Tasquinimod particles and uses thereof

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 tasquinimod or a pharma- ceutically acceptable salt of tasquinimod, and their use in therapy, as well as to pharmaceutical compositions containing such a plurality of particles. The present invention further relates to a solid pharmaceutical dosage unit, e.g., a solid oral pharmaceutical dosage form such as a capsule or tablet for oral administration, containing a plurality of such particles. [Background technology]

[0002] Tasquinimod and methods for its preparation are described in International Application No. PCT / SE99 / 00676, published as WO 99 / 55678, and International Application No. PCT / SE99 / 01270, published as WO 00 / 03991, which also disclose the utility of tasquinimod and several other quinoline carboxamides for the treatment of diseases of autoimmune origin, 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 tasquinimod 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. Deuterated forms of tasquinimod were 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 particularly solid cancers such as prostate and breast cancer, was disclosed in International Application No. PCT / SE00 / 02055, published as WO01 / 30758. These compounds have been found to bind to and inhibit the interaction of an immunomodulatory protein (S100A9), which promotes tumorigenesis, influences suppressive and proangiogenic cells in the tumor microenvironment, and is involved in the establishment of pre-metastatic niches.

[0005] International Application No. PCT / EP2015 / 075769, published as WO2016 / 078921, discloses tasquinimod for use in the treatment of leukemia, including acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia. International Application No. PCT / EP2015 / 071391, published as WO2016 / 042112, discloses tasquinimod for use in the treatment of multiple myeloma. International Application No. PCT / EP2016 / 053288, published as WO2016 / 146329, discloses tasquinimod for use in combination with a PD-1 and / or PD-L1 inhibitor in the treatment of cancer, particularly bladder cancer. The use of tasquinimod 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 tasquinimod for the treatment of myelodysplastic syndromes is described in 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 establish that a certain compound has therapeutic activity useful for treating a certain disease, but it must also be provided in a suitable form for its administration in order to be practically useful. Oral administration of drugs is usually desirable 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 that must be considered relate to the oral dosage form, including ease of manufacture, stability and shelf life of the formulation, and ease of use for patients. For example, to obtain accurate and consistent dosage, unit dosage formulations, such as capsules and tablets, may be preferred compared to liquid formulations, although the former are generally still preferred for ease of transportation and in the case of poor-tasting drug substances. Summary of the Invention [Means for solving the problem]

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

[0008] [ka]

[0009] It is a compound having the formula:

[0010] Tasquinimod is a compound with high gastrointestinal permeability and high water solubility. In fact, in a gastrointestinal permeability test of tasquinimod using a Caco-2 cell model, the permeability coefficient of tasquinimod was 43.5 ± 0.9.10. -6 cm.s -1Therefore, tasquinimod is classified as "highly permeable" by the Biopharmaceutics Classification System (BCS). For a drug compound to be classified as "highly soluble" by the BCS, its maximum single therapeutic dose should be completely soluble in 250 ml or less of aqueous medium over the pH range of 1.2 to 6.8 at 37 ± 1°C. The solubility of tasquinimod exceeds this cutoff value 10 times under defined conditions, whereas at physiological pH 7.4, the solubility is 50 times higher than this cutoff value, i.e., the solubility of tasquinimod at pH 7.4 is as high as 0.25 mg / ml. Based on these properties, tasquinimod is classified as a BCS class I compound. When the highly soluble tasquinimod is formulated into an immediate release formulation, it is expected that 85% or more of the dissolution criteria will be released within 30 minutes at 37°C, and the dissolution rate will be high. However, the inventors have found that the dissolution rate of tasquinimod particles is surprisingly low. Given the high water solubility of tasquinimod, the low dissolution rate of tasquinimod particles in the aqueous phase was completely unexpected. A low dissolution rate is likely to result in low bioavailability and may hinder the efficient oral administration of other therapeutically active compounds.

[0011] Thus, the present invention is based on the surprising discovery that tasquinimod, a highly water-soluble compound, is adversely affected by an unexpectedly low aqueous dissolution rate.

[0012] Thus, a first aspect is 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 up to 30 μm and a D(v,0.5) of up to 15 μm.

