Multiple Taskinimod particles and their use

Abstract

A plurality of particles of tasquinimod in free base form or as a pharma- ceutically acceptable salt, said particles having a D(v,0.9) of at most 30 μm and a D(v,0.5) of at most 15 μm. A pharmaceutical composition comprising said particles and, preferably, one or more pharma- ceutically acceptable excipients. A pharmaceutical dosage unit. These particles, compositions and dosage units are useful in the treatment of cancer.

Description

[Technical Field]

[0001] The present invention relates to a plurality of particles of tascinimod or pharmaceutically acceptable salts thereof, their use in therapy, and pharmaceutical compositions containing such plurality of particles. The present invention further relates to solid pharmaceutical dosage units containing a plurality of such particles, such as solid oral pharmaceutical dosage forms, such as capsules or tablets for oral administration. [Background technology]

[0002] Tascinimod and methods for its preparation are described in International Application No. PCT / SE99 / 00676, published as WO99 / 55678, and International Application No. PCT / SE99 / 01270, published as WO00 / 03991, which also disclose the usefulness of tascinimod and several other quinoline carboxamides for the treatment of autoimmune diseases, such as multiple sclerosis, insulin-dependent diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, and psoriasis, as well as diseases in which pathological inflammation plays a major role, such as asthma, atherosclerosis, stroke, and Alzheimer's disease.

[0003] Methods for preparing tascinimod are also described in International Application No. PCT / SE2003 / 000780, published as WO03 / 106424, and International Application No. PCT / EP2011 / 061490, published as WO2012 / 004338. The deuterated form of tascinimod was described in International Application No. PCT / EP2012 / 061798, published as WO2012 / 175541.

[0004] The use of various quinoline carboxamides for the treatment of cancer, more specifically solid tumors such as prostate cancer and breast cancer, is disclosed in international application number PCT / SE00 / 02055, published as WO01 / 30758. These compounds have been found to bind to and inhibit the interaction of the immunomodulatory protein (S100A9), which promotes tumorigenesis and affects suppressor and pro-angiogenic cells in the tumor microenvironment, and is involved in the establishment of the pre-metastatic niche.

[0005] International application number PCT / EP2015 / 075769, published as WO2016 / 078921, discloses tascinimod for use in the treatment of leukemia, including acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia. International application number PCT / EP2015 / 071391, published as WO2016 / 042112, discloses tascinimod for use in the treatment of multiple myeloma. International application number PCT / EP2016 / 053288, published as WO2016 / 146329, discloses tascinimod for use in combination with PD-1 and / or PD-L1 inhibitors in the treatment of cancer, particularly bladder cancer. The use of tascinimod for the treatment of myeloproliferative neoplasms, such as myelofibrosis, is disclosed in International Application No. PCT / EP2021 / 070629, published as WO2022 / 018240. The use of tascinimod for the treatment of myelodysplastic syndromes is described in the unpublished International Application No. PCT / EP2022 / 050891. All of the above identified prior art documents are incorporated herein by reference.

[0006] As is well known, it is not enough to merely establish that a particular compound has therapeutic activity useful for treating a particular disease; in order to be actually useful, a form suitable for administration must also be provided. Oral administration of drugs is usually preferable for ease of administration and patient compliance. In relation to oral administration, bioavailability is an important factor to consider and is generally governed by the solubility, gastrointestinal permeability, and dissolution rate of the substance to be administered. Further parameters to consider are those related to the oral administration form, including ease of manufacture, formulation stability and shelf life, and ease of use for the patient. For example, to obtain accurate and consistent dosages, unit dosage forms, such as capsules and tablets, may be preferable to liquid formulations, although the former is generally preferred for ease of transport and in the case of unpleasant-tasting active pharmaceutical ingredients. [Overview of the project] [Means for solving the problem]

[0007] Tascinimod, or 4-hydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-[4-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide, has the following structural formula:

[0008] [ka]

[0009] It is a compound that has [a certain characteristic].

[0010] Tascinimod is a compound with high gastrointestinal permeability and high water solubility. In fact, in a gastrointestinal permeability test of tascinimod using a Caco-2 cell model, the permeability coefficient of tascinimod was 43.5 ± 0.9.10. -6 cm.s -1It has been found that tascinimod is classified as "highly permeable" according to the Biopharmaceutical Classification System (BCS). For drug compounds classified as "highly soluble" by the BCS, the maximum single therapeutic dose should be completely dissolved in 250 ml or less of aqueous medium at 37 ± 1°C and within the pH range of 1.2 to 6.8. The solubility of tascinimod exceeds 10 times this cutoff value under certain conditions, while at the physiological pH of 7.4, the solubility is 50 times higher than this cutoff value, meaning that the solubility of tascinimod at pH 7.4 is high at 0.25 mg / ml. Based on these characteristics, tascinimod is classified as a BCS Class I compound. When highly soluble tascinimod is formulated as an immediate-release formulation, it is expected that more than 85% of the dissolution criterion will be released within 30 minutes at 37°C, indicating a high dissolution rate. However, the inventors found that the elution rate of tascinimod particles was surprisingly low. Given the high water solubility of tascinimod, the low elution rate of tascinimod particles in the aqueous phase was completely unexpected. Low elution rates can easily lead to reduced bioavailability and may hinder the efficient oral administration of other therapeutically active compounds.

[0011] Therefore, the present invention is based on the surprising finding that tascinimod, a highly water-soluble compound, is adversely affected by its unexpectedly low aqueous elution rate.

[0012] Accordingly, the first embodiment is a plurality of particles of tascinimod in free base form or as a pharmaceutically acceptable salt, wherein the particles have a maximum D(v,0.9) of 30 μm and a maximum D(v,0.5) of 15 μm.

[0013] A further embodiment is a plurality of particles of tascinimod, either in the free base form as defined herein or as a pharmaceutically acceptable salt, for therapeutic use.

[0014] A further embodiment is a pharmaceutical composition comprising a plurality of particles of tascinimod in the free base form or as a pharmaceutically acceptable salt as defined herein, and preferably one or more pharmaceutically acceptable excipients.

[0015] A further embodiment is a pharmaceutical administration unit comprising a pharmaceutical composition as defined herein.

[0016] Further embodiments include multiple particles of tascinimod, as defined herein, or pharmaceutical compositions or pharmaceutical administration units for use in the treatment of cancer. Cancers can be selected from multiple myeloma, lymphoma, myelodysplastic syndrome, myeloproliferative neoplasm, leukemia, bladder cancer, melanoma, lung cancer, colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, ovarian cancer, neuroendocrine tumors (NETs), and gastrointestinal neuroendocrine tumors (GEP-NETs).

[0017] Further aspects and embodiments thereof will become apparent from the following description and claims. [Brief explanation of the drawing]

[0018] [Figure 1] This figure shows the weight percentage of tascinimod dissolved as a function of time from capsules containing 1 mg of tascinimod particles in Examples 4-6, where D(v,0.5) is 2.3 μm, 4.9 μm, and 6.4 μm, respectively, and from capsules containing 1 mg of tascinimod particles in Comparative Examples 1-3 (not according to the present invention), where D(v,0.5) is 15.9 μm, 22.4 μm, and 39.9 μm, respectively, in an in vitro dissolution test. [Figure 2] This figure shows the density distribution (q3) measured by laser diffraction as a function of particle size (μm) for the Taskinimod particles of Examples 7, 8, and 9. [Figure 3]In the in vitro dissolution test, it is a graph showing the weight % of tasquinimod eluted as a function of time from the capsules of Example 13 and Example 14 each containing 1 mg of tasquinimod particles with D(v,0.5) of 3.4 μm and 8.5 μm, respectively. [Figure 4] It is a graph showing the weight % of tasquinimod eluted as a function of time from the capsule of Example 17 containing 1.0 mg of tasquinimod particles with D(v,0.5) of 4.8 μm, and the capsules of Examples 18 to 20 containing 1.0 mg of tasquinimod particles with D(v,0.5) of 5.2 μm.

Mode for Carrying Out the Invention

[0019] Unless otherwise defined or clearly indicated by the context, all technical terms, scientific terms, and abbreviations used in this specification have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. However, definitions of some of the terms used in this specification are shown below.

[0020] As used in this specification, the term "D(v,0.9)" means that 90% of the particles in the composition (based on volume) have a diameter equal to or less than a specified value. Thus, for example, D(v,0.9) being 25 μm means that 90% of the particles by volume have a diameter of 25 μm or less.

