%, approximately 30.4wt%, approximately 30.5wt%, approximately 30.6wt%, approximately 30.7wt%, approximately 30.8wt%, approximately 30.9wt%, approximately 31.0wt%, approximately 31.1wt%, approximately 31.2wt%, approximately 31.3wt%, approximately 31.4wt%, approximately 31.5wt%, approximately 31.6wt%, approximately 31.7wt%, approximately 31.8wt%, approximately 31.9wt%, approximately 32.0 wt%, about 32.1 wt%, about 32.2 wt%, about 32.3 wt%, about 32.4 wt%, about 32.5 wt%, about 32.6 wt%, about 32.7 wt%, about 32.8 wt%, about 32.9 wt%, about 33.0 wt%, about 33.1 wt%, about 33.2 wt%, about 33.3 wt%, about 33.4 wt%, about 33.5 wt%, about 33.6 wt%, about 33.7 wt%, about 33.8 wt%, about 33.9 wt%, about 34.0 wt%, about 34.1 wt%, about 34.2 wt%, about 34.3 wt%, about 34.4 wt%, about 34.5 wt%, about 34.6 wt%, about 34.7 wt%, about 34.8 wt%, about 34.9 wt%, about 35.0 wt%. Examples of fillers include lactose monohydrate, anhydrous lactose, modified starch, mannitol, and mixtures thereof. In one embodiment, the filler comprises lactose monohydrate and / or anhydrous lactose.

[0045] surfactants

[0046] In some embodiments, the pharmaceutically acceptable excipient includes a surfactant, and the surfactant comprises about 1.0 wt% to about 5.0 wt% of the total weight of the composition, for example, about 1.5 wt% to about 5.0 wt%, for example, about 2.0 wt% to about 5.0 wt%, for example, about 2.5 wt% to about 5.0 wt%, for example, about 3.0 wt% to about 5.0 wt%, for example, about 3.5 wt% to about 5.0 wt%, for example, about 4.0 wt% to about 5.0 wt%, for example, about 4.5 wt% to about 5.0 wt%, for example, about 1.0 wt% to about 4.5 wt%, for example, about 1.5 wt% to about 4.5 wt%, for example, about 1.5 wt% to about 4.0 wt%, for example, about 1.5 wt% to about 4.0 wt%. %, for example, about 2.0 wt% to about 4.0 wt%, for example, about 2.5 wt% to about 4.0 wt%, for example, about 3.0 wt% to about 4.0 wt%, for example, about 3.5 wt% to about 4.0 wt%, for example, about 1.0 wt% to about 3.5 wt%, for example, about 1.5 wt% to about 3.5 wt%, for example, about 2.0 wt% to about 3.5 wt%, for example, about 2.5 wt% to about 3.5 wt%, for example, about 3.0 wt% to about 3.5 wt%, for example, about 1.0 wt%. From % to 3.0 wt%, for example, from about 1.5 wt% to 3.0 wt%, for example, from about 2.0 wt% to 3.0 wt%, for example, from about 2.5 wt% to 3.0 wt%, for example, from about 1.0 wt% to 2.5 wt%, for example, from about 1.5 wt% to 2.5 wt%, for example, from about 2.0 wt% to 2.5 wt%, for example, from about 1.0 wt% to 2.0 wt%, for example, from about 1.5 wt% to 2.0 wt%, for example, from about 1.0 wt% to 1.5 wt%.

[0047] In some embodiments, the surfactant comprises about 1.0 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2.0 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.51 wt%, about 2.52 wt%, about 2.53 wt%, about 2.54 wt%, about 2.55 wt%, about 2.56 wt%, about 2.57 wt%, about 2.58 wt%, about 2.59 wt%, about 2.6 wt%, about 2.61 wt%, about 2.62 wt%, about 2.63 wt%, about 2.64 wt%, about 2.65 wt%, about 2.66 wt%, and about 2. 67wt%, about 2.68wt%, about 2.69wt%, about 2.7wt%, about 2.71wt%, about 2.72wt%, about 2.73wt%, about 2.74wt%, about 2.75wt%, about 2.76wt%, about 2.77wt%, about 2.78wt%, about 2.79wt%, about 2.8wt%, about 2.9wt%, about 3.0wt%, about 3.1wt%, about 3.2wt%, about 3.3wt%, about 3.4wt%, about 3.5wt%, about 3.6wt%, about 3.7wt%, about 3.8wt%, about 3.9wt%, about 4.0wt%, about 4.1wt%, about 4.2wt%, about 4.3wt%, about 4.4wt%, about 4.5wt%, about 4.6wt%, about 4.7wt%, about 4.8wt%, about 4.9wt%, about 5.0wt%.

[0048] In some embodiments, the surfactant is selected from nonionic surfactants, anionic surfactants, cationic surfactants, and mixtures thereof.

[0049] Examples of anionic surfactants include surfactants having at least one hydrophobic chain containing between 4 and 20 carbon atoms. Exemplary surfactants may contain multiple hydrophobic chains, i.e., at least two separate straight-chain or branched alkyl or alkylaryl moieties (i.e., alkyl chains having aromatic substituents (e.g., benzyl groups)), as shown in the following formula:

[0050] RX - -R'M +

[0051] in:

[0052] X represents any common polar hydrophilic group known in anionic surfactants, such as carboxyl, sulfate, sulfonate, ether sulfate, sulfosuccinate, glutamate, or phosphate.

[0053] R represents a straight-chain or branched alkyl group or an alkylaryl group, each having 4 to 20 carbon atoms, preferably 4 to 16 carbon atoms, more preferably 4 to 12 carbon atoms;

[0054] R' can be a hydrogen atom or R; and

[0055] M + It is a pharmaceutically acceptable cation as defined below.

[0056] In one embodiment, the anionic surfactant is selected from the group consisting of:

[0057] - Possesses the formula R-Ar-SO3 - M + Alkylbenzene sulfonates, wherein R is C4-C 20 Alkyl or alkenyl groups, Ar is a phenyl group, and M + A pharmaceutically acceptable cation, for example selected from the group consisting of: ammonium ions, charged alkanolamine ions (such as cationic triethanolamine), alkali metal ions (such as sodium or potassium ions), and mixtures thereof. Examples of alkylbenzene sulfonates include sodium tridecylbenzene sulfonate, sodium dodecylbenzene sulfonate, and mixtures thereof;

[0058] -with formula R-OSO3 - M + Alkyl sulfates, wherein R and M + Each is as defined above. Examples of alkyl sulfates include ammonium lauryl sulfate, ammonium lauryl ether sulfate, triethylamine lauryl sulfate, triethylamine lauryl ether sulfate, triethanolamine lauryl sulfate, triethanolamine lauryl ether sulfate, monoethanolamine lauryl sulfate, monoethanolamine lauryl ether sulfate, diethanolamine lauryl sulfate, diethanolamine lauryl ether sulfate, sodium monolaurate sulfate, sodium lauryl sulfate, sodium lauryl ether sulfate, potassium lauryl sulfate, potassium lauryl ether sulfate, cocoyl ammonium sulfate, lauroyl ammonium sulfate, sodium cocoyl sulfate, sodium lauroyl sulfate, potassium cocoyl sulfate, potassium lauryl sulfate, triethanolamine lauryl sulfate, triethanolamine lauryl sulfate, monoethanolamine cocoyl sulfate, and monoethanolamine lauryl sulfate.

[0059] - Possesses the formula RO(C2H4O) y SO3 - M + Alkyl ether sulfates, wherein R and M+ Each is defined independently as above, and y is an integer between 1 and 10;

[0060] - Possesses the formula RO-P(=O)(OR')O - M + Alkyl phosphates, wherein R, R' and M + Each is independently defined above. Preferably, the alkyl phosphate is a dialkyl phosphate;

[0061] - Possesses the formula ROC(=O)-C2H4-SO3 - M + Alkyl hydroxyethyl sulfonate, wherein R and M + Each as defined above;

[0062] - Possesses the formula R-(C=O)-NH-(C2H4COOH)-COO - M + Alkyl glutamate, wherein R and M + Each as defined above;

[0063] - Sulfosuccinates, such as dialkyl sulfosuccinates; examples of sulfosuccinates include disodium N-octadecyl sulfosuccinate, disodium lauryl sulfosuccinate, diammonium lauryl sulfosuccinate, tetrasodium N-(1,2-dicarboxyethyl)-N-octadecyl sulfosuccinate, sodium dipentyl sulfosuccinate, sodium dihexyl sulfosuccinate, sodium dioctyl sulfosuccinate, and mixtures thereof.

[0064] In some embodiments, the anionic surfactant is selected from alkyl sulfates, sulfosuccinates, and mixtures thereof. In one embodiment, the anionic surfactant includes sodium lauryl sulfate and / or sodium dioctyl sulfosuccinate (also known as sodium docusate).

[0065] Examples of nonionic surfactants include ethoxylated and / or propoxylated C4-C surfactants containing 5 to 60 EO or PO units. 20 Aliphatic alkyl ethers. The aliphatic group can be petrochemically derived, but is preferably derived from vegetable oils such as coconut oil, palm oil, and rapeseed oil, and includes both saturated and unsaturated alkyl chains. A suitable commercial example of an alkyl ethoxylated ether is under the trade name Genapol. TM Those already known. Other suitable nonionic surfactants are polyethylene glycol sorbitol esters containing 3 to 30 ethoxylated units, for example, under the trade name Tween. TM (From Croda) or Glycosperse TM(From Lonza) Known sorbitan esters of lauric acid, oleic acid, myristic acid, stearic acid, and palmitic acid. Other suitable nonionic surfactants are C8-C64 surfactants with 20-80 ethoxy groups. 20 Ethoxylated polyglycerol esters of fatty acids, for example, produced by BASF under the trade name Cremophor TM Commercially available glycerol-poly(ethylene glycol) oxystearate. Polyglycerol esters are also suitable nonionic surfactants; these esters contain one to ten glycerol units and one or two C4 to C5 cells. 20 Aliphatic alkyl groups. An example can be found under the trade name Polyaldo. TM Obtained from Lonza.

[0066] A further suitable nonionic surfactant is N-alkyl-N-acylglucosamine (also known as glucosamide), wherein the acyl group is derived from C8-C. 20 Fatty acids. Preferably, the fatty acids are derived from plant materials such as coconut oil and palm oil. Examples of these surfactants include lauroyl / myristoyl methyl glucamide, cocoyl methyl glucamide, and capryloyl / hexanoyl methyl glucamide. These commercially available surfactants are available in Glucotain Flex, etc. TM Glucotain Care TM and Glucotain Clear TM Obtained.

[0067] Other suitable nonionic surfactants are C6-C of monosaccharides, disaccharides, or polysaccharides. 20 Ethers or esters. Suitable nonionic surfactants are C8-C. 20 Sucrose esters of fatty acids, such as sucrose esters of lauric acid, oleic acid, palmitic acid, or stearic acid, for example, Ryoto, commercially available from Mitsubishi-Kagaku Foods Corporation. TM Sugar surfactants include Seppic's Oramix. TM Series, Seppic's Sepiclear TM Series (e.g., Sepiclear) TM G7) or Sisterna's Sisterna TM Series (e.g., L70-C). Further suitable nonionic surfactants are (C6-C...). 16 alkyl glucosides, such as Cognis under the name Plantacare TM Those sold, such as Plantacare TMC sold for 1200UP 12 -C 16 Fatty alcohol polysaccharides.

[0068] In some embodiments, the nonionic surfactant is selected from the following: sorbitan esters of lauric acid, oleic acid, myristic acid, stearic acid, or palmitic acid; C8-C 20 Sucrose esters of fatty acids; containing 1 to 10 glycerol units and one or two C4 to C5 groups. 20 Polyglycerol esters with aliphatic alkyl groups; (C6-C 16 ) alkyl glucosides; glucosamides; and mixtures thereof.