[0013] A further aspect is a plurality of particles of tasquinimod, in free base form or as a pharma- ceutically acceptable salt, as defined herein, for use in therapy.

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

[0015] A further aspect is a pharmaceutical dosage unit comprising a pharmaceutical composition as defined herein.

[0016] A further embodiment is a plurality of particles, or pharmaceutical composition, or pharmaceutical dosage unit of tasquinimod, as defined herein, for use in the treatment of cancer, which may be selected from multiple myeloma, lymphoma, myelodysplastic syndrome, myeloproliferative neoplasms, leukemia, bladder cancer, melanoma, lung cancer, colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, ovarian cancer, neuroendocrine tumors (NETs) and gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

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

[0018] [Figure 1] FIG. 1 represents the weight percent of tasquinimod dissolved as a function of time from capsules of Examples 4-6 containing 1 mg of tasquinimod particles with D(v,0.5) of 2.3 μm, 4.9 μm, and 6.4 μm, respectively, and from capsules of Comparative Examples 1-3 (not according to the invention) containing 1 mg of tasquinimod particles with D(v,0.5) of 15.9 μm, 22.4 μm, and 39.9 μm, respectively, in an in vitro dissolution test. [Diagram 2] FIG. 13 depicts density distribution (q3) as a function of particle size (μm) for tasquinimod particles of Examples 7, 8 and 9, measured by laser diffraction. [Diagram 3]FIG. 13 depicts the weight percent of tasquinimod dissolved as a function of time from capsules of Examples 13 and 14, each containing 1 mg of tasquinimod particles having D(v,0.5) of 3.4 μm and 8.5 μm, respectively, in an in vitro dissolution study. [Figure 4] FIG. 13 shows the weight percent of tasquinimod dissolved as a function of time from capsules of Example 17 containing 1.0 mg of tasquinimod particles having a D(v,0.5) of 4.8 μm, and capsules of Examples 18-20 containing 1.0 mg of tasquinimod particles having a D(v,0.5) of 5.2 μm. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

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

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

[0022] As used herein, the term "effective" refers to an amount effective to achieve a purpose, i.e., an amount of a component sufficient to bring about an indicated therapeutic response without undue adverse side effects (e.g., toxicity, irritation, or allergic reaction, etc.) commensurate with a reasonable benefit / risk ratio, as in "therapeutically effective amount," when used in the manner of this disclosure. Effective amounts may vary according to factors known in the art, such as the condition, age, sex, and weight of the human or animal being treated.

[0023] The term "excipient" refers to a pharma- ceutically acceptable chemical to aid in the administration of a medicinal agent, as known to those of ordinary skill in the pharmaceutical arts. It is generally a safe, non-toxic, non-biologically undesirable compound that is useful in preparing pharmaceutical compositions, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. Exemplary excipients include encapsulating agents, sweeteners, taste-masking agents, carriers, binders, fillers, diluents, disintegrants, anti-adherents, and lubricants.

[0024] The term "filler" (which may also be referred to in the pharmaceutical arts as a "diluent" or "bulking agent") refers to an ingredient (excipient) in a pharmaceutical composition that lacks pharmacological activity but is pharma- ceutical necessary or desirable to enhance or improve the properties of a pharmaceutical blend, e.g., for manufacturing or physiological purposes. For example, fillers can be used to increase the bulk of an active ingredient whose mass is too small to manufacture or administer.

[0025] The term "lubricant" refers to an excipient that, for example, prevents ingredients and excipients from clumping together and / or sticking to a dosage form filling machine. Lubricants also ensure that the formation, filling, and emptying of the dosage form can be performed reliably, for example, by reducing friction. Examples of lubricants are 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 of a solid material. Usually, the term micronization is used when the resulting product particles are only a few micrometers in diameter (typically less than 10 μm). Atomization techniques are typically based on the use of friction to reduce particle size, for example, by grinding and milling.

[0027] "Optionally" or "in some cases" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur.

[0028] As used herein, the term "pharmaceutical dosage unit" includes any device useful for administering a given dose of a drug to a patient, such as a capsule, tablet, sachet, microcapsule, etc.