[0021] As used in this specification, the term "D(v,0.5)" means that 50% of the particles in the composition (based on volume) have a diameter equal to or less than a specified value. Thus, for example, D(v,0.5) being 15 μm means that 50% of the particles by volume have a diameter of 15 μm or less. D(v,0.5) being in the range of 3 μm to 7 μm means that 50% of the particles by volume have a diameter equal to or less than a value between 7 μm and 3 μm.

[0022] As used herein, the term “effective” means an amount sufficient to produce the intended therapeutic response without excessive adverse side effects (e.g., toxicity, irritation, or allergic reaction) commensurate with a reasonable benefit-risk ratio, as in “therapeutic effective dose.” The effective dose may vary depending on factors known in the art, such as the medical condition, age, sex, and weight of the person or animal being treated.

[0023] The term "excipient" refers to a pharmaceutically acceptable chemical substance used to assist in the administration of a medicinal agent, as is generally known to the ordinarily skilled practitioner in the field of pharmacy. These are generally safe, non-toxic, non-biological, and non-undesirable compounds useful in preparing pharmaceutical compositions, and include excipients acceptable for both veterinary and human pharmaceutical uses. Exemplary excipients include encapsulating agents, sweeteners, taste-masking agents, carriers, binders, fillers, diluents, disintegrants, anti-adhesion agents, and lubricants.

[0024] The term "filler" (also referred to as "diluent" or "bulker" in the pharmaceutical field) refers to a component (excipient) in a pharmaceutical composition that lacks pharmacological activity but is pharmaceutically necessary or desirable to enhance or improve the properties of a pharmaceutical blend, for example, for manufacturing or physiological purposes. For example, fillers can be used to increase the volume of an active ingredient whose mass is too small to manufacture or administer.

[0025] The term "lubricant" refers to an excipient that prevents components and excipients from clumping together and / or sticking to a dosage form filling machine. Lubricants also ensure that the formation, filling, and discharge of dosage forms can be carried out reliably, for example, by reducing friction. Examples of lubricants include vegetable oils, talc, silicon dioxide (silica), and fatty acids or fatty acid salts.

[0026] As used herein, the term “micronization” refers to a method of reducing the average diameter of particles in a solid material. Typically, the term micronization is used when the resulting particles have a diameter of only a few micrometers (typically less than 10 μm). Micronization techniques are typically based on the use of friction to reduce particle size, for example, by grinding and abrasion.

[0027] "Depending on the circumstances" or "depending on the situation" means that the event or situation described below may or may not occur, and that the description includes examples where the event or situation does occur and examples where it does not.

[0028] As used herein, the term “medicinal administration unit” includes any device useful for administering a given dose of a drug to a patient, such as a capsule, tablet, sachet, or microcapsule.

[0029] "Pharmacologically acceptable" means a substance that is not biologically or otherwise undesirable, i.e., a substance that can be administered to an individual together with the relevant active compound without causing a clinically unacceptable biological effect or interacting in a harmful manner with any other component of a preparation containing it.

[0030] As used herein, the term “subject” refers to mammals. Mammals considered in this invention include humans and other mammals, such as primates, domesticated animals, such as farm animals like cattle, sheep, pigs, and horses, and pet animals, such as dogs and cats. Preferably, the mammal is human.

[0031] In the following, the terms "Tascinimod particles" or "Tascinimod particles" should be understood to refer to particles of Tascinimod, and "Tascinimod" should be understood to refer to either Tascinimod free base or Tascinimod in the form of a pharmaceutically acceptable salt, unless otherwise indicated by the context.

[0032] It should be noted that the taschinimods used herein may be deuterated to any degree. In some embodiments, the taschinimods have a degree of deuteration corresponding to the natural abundance of the deuterium isotope. In other embodiments, the taschinimods used herein are as described in WO2012 / 175541 (see above).

[0033] Examples of pharmaceutically acceptable salts include salts with alkali metal ions (as counterions), such as Li+, Na+, or K+, or salts with alkaline earth metal ions, such as Mg2+ or Ca2+, or salts with any other pharmaceutically acceptable metal ion, such as Zn2+ or Al3+; or pharmaceutically acceptable salts formed with organic bases, such as diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, or tromethamine.

[0034] As used herein, “to treat” includes, for example, inducing suppression, regression or cessation of a disease, disorder or condition, or causing remission or relief of the symptoms of a disease, disorder or condition.

[0035] As used herein, “to improve” or “to alleviate” a condition or situation means to alleviate or reduce the symptoms of that condition or situation. As used herein, “to suppress” aggravation of a condition or complications of a disease in a subject means to prevent or reduce aggravation of a condition and / or complications of a disease in a subject.

[0036] Multiple Taskinimodo particles The Tascinimod particles present in any of the Tascinimod particles provided herein consist essentially of Tascinimod, meaning that at least 90% by weight of the particles consist of Tascinimod, for example, at least 95% by weight, preferably at least 96% by weight, more preferably at least 97% by weight, even more preferably at least 98% by weight, at least 98.5% by weight, at least 99% by weight, or at least 99.5% by weight consist of Tascinimod.

[0037] As described herein, in order to have the required elution rate, the Taskinimod particles should have a particle size distribution characterized by a maximum D(v,0.9) of 30 μm.

[0038] In some embodiments, the particles have a maximum D(v,0.9) of 29 μm. In some embodiments, the particles have a maximum D(v,0.9) of 28 μm. In some embodiments, the particles have a maximum D(v,0.9) of 27 μm. In some embodiments, the particles have a maximum D(v,0.9) of 26 μm. In some embodiments, the particles have a maximum D(v,0.9) of 25 μm. In some embodiments, the particles have a maximum D(v,0.9) of 24 μm. In some embodiments, the particles have a maximum D(v,0.9) of 23 μm. In some embodiments, the particles have a maximum D(v,0.9) of 22 μm. In some embodiments, the particles have a maximum D(v,0.9) of 21 μm. In some embodiments, the particles have a maximum D(v,0.9) of 20 μm. In some embodiments, the particles have a maximum D(v,0.9) of 19 μm. In some embodiments, the particles have a maximum D(v,0.9) of 18 μm. In some embodiments, the particles have a maximum D(v,0.9) of 17 μm. In some embodiments, the particles have a maximum D(v,0.9) of 16 μm. In some embodiments, the particles have a maximum D(v,0.9) of 15 μm. In some embodiments, the particles have a maximum D(v,0.9) of 14 μm. In some embodiments, the particles have a maximum D(v,0.9) of 13 μm. In some embodiments, the particles have a maximum D(v,0.9) of 12 μm. In some embodiments, the particles have a maximum D(v,0.9) of 11 μm. In some embodiments, the particles have a maximum D(v,0.9) of 10 μm. In some embodiments, the particles have a maximum D(v,0.9) of 9 μm. In some embodiments, the particles have a maximum D(v,0.9) of 8 μm. In some embodiments, the particles have a maximum D(v,0.9) of 7 μm.

[0039] In some embodiments, the particle has a D(v,0.9) of approximately 30 μm. In some embodiments, the particle has a D(v,0.9) of approximately 29 μm. In some embodiments, the particle has a D(v,0.9) of approximately 28 μm. In some embodiments, the particle has a D(v,0.9) of approximately 27 μm. In some embodiments, the particle has a D(v,0.9) of approximately 26 μm. In some embodiments, the particle has a D(v,0.9) of approximately 25 μm. In some embodiments, the particle has a D(v,0.9) of approximately 24 μm. In some embodiments, the particle has a D(v,0.9) of approximately 23 μm. In some embodiments, the particle has a D(v,0.9) of approximately 22 μm. In some embodiments, the particle has a D(v,0.9) of approximately 21 μm. In some embodiments, the particle has a D(v,0.9) of approximately 20 μm. In some embodiments, the particle has a D(v,0.9) of approximately 19 μm. In some embodiments, the particle has a D(v,0.9) of approximately 18 μm. In some embodiments, the particle has a D(v,0.9) of approximately 17 μm. In some embodiments, the particle has a D(v,0.9) of approximately 16 μm. In some embodiments, the particle has a D(v,0.9) of approximately 15 μm. In some embodiments, the particle has a D(v,0.9) of approximately 14 μm. In some embodiments, the particle has a D(v,0.9) of approximately 13 μm. In some embodiments, the particle has a D(v,0.9) of approximately 12 μm. In some embodiments, the particle has a D(v,0.9) of approximately 11 μm. In some embodiments, the particle has a D(v,0.9) of approximately 10 μm. In some embodiments, the particle has a D(v,0.9) of approximately 9 μm. In some embodiments, the particle has a D(v,0.9) of approximately 8 μm. In some embodiments, the particle has a D(v,0.9) of approximately 7 μm. In some embodiments, the particle has a D(v,0.9) of approximately 6 μm.