[0069] adhesives

[0070] In some embodiments, the pharmaceutically acceptable excipient includes a binder, and the binder constitutes about 1.0 wt% to about 10.0 wt% of the total weight of the composition, for example, 1.5 wt% to about 10.0 wt%, for example, 2.0 wt% to about 10.0 wt%, for example, 2.5 wt% to about 10.0 wt%, for example, 3.0 wt% to about 10.0 wt%, for example, 3.5 wt% to about 10.0 wt%, for example, 4.0 wt% to about 10.0 wt%, for example, 4.5 wt% to about 10.0 wt%, for example, 5.0 wt% to about 10.0 wt%, for example, 5.5 wt% to about 10.0 wt%, for example, 6.0 wt% to about 10.0 wt%, for example, 6.5 wt% to about 10.0 wt%. wt%, for example, 7.0wt% to about 10.0wt%, for example, 7.5wt% to about 10.0wt%, for example, 8.0wt% to about 10.0wt%, for example, 8.5wt% to about 10.0wt%, for example, 9.0wt% to about 10.0wt%, for example, 9.5wt% to about 10.0wt%, for example, about 1.0wt% to about 9.5wt%, for example, 1.5wt% to about 9.5wt%, for example, 2.0wt% to about 9.5wt%, for example, 2.5wt% to about 9.5wt%, for example, 3.0wt% to about 9.5wt%, for example, 3.5wt% to about 9.5wt%, for example, 4.0wt% to about 9.5wt%, for example, 4.5wt% to about 9.5wt%. For example, 5.0 wt% to about 9.5 wt%, for example, 5.5 wt% to about 9.5 wt%, for example, 6.0 wt% to about 9.5 wt%, for example, 6.5 wt% to about 9.5 wt%, for example, 7.0 wt% to about 9.5 wt%, for example, 7.5 wt% to about 9.5 wt%, for example, 8.0 wt% to about 9.5 wt%, for example, 8.5 wt% to about 9.5 wt%, for example, 9.0 wt% to about 9.5 wt%, for example, about 1.0 wt% to about 9.0 wt%, for example, 1.5 wt% to about 9.0 wt%, for example, 2.0 wt% to about 9.0 wt%, for example, 2.5 wt% to about 9.0 wt%, for example, 3.0 wt% to about 9.0 wt%, for example, 3.5 wt% to about 9.0 wt%, for example, 4.0 wt% to about 9.0 wt%, for example, 4.5 wt% to about 9.0 wt%, for example, 5.0 wt% to about 9.0 wt%, for example, 5.5 wt% to about 9.0 wt%, for example, 6.0 wt% to about 9.0 wt%, for example, 6.5 wt% to about 9.0 wt%, for example, 7.0 wt% to about 9.0 wt%, for example, 7.5 wt% to about 9.0 wt%, for example, 8.0 wt% to about 9.0 wt%, for example, 8.5 wt% to about 9.0 wt%, for example, about 1.0 wt% to about 8.5 wt%, for example, 1.5 wt% to about 8.5 wt%, for example, 2.0 wt% to about 8.5 wt%, for example, 2.5 wt% to about 8.5 wt%, for example, 3.0 wt% to about 8.5 wt%, for example, 3.5 wt% to about 8.5 wt%, for example, 4.0 wt% to about 8.5 wt%, for example, 4.5 wt% to about 8.5 wt%, for example, 5.0 wt% to about 8.5 wt%, for example, 5.5 wt% to about 8.5 wt%, for example, 6.0 wt% to about 8.5 wt%, for example, 6.5 wt% to about 8.5 wt%, for example, 7.0 wt% to about 8.5 wt%, for example, 7.5 wt% to about 8.5 wt%, for example, 8.0 wt% to about 8.5 wt%, for example, about 1.0 wt% to about 8.0 wt%, 1.5 wt% to about 8.0 wt%, for example, 2.0 wt% to about 8.0 wt%, for example, 2.5 wt% to about 8.0 wt%. For example, 3.0 wt% to about 8.0 wt%, for example, 3.5 wt% to about 8.0 wt%, for example, 4.0 wt% to about 8.0 wt%, for example, 4.5 wt% to about 8.0 wt%, for example, 5.0 wt% to about 8.0 wt%, for example, 5.5 wt% to about 8.0 wt%, for example, 6.0 wt% to about 8.0 wt%, for example, 6.5 wt% to about 8.0 wt%, for example, 7.0 wt% to about 8.0 wt%, for example, 7.5 wt% to about 8.0 wt%, for example, about 1.0 wt% to about 7.5 wt%, for example, 1.5 wt% to about 7.5 wt%, for example, 2.0 wt% to about 7.5 wt%, for example, 2.5 wt% to about 7.5 wt%, for example, 3.0 wt% to About 7.5 wt%, for example, 3.5 wt% to about 7.5 wt%, for example, 4.0 wt% to about 7.5 wt%, for example, 4.5 wt% to about 7.5 wt%, for example, 5.0 wt% to about 7.5 wt%, for example, 5.5 wt% to about 7.5 wt%, for example, 6.0 wt% to about 7.5 wt%, for example, 6.5 wt% to about 7.5 wt%, for example, 7.0 wt% to about 7.5 wt%, for example, about 1.0 wt% to about 7.0 wt%, for example, 1.5 wt% to about 7.0 wt%, for example, 2.0 wt% to about 7.0 wt%, for example, 2.5 wt% to about 7.0 wt%, for example, 3.0 wt% to about 7.0 wt%, for example, 3.5 wt% to about 7.0 wt%, for example, 4.0 wt% to about 7.0 wt%, for example 4.5 wt% to about 7.0 wt%, for example 5.0 wt% to about 7.0 wt%, for example 5.5 wt% to about 7.0 wt%, for example 6.0 wt% to about 7.0 wt%, for example 6.5 wt% to about 7.0 wt%, for example about 1.0 wt% to about 6.5 wt%, for example 1.5 wt% to about 6.5 wt%, for example 2.0 wt% to about 6.5 wt%, for example 2.5 wt% to about 6.5 wt%, for example 3.0 wt% to about 6.5 wt%, for example 3.5 wt% to about 6.5 wt%, for example 4.0 wt% to about 6.5 wt%, for example 4.5 wt% to about 6.5 wt%, for example 5.0 wt% to about 6.5 wt%.5 wt%, for example, 5.5 wt% to about 6.5 wt%, for example, 6.0 wt% to about 6.5 wt%, for example, about 1.0 wt% to about 6.0 wt%, for example, 1.5 wt% to about 6.0 wt%, for example, 2.0 wt% to about 6.0 wt%, for example, 2.5 wt% to about 6.0 wt%, for example, about 3.0 wt% to about 6.0 wt%, for example, 3.5 wt% to about 6.0 wt%, for example, 4.0 wt% to about 6.0 wt%, for example, 4.5 wt% to about 6.0 wt%, for example, 5.0 wt% to about 6.0 wt%, for example, 5.5 wt% to about 6.0 wt%, for example, about 1.0 wt% to about 5.5 wt%, for example, 1.5 wt% to about 5.5 wt%. For example, 2.0 wt% to about 5.5 wt%, for example, 2.5 wt% to about 5.5 wt%, for example, 3.0 wt% to about 5.5 wt%, for example, 3.5 wt% to about 5.5 wt%, for example, 4.0 wt% to about 5.5 wt%, for example, 4.5 wt% to about 5.5 wt%, for example, 5.0 wt% to about 5.5 wt%, for example, about 1.0 wt% to about 5.0 wt%, for example, 1.5 wt% to about 5.0 wt%, for example, 2.0 wt% to about 5.0 wt%, for example, 2.5 wt% to about 5.0 wt%, for example, about 3.0 wt% to about 5.0 wt%, for example, 3.5 wt% to about 5.0 wt%, for example, 4.0 wt% to about 5.0 wt%, for example, 4. 5 wt% to about 5.0 wt%, for example, about 1.0 wt% to about 4.5 wt%, for example, 1.5 wt% to about 4.5 wt%, for example, 2.0 wt% to about 4.5 wt%, for example, 2.5 wt% to about 4.5 wt%, for example, 3.0 wt% to about 4.5 wt%, for example, 3.5 wt% to about 4.5 wt%, for example, 4.0 wt% to about 4.5 wt%, for example, about 1.0 wt% to about 4.0 wt%, for example, 1.5 wt% to about 4.0 wt%, for example, 2.0 wt% to about 4.0 wt%, for example, 2.5 wt% to about 4.0 wt%, for example, about 3.0 wt% to about 4.0 wt%, for example, 3.5 wt% to about 4.0 wt%, for example, about 1.0 wt%. From % to about 3.5 wt%, for example 1.5 wt% to about 3.5 wt%, for example 2.0 wt% to about 3.5 wt%, for example 2.5 wt% to about 3.5 wt%, for example 3.0 wt% to about 3.5 wt%, for example about 1.0 wt% to about 3.0 wt%, for example 1.5 wt% to about 3.0 wt%, for example 2.0 wt% to about 3.0 wt%, for example 2.5 wt% to about 3.0 wt%, for example about 1.0 wt% to about 2.5 wt%, for example 1.5 wt% to about 2.5 wt%, for example 2.0 wt% to about 2.5 wt%, for example about 1.0 wt% to about 2.0 wt%, for example 1.5 wt% to about 2.0 wt%, for example 1.0 wt% to about 1.5 wt%. In some embodiments, the adhesive comprises about 1.0 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2.0 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3.0 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3 wt% of the total weight of the composition. 0.8 wt%, about 3.9 wt%, about 4.0 wt%, about 4.1 wt%, about 4.11 wt%, about 4.12 wt%, about 4.13 wt%, about 4.14 wt%, about 4.15 wt%, about 4.16 wt%, about 4.17 wt%, about 4.18 wt%, about 4.19 wt%, about 4.2 wt%, about 4.21 wt%, about 4.22 wt%, about 4.23 wt%, about 4.24 wt%, about 4.25 wt%, about 4.26 wt%, about 4.27 wt%, about 4.28 wt%, about 4.29 wt%, about 4.3 wt%, about 4.31 wt%, about 4.32 wt%, about 4.33 wt%, about 4.34 wt%, about 4.3 5 wt%, approximately 4.36 wt%, approximately 4.37 wt%, approximately 4.38 wt%, approximately 4.39 wt%, approximately 4.4 wt%, approximately 4.41 wt%, approximately 4.42 wt%, approximately 4.43 wt%, approximately 4.44 wt%, approximately 4.45 wt%, approximately 4.46 wt%, approximately 4.47 wt%, approximately 4.48 wt%, approximately 4.49 wt%, approximately 4.5 wt%, approximately 4.6 wt%, approximately 4.7 wt%, approximately 4.8 wt%, approximately 4.9 wt%, approximately 5.0 wt%, approximately 5.1 wt%, approximately 5.2 wt%, approximately 5.3 wt%, approximately 5.31 wt%, approximately 5.32 wt%, approximately 5.33 wt%, approximately 5.34 wt%, approximately 5.35 wt%. Approximately 5.36 wt%, approximately 5.37 wt%, approximately 5.38 wt%, approximately 5.39 wt%, approximately 4.4 wt%, approximately 4.41 wt%, approximately 4.42 wt%, approximately 4.43 wt%, approximately 4.44 wt%, approximately 4.45 wt%, approximately 4.46 wt%, approximately 4.47 wt%, approximately 4.48 wt%, approximately 4.49 wt%, approximately 5.4 wt%, approximately 5.5 wt%, approximately 5.6 wt%, approximately 5.7 wt%, approximately 5.8 wt%, approximately 5.9 wt%, approximately 6.0 wt%, approximately 6.1 wt%, approximately 6.2 wt%, approximately 6.3 wt%, approximately 6.4 wt%, approximately 6.5 wt%, approximately 6.6 wt%, approximately 6.7 wt%, approximately 6.8 wt%, approximately 6.9 wt%, about 7.0 wt%, about 7.1 wt%, about 7.2 wt%, about 7.3 wt%, about 7.4 wt%, about 7.5 wt%, about 7.6 wt%, about 7.7 wt%, about 7.8 wt%, about 7.9 wt%, about 8.0 wt%, about 8.1 wt%, about 8.2 wt%, about 8.3 wt%, about 8.4 wt%, about 8.5 wt%, about 8.6 wt%, about 8.7 wt%, about 8.8 wt%, about 8.9 wt%, about 9.0 wt%, about 9.1 wt%, about 9.2 wt%, about 9.3 wt%, about 9.4 wt%, about 9.5 wt%, about 9.6 wt%, about 9.7 wt%, about 9.8 wt%, about 9.9 wt%, about 10.0 wt%. Examples of adhesives include cellulose, modified cellulose (e.g., ethyl cellulose, methyl hydroxyethyl cellulose, and hydroxypropyl methyl cellulose), and microcrystalline cellulose (e.g., Avicel). ® PH101 and Avicel ® PH102), polyvinylpyrrolidone, and mixtures thereof. In one embodiment, the binder is hydroxypropyl methylcellulose.

[0071] lubricant

[0072] In some embodiments, pharmaceutically acceptable excipients include surface lubricants, and the lubricant constitutes about 0.5 wt% to about 5.0 wt% of the total weight of the composition, for example, about 1.0 wt% to about 5.0 wt%, for example, 1.5 wt% to about 5.0 wt%, for example, 2.0 wt% to about 5.0 wt%, for example, 2.5 wt% to about 5.0 wt%. For example, about 3.0 wt% to about 5.0 wt%, for example, 3.5 wt% to about 5.0 wt%, for example, 4.0 wt% to about 5.0 wt%, for example, 4.5 wt% to about 5.0 wt%, for example, about 0.5 wt% to about 4.5 wt%, for example, about 1.0 wt% to about 4.5 wt%, for example, 1.5 wt% to about 4.5 wt%, for example, 2.0 wt% to about 4.5 wt%, for example, 2.5 wt% to about 4.5 wt%, for example, 3.0 wt% to about 4.5 wt%, for example, 3.5 wt% to about 4.5 wt%, for example, 4.0 wt% to about 4.5 wt%, for example, about 0.5 wt% to about 4.0 wt%, for example, about 1.0 wt% to about 4.0 wt%, for example, 1.5 wt% to about 4.0 wt%. For example, 2.0 wt% to about 4.0 wt%, for example, 2.5 wt% to about 4.0 wt%, for example, about 3.0 wt% to about 4.0 wt%, for example, 3.5 wt% to about 4.0 wt%, for example, about 0.5 wt% to about 3.5 wt%, for example, about 1.0 wt% to about 3.5 wt%, for example, 1.5 wt% to about 3.5 wt%, for example, 2.0 wt% to about 3.5 wt%, for example, 2.5 wt% to about 3.5 wt%, for example, 3.0 wt% to about 3.5 wt%, for example, about 0.5 wt% to about 3.0 wt%, for example, about 1.0 wt% to about 3.0 wt%, for example, 1.5 wt% to about 3.0 wt%, for example, 2.0 wt% to about 3.0 wt%, for example, 2.5 wt% to about 3.0 wt%. For example, about 0.5 wt% to about 2.5 wt%, for example, about 1.0 wt% to about 2.5 wt%, for example, 1.5 wt% to about 2.5 wt%, for example, 2.0 wt% to about 2.5 wt%, for example, about 0.5 wt% to about 2.0 wt%, for example, about 1.0 wt% to about 2.0 wt%, for example, 1.5 wt% to about 2.0 wt%, for example, about 0.5 wt% to about 1.5 wt%, for example, 1.0 wt% to about 1.5 wt%, for example, about 0.5 wt% to about 1.0 wt%.In some embodiments, the lubricant comprises about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1.0 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2.0 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, and about 2.6 wt% of the total weight of the composition. t%, about 2.7wt%, about 2.8wt%, about 2.9wt%, about 3.0wt%, about 3.1wt%, about 3.2wt%, about 3.3wt%, about 3.4wt%, about 3.5wt%, about 3.6wt%, about 3.7wt%, about 3.8wt%, about 3.9wt%, about 4.0wt%, about 4.1wt%, about 4.2wt%, about 4.3wt%, about 4.4wt%, about 4.5wt%, about 4.6wt%, about 4.7wt%, about 4.8wt%, about 4.9wt%, about 5.0wt%. Examples of lubricants include talc, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, silica gel, and mixtures thereof. In one embodiment, the lubricant is magnesium stearate.