[0029] "Pharmaceutically acceptable" means a material that is not biologically or otherwise undesirable, i.e., a material that may be administered to an individual, together with the active compound with which it is associated, without causing clinically unacceptable biological effects or interacting in a deleterious manner with any other components of the formulation in which it is contained.

[0030] As used herein, the term "subject" refers to a mammal. Mammals contemplated by the present invention include humans and non-human mammals, such as mammals selected from primates, domesticated animals, such as agricultural livestock such as cows, sheep, pigs, horses, and pet animals, such as dogs and cats. Preferably, the mammal is a human.

[0031] Hereinafter, the expressions "taskinimod particles" or "particles of taskinimod" may be used and should be understood to refer to particles of taskinimod, and "taskinimod," unless clear from the context or otherwise specified, should be understood to refer to either taskinimod free base or taskinimod in the form of a pharma- ceutically acceptable salt.

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

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

[0034] As used herein, "treating" includes, for example, inhibiting, inducing regression or stasis of a disease, disorder or condition, or ameliorating or relieving the symptoms of a disease, disorder or condition.

[0035] As used herein, "ameliorating" or "alleviating" a condition or state shall mean alleviating or lessening the symptoms of the condition or state. As used herein, "inhibiting" a worsening condition or disease complication in a subject means preventing or reducing the worsening condition and / or disease complication in a subject.

[0036] Multiple Tasquinimod Particles The tasquinimod particles present in the plurality of tasquinimod particles provided herein consist essentially of tasquinimod, meaning that at least 90% by weight of the particle consists of tasquinimod, 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 consists of tasquinimod.

[0037] As stated herein, in order to have the required dissolution rate, the tasquinimod particles should have a particle size distribution characterized by a D(v,0.9) of at most 30 μm.

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

[0039] In some embodiments, the particles have a D(v,0.9) of about 30 μm. In some embodiments, the particles have a D(v,0.9) of about 29 μm. In some embodiments, the particles have a D(v,0.9) of about 28 μm. In some embodiments, the particles have a D(v,0.9) of about 27 μm. In some embodiments, the particles have a D(v,0.9) of about 26 μm. In some embodiments, the particles have a D(v,0.9) of about 25 μm. In some embodiments, the particles have a D(v,0.9) of about 24 μm. In some embodiments, the particles have a D(v,0.9) of about 23 μm. In some embodiments, the particles have a D(v,0.9) of about 22 μm. In some embodiments, the particles have a D(v,0.9) of about 21 μm. In some embodiments, the particles have a D(v,0.9) of about 20 μm. In some embodiments, the particles have a D(v,0.9) of about 19 μm. In some embodiments, the particles have a D(v,0.9) of about 18 μm. In some embodiments, the particles have a D(v,0.9) of about 17 μm. In some embodiments, the particles have a D(v,0.9) of about 16 μm. In some embodiments, the particles have a D(v,0.9) of about 15 μm. In some embodiments, the particles have a D(v,0.9) of about 14 μm. In some embodiments, the particles have a D(v,0.9) of about 13 μm. In some embodiments, the particles have a D(v,0.9) of about 12 μm. In some embodiments, the particles have a D(v,0.9) of about 11 μm. In some embodiments, the particles have a D(v,0.9) of about 10 μm. In some embodiments, the particles have a D(v,0.9) of about 9 μm. In some embodiments, the particles have a D(v,0.9) of about 8 μm. In some embodiments, the particles have a D(v,0.9) of about 7 μm. In some embodiments, the particles have a D(v,0.9) of about 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, in the range of 7-12 μm, in the range of 8-12 μm, in the range of 9-12 μm, in the range of 10-12 μm, or in the range of 11-12 μm.

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

[0060] In some embodiments, the particles have a D(v,0.9) in the range of 6-10 μm, in the range of 7-10 μm, in the range of 8-10 μm, or in the range of 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 tasquinimod particles provided herein should have a particle size distribution characterized by a D(v,0.5) of at most 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 particles have a D(v,0.5) of 4 μm. In some embodiments, the particles have a D(v,0.5) of 3 μm. In some embodiments, the particles have a D(v,0.5) of 2 μm. In some embodiments, the particles have a D(v,0.5) of 1 μm.