[0040] In some embodiments, the particles have a D(v,0.9) in the range of 6-30 μm, 7-30 μm, 8-30 μm, 9-30 μm, 10-30 μm, 11-30 μm, 12-30 μm, 13-30 μm, 14-30 μm, 15-30 μm, 16-30 μm, 17-30 μm, 18-30 μm, 19-30 μm, 20-30 μm, 21-30 μm, 22-30 μm, 23-30 μm, 24-30 μm, 25-30 μm, 26-30 μm, 27-30 μm, 28-30 μm, or 29-30 μm.

[0041] In some embodiments, the particles have a D(v,0.9) in the range of 6-29 μm, 7-29 μm, 8-29 μm, 9-29 μm, 10-29 μm, 11-29 μm, 12-29 μm, 13-29 μm, 14-29 μm, 15-29 μm, 16-29 μm, 17-29 μm, 18-29 μm, 19-29 μm, 20-29 μm, 21-29 μm, 22-29 μm, 23-29 μm, 24-29 μm, 25-29 μm, 26-29 μm, 27-29 μm, or 28-29 μm.

[0042] In some embodiments, the particles have a D(v,0.9) in the range of 6-28 μm, 7-28 μm, 8-28 μm, 9-28 μm, 10-28 μm, 11-28 μm, 12-28 μm, 13-28 μm, 14-28 μm, 15-28 μm, 16-28 μm, 17-28 μm, 18-28 μm, 19-28 μm, 20-28 μm, 21-28 μm, 22-28 μm, 23-28 μm, 24-28 μm, 25-28 μm, 26-28 μm, or 27-28 μm.

[0043] In some embodiments, the particles have a D(v,0.9) in the range of 6-27 μm, 7-27 μm, 8-27 μm, 9-27 μm, 10-27 μm, 11-27 μm, 12-27 μm, 13-27 μm, 14-27 μm, 15-27 μm, 16-27 μm, 17-27 μm, 18-27 μm, 19-27 μm, 20-27 μm, 21-27 μm, 22-27 μm, 23-27 μm, 24-27 μm, 25-27 μm, or 26-27 μm.

[0044] In some embodiments, the particles have a D(v,0.9) in the range of 6-26 μm, 7-26 μm, 8-26 μm, 9-26 μm, 10-26 μm, 11-26 μm, 12-26 μm, 13-26 μm, 14-26 μm, 15-26 μm, 16-26 μm, 17-26 μm, 18-26 μm, 19-26 μm, 20-26 μm, 21-26 μm, 22-26 μm, 23-26 μm, 24-26 μm, or 25-26 μm.

[0045] In some embodiments, the particles have a D(v,0.9) in the range of 6-25 μm, 7-25 μm, 8-25 μm, 9-25 μm, 10-25 μm, 11-25 μm, 12-25 μm, 13-25 μm, 14-25 μm, 15-25 μm, 16-25 μm, 17-25 μm, 18-25 μm, 19-25 μm, 20-25 μm, 21-25 μm, 22-25 μm, 23-25 ​​μm, or 24-25 μm.

[0046] In some embodiments, the particles have a D(v,0.9) in the range of 6-24 μm, 7-24 μm, 8-24 μm, 9-24 μm, 10-24 μm, 11-24 μm, 12-24 μm, 13-24 μm, 14-24 μm, 15-24 μm, 16-24 μm, 17-24 μm, 18-24 μm, 19-24 μm, 20-24 μm, 21-24 μm, 22-24 μm, or 23-24 μm.

[0047] In some embodiments, the particles have a D(v,0.9) in the range of 6-23 μm, 7-23 μm, 8-23 μm, 9-23 μm, 10-23 μm, 11-23 μm, 12-23 μm, 13-23 μm, 14-23 μm, 15-23 μm, 16-23 μm, 17-23 μm, 18-23 μm, 19-23 μm, 20-23 μm, 21-23 μm, or 22-23 μm.

[0048] In some embodiments, the particles have a D(v,0.9) in the range of 6-22 μm, 7-22 μm, 8-22 μm, 9-22 μm, 10-22 μm, 11-22 μm, 12-22 μm, 13-22 μm, 14-22 μm, 15-22 μm, 16-22 μm, 17-22 μm, 18-22 μm, 19-22 μm, 20-22 μm, or 21-22 μm.

[0049] In some embodiments, the particles have a D(v,0.9) in the range of 6-21 μm, 7-21 μm, 8-21 μm, 9-21 μm, 10-21 μm, 11-21 μm, 12-21 μm, 13-21 μm, 14-21 μm, 15-21 μm, 16-21 μm, 17-21 μm, 18-21 μm, 19-21 μm, or 20-21 μm.

[0050] In some embodiments, the particles have a D(v,0.9) in the range of 6-20 μm, 7-20 μm, 8-20 μm, 9-20 μm, 10-20 μm, 11-20 μm, 12-20 μm, 13-20 μm, 14-20 μm, 15-20 μm, 16-20 μm, 17-20 μm, 18-20 μm, or 19-20 μm.

[0051] In some embodiments, the particles have a D(v,0.9) in the range of 6-19 μm, 7-19 μm, 8-19 μm, 9-19 μm, 10-19 μm, 11-19 μm, 12-19 μm, 13-19 μm, 14-19 μm, 15-19 μm, 16-19 μm, 17-19 μm, or 18-19 μm.

[0052] In some embodiments, the particles have a D(v,0.9) in the range of 6-18 μm, 7-18 μm, 8-18 μm, 9-18 μm, 10-18 μm, 11-18 μm, 12-18 μm, 13-18 μm, 14-18 μm, 15-18 μm, 16-18 μm, or 17-18 μm.

[0053] In some embodiments, the particles have a D(v,0.9) in the range of 6-17 μm, 7-17 μm, 8-17 μm, 9-17 μm, 10-17 μm, 11-17 μm, 12-17 μm, 13-17 μm, 14-17 μm, 15-17 μm, or 16-17 μm.

[0054] In some embodiments, the particles have a D(v,0.9) in the range of 6-16 μm, 7-16 μm, 8-16 μm, 9-16 μm, 10-16 μm, 11-16 μm, 12-16 μm, 13-16 μm, 14-16 μm, or 15-16 μm.

[0055] In some embodiments, the particles have a D(v,0.9) in the range of 6-15 μm, 7-15 μm, 8-15 μm, 9-15 μm, 10-15 μm, 11-15 μm, 12-15 μm, 13-15 μm, or 14-15 μm.

[0056] In some embodiments, the particles have a D(v,0.9) in the range of 6-14 μm, 7-14 μm, 8-14 μm, 9-14 μm, 10-14 μm, 11-14 μm, 12-14 μm, or 13-14 μm.

[0057] In some embodiments, the particles have a D(v,0.9) in the range of 6-13 μm, 7-13 μm, 8-13 μm, 9-13 μm, 10-13 μm, 11-13 μm, or 12-13 μm.

[0058] In some embodiments, the particles have a D(v,0.9) in the range of 6-12 μm, 7-12 μm, 8-12 μm, 9-12 μm, 10-12 μm, or 11-12 μm.

[0059] In some embodiments, the particles have a D(v,0.9) in the range of 6-11 μm, 7-11 μm, 8-11 μm, 9-11 μm, or 10-11 μm.

[0060] In some embodiments, the particles have a D(v,0.9) in the range of 6-10 μm, 7-10 μm, 8-10 μm, or 9-10 μm.

[0061] In some embodiments, the particles have a D(v,0.9) in the range of 6-9 μm, 7-9 μm, or 8-9 μm. In some embodiments, the particles have a D(v,0.9) in the range of 6-8 μm, or 7-8 μm. In some embodiments, the particles have a D(v,0.9) in the range of 6-7 μm.

[0062] Preferably, the Taskinimod particles provided herein should have a particle size distribution characterized by a maximum D(v,0.5) of 15 μm. In some embodiments, the particles have a D(v,0.5) of 14 μm. In some embodiments, the particles have a D(v,0.5) of 13 μm. In some embodiments, the particles have a D(v,0.5) of 12 μm. In some embodiments, the particles have a D(v,0.5) of 11 μm. In some embodiments, the particles have a D(v,0.5) of 10 μm. In some embodiments, the particles have a D(v,0.5) of 9 μm. In some embodiments, the particles have a D(v,0.5) of 8 μm. In some embodiments, the particles have a D(v,0.5) of 7 μm. In some embodiments, the particles have a D(v,0.5) of 6 μm. In some embodiments, the particles have a D(v,0.5) of 5 μm. In some embodiments, the particle has a D(v,0.5) of 4 μm. In some embodiments, the particle has a D(v,0.5) of 3 μm. In some embodiments, the particle has a D(v,0.5) of 2 μm. In some embodiments, the particle has a D(v,0.5) of 1 μm.