[0073] disintegrants

[0074] In some embodiments, the pharmaceutically acceptable excipient includes a disintegrant, and the disintegrant comprises about 1.0 wt% to about 8.0 wt% of the total weight of the composition, for example, 1.5 wt% to about 8.0 wt%, for example, 2.0 wt% to about 8.0 wt%, for example, 2.5 wt% to about 8.0 wt%, for example, 3.0 wt% to about 8.0 wt%, for example, 3.5 wt% to about 8.0 wt%, for example, 4.0 wt% to about 8.0 wt%, for example, 4.5 wt% to about 8.0 wt%, for example, 5.0 wt% to about 8.0 wt%, for example, 5.5 wt% to about 8.0 wt%, for example, 6.0 wt% to about 8.0 wt%, for example, 6.5 wt% to about 8.0 wt%, for example, 7.0 wt%. From to about 8.0 wt%, for example, 7.5 wt% to to 8.0 wt%, for example, about 1.0 wt% to to 7.5 wt%, for example, 1.5 wt% to to 7.5 wt%, for example, 2.0 wt% to to 7.5 wt%, for example, 2.5 wt% to to 7.5 wt%, for example, 3.0 wt% to to 7.5 wt%, for example, 3.5 wt% to to 7.5 wt%, for example, 4.0 wt% to to 7.5 wt%, for example, 4.5 wt% to to 7.5 wt%, for example, 5.0 wt% to to 7.5 wt%, for example, 5.5 wt% to to 7.5 wt%, for example, 6.0 wt% to to 7.5 wt%, for example, 6.5 wt% to to 7.5 wt%, for example, 7.0 wt% to to 7.5 wt%, for example, About 1.0 wt% to about 7.0 wt%, for example 1.5 wt% to about 7.0 wt%, for example 2.0 wt% to about 7.0 wt%, for example 2.5 wt% to about 7.0 wt%, for example 3.0 wt% to about 7.0 wt%, for example 3.5 wt% to about 7.0 wt%, for example 4.0 wt% to about 7.0 wt%, for example 4.5 wt% to about 7.0 wt%, for example 5.0 wt% to about 7.0 wt%, for example 5.5 wt% to about 7.0 wt%, for example 6.0 wt% to about 7.0 wt%, for example 6.5 wt% to about 7.0 wt%, for example about 1.0 wt% to about 6.5 wt%, for example 1.5 wt% to about 6.5 wt%, for example 2.0 wt% to about 6. 5 wt%, for example, 2.5 wt% to about 6.5 wt%, for example, 3.0 wt% to about 6.5 wt%, for example, 3.5 wt% to about 6.5 wt%, for example, 4.0 wt% to about 6.5 wt%, for example, 4.5 wt% to about 6.5 wt%, for example, 5.0 wt% to about 6.5 wt%, for example, 5.5 wt% to about 6.5 wt%, for example, 6.0 wt% to about 6.5 wt%, for example, about 1.0 wt% to about 6.0 wt%, for example, 1.5 wt% to about 6.0 wt%, for example, about 2.0 wt% to about 6.0 wt%, for example, 2.5 wt% to about 6.0 wt%, for example, about 3.0 wt% to about 6.0 wt%, for example, 3.5 wt% to about 6.0 wt%, for example, 4.0 wt% to about 6.0 wt%, for example 4.5 wt% to about 6.0 wt%, for example 5.0 wt% to about 6.0 wt%, for example 5.5 wt% to about 6.0 wt%, for example about 1.0 wt% to about 5.5 wt%, for example 1.5 wt% to about 5.5 wt%, for example 2.0 wt% to about 5.5 wt%, for example 2.5 wt% to about 5.5 wt%, for example 3.0 wt% to about 5.5 wt%, for example 3.5 wt% to about 5.5 wt%, for example 4.0 wt% to about 5.5 wt%, for example 4.5 wt% to about 5.5 wt%, for example 5.0 wt% From about 5.5 wt%, for example, about 1.0 wt% to about 5.0 wt%, for example, 1.5 wt% to about 5.0 wt%, for example, 2.0 wt% to about 5.0 wt%, for example, 2.5 wt% to about 5.0 wt%, for example, about 3.0 wt% to about 5.0 wt%, for example, 3.5 wt% to about 5.0 wt%, for example, 4.0 wt% to about 5.0 wt%, for example, 4.5 wt% to about 5.0 wt%, for example, about 1.0 wt% to about 4.5 wt%, for example, 1.5 wt% to about 4.5 wt%, for example, 2.0 wt% to about 4.5 wt%, for example, 2.5 wt% to about 4.5 wt%. 0.5wt%, for example, 3.0wt% to about 4.5wt%, for example, 3.5wt% to about 4.5wt%, for example, 4.0wt% to about 4.5wt%, for example, about 1.0wt% to about 4.0wt%, for example, 1.5wt% to about 4.0wt%, for example, 2.0wt% to about 4.0wt%, for example, 2.5wt% to about 4.0wt%, for example, about 3.0wt% to about 4.0wt%, for example, 3.5wt% to about 4.0wt%, for example, about 1.0wt% to about 3.5wt%, for example, 1.5wt% to about 3.5wt%, for example, 2.0wt% to about 3.5wt%. t%, for example 2.5wt% to about 3.5wt%, for example 3.0wt% to about 3.5wt%, for example about 1.0wt% to about 3.0wt%, for example 1.5wt% to about 3.0wt%, for example 2.0wt% to about 3.0wt%, for example 2.5wt% to about 3.0wt%, for example about 1.0wt% to about 2.5wt%, for example 1.5wt% to about 2.5wt%, for example 2.0wt% to about 2.5wt%, for example about 1.0wt% to about 2.0wt%, for example 1.5wt% to about 2.0wt%, for example 1.0wt% to about 1.5wt%. In some embodiments, the adhesive comprises about 1.0 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, about 2.0 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, and about 2% of the total weight of the composition.7wt%, approximately 2.8wt%, approximately 2.9wt%, approximately 3.0wt%, approximately 3.1wt%, approximately 3.2wt%, approximately 3.3wt%, approximately 3.4wt%, approximately 3.5wt%, approximately 3.6wt%, approximately 3.7wt%, approximately 3.8wt%, approximately 3.9wt%, approximately 4.0wt%, approximately 4.1wt%, approximately 4.11wt%, approximately 4.12wt%, approximately 4.13wt%, approximately 4.14wt%, approximately 4.15wt%, approximately 4.16wt%, approximately 4.17wt%, approximately 4.18wt%, approximately 4.19wt%, approximately 4.2wt%, approximately 4.21wt%, approximately 4.22wt%, approximately 4.23wt% t%, approximately 4.24wt%, approximately 4.25wt%, approximately 4.26wt%, approximately 4.27wt%, approximately 4.28wt%, approximately 4.29wt%, approximately 4.3wt%, approximately 4.31wt%, approximately 4.32wt%, approximately 4.33wt%, approximately 4.34wt%, approximately 4.35wt%, approximately 4.36wt%, approximately 4.37wt%, approximately 4.38wt%, approximately 4.39wt%, approximately 4.4wt%, approximately 4.41wt%, approximately 4.42wt%, approximately 4.43wt%, approximately 4.44wt%, approximately 4.45wt%, approximately 4.46wt%, approximately 4.47wt%, approximately 4.48wt%, approximately 4.49 wt%, approximately 4.5wt%, approximately 4.6wt%, approximately 4.7wt%, approximately 4.8wt%, approximately 4.9wt%, approximately 5.0wt%, approximately 5.1wt%, approximately 5.2wt%, approximately 5.3wt%, approximately 5.31wt%, approximately 5.32wt%, approximately 5.33wt%, approximately 5.34wt%, approximately 5.35wt%, approximately 5.36wt%, approximately 5.37wt%, approximately 5.38wt%, approximately 5.39wt%, approximately 4.4wt%, approximately 4.41wt%, approximately 4.42wt%, approximately 4.43wt%, approximately 4.44wt%, approximately 4.45wt%, approximately 4.46wt%, approximately 4.47wt%, approximately 4. 48wt%, approximately 4.49wt%, approximately 5.4wt%, approximately 5.5wt%, approximately 5.6wt%, approximately 5.7wt%, approximately 5.8wt%, approximately 5.9wt%, approximately 6.0wt%, approximately 6.1wt%, approximately 6.2wt%, approximately 6.3wt%, approximately 6.4wt%, approximately 6.5wt%, approximately 6.6wt%, approximately 6.7wt%, approximately 6.8wt%, approximately 6.9wt%, approximately 7.0wt%, approximately 7.1wt%, approximately 7.2wt%, approximately 7.3wt%, approximately 7.4wt%, approximately 7.5wt%, approximately 7.6wt%, approximately 7.7wt%, approximately 7.8wt%, approximately 7.9wt%, approximately 8.0wt%.

[0075] Examples of disintegrants include starch, modified starch, croscarmellose sodium, croscarmellose, sodium glycolate starch, and mixtures thereof. In some embodiments, the disintegrant is sodium glycolate starch.