[0063] In some embodiments, the particles have a D(v,0.5) in the range 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, or 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, in the range of 2-11 μm, in the range of 3-11 μm, in the range of 4-11 μm, in the range of 5-11 μm, in the range of 6-11 μm, in the range of 7-11 μm, in the range of 8-11 μm, in the range of 9-11 μm, or in the range of 10-11 μm.

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

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

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

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

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

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

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

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

[0076] Typically, 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] Thus, 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 2 μm to 9 μm, in the range of 2 μm to 8 μm, in the range of 2 μm to 7 μm, in the range of 3 μm to 9 μm, in the range of 3 μm to 8 μm, or in the range of 3 μm to 7 μm, and D(v,0.9) is at most 20 μm, e.g., in the range of 10 to 20 μm.

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

[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 preferred that the difference between D(v,0.5) and D(v,0.9) is as small as possible, corresponding to the narrowest possible particle size distribution.

[0083] A narrow particle size distribution corresponds to a low value of the ratio r, 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] [wherein r is >0].

[0086] In some embodiments, 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, 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, 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 to 5, 2 to 4, 2 to 3.5, 2 to 3, 2 to 2.5, 2 to 2.4, 2 to 2.3, 2 to 2.2, or 2 to 2.1.

[0087] Preparation of tasquinimod particles Powder form of tasquinimod is commercially available, for example, from MilliporeSigma, and can also be prepared, for example, by following the methods described in WO03 / 106424 and WO2012 / 004338 (see herein above). As used herein, tasquinimod particles can be prepared by starting from powder form of tasquinimod and applying any suitable method to obtain particles of the required particle size distribution, for example, by micronization, using common micronization equipment, such as mechanical impact mills (spiral jet mills) or fluid energy (fluidized bed) impact mills. In some embodiments, tasquinimod particles are prepared by micronizing tasquinimod powder in a fluid energy jet mill using nitrogen as the process gas. In some embodiments, the tasquinimod particles are prepared by preparing tasquinimod as described in WO2012 / 004338, e.g., in Example 4 of WO2012 / 004338, and micronizing the resulting product, e.g., using a fluid energy jet mill using nitrogen as the process gas.

[0088] The taskinimod particles of the present invention can include crystalline taskinimod as well as amorphous taskinimod. In some embodiments, the particles are at least partially composed of crystalline taskinimod, for example, at least 50% by weight of the total amount of taskinimod 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 taskinimod is crystalline. In some embodiments, the particles are composed of crystalline taskinimod. In some other embodiments, at least a portion of the particles are composed of amorphous taskinimod, or most of the particles are composed of amorphous taskinimod, or all of the particles are composed of amorphous taskinimod.

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

[0090] Pharmaceutical Compositions The pharmaceutical composition provided herein comprises the tasquinimod particles of the present invention, preferably one or more pharma- ceutically 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 may be, for example, silicified microcrystalline cellulose, pregelatinized starch, such as from corn, mannitol, lactose monohydrate, microcrystalline cellulose, or calcium hydrogen phosphate. Suitable lubricants may be, for example, hydrogenated vegetable oil, magnesium stearate, or sodium stearate fumarate.

[0091] In some embodiments, the lubricant is hydrogenated vegetable oil. Hydrogenated vegetable oil occurs as white to off-white flakes or pellets. It is made from fully hydrogenated refined vegetable oils, which are atomized into a dry fine powder. The molecular formula of hydrogenated vegetable oil is R 1 COOCH2-CH(OOCR 2 )-CH2COOR 3 (In the formula, R 1 , R 2 and R 3 are primarily C15 and C17 alkyl). Examples of hydrogenated vegetable oils that can be used in the pharmaceutical compositions are Sterotex® available from Abitec Corp. and Lubritab® available from JRS Pharma.

[0092] In some embodiments, the filler is pregelatinized starch, i.e., it has been chemically and / or mechanically treated to rupture all or part of the starch granules, and has the molecular formula (CH 10 O5) nwhere n=300-1000. Non-limiting examples of pregelatinized starches that can be used in the pharmaceutical composition are Starch 1500® available from Colorcon Inc. and Lycatab C® 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 tasquinimod particles, pregelatinized starch, and hydrogenated vegetable oil.