[0063] In some embodiments, the particles have a D(v,0.5) in the ranges of 1-15 μm, 2-15 μm, 3-15 μm, 4-15 μm, 5-15 μm, 6-15 μm, 7-15 μm, 8-15 μm, 9-15 μm, 10-15 μm, 11-15 μm, 12-15 μm, 13-15 μm, and 14-15 μm.

[0064] In some embodiments, the particles have a D(v,0.5) in the range of 1-14 μm, 2-14 μm, 3-14 μm, 4-14 μm, 5-14 μm, 6-14 μm, 7-14 μm, 8-14 μm, 9-14 μm, 10-14 μm, 11-14 μm, 12-14 μm, or 13-14 μm.

[0065] In some embodiments, the particles have a D(v,0.5) in the range of 1-13 μm, 2-13 μm, 3-13 μm, 4-13 μm, 5-13 μm, 6-13 μm, 7-13 μm, 8-13 μm, 9-13 μm, 10-13 μm, 11-13 μm, or 12-13 μm.

[0066] In some embodiments, the particles have a D(v,0.5) in the range of 1-12 μm, 2-12 μm, 3-12 μm, 4-12 μm, 5-12 μm, 6-12 μm, 7-12 μm, 8-12 μm, 9-12 μm, 10-12 μm, or 11-12 μm.

[0067] In some embodiments, the particles have a D(v,0.5) in the range of 1-11 μm, 2-11 μm, 3-11 μm, 4-11 μm, 5-11 μm, 6-11 μm, 7-11 μm, 8-11 μm, 9-11 μm, or 10-11 μm.

[0068] In some embodiments, the particles have a D(v,0.5) in the range of 1-10 μm, 2-10 μm, 3-10 μm, 4-10 μm, 5-10 μm, 6-10 μm, 7-10 μm, 8-10 μm, or 9-10 μm.

[0069] In some embodiments, the particles have a D(v,0.5) in the range of 1-9 μm, 2-9 μm, 3-9 μm, 4-9 μm, 5-9 μm, 6-9 μm, 7-9 μm, or 8-9 μm.

[0070] In some embodiments, the particles have a D(v,0.5) in the range of 1-8 μm, 2-8 μm, 3-8 μm, 4-8 μm, 5-8 μm, 6-8 μm, or 7-8 μm.

[0071] In some embodiments, the particles have a D(v,0.5) in the range of 1-7 μm, 2-7 μm, 3-7 μm, 4-7 μm, 5-7 μm, or 6-7 μm.

[0072] In some embodiments, the particles have a D(v,0.5) in the range of 1-6 μm, 2-6 μm, 3-6 μm, 4-6 μm, or 5-6 μm.

[0073] In some embodiments, the particles have a D(v,0.5) in the range of 1-5 μm, 2-5 μm, 3-5 μm, or 4-5 μm.

[0074] In some embodiments, the particles have a D(v,0.5) in the range of 1-4 μm, 2-4 μm, or 3-4 μm.

[0075] In some embodiments, the particles have a D(v,0.5) in the range of 1–3 μm, 2–3 μm, or 1–2 μm.

[0076] Generally, D(v,0.5) is in the range of 1 μm to 15 μm, and D(v,0.9) is at most 30 μm, for example, D(v,0.9) is in the range of 6 to 30 μm. In some embodiments, D(v,0.5) is in the range of 1 μm to 10 μm, and D(v,0.9) is at most 27 μm, for example, D(v,0.9) is in the range of 6 to 27 μm. In some further embodiments, D(v,0.5) is in the range of 1 μm to 9 μm, and D(v,0.9) is at most 25 μm, for example, D(v,0.9) is in the range of 6 to 25 μm.

[0077] In some further embodiments, D(v,0.5) is in the range of 2 μm to 10 μm, and D(v,0.9) is at most 25 μm, for example, D(v,0.9) is in the range of 6 to 25 μm. In some further embodiments, D(v,0.5) is in the range of 2 μm to 9 μm, and D(v,0.9) is at most 25 μm, for example, D(v,0.9) is in the range of 6 to 25 μm.

[0078] In some further embodiments, D(v,0.5) is in the range of 3 μm to 9 μm, and D(v,0.9) is at most 25 μm, for example, D(v,0.9) is in the range of 6 to 25 μm. In some further embodiments, D(v,0.5) is in the range of 3 μm to 8 μm, and D(v,0.9) is at most 25 μm, for example, D(v,0.9) is in the range of 6 to 25 μm. In some further embodiments, D(v,0.5) is in the range of 3 μm to 7 μm, and D(v,0.9) is at most 25 μm, for example, D(v,0.9) is in the range of 6 to 25 μm. In some of these embodiments, D(v,0.9) is in the range of 7 to 25 μm, or 8 to 25 μm, or 9 to 25 μm, or 10 to 25 μm.

[0079] Therefore, in some further embodiments, D(v,0.5) is in the range of 3 μm to 9 μm and D(v,0.9) is in the range of 10 to 25 μm, or D(v,0.5) is in the range of 3 μm to 8 μm and D(v,0.9) is in the range of 10 to 25 μm, or D(v,0.5) is in the range of 3 μm to 7 μm and D(v,0.9) is in the range of 10 to 25 μm.

[0080] In some further embodiments, D(v,0.5) is in the range of 2μm to 9μm, 2μm to 8μm, 2μm to 7μm, 3μm to 9μm, 3μm to 8μm, or 3μm to 7μm, and D(v,0.9) is at most 20μm, for example, in the range of 10 to 20μm.

[0081] In some further embodiments, D(v,0.5) is in the range of 2μm to 9μm, 2μm to 8μm, 2μm to 7μm, 3μm to 9μm, 3μm to 8μm, or 3μm to 7μm, and D(v,0.9) is at most 16μm, for example, in the range of 10 to 16μm.

[0082] It goes without saying that for any given particle population, the value of D(v,0.9) will always be higher than the value of D(v,0.5). It is preferable that the difference between D(v,0.5) and D(v,0.9) be as small as possible, corresponding to the narrowest possible particle size distribution.

[0083] A narrow particle size distribution corresponds to a low ratio r, which is obtained by dividing the difference between the values ​​of D(v,0.9) and D(v,0.5) by the value of D(v,0.5), as expressed by the equation:

[0084]

number

[0085] [In the formula, r is > 0].

[0086] In some embodiments, the particle populations provided herein have a ratio r of at most 6, at most 5, at most 4.5, at most 4, at most 3.5, at most 3, at most 2.5, at most 2.4, at most 2.3, at most 2.2, at most 2.1, or at most 2. For example, in some embodiments, the particle populations provided herein have a ratio r in the range of 1 to 6, 1 to 5, 1 to 4, 1 to 3.5, 1 to 3, 1 to 2.5, 1 to 2.4, 1 to 2.3, 1 to 2.2, 1 to 2.1, or 1 to 2. In some embodiments, the particle populations provided herein have a ratio r in the range of 1.5 to 5, 1.5 to 4, 1.5 to 3.5, 1.5 to 3, 1.5 to 2.5, 1.5 to 2.4, 1.5 to 2.3, 1.5 to 2.2, 1.5 to 2.1, or 1.5 to 2. In some further embodiments, the particle populations provided herein have a ratio r in the range of 2–5, 2–4, 2–3.5, 2–3, 2–2.5, 2–2.4, 2–2.3, 2–2.2, or 2–2.1.

[0087] Preparation of Taskinimod particles Tuscinimod in powder form is commercially available, for example, from MilliporeSigma, and can also be prepared by following the methods described in, for example, WO03 / 106424 and WO2012 / 004338 (see above in this specification). As used herein, Tuscinimod particles can be prepared, for example, by micronization, starting from Tuscinimod in powder form and applying any suitable method to obtain particles with the desired particle size distribution using a general micronizer, such as a mechanical impact mill (spiral jet mill) or a fluid energy (fluidized bed) impact mill. In some embodiments, Tuscinimod particles are prepared by micronizing Tuscinimod powder in a fluid energy jet mill using nitrogen as the process gas. In some embodiments, tascinimod particles are prepared by preparing tascinimod as described in WO2012 / 004338, for example, Example 4 of WO2012 / 004338, and then pulverizing the resulting product, for example, using a fluid energy jet mill with nitrogen as the processing gas.