[0076] Flow aid

[0077] In some embodiments, the pharmaceutically acceptable excipient includes a gliding agent, and the gliding agent constitutes about 0.1 wt% to about 5.0 wt% of the total weight of the composition, for example, about 0.2 wt% to about 5.0 wt%, for example, about 0.3 wt% to about 5.0 wt%, for example, about 0.4 wt% to about 5.0 wt%, for example, about 0.5 wt% to about 5.0 wt%, for example, about 0.6 wt% to about 5.0 wt%, for example, about 0.7 wt% to about 5.0 wt%, for example, about 0.8 wt% to about 5.0 wt%, for example, about 0.9 wt% to about 5.0 wt%, for example, about 1.0 wt% to about 5.0 wt%, for example, about 1.5 wt% to about 5.0 wt%, for example, about 2.0 wt% to about 5.0 wt%. wt%, for example, about 2.5wt% to about 5.0wt%, for example, about 3.0wt% to about 5.0wt%, for example, about 3.5wt% to about 5.0wt%, for example, about 4.0wt% to about 5.0wt%, for example, about 4.5wt% to about 5.0wt%, for example, about 0.1wt% to about 4.5wt%, for example, about 0.2wt% to about 4.5wt%, for example, about 0.3wt% to about 4.5wt%, for example, about 0.4wt% to about 4.5wt%, for example, about 0.5wt% to about 4.5wt%, for example, about 0.6wt% to about 4.5wt%, for example, about 0.7wt% to about 4.5wt%, for example, about 0.8wt% to about 4.5wt%, for example, about 0.9wt% to about 4.5 wt%, for example, about 1.0 wt% to about 4.5 wt%, for example, about 1.5 wt% to about 4.5 wt%, for example, about 2.0 wt% to about 4.5 wt%, for example, about 2.5 wt% to about 4.5 wt%, for example, about 3.0 wt% to about 4.5 wt%, for example, about 3.5 wt% to about 4.5 wt%, for example, about 4.0 wt% to about 4.5 wt%, for example, about 0.1 wt% to about 4.0 wt%, for example, about 0.2 wt% to about 4.0 wt%, for example, about 0.3 wt% to about 4.0 wt%, for example, about 0.4 wt% to about 4.0 wt%, for example, about 0.5 wt% to about 4.0 wt%, for example, about 0.6 wt% to about 4.0 wt%, for example, about 0.7 wt%. From % to 4.0 wt%, for example, from about 0.8 wt% to 4.0 wt%, for example, from about 0.9 wt% to 4.0 wt%, for example, from about 1.0 wt% to 4.0 wt%, for example, from about 1.5 wt% to 4.0 wt%, for example, from about 2.0 wt% to 4.0 wt%, for example, from about 2.5 wt% to 4.0 wt%, for example, from about 3.0 wt% to 4.0 wt%, for example, from about 3.5 wt% to 4.0 wt%, for example, from about 0.1 wt% to 3.5 wt%, for example, from about 0.2 wt% to 3.5 wt%, for example, from about 0.3 wt% to 3.5 wt%, for example, from about 0.4 wt% to 3.5 wt%, for example, from about 0.5 wt% to 3.5 wt%, for example, from about 0.6 wt% to about 3.5 wt%, for example, about 0.7 wt% to about 3.5 wt%, for example, about 0.8 wt% to about 3.5 wt%, for example, about 0.9 wt% to about 3.5 wt%, for example, about 1.0 wt% to about 3.5 wt%, for example, about 1.5 wt% to about 3.5 wt%, for example, about 2.0 wt% to about 3.5 wt%, for example, about 2.5 wt% to about 3.5 wt%, for example, about 3.0 wt% to about 3.5 wt%, for example, about 0.1 wt% to about 3.0 wt%, for example, about 0.2 wt% to about 3.0 wt%, for example, about 0.3 wt% to about 3.0 wt%, for example, about 0.4 wt% to about 3.0 wt%, for example, about 0.5 wt% to about 3.0 wt%, for example, From about 0.6 wt% to about 3.0 wt%, for example, from about 0.7 wt% to about 3.0 wt%, for example, from about 0.8 wt% to about 3.0 wt%, for example, from about 0.9 wt% to about 3.0 wt%, for example, from about 1.0 wt% to about 3.0 wt%, for example, from about 1.5 wt% to about 3.0 wt%, for example, from about 2.0 wt% to about 3.0 wt%, for example, from about 2.5 wt% to about 3.0 wt%, for example, from about 0.1 wt% to about 2.5 wt%, for example, from about 0.2 wt% to about 2.5 wt%, for example, from about 0.3 wt% to about 2.5 wt%, for example, from about 0.4 wt% to about 2.5 wt%, for example, from about 0.5 wt% to about 2.5 wt%, for example, from about 0.6 wt% to about 2.5 wt%. For example, about 0.7 wt% to about 2.5 wt%, for example, about 0.8 wt% to about 2.5 wt%, for example, about 0.9 wt% to about 2.5 wt%, for example, about 1.0 wt% to about 2.5 wt%, for example, about 1.5 wt% to about 2.5 wt%, for example, about 2.0 wt% to about 2.5 wt%, for example, about 0.1 wt% to about 2.0 wt%, for example, about 0.2 wt% to about 2.0 wt%, for example, about 0.3 wt% to about 2.0 wt%, for example, about 0.4 wt% to about 2.0 wt%, for example, about 0.5 wt% to about 2.0 wt%, for example, about 0.6 wt% to about 2.0 wt%, for example, about 0.7 wt% to about 2.0 wt%, for example, about 0.8 wt% to about 2.0 wt%. t%, for example about 0.9wt% to about 2.0wt%, for example about 1.0wt% to about 2.0wt%, for example about 1.5wt% to about 2.0wt%, for example about 0.1wt% to about 1.5wt%, for example about 0.2wt% to about 1.5wt%, for example about 0.3wt% to about 1.5wt%, for example about 0.4wt% to about 1.5wt%, for example about 0.5wt% to about 1.5wt%, for example about 0.6wt% to about 1.5wt%, for example about 0.7wt% to about 1.5wt%, for example about 0.8wt% to about 1.5wt%, for example about 0.9wt% to about 1.5wt%, for example about 1.0wt% to about 1.5wt%, for example about 0.1wt% to about 1.0 wt%, for example about 0.2 wt% to about 1.0 wt%, for example about 0.3 wt% to about 1.0 wt%, for example about 0.4 wt% to about 1.0 wt%, for example about 0.5 wt% to about 1.0 wt%, for example about 0.6 wt% to about 1.0 wt%, for example about 0.7 wt% to about 1.0 wt%, for example about 0.8 wt% to about 1.0 wt%, for example about 0.9 wt% to about 1.0 wt%, for example about 0.1 wt% to about 0.5 wt%, for example about 0.2 wt% to about 0.5 wt%, for example about 0.3 wt% to about 0.5 wt%, for example about 0.4 wt% to about 0.5 wt%. In some embodiments, the gliding agent comprises about 0.1 wt%, about 0.11 wt%, about 0.12 wt%, about 0.13 wt%, about 0.14 wt%, about 0.15 wt%, about 0.16 wt%, about 0.17 wt%, about 0.18 wt%, about 0.19 wt%, about 0.2 wt%, about 0.21 wt%, about 0.22 wt%, about 0.23 wt%, about 0.24 wt%, about 0.25 wt%, about 0.26 wt%, about 0.27 wt%, about 0.28 wt%, or about 0. 29wt%, about 0.3wt%, about 0.31wt%, about 0.32wt%, about 0.33wt%, about 0.34wt%, about 0.35wt%, about 0.36wt%, about 0.37wt%, about 0.38wt%, about 0.39wt%, about 0.4wt%, about 0.41wt%, about 0.42wt%, about 0.43wt%, about 0.44wt%, about 0.45wt%, about 0.46wt%, about 0.47wt%, about 0.48wt%, about 0.49wt%, about 0.5wt%, about 0 0.51wt%, approximately 0.52wt%, approximately 0.53wt%, approximately 0.54wt%, approximately 0.55wt%, approximately 0.56wt%, approximately 0.57wt%, approximately 0.58wt%, approximately 0.59wt%, approximately 0.6wt%, approximately 0.61wt%, approximately 0.62wt%, approximately 0.63wt%, approximately 0.64wt%, approximately 0.65wt%, approximately 0.66wt%, approximately 0.67wt%, approximately 0.68wt%, approximately 0.69wt%, approximately 0.7wt%, approximately 0.8wt%, approximately 0.9wt%, approximately 1.0wt%, about 1.1wt%, about 1.2wt%, about 1.3wt%, about 1.4wt%, about 1.5wt%, about 1.6wt%, about 1.7wt%, about 1.8wt%, about 1.9wt%, about 2.0wt%, about 2.1wt%, about 2.2wt%, about 2.3wt%, about 2.4wt%, about 2.5wt%, about 2.6wt%, about 2.7wt%, about 2.8wt%, about 2.9wt%, about 3.0wt%, about 3.1wt%, about 3.2wt%, about 3.3wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4.0 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, about 5.0 wt%. Examples of flow aids include ascorbate palmitate, calcium palmitate, fumed silica (colloidal silica), and mixtures thereof. In some embodiments, the flow aid is colloidal silica.

[0078] Other excipients

[0079] The pharmaceutical composition may optionally further comprise one or more additional excipients, such as colorants, flavoring agents, preservatives, and / or sweeteners. Examples of sweeteners include any natural or artificial sweeteners, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame potassium. Examples of flavoring agents include Magnasweet. ® Examples of preservatives include potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of benzoic acid (such as butylparaben), alcohols (such as ethanol or benzyl alcohol), phenolic compounds (such as phenol), or quaternary ammonium compounds (such as benzalkonium chloride).

[0080] In some embodiments, the pharmaceutical composition comprises, based on the total weight of the composition:

[0081] 55.0 wt% to 75.0 wt% of Lanilandro; and

[0082] Pharmaceutically acceptable excipients, ranging from 25.0 wt% to 45.0 wt%.

[0083] In some embodiments, the pharmaceutical composition comprises, based on the total weight of the composition:

[0084] 55.0 wt% to 75.0 wt% of Lanilandro; and

[0085] 25.0 wt% to 45.0 wt% of pharmaceutically acceptable excipients, wherein, among the pharmaceutically acceptable excipients, surfactants account for about 1.0 wt% to about 5.0 wt% of the total weight of the composition.

[0086] In some embodiments, the pharmaceutical composition comprises, based on the total weight of the composition:

[0087] 55.0 wt% to 75.0 wt% of Lanilandro; and

[0088] 25.0 wt% to 45.0 wt% of pharmaceutically acceptable excipients, wherein, among the pharmaceutically acceptable excipients, surfactants account for about 1.0 wt% to about 3.0 wt% of the total weight of the composition.

[0089] In some embodiments, the pharmaceutical composition comprises, based on the total weight of the composition:

[0090] 55.0 wt% to 75.0 wt% of Lanilandro; and

[0091] 10.0 wt% to 35.0 wt% of filler, advantageously, 15.0 wt% to 35.0 wt% of filler; advantageously, 20.0 wt% to 35.0 wt% of filler;

[0092] 1.0 wt% to 5.0 wt% of surfactant, advantageously, 1.0 wt% to 3.0 wt% of surfactant;

[0093] 1.0 wt% to 10.0 wt% of adhesive, advantageously, 2.0 wt% to 8.0 wt% of adhesive, advantageously, 3.0 wt% to 6.0 wt% of adhesive;

[0094] 0.5 wt% to 5.0 wt% of lubricant, advantageously, 0.5 wt% to 3.0 wt% of lubricant;

[0095] 1.0 wt% to 8.0 wt% of disintegrant, advantageously 2.0 wt% to 6.0 wt% of disintegrant;

[0096] Advantageously, 0.1 wt% to 5.0 wt% of a flow aid, and 0.1 wt% to 2.0 wt% of a flow aid, and

[0097] Optionally, one or more additional excipients as defined above,

[0098] The total of all the above components is 100 wt%.

[0099] In some embodiments, the pharmaceutical composition consists essentially of the following components based on the total weight of the composition:

[0100] 55.0 wt% to 75.0 wt% of Lanilandro; and

[0101] Pharmaceutically acceptable excipients, ranging from 25.0 wt% to 45.0 wt%.

[0102] In some embodiments, the pharmaceutical composition consists essentially of the following components based on the total weight of the composition:

[0103] 55.0 wt% to 75.0 wt% of Lanilandro; and

[0104] 25.0 wt% to 45.0 wt% of pharmaceutically acceptable excipients, wherein, among the pharmaceutically acceptable excipients, surfactants account for about 1.0 wt% to about 5.0 wt% of the total weight of the composition.

[0105] In some embodiments, the pharmaceutical composition consists essentially of the following components based on the total weight of the composition:

[0106] 55.0 wt% to 75.0 wt% of Lanilandro; and

[0107] 25.0 wt% to 45.0 wt% of pharmaceutically acceptable excipients, wherein, among the pharmaceutically acceptable excipients, surfactants account for about 1.0 wt% to about 3.0 wt% of the total weight of the composition.

[0108] In some embodiments, the pharmaceutical composition consists essentially of the following components based on the total weight of the composition:

[0109] 55.0 wt% to 75.0 wt% of Lanilandro; and

[0110] 10.0 wt% to 35.0 wt% of filler, advantageously, 15.0 wt% to 35.0 wt% of filler; advantageously, 20.0 wt% to 35.0 wt% of filler;

[0111] 1.0 wt% to 5.0 wt% of surfactant, advantageously, 1.0 wt% to 3.0 wt% of surfactant;

[0112] 1.0 wt% to 10.0 wt% of adhesive, advantageously, 2.0 wt% to 8.0 wt% of adhesive, advantageously, 3.0 wt% to 6.0 wt% of adhesive;

[0113] Lubricant of 0.5 wt% to 5.0 wt%, advantageously, lubricant of 0.5 wt% to 3.0 wt%;

[0114] 1.0 wt% to 8.0 wt% of disintegrant, advantageously 2.0 wt% to 6.0 wt% of disintegrant;

[0115] Advantageously, 0.1 wt% to 5.0 wt% of a flow aid, and 0.1 wt% to 2.0 wt% of a flow aid, and

[0116] Optionally, one or more additional excipients as defined above.

[0117] In some embodiments, the pharmaceutical composition consists essentially of the following components based on the total weight of the composition:

[0118] 55.0 wt% to 75.0 wt% of Lanilandro; and

[0119] Pharmaceutically acceptable excipients, ranging from 25.0 wt% to 45.0 wt%.

[0120] In some embodiments, the pharmaceutical composition consists essentially of the following components based on the total weight of the composition:

[0121] 55.0 wt% to 75.0 wt% of Lanilandro; and

[0122] 25.0 wt% to 45.0 wt% of pharmaceutically acceptable excipients, wherein, among the pharmaceutically acceptable excipients, surfactants account for about 1.0 wt% to about 5.0 wt% of the total weight of the composition.

[0123] In some embodiments, the pharmaceutical composition consists essentially of the following components based on the total weight of the composition:

[0124] 55.0 wt% to 75.0 wt% of Lanilandro; and

[0125] 25.0 wt% to 45.0 wt% of pharmaceutically acceptable excipients, wherein, among the pharmaceutically acceptable excipients, surfactants account for about 1.0 wt% to about 3.0 wt% of the total weight of the composition.

[0126] In some embodiments, the pharmaceutical composition consists essentially of the following components based on the total weight of the composition:

[0127] 55.0 wt% to 75.0 wt% of Lanilandro; and

[0128] 10.0 wt% to 35.0 wt% of filler, advantageously, 15.0 wt% to 35.0 wt% of filler; advantageously, 20.0 wt% to 35.0 wt% of filler;

[0129] 1.0 wt% to 5.0 wt% of surfactant, advantageously, 1.0 wt% to 3.0 wt% of surfactant;

[0130] 1.0 wt% to 10.0 wt% of adhesive, advantageously, 2.0 wt% to 8.0 wt% of adhesive, advantageously, 3.0 wt% to 6.0 wt% of adhesive;

[0131] Lubricant of 0.5 wt% to 5.0 wt%, advantageously, lubricant of 0.5 wt% to 3.0 wt%;

[0132] 1.0 wt% to 8.0 wt% of disintegrant, advantageously 2.0 wt% to 6.0 wt% of disintegrant;

[0133] Advantageously, 0.1 wt% to 5.0 wt% of a flow aid, and 0.1 wt% to 2.0 wt% of a flow aid, and

[0134] Optionally, one or more additional excipients as defined above.

[0135] In some embodiments, the pharmaceutical composition is in a solid dosage form. Exemplary solid dosage forms include tablets, capsules, strips, sachets, lozenges, powders, pills, or granules. Preferred solid dosage forms include tablets, capsules, and strips, with tablets being particularly preferred.

[0136] In some embodiments, the pharmaceutical composition comprises 200 mg to 1200 mg of lanilanol. Exemplary pharmaceutical compositions comprise 200 mg, 400 mg, 600 mg, 800 mg, 1000 mg, or 1200 mg of lanilanol.

[0137] In any of the above embodiments, lanilanol may be present in the pharmaceutical composition in crystalline form.

[0138] Dissolution characteristics

[0139] When the pharmaceutical composition of the present invention is in the form of a solid dosage form, the dosage form has a rapid dissolution characteristic. Specifically, the solid pharmaceutical composition of the present invention has the following dissolution characteristics: at least 30% and at most 60% of the composition dissolves within 15 minutes; and at least 80%, advantageously at least 85%, of the composition dissolves within 45 minutes.

[0140] Preferably, dissolution is measured in a discriminative medium. Such a dissolution medium will produce two very different dissolution profiles for two products with very different dissolution characteristics in gastric fluid; that is, the dissolution medium can predict the dissolution of the composition in vivo. An exemplary dissolution medium is an aqueous medium containing about 0.7% to about 1.7% cetrimide. Specifically, dissolution is measured using a USP test apparatus 1 (basket 10 mesh) at a constant temperature of 37°C ± 0.5°C at 100 rpm in 1000 mL of a sodium phosphate buffer solution containing about 0.7% to about 1.7% cetrimide at pH 6.8. Those skilled in the art will be able to determine the appropriate cetrimide concentration by applying sink conditions (i.e., the ability of the dissolution medium to dissolve at least three times the amount of the drug present in the dosage form).