[0095] Pharmaceutical compositions provided herein can contain tasquinimod particles in an amount of, for example, about 0.1 to about 10% by total weight of the composition, or about 0.1 to about 9% by total weight of the composition, e.g., 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% by total weight of the composition.

[0096] The pharmaceutical compositions provided herein can comprise an excipient(s) in an amount of, for example, 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, e.g., 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 major portion of the excipients will consist of fillers, while the amount of lubricant, if present, will generally be rather small, e.g., about 0.5-4%, about 0.5-3%, about 1-3%, or about 1.5-2.5% by weight of the total weight of the composition.

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

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

[0100] An advantageous feature of the pharmaceutical compositions provided herein is the rapid dissolution of the tasquinimod particles contained in the composition. In some embodiments, at least 80% by weight, more preferably at least 85% by weight, of the tasquinimod particles of the composition dissolves 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 an agitation speed of 100 rpm. Such a high dissolution rate corresponds to an immediate release in vivo, and therefore, in some embodiments, the compositions of the present invention are useful as immediate release formulations.

[0101] Pharmaceutical Dosage Unit Also provided herein is a pharmaceutical dosage unit containing a therapeutically effective amount of tasquinimod in the form of tasquinimod particles as disclosed herein.

[0102] A pharmaceutical dosage unit can, for example, contain 0.1 to 2 mg of tasquinimod particles, such as about 0.25 to 1.5 mg, particularly about 0.5 to about 1.25 mg, such as 1.0 mg of tasquinimod particles, and optionally one or more excipients.

[0103] In some embodiments, the pharmaceutical dosage unit comprises an amount of a pharmaceutical composition as defined herein that corresponds to a therapeutically effective amount of tasquinimod particles, e.g., 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., about 1.0 mg.

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

[0105] In some embodiments, the pharmaceutical dosage unit is an immediate release pharmaceutical dosage unit.

[0106] In some embodiments, the pharmaceutical dosage unit is a capsule suitable for oral administration (also referred to as an oral capsule), such as a hard or soft shell capsule, that contains a pharma- ceutical 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 dosage unit is a hard shell capsule, e.g., a size 4 capsule, containing an effective amount of tasquinimod particles and one or more pharma- ceutically acceptable excipients, e.g., fillers and lubricants. In some embodiments, the capsule is a hard shell capsule containing about 100-250 mg, e.g., about 150-200 mg, of a pharmaceutical composition provided herein. In some embodiments, the pharmaceutical dosage unit is a size 4 or size 3 hard shell capsule containing about 0.1-2 mg, e.g., about 0.25-1.5 mg, particularly about 0.5-1.25 mg, e.g., 1.0 mg, of tasquinimod particles, in combination with fillers and lubricants, e.g., pregelatinized starch and hydrogenated vegetable oil. In some embodiments, the pharmaceutical dosage unit is a size 4 hard shell capsule containing about 0.5 to about 1.25 mg of tasquinimod particles, e.g., 1.0 mg of tasquinimod particles, in combination with a filler and a lubricant, e.g., pregelatinized starch and hydrogenated vegetable oil.

[0108] The pharmaceutical compositions provided herein contain small, uniformly sized tasquinimod particles, allowing for consistent and rapid release of tasquinimod in the gastrointestinal tract of a treated subject, which is advantageous for the purpose of providing a dosage unit with high and uniform bioavailability of tasquinimod. As provided herein, the pharmaceutical compositions of the present invention can be used to prepare an immediate release pharmaceutical dosage unit. Thus, in some embodiments, the pharmaceutical dosage unit is an immediate release oral dosage unit, e.g., 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 dissolves only in the intestine, to provide immediate release of tasquinimod 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 methacrylic acid co-agent-ethyl acrylate copolymer. Thus, in some embodiments, the pharmaceutical dosage unit provided herein is a delayed immediate release oral dosage unit, e.g., an enteric capsule.

[0110] Use of Several Particles and Compositions As mentioned hereinabove, the therapeutic activity of tasquinimod in the treatment of various diseases has been previously demonstrated. It is believed that the tasquinimod particles, pharmaceutical compositions and pharmaceutical dosage units prepared with such particles are useful in therapy, particularly in the treatment of any of the diseases for which tasquinimod has previously been shown to have therapeutic activity. Thus, a further aspect is said particles, pharmaceutical compositions and pharmaceutical dosage units for use in the treatment of cancer.