[0088] The taschinimod particles of the present invention may include crystalline taschinimod and amorphous taschinimod. In some embodiments, the particles consist at least partially of crystalline taschinimod, for example, at least 50% by weight of the total amount of taschinimod is crystalline, or at least 60% by weight, or at least 70% by weight, or at least 80% by weight, or at least 90% by weight, or at least 95% by weight, or at least 96% by weight, or at least 97% by weight, or at least 98% by weight, or at least 99% by weight of the total amount of taschinimod is crystalline. In some embodiments, the particles consist of crystalline taschinimod. In some other embodiments, at least a portion of the particles consist of amorphous taschinimod, or most of the particles consist of amorphous taschinimod, or all of the particles consist of amorphous taschinimod.

[0089] The particle size distribution of tasquinimod particles can be determined using laser diffraction techniques, such as a laser particle size analyzer, for example, a Malvern Mastersizer device commercially available from Malvern Panalytical.

[0090] Pharmaceutical composition The pharmaceutical compositions provided herein comprise the tasquinimod particles of the present invention, preferably one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises a filler (which may also be referred to as a "diluent") and / or a lubricant. Suitable fillers can be, for example, microcrystalline cellulose phthalate, pregelatinized starch such as corn-derived, mannitol, lactose monohydrate, microcrystalline cellulose, or calcium hydrogen phosphate. Suitable lubricants can be, for example, hardened vegetable oil, magnesium stearate, or sodium fumarate stearate.

[0091] In some embodiments, the lubricant is hardened vegetable oil. Hardened vegetable oil occurs as white to pale yellowish flakes or pellets. It is made from fully hydrogenated refined vegetable oil and spray-dried into fine powder. The molecular formula of hardened vegetable oil is R 1 COOCH2-CH(OOCR 2 )-CH2COOR 3 (where R 1 , R 2 and R 3 are mainly C15 and C17 alkyl). Examples of hardened vegetable oil that can be used in pharmaceutical compositions are Sterotex® commercially available from Abitec Corp. and Lubritab® commercially available from JRS Pharma.

[0092] In some embodiments, the filler is pregelatinized starch, i.e., starch granules that have been chemically and / or mechanically treated to rupture all or part of them, and has the molecular formula (C6H 10 O5) nThe formula is a starch having n = 300 to 1000. Non-limiting examples of pregelatinized starch that can be used in pharmaceutical compositions include Starch1500®, commercially available from Colorcon Inc., and Lycatab C®, commercially available from Roquette.

[0093] In some embodiments, the composition includes a filler such as pregelatinized starch and a lubricant such as hydrogenated vegetable oil.

[0094] In some embodiments, the composition comprises tascinimod particles, pregelatinized starch, and hydrogenated vegetable oil.

[0095] The pharmaceutical compositions provided herein may contain, for example, tascinimod particles in amounts of about 0.1 to about 10% of the total weight of the composition, or about 0.1 to about 9% of the total weight of the composition, for example, about 0.1 to about 8%, about 0.1 to about 7%, about 0.1 to about 6%, about 0.1 to about 5%, about 0.1 to about 4%, or about 0.1 to about 3%, about 0.1 to about 2%, or about 0.1 to about 1% of the total weight of the composition.

[0096] The pharmaceutical compositions provided herein may contain, for example, excipients in amounts of about 90 to about 99.9% of the total weight of the composition, or about 95 to about 99.9% of the total weight of the composition, for example, about 96 to about 99.9%, about 97 to about 99.9%, about 97.5 to about 99.9%, about 98 to about 99.9%, about 98.5 to about 99.9%, or about 99 to about 99.9% of the total weight of the composition.

[0097] Generally, the main component of excipients consists of fillers, while the amount of lubricant, if present, is generally a rather small amount of the total weight of the composition, for example, about 0.5–4% by weight, about 0.5–3% by weight, about 1–3% by weight, or about 1.5–2.5% by weight.

[0098] In some embodiments, the pharmaceutical compositions provided herein contain, based on the total weight of the composition, about 0.1 to 2% by weight of tascinimod particles, about 0.5 to 4% by weight of a lubricant, and about 94 to about 99.4% by weight of a filler; for example, about 0.1 to 1% by weight of tascinimod particles, about 1 to 3% by weight of a lubricant, and about 96 to about 98.9% by weight of a filler, based on the total weight of the composition.

[0099] In some embodiments, the composition comprises, based on the total weight of the composition, about 0.1 to 1% of Taskinimod particles, about 1.5 to 2.5% by weight of a lubricant, and about 96.5 to about 98.4% by weight of a filler.

[0100] A favorable feature of the pharmaceutical compositions provided herein is the rapid dissolution of tascinimod particles contained in the compositions. In some embodiments, at least 80% by weight, more preferably at least 85% by weight, of the tascinimod particles in the compositions dissolve within 30 minutes when tested in a Type I basket apparatus using 1 mg of the composition in 500 ml of 0.05 M phosphate buffer (pH 6.8) at a bath temperature of 37°C and a stirring speed of 100 rpm. Such a high dissolution rate corresponds to immediate release in vivo, and therefore, in some embodiments, the compositions of the present invention are useful as immediate-release formulations.

[0101] Medical dosage units Furthermore, pharmaceutical administration units containing a therapeutically effective amount of tascinimod in the form of tascinimod particles are also provided herein, as disclosed herein.

[0102] The pharmaceutical dosage unit may include, for example, 0.1 to 2 mg of tascinimod particles, for example, about 0.25 to 1.5 mg, particularly about 0.5 to about 1.25 mg, for example, 1.0 mg of tascinimod particles, and may optionally include one or more excipients.

[0103] In some embodiments, a pharmaceutical dose unit comprises a pharmaceutical composition as defined herein in an amount equivalent to a therapeutically effective dose of tascinimod particles, for example, 0.1 to 2 mg, for example, about 0.25 to 1.5 mg, and in particular about 0.5 to about 1.25 mg, for example, about 1.0 mg.

[0104] In some embodiments, the drug administration unit is suitable for oral administration, for example, it may be a capsule or tablet for oral administration.

[0105] In some embodiments, the drug administration unit is an immediate-release drug administration unit.

[0106] In some embodiments, the pharmaceutical administration unit is an orally administered capsule (which may also be referred to as an oral capsule), such as a hard-shell or soft-shell capsule, containing a pharmaceutically effective amount of the pharmaceutical composition disclosed herein. In some embodiments, the capsule is a hard-shell capsule, such as an HMPC or gelatin capsule. In some embodiments, the capsule is a size 4 or size 3 capsule. In some embodiments, the capsule is a hard-shell size 4 capsule, such as a hard-shell size 4 gelatin capsule.

[0107] In some embodiments, the pharmaceutical administration unit is a hard-shell capsule, e.g., a size 4 capsule, containing an effective amount of tascinimod particles and one or more pharmaceutically acceptable excipients, e.g., fillers and lubricants. In some embodiments, the capsule is a hard-shell capsule containing about 100 to 250 mg, e.g., about 150 to 200 mg, of the pharmaceutical composition provided herein. In some embodiments, the pharmaceutical administration unit is a size 4 or size 3 hard-shell capsule containing about 0.1 to 2 mg, e.g., about 0.25 to 1.5 mg, particularly about 0.5 to about 1.25 mg, e.g., 1.0 mg, of tascinimod particles, in combination with fillers and lubricants, e.g., pregelatinized starch and hydrogenated vegetable oil. In some embodiments, the pharmaceutical administration unit is a size 4 hard shell capsule containing about 0.5 to about 1.25 mg of tascinimod particles, for example, 1.0 mg of tascinimod particles, in combination with a filler and lubricant, for example, pregelatinized starch and hydrogenated vegetable oil.

[0108] The pharmaceutical compositions provided herein contain small, homogeneous tascinimod particles, enabling consistent and rapid release of tascinimod in the gastrointestinal tract of the treated subject, which is advantageous for the purpose of providing a dosage unit with high and uniform bioavailability of tascinimod. As shown herein, the pharmaceutical compositions of the present invention can be used to prepare immediate-release pharmaceutical dosage units. Thus, in some embodiments, the pharmaceutical dosage unit is an immediate-release oral dosage unit, such as an immediate-release capsule.

[0109] In some embodiments, the composition is provided in the form of an oral capsule having an enteric coating, i.e., a coating that resists dissolution under acidic conditions, and that dissolves only in the intestine, in order to provide immediate release of tascinimod in the intestinal compartment (delayed immediate release). Enteric coating materials are well known to those skilled in the art and are commercially available. A non-limiting example is Kollicoat® 100P, a coating material based on a methacrylic acid additive-ethyl acrylate copolymer. Thus, in some embodiments, the pharmaceutical administration units provided herein are delayed immediate release oral administration units, e.g., enteric capsules.