[0141] In some embodiments, as determined by USP testing apparatus 1 (basket 10 mesh) at a constant temperature of 37°C ± 0.5°C at 100 rpm in 1000 mL of sodium phosphate buffer containing about 0.7% to about 1.7% bromobrown trimethylammonium at pH 6.8, the pharmaceutical compositions of the present invention have the following dissolution characteristics:

[0142] - After oral ingestion, 30% to 60% is released within 15 minutes.

[0143] - After oral ingestion, at least 80% is released within 45 minutes, advantageously, at least 85% is released.

[0144] Due to its rapid dissolution characteristics, the pharmaceutical compositions of the present invention are stable, immediate-release pharmaceutical compositions. As used herein, the term "immediate-release" refers to any type of release that causes the active ingredient (lanilanol) to be released from the pharmaceutical composition of the present invention in vitro over a short period of time (i.e., less than one hour). Preferably, more than 85% of the lanilanol is released within 45 minutes after oral ingestion.

[0145] Advantageously, the pharmaceutical composition of the present invention releases about 30% to 60% of lanilanol within 15 minutes after oral ingestion.

[0146] Advantageously, the pharmaceutical composition of the present invention releases at least 80%, preferably at least 85%, of lanilanol within 45 minutes after oral ingestion.

[0147] In some embodiments, based on the total weight of the composition, the immediate-release pharmaceutical composition comprises, is substantially composed of, or consists of: 55.0 wt% to 75.0 wt% of lanilanol and 25.0 wt% to 45.0 wt% of pharmaceutically acceptable excipients, wherein the immediate-release pharmaceutical composition has lanilanol dissolution characteristics that meet the following constraints:

[0148] - After oral ingestion, 30% to 60% is released within 15 minutes.

[0149] - After oral ingestion, at least 80% is released within 45 minutes, advantageously, at least 85% is released.

[0150] In some embodiments, based on the total weight of the composition, the immediate-release pharmaceutical composition comprises, is substantially composed of, or consists of: 55.0 wt% to 75.0 wt% of lanilanol and 25.0 wt% to 45.0 wt% of pharmaceutically acceptable excipients; wherein the lanilanol has a particle size distribution such that D50 ≤ 30 μm and D90 ≤ 50 μm, preferably D50 ≤ 10 μm and D90 ≤ 30 μm.

[0151] In some embodiments, based on the total weight of the composition, the immediate-release pharmaceutical composition comprises, is substantially composed of, or consists of: 55.0 wt% to 75.0 wt% of lanilanol and 25.0 wt% to 45.0 wt% of pharmaceutically acceptable excipients, wherein, among the pharmaceutically acceptable excipients, the surfactant comprises about 1.0 wt% to about 5.0 wt%, advantageously about 1.0 wt% to about 3.0 wt% of the total weight of the immediate-release pharmaceutical composition.

[0152] In some embodiments, based on the total weight of the composition, the immediate-release pharmaceutical composition comprises, is substantially composed of, or consists of the following:

[0153] 55.0 wt% to 75.0 wt% of Lanilandro

[0154] 10.0 wt% to 35.0 wt% of filler, advantageously, 15.0 wt% to 35.0 wt% of filler, advantageously, 20.0 wt% to 35.0 wt% of filler;

[0155] 1.0 wt% to 5.0 wt% of surfactant, advantageously, 1.0 wt% to 3.0 wt% of surfactant;

[0156] 1.0 wt% to 10.0 wt% of adhesive, advantageously, 2.0 wt% to 8.0 wt% of adhesive, advantageously, 3.0 wt% to 6.0 wt% of adhesive;

[0157] Lubricant of 0.5 wt% to 5.0 wt%, advantageously, lubricant of 0.5 wt% to 3.0 wt%;

[0158] 1.0 wt% to 8.0 wt% of disintegrant, advantageously 2.0 wt% to 6.0 wt% of disintegrant;

[0159] Advantageously, 0.1 wt% to 5.0 wt% of a flow aid, and 0.1 wt% to 2.0 wt% of a flow aid, and

[0160] Optionally, one or more additional excipients as defined above.

[0161] In some embodiments, based on the total weight of the composition, the immediate-release pharmaceutical composition comprises, is substantially composed of, or consists of: 55.0 wt% to 75.0 wt% of lanyllanol and 25.0 wt% to 45.0 wt% of pharmaceutically acceptable excipients, wherein:

[0162] -The immediate-release pharmaceutical composition has a lanilano dissolution characteristic that meets the following constraints:

[0163] ○ After oral ingestion, 30% to 60% is released within 15 minutes.

[0164] ○ After oral ingestion, at least 80% is released within 45 minutes, advantageously, at least 85% is released, and

[0165] -Lanilano has a particle size distribution such that D50≤30 μm and D90≤50 μm, preferably D50≤10 μm and D90≤30 μm.

[0166] In some embodiments, based on the total weight of the composition, the immediate-release pharmaceutical composition comprises, is substantially composed of, or consists of: 55.0 wt% to 75.0 wt% of lanyllanol and 25.0 wt% to 45.0 wt% of pharmaceutically acceptable excipients, wherein:

[0167] - In pharmaceutically acceptable excipients, the surfactant comprises about 1.0 wt% to 5.0 wt% of the total weight of the immediate-release pharmaceutical composition, advantageously about 1.0 wt% to 3.0 wt%, and

[0168] -The immediate-release pharmaceutical composition has a lanilano dissolution characteristic that meets the following constraints:

[0169] ○ After oral ingestion, approximately 30% to 60% is released within 15 minutes.

[0170] ○ After oral ingestion, at least 80% is released within 45 minutes, advantageously, at least 85% is released.

[0171] In some embodiments, based on the total weight of the composition, the immediate-release pharmaceutical composition comprises, is substantially composed of, or consists of: 55.0 wt% to 75.0 wt% of lanyllanol and 25.0 wt% to 45.0 wt% of pharmaceutically acceptable excipients, wherein:

[0172] - In pharmaceutically acceptable excipients, the surfactant comprises about 1.0 wt% to 5.0 wt% of the total weight of the immediate-release pharmaceutical composition, advantageously about 1.0 wt% to 3.0 wt%, and

[0173] -The immediate-release pharmaceutical composition has a lanilano dissolution characteristic that meets the following constraints:

[0174] ○ After oral ingestion, 30% to 60% is released within 15 minutes.

[0175] ○ After oral ingestion, at least 80% is released within 45 minutes, advantageously, at least 85% is released, and

[0176] -Lanilano has a particle size distribution such that D50≤30 μm and D90≤50 μm, preferably D50≤10 μm and D90≤30 μm.

[0177] In some embodiments, based on the total weight of the composition, the immediate-release pharmaceutical composition comprises, is substantially composed of, or consists of the following:

[0178] 55.0 wt% to 75.0 wt% of Lanilandro

[0179] 10.0 wt% to 35.0 wt% of filler; advantageously, 15.0 wt% to 35.0 wt% of filler; advantageously, 20.0 wt% to 35.0 wt% of filler;

[0180] 1.0 wt% to 5.0 wt% of surfactant, advantageously, 1.0 wt% to 3.0 wt% of surfactant;

[0181] 1.0 wt% to 10.0 wt% of adhesive, advantageously, 2.0 wt% to 8.0 wt% of adhesive, advantageously, 3.0 wt% to 6.0 wt% of adhesive;

[0182] Lubricant of 0.5 wt% to 5.0 wt%, advantageously, lubricant of 0.5 wt% to 3.0 wt%;

[0183] 1.0 wt% to 8.0 wt% of disintegrant, advantageously 2.0 wt% to 6.0 wt% of disintegrant;

[0184] 0.1 wt% to 5.0 wt% of a flow aid, advantageously 0.1 wt% to 2.0 wt% of a flow aid, and optionally, one or more additional excipients as defined above, wherein:

[0185] Immediate-release pharmaceutical compositions have lanilanol dissolution characteristics that meet the following constraints:

[0186] - After oral ingestion, 30% to 60% is released within 15 minutes.

[0187] - After oral ingestion, at least 80% is released within 45 minutes, advantageously, at least 85% is released.

[0188] In some embodiments, based on the total weight of the composition, the immediate-release pharmaceutical composition comprises, is substantially composed of, or consists of the following:

[0189] 55.0 wt% to 75.0 wt% of Lanilandro

[0190] 10.0 wt% to 35.0 wt% of filler; advantageously, 15.0 wt% to 35.0 wt% of filler; advantageously, 20.0 wt% to 35.0 wt% of filler;

[0191] 1.0 wt% to 5.0 wt% of surfactant, advantageously, 1.0 wt% to 3.0 wt% of surfactant;

[0192] 1.0 wt% to 10.0 wt% of adhesive, advantageously, 2.0 wt% to 8.0 wt% of adhesive, advantageously, 3.0 wt% to 6.0 wt% of adhesive;

[0193] Lubricant of 0.5 wt% to 5.0 wt%, advantageously, lubricant of 0.5 wt% to 3.0 wt%;

[0194] 1.0 wt% to 8.0 wt% of disintegrant, advantageously 2.0 wt% to 6.0 wt% of disintegrant;

[0195] 0.1 wt% to 5.0 wt% of a flow aid, advantageously 0.1 wt% to 2.0 wt% of a flow aid, and optionally, one or more additional excipients as defined above, wherein:

[0196] -The immediate-release pharmaceutical composition has a lanilano dissolution characteristic that meets the following constraints:

[0197] ○ After oral ingestion, 30% to 60% is released within 15 minutes.

[0198] ○ After oral ingestion, at least 80% is released within 45 minutes, advantageously, at least 85% is released, and

[0199] -Lanilano has a particle size distribution such that D50≤30 μm and D90≤50 μm, preferably D50≤10 μm and D90≤30 μm.

[0200] In some embodiments, the immediate-release pharmaceutical composition described above is in a solid dosage form. Advantageously, solid dosage forms include tablets, capsules, strips, sachets, lozenges, powders, pills, or granules. Preferred solid dosage forms include tablets, capsules, and strips, with tablets being particularly preferred.

[0201] In some embodiments, the immediate-release pharmaceutical composition described above comprises 200 mg to 1200 mg of lanilanol. Advantageously, the pharmaceutical composition comprises 200 mg, 400 mg, 600 mg, 800 mg, 1000 mg, or 1200 mg of lanilanol.

[0202] In some embodiments, the immediate-release pharmaceutical composition described above is for oral administration.

[0203] In another aspect of the invention, an immediate-release tablet is disclosed, which, based on the total weight of the tablet, comprises, is substantially composed of, or is composed of: 55.0 wt% to 75.0 wt% of lanyllanol and 25.0 wt% to 45.0 wt% of pharmaceutically acceptable excipients.

[0204] In some embodiments, based on the total weight of the tablets, the immediate-release tablets comprise, are substantially composed of, or consist of: 55.0 wt% to 75.0 wt% of lanilanol and 25.0 wt% to 45.0 wt% of pharmaceutically acceptable excipients, wherein: the immediate-release tablets have lanilanol dissolution characteristics that meet the following constraints:

[0205] - After oral ingestion, 30% to 60% is released within 15 minutes.

[0206] - After oral ingestion, at least 80% is released within 45 minutes, advantageously, at least 85% is released.

[0207] In some embodiments, based on the total weight of the tablets, the immediate-release tablets comprise, consist substantially of, or consist of: 55.0 wt% to 75.0 wt% of lanilanol and 25.0 wt% to 45.0 wt% of pharmaceutically acceptable excipients, wherein: the lanilanol has a particle size distribution such that D50 ≤ 30 μm and D90 ≤ 50 μm, preferably D50 ≤ 10 μm and D90 ≤ 30 μm.

[0208] In some embodiments, based on the total weight of the tablets, the immediate-release tablets comprise, are substantially composed of, or consist of: 55.0 wt% to 75.0 wt% of lanyllanol and 25.0 wt% to 45.0 wt% of pharmaceutically acceptable excipients, wherein:

[0209] - Immediate-release tablets have a lanilano dissolution characteristic that meets the following constraints:

[0210] ○ After oral ingestion, 30% to 60% is released within 15 minutes.

[0211] ○ After oral ingestion, at least 80% is released within 45 minutes, advantageously, at least 85% is released, and

[0212] -Lanilano has a particle size distribution such that D50≤30 μm and D90≤50 μm, preferably D50≤10 μm and D90≤30 μm.

[0213] In some embodiments, based on the total weight of the tablets, the immediate-release tablets comprise, consist substantially of, or consist of: 55.0 wt% to 75.0 wt% of lanilano and 25.0 wt% to 45.0 wt% of pharmaceutically acceptable excipients, wherein among the pharmaceutically acceptable excipients, surfactants comprise 1.0 wt% to 5.0 wt%, advantageously 1.0 wt% to 3.0 wt% of the total weight of the immediate-release tablets.

[0214] In some embodiments, based on the total weight of the tablets, the immediate-release tablets comprise, are substantially composed of, or consist of the following:

[0215] 55.0 wt% to 75.0 wt% of Lanilandro

[0216] 10.0 wt% to 35.0 wt% of filler; advantageously, 15.0 wt% to 35.0 wt% of filler; advantageously, 20.0 wt% to 35.0 wt% of filler;

[0217] 1.0 wt% to 5.0 wt% of surfactant, advantageously, 1.0 wt% to 3.0 wt% of surfactant;

[0218] 1.0 wt% to 10.0 wt% of adhesive, advantageously, 2.0 wt% to 8.0 wt% of adhesive, advantageously, 3.0 wt% to 6.0 wt% of adhesive;

[0219] 0.5 wt% to 5.0 wt% of lubricant, advantageously, 0.5 wt% to 3.0 wt% of lubricant;

[0220] 1.0 wt% to 8.0 wt% of disintegrant, advantageously 2.0 wt% to 6.0 wt% of disintegrant;

[0221] 0.1 wt% to 5.0 wt% of a flow aid, advantageously 0.1 wt% to 2.0 wt% of a flow aid, and optionally, one or more additional excipients as defined above.