[0111] A further aspect is the use of a plurality of particles of tasquinimod, or a pharmaceutical composition containing such a plurality of particles, in the manufacture of a medicament for the treatment of cancer. In some embodiments, the manufacture comprises encapsulating a pharmaceutical composition as defined herein by applying encapsulation techniques well known in the art. In some other embodiments, the manufacture comprises preparing a tablet using tabletting techniques also well known in the art.

[0112] Yet a further aspect is a method for the treatment of cancer by administering an effective amount of a plurality of particles or pharmaceutical compositions or dosage units of tasquinimod provided herein to a mammal in need of such treatment. Preferably, the method comprises oral administration of the composition, e.g., in the form of an oral dosage unit such as an oral tablet or capsule, preferably an oral capsule.

[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 pancreatic neuroendocrine tumors (GEP-NETs). The cancer treated with the compositions of the present invention can be at any stage, for example, early or late. In some embodiments, the treatment results in a sustained response in the individual after cessation of treatment. In some embodiments, the treatment results in a complete response, partial response, or stable disease 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 hematological cancer is leukemia. In some embodiments, the hematological cancer is lymphoma. In some embodiments, the hematological cancer is myelodysplastic syndrome. In some embodiments, the hematological cancer is a myeloproliferative neoplasm. In some embodiments, the hematological cancer is multiple myeloma.

[0116] The leukemia can be selected from chronic lymphocytic leukemia, including hairy cell leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, and acute myelogenous leukemia and its precursor myelodysplastic syndrome. In some embodiments, the leukemia is acute lymphocytic leukemia or acute myelogenous leukemia and its precursor myelodysplastic syndrome. In some embodiments, the leukemia is acute lymphocytic leukemia. In some embodiments, the leukemia is acute myelogenous 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 can develop into myelofibrosis. Therefore, in some embodiments, the particles of the present invention or pharmaceutical compositions or medicines prepared with the particles of the present invention are for preventing or reducing the progression of myeloproliferative neoplasms, such as essential thrombocythemia or polycythemia vera, to the fibrotic phase.Therefore, as used herein, the term "myelofibrosis" refers to primary myelofibrosis and 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 cancer, 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 and 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 by use of a plurality of particles, pharmaceutical compositions, or pharmaceutical dosage units provided herein, dosage levels and frequency of administration will generally be determined by the treating physician, with due consideration of factors such as the sex, age, corporal weight, and relative health of the subject being treated, the selected route and form of administration, the additional use of other drugs, e.g., in combination therapy.

[0120] In general, daily dosages are contemplated to be a minimum of 0.001 mg / kg body weight, or 0.002 mg / kg body weight, or 0.005 mg / kg body weight, or 0.01 mg / kg body weight, to a maximum of 0.2 mg / kg body weight, or 0.1 mg / kg body weight, or 0.05 mg / kg body weight, or 0.02 mg / kg body weight.

[0121] In some embodiments, the particles of tasquinimod are administered in an amount 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, e.g., 1 mg / day.

[0122] In some embodiments, the dosage can be gradually adjusted to reach optimal results, so-called dose titration. For example, dose titration involves starting with a low daily dosage of, for example, 0.25 mg, and maintaining this dosage level for a period of 1-2 weeks. If there are no significant side effects that may 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, to a daily dosage of 1 mg, etc. In such a manner, if any significant side effects occur after the dosage escalation, the dosage may be reduced again to the previous level. Possible side effects include those that may be commonly encountered with this type of treatment, such as gastrointestinal upset, fatigue, and flu-like syndrome, which may be related to the dosage.

[0123] Tasquinimod is preferably administered daily, e.g., 1-3 times daily, or 1-2 times daily, e.g., once daily, however, in some embodiments, the drug is administered less frequently, e.g., once every two days, once a week, etc.

[0124] It should be noted that if a pharma- ceutically acceptable salt of tasquinimod is administered, the equivalent dosage would result in the indicated dosage of tasquinimod in the non-salt form (i.e., as the free base).