[0110] Use of multiple particles and compositions As mentioned above in this specification, the therapeutic activity of tascinimod in the treatment of various diseases has been previously demonstrated. Multiple tascinimod particles, pharmaceutical compositions and pharmaceutical administration units prepared using such particles are considered useful in therapy, particularly in the treatment of any of the diseases for which tascinimod has been previously shown to have therapeutic activity. Therefore, further embodiments include the multiple particles, pharmaceutical compositions and pharmaceutical administration units for use in the treatment of cancer.

[0111] Further embodiments include the use of multiple particles of tascinimod, or the use of a pharmaceutical composition containing such multiple particles in the manufacture of a pharmacopoeia for the treatment of cancer. In some embodiments, the manufacture includes encapsulating the pharmaceutical composition as defined herein by applying encapsulation techniques well known in the art. In other embodiments, the manufacture includes preparing tablets using tableting techniques well known in the art.

[0112] Further embodiments include a method for treating cancer by administering an effective amount of multiple particles or pharmaceutical compositions or dosage units of tascinimod provided herein to a mammal in need of such treatment. Preferably, the method includes oral administration of the composition, for example, in the form of oral tablets or capsules, preferably oral dosage units such as oral capsules.

[0113] In some embodiments, the cancer is selected from bladder cancer, melanoma, lung cancer, such as NSCLC (non-small cell lung cancer), colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, hematological malignancies, particularly advanced hematological malignancies, ovarian cancer, particularly platinum-resistant ovarian cancer, neuroendocrine tumors (NETs), and gastrointestinal neuroendocrine tumors (GEP-NETs). The cancer treated with the compositions of the present invention may be at any stage, e.g., early or late. In some embodiments, the treatment results in a sustained response in the individual after discontinuation of treatment. In some embodiments, the treatment results in a complete response, partial response, or disease stabilization in the individual.

[0114] In some embodiments, the cancer is a hematological cancer, such as leukemia, lymphoma, myelodysplastic syndrome, myeloproliferative neoplasm, or multiple myeloma. In some embodiments, the hematological cancer is selected from leukemia and multiple myeloma. In some embodiments, the hematological cancer is selected from leukemia, myelodysplastic syndrome, and myeloproliferative neoplasm.

[0115] In some embodiments, the blood cancer is leukemia. In some embodiments, the blood cancer is lymphoma. In some embodiments, the blood cancer is myelodysplastic syndrome. In some embodiments, the blood cancer is myeloproliferative neoplasm. In some embodiments, the blood cancer is multiple myeloma.

[0116] Leukemia can be selected from chronic lymphocytic leukemia, including hairy cell leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, and acute myeloid leukemia and its precursor, myelodysplastic syndrome. In some embodiments, leukemia is acute lymphoblastic leukemia, or acute myeloid leukemia and its precursor, myelodysplastic syndrome. In some embodiments, leukemia is acute lymphoblastic leukemia. In some embodiments, leukemia is acute myeloid leukemia.

[0117] In some embodiments, the myeloproliferative neoplasm is selected from the group consisting of myelofibrosis, essential thrombocythemia (ET), polycythemia vera (PV), chronic neutrophilic leukemia, chronic myeloid leukemia, acute myeloid leukemia, chronic eosinophilic leukemia, and mastocytosis. In some embodiments, the myeloproliferative neoplasm is selected from the group consisting of myelofibrosis, essential thrombocythemia, polycythemia vera, chronic neutrophilic leukemia, chronic eosinophilic leukemia, and mastocytosis. In some embodiments, the myeloproliferative neoplasm is selected from the group consisting of myelofibrosis, essential thrombocythemia, and polycythemia vera. In some embodiments, the myeloproliferative neoplasm is myelofibrosis. In some embodiments, the myeloproliferative neoplasm is essential thrombocythemia or polycythemia vera. Both essential thrombocythemia and polycythemia vera may develop into myelofibrosis. Accordingly, in some embodiments, the particles of the present invention or pharmaceutical compositions or pharmaceuticals prepared using the particles of the present invention are used to prevent or reduce the progression to the fibrotic phase of myeloproliferative neoplasms such as essential thrombocytosis or polycythemia vera. Accordingly, as used herein, the term "myelofibrosis" refers to primary myelofibrosis, as well as secondary myelofibrosis, including post-ET myelofibrosis and post-PV myelofibrosis. In some embodiments, myelofibrosis is primary myelofibrosis. In some embodiments, myelofibrosis is secondary myelofibrosis.

[0118] In some further embodiments, the cancer is a solid tumor, such as bladder cancer, prostate cancer, or breast cancer. In some embodiments, the cancer is selected from bladder cancer (e.g., certain non-muscle-invasive bladder cancer, muscle-invasive bladder cancer, metastatic bladder cancer, and urothelial bladder cancer), prostate cancer, and renal cell carcinoma. In some embodiments, the cancer is bladder cancer.

[0119] In the medical treatment of any given subject using any of the particles, pharmaceutical compositions, or pharmaceutical dosage units provided herein, the dosage level and frequency of administration are generally determined by the treating physician, taking into full consideration factors such as the sex, age, corporal weight, and relative health status of the subject being treated, the chosen route and form of administration, and the additional use of other drugs, such as in combination therapy.

[0120] Generally, the daily dose can range from a minimum of 0.001 mg per kg of body weight, or 0.002 mg per kg of body weight, or 0.005 mg per kg of body weight, or 0.01 mg per kg of body weight, to a maximum of 0.2 mg per kg of body weight, or 0.1 mg per kg of body weight, or 0.05 mg per kg of body weight, or 0.02 mg per kg of body weight.

[0121] In some embodiments, tascinimod particles are administered in doses of 0.1–4 mg / day, or 0.2–2 mg / day, 0.4–1.8 mg / day, 0.5–1.5 mg / day, or 0.6–1.2 mg / day, for example, 1 mg / day.

[0122] In some embodiments, the dosage can be gradually adjusted to achieve optimal results, a so-called dosage setting. For example, dosage setting may involve starting with a low dose of, for example, 0.25 mg per day and maintaining this dose level for a period of 1 to 2 weeks. If there are no serious side effects that would contraindicate increasing the dosage, the level may then be increased to, for example, 0.5 mg / day for 1 or 2 weeks, after which further increases may be considered, up to a daily dose of 1 mg. In such a method, if any serious side effects occur after dose escalation, the dosage may be reduced again to the previous level. Possible side effects include those commonly encountered in this type of treatment, such as gastrointestinal disorders, fatigue, and flu-like syndrome, which are thought to be dose-related.

[0123] Tascinimod is preferably administered daily, for example, 1 to 3 times a day, or 1 to 2 times a day, for example, once a day. However, in some embodiments, the drug is administered less frequently, for example, once every two days or once a week.

[0124] It should be noted that when a pharmaceutically acceptable salt of tascinimod is administered, the equivalent dose should result in the indicated dose of tascinimod in its non-salt form (i.e., as a free base).

[0125] The present invention is further illustrated by the following non-limiting embodiments. [Examples]

[0126] In the examples, the particle size distribution of Tuscinimod was determined using laser diffraction with a Malvern Mastersizer to determine the D(v,0.5) and D(v,0.9) values ​​for the finely milled Tuscinimod.

[0127] The analysis conditions are shown in Table 1.

[0128] [Table 1]

[0129] The filler used in the examples was pregelatinized starch, i.e., either Starch1500® or Lycatab C®, and the lubricant was hydrogenated vegetable oil, i.e., either Sterotex® or Lubritab®.

[0130] Example 1 Taskinimod particles with D(v,0.5) of 2.3 μm and D(v,0.9) of 6.9 μm. Tascinimod powder (80g) was atomized using a fluid energy jet mill with nitrogen as the processing gas. The supply rate of the unatomized material was controlled at 6 kg / h using a loss-in-weight screw feeder, and the Venturi pressure was set to 69-103 kPa (10-15 psi). The pulverizer pressure was set to 276 kPa (40 psi) or less and adjusted according to the results of in-process control analysis to obtain the desired particle size distribution parameters (D(v,0.5) and D(v,0.9)).

[0131] Example 2 Taskinimod particles with D(v,0.5) of 4.9 μm and D(v,0.9) of 14.0 μm. Taskinimod particles were prepared as described in Example 1.

[0132] Example 3 Taskinimod particles with D(v,0.5) of 6.4 μm and D(v,0.9) of 16.9 μm. Taskinimod particles were prepared as described in Example 1.