[0222] In some embodiments, based on the total weight of the tablets, the immediate-release tablets comprise, are substantially composed of, or consist of: 55.0 wt% to 75.0 wt% of lanyllanol and 25.0 wt% to 45.0 wt% of pharmaceutically acceptable excipients, wherein:

[0223] - In pharmaceutically acceptable excipients, the surfactant comprises 1.0 wt% to 5.0 wt% of the total weight of the immediate-release tablet, advantageously 1.0 wt% to 3.0 wt%, and

[0224] - Immediate-release tablets have a lanilano dissolution characteristic that meets the following constraints:

[0225] ○ After oral ingestion, 30% to 60% is released within 15 minutes.

[0226] ○ After oral ingestion, at least 80% is released within 45 minutes, advantageously, at least 85% is released.

[0227] In some embodiments, based on the total weight of the tablets, the immediate-release tablets comprise, are substantially composed of, or consist of: 55.0 wt% to 75.0 wt% of lanyllanol and 25.0 wt% to 45.0 wt% of pharmaceutically acceptable excipients, wherein:

[0228] - In pharmaceutically acceptable excipients, the surfactant comprises 1.0 wt% to 5.0 wt% of the total weight of the immediate-release tablets, advantageously 1.0 wt% to 3.0 wt%, and

[0229] - Immediate-release tablets have a lanilano dissolution characteristic that meets the following constraints:

[0230] ○ After oral ingestion, 30% to 60% is released within 15 minutes.

[0231] ○ After oral ingestion, at least 80% is released within 45 minutes, advantageously, at least 85% is released, and

[0232] -Lanilano has a particle size distribution such that D50≤30 μm and D90≤50 μm, preferably D50≤10 μm and D90≤30 μm.

[0233] In some embodiments, based on the total weight of the tablets, the immediate-release tablets comprise, are substantially composed of, or consist of the following:

[0234] 55.0 wt% to 75.0 wt% of Lanilandro

[0235] 10.0 wt% to 35.0 wt% of filler; advantageously, 15.0 wt% to 35.0 wt% of filler; advantageously, 20.0 wt% to 35.0 wt% of filler;

[0236] 1.0 wt% to 5.0 wt% of surfactant, advantageously, 1.0 wt% to 3.0 wt% of surfactant;

[0237] 1.0 wt% to 10.0 wt% of adhesive, advantageously, 2.0 wt% to 8.0 wt% of adhesive, advantageously, 3.0 wt% to 6.0 wt% of adhesive;

[0238] 0.5 wt% to 5.0 wt% of lubricant, advantageously, 0.5 wt% to 3.0 wt% of lubricant;

[0239] 1.0 wt% to 8.0 wt% of disintegrant, advantageously 2.0 wt% to 6.0 wt% of disintegrant;

[0240] 0.1 wt% to 5.0 wt% of a flow aid, advantageously 0.1 wt% to 2.0 wt% of a flow aid, and optionally, one or more additional excipients as defined above, wherein:

[0241] Immediate-release tablets have lanilano dissolution characteristics that meet the following constraints:

[0242] - After oral ingestion, 30% to 60% is released within 15 minutes.

[0243] - After oral ingestion, at least 80% is released within 45 minutes, advantageously, at least 85% is released.

[0244] In some embodiments, based on the total weight of the tablets, the immediate-release tablets comprise, are substantially composed of, or consist of the following:

[0245] Approximately 55.0 wt% to 75.0 wt% of Lanilandro

[0246] About 10.0 wt% to 35.0 wt% of filler; advantageously, 15.0 wt% to 35.0 wt% of filler; advantageously, 20.0 wt% to 35.0 wt% of filler;

[0247] About 1.0 wt% to 5.0 wt% of surfactant, advantageously, 1.0 wt% to 3.0 wt% of surfactant;

[0248] About 1.0 wt% to 10.0 wt% of adhesive, advantageously, 2.0 wt% to 8.0 wt% of adhesive, advantageously, 3.0 wt% to 6.0 wt% of adhesive;

[0249] About 0.5 wt% to 5.0 wt% of lubricant, advantageously, 0.5 wt% to 3.0 wt% of lubricant;

[0250] About 1.0 wt% to 8.0 wt% of disintegrant, advantageously 2.0 wt% to 6.0 wt% of disintegrant;

[0251] About 0.1 wt% to 5.0 wt% of a flow aid, advantageously 0.1 wt% to 2.0 wt% of a flow aid, and optionally, one or more additional excipients as defined above.

[0252] in:

[0253] - Immediate-release tablets have a lanilano dissolution characteristic that meets the following constraints:

[0254] ○ After oral ingestion, approximately 30% to 60% is released within 15 minutes.

[0255] ○ After oral ingestion, at least 80% is released within 45 minutes, advantageously, at least 85% is released, and

[0256] -Lanilano has a particle size distribution such that D50≤30 μm and D90≤50 μm, preferably D50≤10 μm and D90≤30 μm.

[0257] In some embodiments, the immediate-release tablets described above contain 200 mg to 1200 mg of lanyllanthol. Advantageously, the immediate-release tablets contain 200 mg, 400 mg, 600 mg, 800 mg, 1000 mg, or 1200 mg of lanyllanthol.

[0258] In some embodiments, the immediate-release tablets described above are for oral administration.

[0259] Method using the Lanilano composition

[0260] The pharmaceutical compositions, immediate-release pharmaceutical compositions, and immediate-release tablets of the present invention, as described above, are used to treat fibrotic diseases, such as non-alcoholic fatty liver disease (NAFLD), including non-alcoholic fatty liver and non-alcoholic steatohepatitis (NASH). The pharmaceutical compositions, immediate-release pharmaceutical compositions, and immediate-release tablets of the present invention, as described above, are also used to treat subjects with cirrhosis at risk of progressing from compensated to decompensated stages. The pharmaceutical compositions, immediate-release pharmaceutical compositions, and immediate-release tablets of the present invention, as described above, are also used to treat diseases selected from: cirrhosis, liver fibrosis, hepatic steatosis, fatty liver disease, acute decompensation, acute-on-chronic liver failure (ACLF), acute liver failure (ALF), decompensated cirrhosis, compensated cirrhosis, metabolic-associated fatty liver disease (MAFLD), metabolic-associated steatohepatitis (MASH), diabetes, and cirrhosis.

[0261] Therefore, in one respect, this disclosure relates to pharmaceutical compositions, immediate-release pharmaceutical compositions, or immediate-release tablets as defined above for use in methods of treating NAFLD (including non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH)). This disclosure also relates to pharmaceutical compositions, immediate-release pharmaceutical compositions, or immediate-release tablets as defined above for use in methods of treating subjects with cirrhosis at risk of progressing from compensated to decompensated stages. This disclosure further relates to pharmaceutical compositions, immediate-release pharmaceutical compositions, or immediate-release tablets as defined above for use in methods of treating diseases selected from: cirrhosis, liver fibrosis, hepatic steatosis, fatty liver disease, acute decompensation, acute-on-chronic liver failure (ACLF), acute liver failure (ALF), decompensated cirrhosis, compensated cirrhosis, metabolic-associated fatty liver disease (MAFLD), metabolic-associated steatohepatitis (MASH), diabetes, and cirrhosis.

[0262] On one hand, this disclosure relates to a method for treating non-alcoholic fatty liver disease (NAFLD), the method comprising administering to a subject in need a pharmaceutical composition, immediate-release pharmaceutical composition, or immediate-release tablet as defined above. This disclosure also relates to a method for treating a subject with cirrhosis at risk of progressing from compensated to decompensated liver disease, the method comprising administering to the subject a pharmaceutical composition, immediate-release pharmaceutical composition, or immediate-release tablet as defined above.

[0263] This disclosure also relates to methods for treating diseases selected from the following: cirrhosis, liver fibrosis, hepatic steatosis, fatty liver disease, acute decompensation, acute-on-chronic liver failure (ACLF), acute liver failure (ALF), decompensated cirrhosis, compensated cirrhosis, metabolic-associated fatty liver disease (MAFLD), metabolic-associated steatohepatitis (MASH), diabetes, or cirrhosis, wherein the methods include administering to a subject in need a pharmaceutical composition, immediate-release pharmaceutical composition, or immediate-release tablet as defined above.

[0264] As used herein, the term "subject" refers to an animal, preferably a mammal, including humans or non-humans. For example, a subject is a person or animal susceptible to or suffering from fibrotic diseases. Advantageously, the subject is a human. A patient can be a child (a human patient under the age of 18) or an adult (a human patient over the age of 18). In some embodiments, the subject is a non-human animal, including but not limited to: dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, bears, dairy cows, apes, monkeys, orangutans, and chimpanzees. The terms patient and subject are used interchangeably.

[0265] In some implementations, patients are given a daily dose of 400 mg to 1200 mg of lanyllanol, such as 400 mg, 600 mg, 800 mg, 1000 mg, or 1200 mg.

[0266] Method for preparing lanilanol composition

[0267] It should be understood that although the following mentions processes suitable for preparing tablets, other solid dosage forms can be prepared using suitable techniques known to those skilled in the art. Exemplary pharmaceutical compositions comprise, as excipients, the following: binders, disintegrants, fillers, flow aids, lubricants, and surfactants, said pharmaceutical compositions can be prepared by a process comprising:

[0268] a) Provide Lanilandro with a particle size distribution such that D50 ≤ 30 μm and D90 ≤ 50 μm;

[0269] b) Provide a granulation solution consisting of an aqueous solution of a surfactant;

[0270] c) Prepare a mixture of lanilanol, filler, disintegrant and binder;

[0271] d) Spray the granulation solution (obtained in step b) onto the resulting mixture to obtain granules (wet granulation);

[0272] e) Prepare a mixture of filler and flow aid, and then add another portion of filler and disintegrant to the mixture;

[0273] f) Mix the particles obtained in step d) with the mixture obtained in step e) and the lubricant, and then mix the resulting mixture;

[0274] g) Process the mixture obtained in step f) into the desired dosage form.

[0275] In some embodiments, the aqueous solution of the surfactant used in step c) comprises about 80.0 wt% to about 90.0 wt% (purified) water. In some embodiments, the surfactant comprises about 10.0 wt% to about 20.0 wt% of the aqueous solution, and said surfactant is a mixture of sodium lauryl sulfate (SLS) and sodium dioctyl sulfosuccinate (DOSS) in a weight ratio (SLS / DOSS) of about 2.5 to about 5.0.

[0276] In some implementations, the adhesive is added last during the mixing process in step c).

[0277] The wet granulation in step d) is carried out by methods known in the art, such as in a high-shear mixer. In some embodiments, the granulation time is from about 10 s to about 30 min, for example from about 30 s to about 15 min.

[0278] In some embodiments, the same filler is used twice in step e). In some embodiments, different fillers are used in step e). In the latter embodiment, at least one of the fillers used is the same as the filler used in step c).

[0279] In some embodiments, the desired dosage form is a tablet, and the above method may further include a step of coating the tablet with a film.

[0280] The invention will be illustrated by the following non-limiting embodiments.

[0281] Example

[0282] In the following embodiments, crystalline lanilanol was provided, characterized by XRPD, DSC, and TGA as described in Example 5. It was micronized prior to processing such that its particle size distribution was characterized by D50 ≤ 10 μm and D90 ≤ 30 μm.

[0283] XRPD

[0284] Powder X-ray diffraction analysis was performed using a Panalytical Empyrean S3 diffractometer equipped with a Cu radiation source (Cu wavelength = 1.5406 Å). Analysis was conducted in transmission mode (samples were placed in Kapton). ® Between the polypropylene foil and the polypropylene foil, the angle range is 2θ = 2°-50°, the step size is 0.026°, and the time for each step is 20.4 s.

[0285] DSC

[0286] DSC analysis was performed on a Mettler Toledo DSC3+ calorimeter. A few milligrams of sample in a 40 μL sealed aluminum dish (perforated before analysis) were analyzed under nitrogen purging at 50 mL / min. The temperature range from 20 °C to 300 °C was scanned at a rate of 10 °C / min.

[0287] TGA

[0288] TGA analysis was performed on a Mettler Toledo TGA / DSC3+ thermogravimetric analyzer. A few milligrams of sample in a 100 μL sealed aluminum disk (perforated before analysis) were analyzed under nitrogen purging at 50 mL / min. The temperature range from 25 °C to 300 °C was scanned at a rate of 10 °C / min.

[0289] Example 1: Wettability Test

[0290] Mixtures and granulation solutions (GS) are prepared by combining the materials listed in Table 1.

[0291] Table 1

[0292]

[0293] Spread samples of each mixture onto a flat surface and press gently to make the powder bed almost flat. Using a dropper, gently drop a drop of GS1 or GS2 onto the powder bed. If the drop remains on the powder, the mixture has poor wettability; if the drop spreads across the surface and penetrates the powder, the mixture has good wettability. The results are shown in Table 2.

[0294] Table 2

[0295]

[0296] These observations confirm that lanilano is hydrophobic, as it exhibits poor wetting properties when wetted with water alone (GS1). When the granulation solution contains a surfactant, lanilano is wetted regardless of the presence of lactose.

[0297] Example 2: Lanilanol formulation

[0298] The purpose of this embodiment is to prepare lanilanol tablets using the general method described above, by combining the materials listed in Table 3, i.e., by preparing tablets using a spray granulation step. During tablet manufacturing, careful adherence to the required weight percentages of lanilanol and excipients is maintained, i.e., 55wt%-75wt% lanilanol and 25wt%-45wt% excipients.

[0299] Table 3

[0300]

[0301] Example 3: Stability Study

[0302] Laniello tablets of 600 mg each were prepared using the materials listed in Table 3 and the general methods described above, resulting in a laniello content of 57 wt% in the tablets. These tablets were then packaged in HDPE bottles with PP caps and silicone sleeves, and stability studies were conducted. The results are shown in Table 4.