[0125] The present invention is further illustrated in the following non-limiting examples. EXAMPLES

[0126] In the examples, the particle size distribution of tasquinimod was determined using laser light diffraction on a Malvern Mastersizer instrument to determine the D(v,0.5) and D(v,0.9) values ​​for micronized tasquinimod.

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

[0128] [Table 1]

[0129] The fillers used in the examples were pregelatinized starches, i.e., either Starch 1500® or Lycatab C®, and the lubricants were hydrogenated vegetable oils, i.e., either Sterotex® or Lubritab®.

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

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

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

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

[0134] Example 5 Oral capsule containing 1.0 mg of tasquinimod (D(v,0.5) 4.9 μm, D(v,0.9) 14.0 μm) The procedure of Example 4 was repeated using the tasquinimod particles of Example 2 to obtain 500 capsules, each having a dosage strength of 1.0 mg of tasquinimod.

[0135] Example 6 Oral capsule containing 1.0 mg of tasquinimod (D(v,0.5) 6.4 μm, D(v,0.9) 16.9 μm) The procedure of Example 4 was repeated using the tasquinimod particles of Example 3 to obtain 500 capsules, each having a dosage strength of 1.0 mg of tasquinimod.

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

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

[0138] Comparative Example 3 Oral capsule containing 1.0 mg of tasquinimod (D(v,0.5) 39.9 μm, D(v,0.9) 121.1 μm) Capsules containing non-micronized tasquinimod particles having a D(v,0.5) of 39.9 μm and a D(v,0.9) of 121.0 μm as a mixture with a filler and a lubricant were prepared by following the procedure of Example 4. Each capsule contained 150 mg of the mixture, corresponding to a dosage strength of 1.0 mg of tasquinimod.

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

[0140] The dissolution medium was 0.05 M phosphate buffer (pH 6.8), chosen to ensure that at least 85% of tasquinimod was dissolved at the end of the study; tasquinimod is a weak acid with a pKa of 6.5 and solubility increased with pH. The resulting dissolution profile is shown in Figure 1. The dissolution rate of tasquinimod particles is surprisingly low, even though D(v,0.5) is only 15.9 μm.

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

[0142] [Table 2]

[0143] In comparing dissolution profiles using f1 / f2 values, f1 values ​​up to 15 (0-15) and f2 values ​​above 50 (50-100) are considered to indicate similarity or equivalence of the two dissolution profiles. The f1 / f2 statistical comparison test showed that capsules of Examples 4 and 6 containing tasquinimod particles with D(v,0.5) of 2.3 μm and 6.4 μm, respectively, had dissolution profiles similar to Example 5, whereas Comparative Examples 1-3 containing tasquinimod 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 Tasquinimod particles with D(v,0.5) of 7.5 μm and D(v,0.9) of 24.7 μm Tasquinimod particles (4.5 kg total) were prepared essentially as described in Example 1.

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

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

[0147] The particle size distribution was measured for the particles of Examples 7 to 9. The results are shown in FIG.

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

[0149] Example 11 Oral capsule containing 0.25 mg of tasquinimod (D(v,0.5) 7.5 μm, D(v,0.9) 24.7 μm) Capsules for oral administration containing the tasquinimod particles of Example 7 as a mixture with a filler and a lubricant were prepared on an industrial scale as follows: the tasquinimod 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 white hard gelatin size 4 capsules. Each capsule contained 150 mg of the mixture, corresponding to a dosage strength of 0.25 mg of tasquinimod, with a maximum batch size of 1,200,000 capsules.

[0150] Example 12 Oral capsule containing 0.5 mg of tasquinimod (D(v,0.5) 4.3 μm, D(v,0.9) 18.3 μm) Capsules for oral administration containing the tasquinimod particles of Example 8 in a mixture with a filler and a lubricant were prepared on an industrial scale as follows: the tasquinimod 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 white hard gelatin size 4 capsules. Each capsule contained 150 mg of the mixture, corresponding to a dosage strength of 0.5 mg of tasquinimod, with a maximum batch size of 1,200,000 capsules.