[0133] Example 4 Oral capsules containing 1.0 mg of tascinimod (D(v,0.5)2.3μm, D(v,0.9)6.9μm). Oral capsules containing the tascinimod particles of Example 1 as a mixture with a filler and a lubricant were prepared as follows: Tascinimod particles (0.5 g) were first blended with a filler (73 g), and then a lubricant (1.5 g) was added. The resulting mixture was filled into four-size white hard gelatin capsules. A total of 500 capsules were obtained, each capsule containing 150 mg of the mixture, which corresponds to an administration strength of 1.0 mg of tascinimod.

[0134] Example 5 Oral capsules containing 1.0 mg of tascinimod (D(v,0.5)4.9μm, D(v,0.9)14.0μm). Using the tascinimod particles from Example 2, the procedure of Example 4 was repeated to obtain 500 capsules, each containing a tascinimod dose of 1.0 mg.

[0135] Example 6 Oral capsules containing 1.0 mg of tascinimod (D(v,0.5)6.4μm, D(v,0.9)16.9μm). Using the tascinimod particles from Example 3, the procedure of Example 4 was repeated to obtain 500 capsules, each containing a tascinimod dose of 1.0 mg.

[0136] Comparative Example 1 Oral capsules containing 1.0 mg of tascinimod (D(v,0.5)15.9μm, D(v,0.9)38.1μm). Capsules containing micronized tascinimod particles with D(v,0.5) of 15.9 μm and D(v,0.9) of 38.1 μm were prepared according to the procedure of Example 4 as a mixture of a filler and a lubricant. Each capsule contained 150 mg of the mixture, corresponding to a tascinimod dose of 1.0 mg.

[0137] Comparative Example 2 Oral capsules containing 1.0 mg of tascinimod (D(v,0.5)22.4μm, D(v,0.9)63.8μm). Capsules containing micronized tascinimod particles with D(v,0.5) of 22.4 μm and D(v,0.9) of 63.8 μm were prepared according to the procedure of Example 4 as a mixture of a filler and a lubricant. Each capsule contained 150 mg of the mixture, corresponding to an administration strength of 1.0 mg of tascinimod.

[0138] Comparative Example 3 Oral capsules containing 1.0 mg of tascinimod (D(v,0.5)39.9μm, D(v,0.9)121.1μm). Capsules containing unparticulated taskinimod particles with D(v,0.5) of 39.9 μm and D(v,0.9) of 121.0 μm as a mixture of a filler and a lubricant were prepared according to the procedure of Example 4. Each capsule contained 150 mg of the mixture, corresponding to an administration strength of 1.0 mg of taskinimod.

[0139] Dissolution Profile The elution rates of Examples 4-6 and Comparative Examples 1-3 were tested using a European Pharmacopoeia / United States Pharmacopoeia elution apparatus 1 (Type I basket) with a volume of 500 mL of elution medium, at a bath temperature of 37°C and a stirring speed of 100 rpm, and also by liquid chromatography (LC) sample testing.

[0140] The elution medium was 0.05 M phosphate buffer (pH 6.8), selected to ensure that at least 85% of tascinimod would elute at the end of the test. Tascinimod is a weak acid with a pKa of 6.5, and its solubility increased with pH. The resulting elution profile is shown in Figure 1. Even with a D(v,0.5) of only 15.9 μm, the elution rate of tascinimod particles was surprisingly low.

[0141] For further investigation, the obtained elution profiles were statistically compared with those of Example 5, which was selected as a reference, using the f1 / f2 test (model independent approach with similarity factors) (see Table 2).

[0142] [Table 2]

[0143] In a comparison of dissolution profiles using f1 / f2 values, f1 values ​​up to 15 (0-15) and f2 values ​​greater than 50 (50-100) are considered to indicate similarity or equivalence between the two dissolution profiles. The f1 / f2 statistical comparison test showed that capsules in Examples 4 and 6 containing tascinimod particles with D(v,0.5) of 2.3 μm and 6.4 μm, respectively, had dissolution profiles similar to Example 5, while Comparative Examples 1-3 containing tascinimod particles with D(v,0.5) of 15.9-39.9 μm had dissolution profiles corresponding to significantly slower dissolution rates than Example 5.

[0144] Example 7 Taskinimod particles with D(v,0.5) of 7.5 μm and D(v,0.9) of 24.7 μm. Taskinimod particles (total amount 4.5 kg) were prepared essentially as described in Example 1.

[0145] Example 8 Taskinimod particles with D(v,0.5) being 4.3 μm and D(v,0.9) being 18.3 μm. Taskinimod particles (total amount 0.9 kg) were prepared essentially as described in Example 1.

[0146] Example 9 Taskinimod particles with D(v,0.5) of 3.4 μm and D(v,0.9) of 11.5 μm. Taskinimod particles (total amount 4.5 kg) were prepared essentially as described in Example 1.

[0147] The particle size distribution was measured for the particles in Examples 7-9. The results are shown in Figure 2.

[0148] Example 10 Taskinimod particles with D(v,0.5) of 8.5 μm and D(v,0.9) of 21.7 μm. Tascinimod particles (total amount 2.8 kg) were prepared essentially as described in Example 1.

[0149] Example 11 Oral capsules containing 0.25 mg of tascinimod (D(v,0.5)7.5μm, D(v,0.9)24.7μm). Oral capsules containing the tascinimod particles of Example 7 were prepared on an industrial scale as a mixture of filler and lubricant as follows: Tascinimod particles (0.17% of the total weight of the mixture) were first blended with the filler (97.83% of the total weight of the mixture), and then the lubricant (2.00% of the total weight of the mixture) was added. The resulting mixture (180 kg) was filled into four-size white hard gelatin capsules. Each capsule contained 150 mg of the mixture, corresponding to an administration strength of 0.25 mg of tascinimod, and the maximum batch size was 1,200,000 capsules.

[0150] Example 12 Oral capsules containing 0.5 mg of tascinimod (D(v,0.5)4.3μm, D(v,0.9)18.3μm). Oral capsules containing the tascinimod particles of Example 8 were prepared on an industrial scale as a mixture of filler and lubricant as follows: Tascinimod particles (0.33% of the total weight of the mixture) were first blended with the filler (97.67% of the total weight of the mixture), and then the lubricant (2.00% of the total weight of the mixture) was added. The resulting mixture (180 kg) was filled into four-size white hard gelatin capsules. Each capsule contained 150 mg of the mixture, corresponding to an administration strength of 0.5 mg of tascinimod, and the maximum batch size was 1,200,000 capsules.

[0151] Example 13 Oral capsules containing 1.0 mg of tascinimod (D(v,0.5)3.4μm, D(v,0.9)11.5μm). Oral capsules containing the tascinimod particles of Example 9 were prepared on an industrial scale as a mixture of filler and lubricant as follows: Tascinimod particles (0.67% of the total weight of the mixture) were first blended with the filler (97.33% of the total weight of the mixture), and then the lubricant (2.00% of the total weight of the mixture) was added. The resulting mixture (180 kg) was filled into four-size white hard gelatin capsules. Each capsule contained 150 mg of the mixture, corresponding to an administration strength of 1.0 mg of tascinimod, and the maximum batch size was 1,200,000 capsules.

[0152] Example 14 Oral capsules containing 1.0 mg of tascinimod (D(v,0.5)8.5μm, D(v,0.9)21.7μm). Oral capsules containing tascinimod particles from Example 10 were prepared on an industrial scale as a mixture of filler and lubricant as follows: Tascinimod particles (0.67% of the total weight of the mixture) were first blended with the filler (97.33% of the total weight of the mixture), and then the lubricant (2.00% of the total weight of the mixture) was added. The resulting mixture (180 kg) was filled into four-size white hard gelatin capsules. Each capsule contained 150 mg of the mixture, corresponding to a tascinimod dosage strength of 1.0 mg, and the maximum batch size was 1,200,000 capsules. The dissolution rates of the capsules from Examples 13 and 14 were measured using the assays described above in this specification. The results are shown in Figure 3.

[0153] Example 15 Taskinimod particles with D(v,0.5) of 4.8 μm and D(v,0.9) of 16.0 μm. Taskinimod particles (total amount 0.9 kg) were prepared essentially as described in Example 1.

[0154] Example 16 Taskinimod particles with D(v,0.5) of 5.2 μm and D(v,0.9) of 16.0 μm. Taskinimod particles (total amount 2.0 kg) were prepared essentially as described in Example 1.

[0155] Example 17 Oral capsules containing 1.0 mg of tascinimod (D(v,0.5)4.8μm, D(v,0.9)16μm). Using the tascinimod particles from Example 15, the procedure of Example 13 was repeated to obtain 200,000 capsules, each containing 1.0 mg of tascinimod.