[0303] Table 4

[0304]

[0305] mo=month

[0306] x = No changes were observed in the appearance, content determination, impurity distribution, disintegration time, anti-fragmentation properties, loss on drying, and dissolution of the drug product.

[0307] m = Microbial contamination (<100 CFU / g)

[0308] As can be seen from the table above, no OOT (Out-of-Trend) or OOS (Out-of-Specification) was observed after 6 months of storage. Specifically, after 6 months of storage at 25°C / 60% RH, 30°C / 70% RH, and 40°C / 75% RH in HDPE bottles sealed with desiccant, no significant changes were observed in the appearance, content determination, impurity distribution, disintegration time, brittleness resistance, loss on drying, and dissolution rate of the drug product.

[0309] As can be seen from the table above, no OOT (Out of Trend) or OOS (Out of Specification) was observed after 24 months of storage. Specifically, after 24 months at 25°C / 60% RH and 30°C / 70% RH, no significant changes were observed in the appearance, content determination, impurity distribution, disintegration time, brittleness resistance, loss on drying, and dissolution of the drug products.

[0310] Example 4: Dissolution Characteristics

[0311] The dissolution characteristics of 600 mg of lanyllanol (for stability studies) were measured using USP test apparatus 1 (basket type, 10 mesh) at a constant temperature of 37℃ ± 0.5℃ and at 100 rpm in 1000 mL of sodium phosphate buffer containing 1.7% tetradecyltrimethylammonium bromide at pH 6.8. The results are shown in Table 5.

[0312] Table 5

[0313]

[0314] * The average of 6 measurements

[0315] Example 5: Dissolution Characteristics

[0316] 400 mg lanilanol tablets were prepared using the materials listed in Table 3 and the general method described above, resulting in a lanilanol content of 57 wt%. The dissolution characteristics of these tablets were measured using a USP test apparatus 1 (basket 10 mesh) at a constant temperature of 37 °C ± 0.5 °C at 100 rpm in 1000 mL of sodium phosphate buffer containing 1.7% tetradecyltrimethylammonium bromide at pH 6.8. The results are shown in Table 6.

[0317] Table 6

[0318]

[0319] * The average of 6 measurements

[0320] Example 6: Crystallography

[0321] The active pharmaceutical ingredient (API) lanilanol present in the 600 mg tablets of Example 3 was analyzed by XRPD. It was found that its characteristics were identical to those of the initial API before tableting. Specifically, the lanilanol analyzed from the tablets is as follows:

[0322] - XRPD spectra including the peaks shown in Table 7 (2θ positions may vary, typically up to ±0.2°, and relative peak intensities may vary between devices).

[0323] Table 7

[0324]

[0325]

[0326] Example 7: Preparation of large-scale coated tablets

[0327] a) Prepare a granulation solution in 6750.0 g of water using 1125.0 g of sodium lauryl sulfate and 300.0 g of sodium docusate. Stir until completely dissolved.

[0328] b) Prepare a mixture of lanilano (30000.0 g), lactose monohydrate (12150 g), sodium glycolate starch (1500.0 g), and hydroxypropyl methylcellulose (2250.0 g) separately by mixing.

[0329] c) Spray the granulation solution onto the mixture obtained in step b) and dry the resulting granules.

[0330] d) Then prepare a mixture of spray-dried lactose monohydrate (3650.0 g), sodium glycolate starch (700.0 g), and colloidal silica (240 g).

[0331] e) The particles obtained in step c), the mixture obtained in step d), and magnesium stearate (500.0 g) are mixed together to form the final mixture.

[0332] f) The mixture obtained in step e) is processed into tablets using a tablet press equipped with a metal check.

[0333] g) Finally, use Opadry TM The tablets obtained in step f) are coated.

[0334] Example 8: Effect of surfactants on granulation and tableting performance

[0335] As described in Table 8, the pharmaceutical compositions according to the present invention were prepared and tested.

[0336] Table 8

[0337]

[0338] For each pharmaceutical composition in Table 8, sodium lauryl sulfate and sodium docusate were mixed with water and stirred until completely dissolved to obtain a granulation solution. A mixture of lanyllanol, lactose monohydrate, sodium glycolate starch, and hydroxypropyl methylcellulose was prepared separately by mixing. A granulation step was performed by spraying the granulation solution onto the mixture. This step resulted in granule formation, which was then dried. A mixture of lactose monohydrate, sodium glycolate starch, and colloidal silica was then prepared. The granules, mixture, and magnesium stearate were combined to obtain a final mixture. The final mixture was prepared into tablets using a tableting machine equipped with a metal detector and tableted with Opadry. TM Coating is performed.

[0339] The observations during tablet preparation are reported in Table 9.

[0340] Table 9

[0341]

[0342] These observations confirm that variations in the amount of surfactant affect the granulation process and tableting. In fact, even when granules are formed, a non-negligible amount of lanilanol remains on the granulator walls when the total surfactant content is less than 1.0%. Furthermore, tablets cannot be obtained when the surfactant content is below 1.0 wt%. Therefore, the amount of surfactant plays a crucial role in the success of granulation and tableting.

[0343] ***

[0344] Various aspects of this disclosure will be further illustrated by the non-limiting embodiments mentioned below.

[0345] 1. A pharmaceutical composition, comprising, based on the total weight of the composition:

[0346] 55.0 wt% to 75.0 wt% of Lanilandro; and

[0347] 25.0 wt% to 45.0 wt% pharmaceutically acceptable excipients;

[0348] Among them, the lanilano has a particle size distribution such that D50≤30 μm and D90≤50 μm, preferably D50≤10 μm and D90≤30 μm.

[0349] 2. The pharmaceutical composition according to paragraph 1, wherein the pharmaceutical composition releases 30% to 60% of the lanilanol within 15 minutes after oral ingestion.

[0350] 3. The pharmaceutical composition according to any one of paragraphs 1 to 2, wherein the pharmaceutical composition releases at least 80% of the lanilanol within 45 minutes after oral ingestion.

[0351] 4. The pharmaceutical composition according to any of the preceding paragraphs, wherein the pharmaceutically acceptable excipients include two or more of the following: binders, colorants, disintegrants, fillers, flow aids, lubricants, preservatives, surfactants, and sweeteners.

[0352] 5. The pharmaceutical composition according to any of the preceding paragraphs, wherein the pharmaceutically acceptable excipient comprises a filler, and the filler comprises 10.0 wt% to 35.0 wt% of the total weight of the composition.

[0353] 6. The pharmaceutical composition according to paragraph 5, wherein the filler is selected from the following: lactose monohydrate, anhydrous lactose, starch, modified starch, mannitol, and mixtures thereof.

[0354] 7. The pharmaceutical composition according to any of the preceding paragraphs, wherein the pharmaceutically acceptable excipient comprises a surfactant, and the surfactant comprises 1.0 wt% to 5.0 wt% of the total weight of the composition.

[0355] 8. The pharmaceutical composition according to paragraph 7, wherein the surfactant is selected from nonionic surfactants, anionic surfactants, cationic surfactants, and mixtures thereof.

[0356] 9. The pharmaceutical composition according to any of the preceding paragraphs, wherein the pharmaceutically acceptable excipient comprises a binder, and the binder comprises 1.0 wt% to 10.0 wt% of the total weight of the composition.

[0357] 10. The pharmaceutical composition according to paragraph 9, wherein the binder is selected from cellulose, modified cellulose, microcrystalline cellulose, polyvinylpyrrolidone, and mixtures thereof.

[0358] 11. The pharmaceutical composition according to any of the preceding paragraphs, wherein the pharmaceutically acceptable excipient comprises a lubricant, and the lubricant comprises 0.5 wt% to 5.0 wt% of the total weight of the composition.

[0359] 12. The pharmaceutical composition according to paragraph 11, wherein the lubricant is selected from the following: talc, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, silica gel, and mixtures thereof.

[0360] 13. The pharmaceutical composition according to any of the preceding paragraphs, wherein the pharmaceutically acceptable excipient comprises a disintegrant, and the disintegrant accounts for 1.0 wt% to 8.0 wt% of the total weight of the composition.

[0361] 14. The pharmaceutical composition according to paragraph 13, wherein the disintegrant is selected from the following: starch, modified starch, croscarmellose sodium, croscarmellose, sodium glycolate starch, and mixtures thereof.

[0362] 15. The pharmaceutical composition according to any of the preceding paragraphs, wherein the pharmaceutically acceptable excipient comprises a gliding agent, and the gliding agent comprises 0.1 wt% to 5.0 wt% of the total weight of the composition.

[0363] 16. The pharmaceutical composition according to any of the preceding paragraphs, wherein the pharmaceutical composition is in solid dosage form.

[0364] 17. The pharmaceutical composition according to paragraph 16, wherein the pharmaceutical composition is in tablet, capsule or strip packaging, preferably tablet.

[0365] 18. The pharmaceutical composition according to paragraph 16 or 17, wherein the pharmaceutical composition comprises 200 mg to 1200 mg of lanyllanol.

[0366] 19. The pharmaceutical composition according to any of the preceding paragraphs, wherein the lanilanol is in crystalline form.

[0367] 20. A pharmaceutical composition as defined in any one of paragraphs 1 through 19 for use in a method of treating non-alcoholic fatty liver disease (NAFLD).

[0368] 21. The pharmaceutical composition for the stated use as described in paragraph 20, wherein NAFLD includes non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH).

[0369] 22. A pharmaceutical composition as defined in any one of paragraphs 1 through 19 for use in a method of treating a subject with cirrhosis at risk of progressing from compensated to decompensated liver disease.

[0370] 23. A pharmaceutical composition as defined in any one of paragraphs 1 through 19 for the treatment of the following conditions: cirrhosis, liver fibrosis, hepatic steatosis, fatty liver disease, acute decompensation, acute-on-chronic liver failure (ACLF), acute liver failure (ALF), decompensated cirrhosis, compensated cirrhosis, metabolic-associated fatty liver disease (MAFLD), metabolic-associated steatohepatitis (MASH), diabetes, or cirrhosis.

[0371] 24. A method for treating non-alcoholic fatty liver disease (NAFLD), the method comprising administering to a subject in need a pharmaceutical composition as defined in any one of paragraphs 1 to 19.

[0372] 25. The method according to paragraph 24, wherein NAFLD includes non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH).

[0373] 26. A method for treating a subject with cirrhosis at risk of progressing from compensated to decompensated liver, the method comprising administering to the subject a pharmaceutical composition as defined in any one of paragraphs 1 through 19.

[0374] 27. A method of treating a disease selected from the group consisting of: cirrhosis, liver fibrosis, hepatic steatosis, fatty liver disease, acute decompensation, acute-on-chronic liver failure (ACLF), acute liver failure (ALF), decompensated cirrhosis, compensated cirrhosis, metabolic-associated fatty liver disease (MAFLD), metabolic-associated steatohepatitis (MASH), diabetes, or cirrhosis, said method comprising administering to a subject in need a pharmaceutical composition as defined in any one of paragraphs 1 to 19.

[0375] 28. The method according to any one of paragraphs 24 to 27, wherein the subject is given a daily dose of 400 mg to 1200 mg of lanyllanol.

[0376] 29. A pharmaceutical composition as defined in any one of paragraphs 1 to 3, comprising, based on the total weight of the composition:

[0377] 55.0 wt% to 75.0 wt% of Lanilandro; and

[0378] 25.0 wt% to 45.0 wt% pharmaceutically acceptable excipients;

[0379] Among them, lanilano has a particle size distribution such that D50 ≤ 30 μm and D90 ≤ 50 μm, preferably D50 ≤ 10 μm and D90 ≤ 30 μm, and

[0380] Among the pharmaceutically acceptable excipients, the surfactant accounts for 1.0 wt% to 5.0 wt% of the total weight of the composition.

[0381] 30. A stable immediate-release pharmaceutical composition, wherein, based on the total weight of the composition, the pharmaceutical composition comprises:

[0382] 55.0 wt% to 75.0 wt% of Lanilandro; and

[0383] 25.0 wt% to 45.0 wt% pharmaceutically acceptable excipients;

[0384] Among them, the lanilano has a particle size distribution such that D50≤30 μm and D90≤50 μm, preferably D50≤10 μm and D90≤30 μm.

[0385] 31. The stable immediate-release pharmaceutical composition according to paragraph 30, wherein the pharmaceutical composition releases 30% to 60% of the lanilanol within 15 minutes after oral ingestion.

[0386] 32. A stable immediate-release pharmaceutical composition according to any one of paragraphs 30 to 31, wherein the pharmaceutical composition releases at least 80% of the lanilanol within 45 minutes after oral ingestion.

[0387] 33. A stable immediate-release pharmaceutical composition according to any one of paragraphs 30 to 32, wherein the pharmaceutically acceptable excipients include two or more of binders, colorants, disintegrants, fillers, flow aids, lubricants, preservatives, surfactants, and sweeteners.

[0388] 34. A stable immediate-release pharmaceutical composition according to any one of paragraphs 30 to 33, wherein the pharmaceutically acceptable excipient comprises a filler, and the filler comprises 10.0 wt% to 35.0 wt% of the total weight of the composition.

[0389] 35. The stable immediate-release pharmaceutical composition according to paragraph 34, wherein the filler is selected from the following: lactose monohydrate, anhydrous lactose, starch, modified starch, mannitol, and mixtures thereof.

[0390] 36. A stable immediate-release pharmaceutical composition according to any one of paragraphs 30 to 35, wherein the pharmaceutically acceptable excipient comprises a surfactant, and the surfactant comprises 1.0 wt% to 5.0 wt% of the total weight of the composition.

[0391] 37. The stable immediate-release pharmaceutical composition according to paragraph 36, wherein the surfactant is selected from nonionic surfactants, anionic surfactants, cationic surfactants, and mixtures thereof.