[0151] Example 13 Oral capsule containing 1.0 mg of tasquinimod (D(v,0.5) 3.4 μm, D(v,0.9) 11.5 μm) Capsules for oral administration containing the tasquinimod particles of Example 9 in a mixture with a filler and a lubricant were prepared on an industrial scale as follows: the tasquinimod 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 white hard gelatin size 4 capsules. Each capsule contained 150 mg of the mixture, corresponding to a dosage strength of 1.0 mg of tasquinimod, with a maximum batch size of 1,200,000 capsules.

[0152] Example 14 Oral capsule containing 1.0 mg of tasquinimod (D(v,0.5) 8.5 μm, D(v,0.9) 21.7 μm) Capsules for oral administration containing the tasquinimod particles of Example 10 in a mixture with a filler and a lubricant were prepared on an industrial scale as follows: the tasquinimod 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 white hard gelatin size 4 capsules. Each capsule contained 150 mg of the mixture, corresponding to a dosage strength of 1.0 mg of tasquinimod, with a maximum batch size of 1,200,000 capsules. The dissolution rates of the capsules of Examples 13 and 14 were measured by the assay described herein above. The results are shown in Figure 3.

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

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

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

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

[0157] The dissolution rates of the capsules of Examples 17-20 were measured by the assay described hereinabove, and the results are shown in FIG.

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

[0159] Example 21 Tasquinimod particles with D(v,0.5) of 6.0 μm and D(v,0.9) of 16 μm Tasquinimod powder (300 g) was micronized in an Alpine® Spiral Jet Mill 50 AS (Hosokawa Alpine AG, Germany) using nitrogen as the process gas. The feed rate for the unmicronized material was controlled at 10 g / min using a vibratory feeder and the injector pressure was set at 1.8-5 bar (180-500 kPa). The mill pressure was set at 0.5-1 bar to obtain the desired particle size distribution parameters (D(v,0.5) and D(v,0.9)).

[0160] Example 22 Oral capsule containing 0.25 mg of tasquinimod (D(v,0.5) 6.0 μm, D(v,0.9) 16 μm) Capsules for oral administration containing the tasquinimod particles of Example 21 in a mixture with a filler and a lubricant were prepared on an industrial scale as follows: the tasquinimod 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 white hard gelatin size 4 capsules. Each capsule contained 150 mg of the mixture, corresponding to a dosage strength of 0.25 mg of tasquinimod, with a maximum batch size of 50,000 capsules.

[0161] The dissolution rate of the capsules of Example 22 was measured by the assay described hereinabove. The resulting dissolution profile was similar to that of Examples 17-20 and corresponded to an immediate release formulation.

Claims

1. A plurality of particles comprising tasquinimod in free base form or as a pharma- ceutically acceptable salt, wherein D(v,0.9) is at most 30 μm and D(v,0.5) is at most 15 μm.

2. 2. The plurality of particles of 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. 3. The plurality of particles of 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 according to claim 1 and one or more pharma- ceutically acceptable excipients.

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

6. 5. The pharmaceutical composition of claim 4, wherein the pharma- ceutically acceptable excipients include a filler and a lubricant.

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

8. The pharmaceutical composition described in claim 7, wherein the cancer is a blood cancer or a solid cancer.

9. The pharmaceutical composition described in claim 8, wherein the blood cancer is selected from multiple myeloma, lymphoma, myelodysplastic syndrome, myeloproliferative neoplasms and leukemia, and / or the solid cancer 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 enteropancreatic neuroendocrine tumors (GEP-NETs).

10. A pharmaceutical dosage unit comprising the pharmaceutical composition of claim 4.

11. 11. The pharmaceutical dosage unit of claim 10, containing 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. 11. A pharmaceutical dosage unit according to claim 10 for oral administration.

13. 13. The pharmaceutical dosage unit of claim 12 which is a capsule or a tablet.

14. 11. The pharmaceutical dosage unit of claim 10 which is an immediate release pharmaceutical dosage unit.

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

16. 16. The pharmaceutical dosage unit of claim 15, wherein the cancer is a blood cancer or a solid cancer.

17. 17. The pharmaceutical dosage unit of claim 16, wherein the hematological cancer is selected from multiple myeloma, lymphoma, myelodysplastic syndrome, myeloproliferative neoplasms, and leukemia, and / or the solid cancer 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 gastro-pancreatic neuroendocrine tumors (GEP-NETs).

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