[0156] Examples 18-20 Oral capsules containing 1.0 mg of tascinimod (D(v,0.5) 5.2 μm, D(v,0.9) 16 μm). Using the tascinimod particles from Example 16, the procedure of Example 13 was repeated to obtain three batches of 200,000 capsules, each containing 1.0 mg of tascinimod.

[0157] The dissolution rates of the capsules from Examples 17-20 were measured using the assay described above in this specification. The results are shown in Figure 4.

[0158] As illustrated in Figure 4, the dissolution profiles of capsules from different batches are very similar for capsules containing tascinimod particles with D(v,0.5) of 4.8 μm (Example 17) and 5.2 μm (Examples 18-20), respectively, and the dissolution profiles correspond to immediate-release formulations.

[0159] Example 21 Taskinimod particles with D(v,0.5) of 6.0 μm and D(v,0.9) of 16 μm. Tascinimod powder (300g) was atomized using an Alpine® Spiral Jet Mill 50 AS (manufactured by Hosokawa Alpine AG, Germany) with nitrogen as the processing gas. The supply rate of unatomized material was controlled at 10g / min using a vibrating feeder, and the injector pressure was set to 1.8 to 5 bar (180 to 500kPa). The pulverizer pressure was set to 0.5 to 1 bar to obtain the desired particle size distribution parameters (D(v,0.5) and D(v,0.9)).

[0160] Example 22 Oral capsules containing 0.25 mg of tascinimod (D(v,0.5)6.0μm, D(v,0.9)16μm). Oral capsules containing the tascinimod particles of Example 21 were prepared on an industrial scale as a mixture of filler and lubricant as follows: Tascinimod particles (0.17% of the total weight of the mixture) were first blended with the filler (97.83% of the total weight of the mixture), and then the lubricant (2.00% of the total weight of the mixture) was added. The resulting mixture (7.5 kg) was filled into four-size white hard gelatin capsules. Each capsule contained 150 mg of the mixture, corresponding to an administration strength of 0.25 mg of tascinimod, and the maximum batch size was 50,000 capsules.

[0161] The dissolution rate of the capsules in Example 22 was measured using the assay described above in this specification. The resulting dissolution profile was similar to that of Examples 17-20 and corresponded to an immediate-release formulation. The following is a description of the claims as they were at the time of filing the application. [Claim 1] Multiple particles comprising tascinimod in free base form or as a pharmaceutically acceptable salt, wherein D(v,0.9) is at most 30 μm and D(v,0.5) is at most 15 μm. [Claim 2] A plurality of particles according to claim 1, wherein D(v,0.9) is at most 25 μm and D(v,0.5) is in the range of 2 μm to 9 μm. [Claim 3] A plurality of particles according to claim 1 or 2, wherein D(v,0.5) is in the range of 3 to 7 μm. [Claim 4] A plurality of particles according to any one of claims 1 to 3, for use in therapy. [Claim 5] A pharmaceutical composition comprising a plurality of particles according to any one of claims 1 to 3, and one or more pharmaceutically acceptable excipients. [Claim 6] A pharmaceutical composition according to claim 5, comprising the plurality of particles in an amount of 0.1 to 10% by weight of the composition. [Claim 7] The pharmaceutical composition according to claim 5 or 6, wherein the pharmaceutically acceptable excipients include a filler and a lubricant. [Claim 8] A pharmaceutical administration unit comprising the pharmaceutical composition according to any one of claims 5 to 7. [Claim 9] The pharmaceutical administration unit according to claim 8, comprising a plurality of particles in an amount ranging from 0.1 mg to 2 mg, preferably ranging from 0.2 mg to 1 mg. [Claim 10] A pharmaceutical administration unit according to claim 8 or 9 for oral administration. [Claim 11] A pharmaceutical administration unit according to claim 10, which is a capsule or a tablet. [Claim 12] A drug administration unit according to any one of claims 8 to 11, which is an immediate-release drug administration unit. [Claim 13] A plurality of particles according to any one of claims 1 to 3, or a pharmaceutical composition according to any one of claims 5 to 7, or a pharmaceutical administration unit according to any one of claims 8 to 12, for use in the treatment of cancer. [Claim 14] A plurality of particles, a pharmaceutical composition, or a pharmaceutical administration unit for use according to claim 13, wherein the cancer is a blood cancer or a solid tumor. [Claim 15] A plurality of particles, pharmaceutical compositions, or pharmaceutical administration units for use according to claim 14, wherein the hematological cancer is selected from multiple myeloma, lymphoma, myelodysplastic syndrome, myeloproliferative neoplasm, and leukemia, and / or the solid tumor is selected from bladder cancer, melanoma, lung cancer, colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, ovarian cancer, neuroendocrine tumors (NETs), and gastrointestinal neuroendocrine tumors (GEP-NETs). [Claim 16] Use of a plurality of particles according to any one of claims 1 to 3 or a pharmaceutical composition according to any one of claims 5 to 7 in the manufacture of a pharmaceutical for the treatment of cancer. [Claim 17] The use according to claim 16, wherein the cancer is a blood cancer or a solid tumor. [Claim 18] The use according to claim 17, wherein the hematological cancer is selected from multiple myeloma, lymphoma, myelodysplastic syndrome, myeloproliferative neoplasm and leukemia, and / or the solid tumor is selected from bladder cancer, melanoma, lung cancer, colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, ovarian cancer, neuroendocrine tumors (NETs) and gastrointestinal neuroendocrine tumors (GEP-NETs). [Claim 19] A method for treating cancer, comprising administering to a mammal in need of treatment a therapeutically effective amount of a plurality of particles according to any one of claims 1 to 3, or a pharmaceutical composition according to any one of claims 5 to 7, or a pharmaceutical administration unit according to any one of claims 8 to 12. [Claim 20] The method according to claim 19, wherein the cancer is a blood cancer or a solid tumor. [Claim 21] The method according to claim 20, wherein the hematological cancer is selected from multiple myeloma, lymphoma, myelodysplastic syndrome, myeloproliferative neoplasm and leukemia, and / or the solid tumor is selected from bladder cancer, melanoma, lung cancer, colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, ovarian cancer, neuroendocrine tumors (NETs) and gastrointestinal neuroendocrine tumors (GEP-NETs).

Claims

1. Multiple particles comprising tascinimod in free base form or as a pharmaceutically acceptable salt, wherein D(v, 0.9) is at most 30 μm and D(v, 0.5) is at most 15 μm.

2. A plurality of particles according to claim 1, wherein D(v, 0.9) is at most 25 μm and D(v, 0.5) is in the range of 2 μm to 9 μm.

3. A plurality of particles according to claim 1 or 2, wherein D(v, 0.5) is in the range of 3 to 7 μm.

4. A pharmaceutical composition comprising a plurality of particles as described in claim 1, and one or more pharmaceutically acceptable excipients.

5. A pharmaceutical composition according to claim 4, comprising the plurality of particles in an amount of 0.1 to 10% by weight of the composition.

6. The pharmaceutical composition according to claim 4, wherein the pharmaceutically acceptable excipients include a filler and a lubricant.

7. A pharmaceutical composition according to any one of claims 4 to 6 for the treatment of cancer.

8. The pharmaceutical composition according to claim 7, wherein the cancer is a blood cancer or a solid tumor.

9. The pharmaceutical composition according to claim 8, wherein the hematological cancer is selected from multiple myeloma, lymphoma, myelodysplastic syndrome, myeloproliferative neoplasm and leukemia, and / or the solid tumor is selected from bladder cancer, melanoma, lung cancer, colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, ovarian cancer, neuroendocrine tumor (NET) and gastrointestinal neuroendocrine tumor (GEP-NET).

10. A pharmaceutical administration unit comprising the pharmaceutical composition described in claim 4.

11. The pharmaceutical administration unit according to claim 10, comprising a plurality of particles in an amount ranging from 0.1 mg to 2 mg, preferably in the range of 0.2 mg to 1 mg.

12. A pharmaceutical administration unit according to claim 10 for oral administration.

13. The pharmaceutical administration unit according to claim 12, which is a capsule or a tablet.

14. The drug administration unit according to claim 10, which is an immediate-release drug administration unit.

15. A pharmaceutical administration unit according to any one of claims 10 to 14 for the treatment of cancer.

16. The pharmaceutical administration unit according to claim 15, wherein the cancer is a blood cancer or a solid tumor.

17. The pharmaceutical administration unit according to claim 16, wherein the hematological cancer is selected from multiple myeloma, lymphoma, myelodysplastic syndrome, myeloproliferative neoplasm, and leukemia, and / or the solid tumor is selected from bladder cancer, melanoma, lung cancer, colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, ovarian cancer, neuroendocrine tumor (NET), and gastrointestinal neuroendocrine tumor (GEP-NET).

Images