[0392] 38. A stable immediate-release pharmaceutical composition according to any one of paragraphs 30 to 37, wherein the pharmaceutically acceptable excipient comprises a binder, and the binder comprises 1.0 wt% to 10.0 wt% of the total weight of the composition.

[0393] 39. The stable immediate-release pharmaceutical composition according to paragraph 38, wherein the binder is selected from cellulose, modified cellulose, microcrystalline cellulose, polyvinylpyrrolidone, and mixtures thereof.

[0394] 40. A stable immediate-release pharmaceutical composition according to any one of paragraphs 30 to 39, wherein the pharmaceutically acceptable excipient comprises a lubricant, and the lubricant comprises 0.5 wt% to 5.0 wt% of the total weight of the composition.

[0395] 41. The stable immediate-release pharmaceutical composition according to paragraph 40, wherein the lubricant is selected from the following: talc, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, silica gel, and mixtures thereof.

[0396] 42. The stable immediate-release pharmaceutical composition according to any one of paragraphs 30 to 41, wherein the pharmaceutically acceptable excipient comprises a disintegrant, and the disintegrant accounts for 1.0 wt% to 8.0 wt% of the total weight of the composition.

[0397] 43. The stable immediate-release pharmaceutical composition according to paragraph 42, wherein the disintegrant is selected from the following: starch, modified starch, croscarmellose sodium, croscarmellose, sodium glycolate starch, and mixtures thereof.

[0398] 44. A stable immediate-release pharmaceutical composition according to any one of paragraphs 30 to 33, wherein the pharmaceutically acceptable excipient comprises a flow aid and the flow aid comprises 0.1 wt% to 5.0 wt% of the total weight of the composition.

[0399] 45. A stable immediate-release pharmaceutical composition according to any one of paragraphs 30 to 44, wherein the pharmaceutical composition is in solid dosage form.

[0400] 46. ​​The stable immediate-release pharmaceutical composition according to paragraph 45, wherein the pharmaceutical composition is in tablet, capsule or strip packaging, preferably tablet.

[0401] 47. A stable, immediate-release pharmaceutical composition according to paragraph 45 or 46, wherein the pharmaceutical composition comprises 200 mg to 1200 mg of lanyllanol.

[0402] 48. A stable immediate-release pharmaceutical composition according to any one of paragraphs 30 to 47, wherein lanilanol is in crystalline form.

[0403] 49. A stable immediate-release tablet, based on the total weight of the composition, said tablet comprises:

[0404] 55.0 wt% to 75.0 wt% of Lanilandro; and

[0405] 25.0 wt% to 45.0 wt% pharmaceutically acceptable excipients;

[0406] Among them, the lanilano has a particle size distribution such that D50≤30 μm and D90≤50 μm, preferably D50≤10 μm and D90≤30 μm.

[0407] 50. The stable immediate-release tablet according to paragraph 49, wherein the tablet releases 30% to 60% of the lanilanol within 15 minutes after oral ingestion.

[0408] 51. A stable immediate-release tablet according to any one of paragraphs 49 to 50, wherein the tablet releases at least 80% of the lanilanol within 45 minutes after oral ingestion.

[0409] 52. A stable immediate-release tablet as described in any one of paragraphs 49 to 51, wherein the pharmaceutically acceptable excipients include two or more of binders, colorants, disintegrants, fillers, flow aids, lubricants, preservatives, surfactants, and sweeteners.

[0410] 53. The stable immediate-release tablet according to any one of paragraphs 49 to 52, wherein the pharmaceutically acceptable excipient comprises a filler, and the filler comprises 10.0 wt% to 35.0 wt% of the total weight of the composition.

[0411] 54. The stable immediate-release tablet according to paragraph 53, wherein the filler is selected from the following: lactose monohydrate, anhydrous lactose, starch, modified starch, mannitol, and mixtures thereof.

[0412] 55. The stable immediate-release tablet according to any one of paragraphs 49 to 54, wherein the pharmaceutically acceptable excipient comprises a surfactant, and the surfactant comprises 1.0 wt% to 5.0 wt% of the total weight of the composition.

[0413] 56. The stable immediate-release tablet according to paragraph 55, wherein the surfactant is selected from nonionic surfactants, anionic surfactants, cationic surfactants, and mixtures thereof.

[0414] 57. The stable immediate-release tablet according to any one of paragraphs 49 to 56, wherein the pharmaceutically acceptable excipient comprises a binder, and the binder comprises 1.0 wt% to 10.0 wt% of the total weight of the composition.

[0415] 58. The stable immediate-release tablet according to paragraph 57, wherein the binder is selected from cellulose, modified cellulose, microcrystalline cellulose, polyvinylpyrrolidone, and mixtures thereof.

[0416] 59. The stable immediate-release tablet according to any one of paragraphs 49 to 58, wherein the pharmaceutically acceptable excipient comprises a lubricant, and the lubricant comprises 0.5 wt% to 5.0 wt% of the total weight of the composition.

[0417] 60. The stable immediate-release tablet according to paragraph 59, wherein the lubricant is selected from the following: talc, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, silica gel, and mixtures thereof.

[0418] 61. The stable immediate-release tablet according to any one of paragraphs 49 to 60, wherein the pharmaceutically acceptable excipient comprises a disintegrant, and the disintegrant accounts for 1.0 wt% to 8.0 wt% of the total weight of the composition.

[0419] 62. The stable immediate-release tablet according to paragraph 61, wherein the disintegrant is selected from the following: starch, modified starch, croscarmellose sodium, croscarmellose, sodium glycolate starch, and mixtures thereof.

[0420] 63. The stable immediate-release tablet according to any one of paragraphs 49 to 62, wherein the pharmaceutically acceptable excipient comprises a gliding agent, and the gliding agent comprises 0.1 wt% to 5.0 wt% of the total weight of the composition.

[0421] 64. A stable immediate-release pharmaceutical composition as defined in any one of paragraphs 30 to 48 or a stable immediate-release tablet as defined in any one of paragraphs 49 to 63, used in a method for treating non-alcoholic fatty liver disease (NAFLD).

[0422] 65. A stable immediate-release pharmaceutical composition as defined in any one of paragraphs 30 to 48 or a stable immediate-release tablet as defined in any one of paragraphs 49 to 63, for use in the treatment of non-alcoholic fatty liver disease (NAFLD), wherein NAFLD includes non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH).

[0423] 66. A stable immediate-release pharmaceutical composition as defined in any one of paragraphs 30 to 48 or a stable immediate-release tablet as defined in any one of paragraphs 49 to 63, for use in the treatment of subjects with cirrhosis at risk of progressing from compensated to decompensated liver disease.

[0424] 67. A stable immediate-release pharmaceutical composition or a stable immediate-release tablet as defined in any one of paragraphs 30 to 48 for the treatment of the following: cirrhosis, liver fibrosis, hepatic steatosis, fatty liver disease, acute decompensation, acute-on-chronic liver failure (ACLF), acute liver failure (ALF), decompensated cirrhosis, compensated cirrhosis, metabolic-associated fatty liver disease (MAFLD), metabolic-associated steatohepatitis (MASH), diabetes, or cirrhosis.

Claims

1. A pharmaceutical composition, comprising, based on the total weight of the composition: 55.0 wt% to 75.0 wt% of Lanilandro; and 25.0 wt% to 45.0 wt% pharmaceutically acceptable excipients; in, Lanilano has a particle size distribution such that D50≤30 μm and D90≤50 μm, preferably D50≤10 μm and D90≤30 μm.

2. The pharmaceutical composition according to claim 1, wherein, The pharmaceutical composition releases approximately 30% to 60% of the lanilanol within 15 minutes after oral ingestion.

3. The pharmaceutical composition according to any one of claims 1-2, wherein, The pharmaceutical composition releases at least 80% of the lanilanol within 45 minutes after oral ingestion.

4. The pharmaceutical composition according to any one of the preceding claims, wherein, The pharmaceutically acceptable excipients include two or more of the following: binders, colorants, disintegrants, fillers, flow aids, lubricants, preservatives, surfactants, and sweeteners.

5. The pharmaceutical composition according to any one of the preceding claims, wherein, The pharmaceutically acceptable excipients include fillers, and the fillers account for 10.0 wt% to 35.0 wt% of the total weight of the composition.

6. The pharmaceutical composition according to claim 5, wherein, The filler is selected from the following: lactose monohydrate, anhydrous lactose, starch, modified starch, mannitol, and mixtures thereof.

7. The pharmaceutical composition according to any one of the preceding claims, wherein, The pharmaceutically acceptable excipients include surfactants, and the surfactants account for 1.0 wt% to 5.0 wt% of the total weight of the composition.

8. The pharmaceutical composition according to claim 7, wherein, The surfactant is selected from the following: nonionic surfactants, anionic surfactants, cationic surfactants, and mixtures thereof.

9. The pharmaceutical composition according to any one of the preceding claims, wherein, The pharmaceutically acceptable excipients include binders, and the binders comprise 1.0 wt% to 10.0 wt% of the total weight of the composition.

10. The pharmaceutical composition according to claim 9, wherein, The adhesive is selected from the following: cellulose, modified cellulose, microcrystalline cellulose, polyvinylpyrrolidone, and mixtures thereof.

11. The pharmaceutical composition according to any one of the preceding claims, wherein, The pharmaceutically acceptable excipients include lubricants, and the lubricants account for 0.5 wt% to 5.0 wt% of the total weight of the composition.

12. The pharmaceutical composition according to claim 11, wherein, The lubricant is selected from the following: talc, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, silica gel, and mixtures thereof.

13. The pharmaceutical composition according to any one of the preceding claims, wherein, The pharmaceutically acceptable excipients include disintegrants, and the disintegrants account for 1.0 wt% to 8.0 wt% of the total weight of the composition.

14. The pharmaceutical composition according to claim 13, wherein, The disintegrant is selected from the following: starch, modified starch, croscarmellose sodium, croscarmellose, glycolic acid starch sodium, and mixtures thereof.

15. The pharmaceutical composition according to any one of the preceding claims, wherein, The pharmaceutically acceptable excipients include gliding agents, and the gliding agents constitute 0.1 wt% to 5.0 wt% of the total weight of the composition.

16. The pharmaceutical composition according to any one of claims 1-15, wherein, based on the total weight of the composition, the pharmaceutical composition comprises: 55.0 wt% to 75.0 wt% of Lanilandro 10.0wt% to 35.0wt% of filler; 1.0wt% to 5.0wt% of surfactant; 1.0wt% to 10.0wt% of adhesives; Lubricant ranging from 0.5 wt% to 5.0 wt%; 1.0 wt% to 8.0 wt% disintegrant; 0.1wt% to 5.0wt% of gliding agent.

17. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition is in solid dosage form.

18. The pharmaceutical composition according to claim 17, wherein the pharmaceutical composition is in tablet, capsule or strip form, preferably tablet.

19. The pharmaceutical composition according to claim 17 or 18, wherein the pharmaceutical composition comprises 200 mg to 1200 mg of lanyllanol.

20. The pharmaceutical composition according to any one of the preceding claims, wherein, Lanilano exists in crystalline form.

21. The pharmaceutical composition according to any one of claims 1-20 for use in a method of treating non-alcoholic fatty liver disease (NAFLD).

22. The pharmaceutical composition for said use according to claim 21, wherein, NAFLD includes non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH).

23. The pharmaceutical composition according to any one of claims 1-20 for use in a method of treating a subject with cirrhosis at risk of progressing from compensated to decompensated stage.

24. A pharmaceutical composition according to any one of claims 1-20 for use in treating the following conditions: cirrhosis, liver fibrosis, hepatic steatosis, fatty liver disease, acute decompensation, acute-on-chronic liver failure, acute liver failure, decompensated cirrhosis, compensated cirrhosis, metabolic-associated fatty liver disease, metabolic-associated steatohepatitis, diabetes, or cirrhosis.

25. The pharmaceutical composition according to any one of claims 1-3, wherein, based on the total weight of the composition, the pharmaceutical composition comprises: 55.0 wt% to 75.0 wt% of Lanilandro; and 25.0 wt% to 45.0 wt% pharmaceutically acceptable excipients; in, Lanilano has a particle size distribution such that D50 ≤ 30 μm and D90 ≤ 50 μm, preferably D50 ≤ 10 μm and D90 ≤ 30 μm, and In the pharmaceutically acceptable excipients, the surfactant accounts for 1.0 wt% to 5.0 wt% of the total weight of the composition.

26. The pharmaceutical composition according to claim 25, wherein, The pharmaceutically acceptable excipients further include two or more of the following: binders, colorants, disintegrants, fillers, flow aids, lubricants, preservatives, surfactants, and sweeteners.

27. The pharmaceutical composition according to claim 25 or 26, wherein the pharmaceutical composition is in solid dosage form.

28. The pharmaceutical composition according to any one of claims 25-27, wherein the pharmaceutical composition is in tablet, capsule or strip packaging, preferably tablet.

29. The pharmaceutical composition according to any one of claims 25-28, wherein the pharmaceutical composition comprises 200 mg to 1200 mg of lanyllanol.

30. The pharmaceutical composition according to any one of claims 25-29, wherein, Lanilano exists in crystalline form.

31. The pharmaceutical composition according to any one of claims 25-30 for use in a method of treating non-alcoholic fatty liver disease (NAFLD).

32. The pharmaceutical composition for said use according to claim 31, wherein, NAFLD includes non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH).

33. The pharmaceutical composition according to any one of claims 25-30 for use in a method of treating a subject with cirrhosis at risk of progressing from compensated to decompensated liver disease.

34. A pharmaceutical composition according to any one of claims 25-30 for use in treating the following conditions: cirrhosis, liver fibrosis, hepatic steatosis, fatty liver disease, acute decompensation, acute-on-chronic liver failure, acute liver failure, decompensated cirrhosis, compensated cirrhosis, metabolic-associated fatty liver disease, metabolic-associated steatohepatitis, diabetes, or cirrhosis.

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