Pharmaceutical products containing tasquinimod and methods for assessing the purity of said products

Abstract

Pharmaceutical compositions containing tasquinimod or a pharmaceutical salt of tasquinimod, methods for evaluating same and processes for their manufacture. Use of pharmaceutical compositions containing tasquinimod or a pharma- ceutically acceptable salt of tasquinimod in therapy. The compound 3,3'-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one) and its use in methods for evaluating pharmaceutical compositions containing tasquinimod or a pharma- ceutically acceptable salt of tasquinimod.

Description

[Technical field]

[0001] The present invention relates to pharmaceutical products containing tasquinimod or pharma- ceutically acceptable salts of tasquinimod. The present invention also relates to methods of making such products and methods of evaluating such products. The present invention also relates to novel compounds particularly useful in such methods. [Background technology]

[0002] Tasquinimod, or 4-hydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-[4-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide, has the structural formula:

[0003] [ka]

[0004] It is a compound having the formula:

[0005] Tasquinimod and methods for its preparation were described in International Application No. PCT / SE99 / 00676, published as WO99 / 55678, and International Application No. PCT / SE99 / 01270, published as WO00 / 03991. These applications also disclosed the utility of tasquinimod and some 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.

[0006] Processes 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. Although these applications disclose processes for preparing quinoline carboxamides such as tasquinimod in high yield and purity, they do not address the subsequent preparation and evaluation of pharmaceutical compositions containing such quinoline carboxamides as active ingredients, including any mention of the potential for tasquinimod to degrade when incorporated into pharmaceutical compositions.

[0007] Deuterated forms of tasquinimod and processes for its preparation were described in International Application No. PCT / EP2012 / 061798, published as WO2012 / 175541.

[0008] Pharmaceutical compositions containing tasquinimod particles having high dissolution rates are described in International Application No. PCT / EP2022 / 063887 (unpublished), which also discloses solid pharmaceutical dosage units, such as capsules or tablets for oral administration, containing such particles.

[0009] 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). This protein promotes tumorigenesis, influences anti-angiogenic and pro-angiogenic cells in the tumor microenvironment, and is involved in the establishment of the pre-metastatic niche.

[0010] 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 disclosed in unpublished International Application No. PCT / EP2022 / 050891.

[0011] All of the above identified prior art publications are incorporated herein by reference.

[0012] To be substantially useful in treatment, therapeutically active agents should usually be provided as pharmaceutical products suitable for administration to users, which must meet various quality and safety requirements. Therefore, it is important to be able to evaluate the suitability of any pharmaceutical product, for example in terms of purity and stability, before allowing the product to be used or distributed. Such evaluation may include identifying and quantifying the decomposition and reaction products of the active ingredient in the pharmaceutical product. Summary of the Invention [Means for solving the problem]

[0013] A first aspect is a pharmaceutical composition comprising a therapeutically effective amount of tasquinimod or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, said pharmaceutical composition comprising:

[0014] [ka]

[0015] N-methyl-4-(trifluoromethyl)aniline,

[0016] [ka]

[0017] 4-hydroxy-5-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid,

[0018] [ka]

[0019] 4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one, and

[0020] [ka]

[0021] 3,3'-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one), and pharma- ceutically acceptable salts thereof.

[0022] A further aspect is a pharmaceutical dosage unit for oral administration comprising a pharmaceutical composition as defined herein.

[0023] A further aspect is a pharmaceutical composition or pharmaceutical dosage unit as defined herein for use in the treatment of cancer.

[0024] A further aspect is a method of evaluating a pharmaceutical product containing a therapeutically effective amount of tasquinimod or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, by obtaining a sample of the product and determining the amount of tasquinimod degradation products in the sample, the tasquinimod degradation products comprising one or more compounds selected from N-methyl-4-(trifluoromethyl)aniline, 4-hydroxy-5-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, 4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one, and 3,3'-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one), and pharma- ceutically acceptable salts thereof. In some embodiments, the method comprises subjecting a sample of the pharmaceutical product to a stability test, followed by determining the amount of the tasquinimod degradation products in the sample. The methods of the invention are useful for evaluating a pharmaceutical product containing a therapeutically effective amount of tasquinimod or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier, e.g., to determine whether the pharmaceutical product is suitable for distribution. In some embodiments, a pharmaceutical product is determined to be suitable for distribution only if a sample of the product contains about 5% w / w or less of said degradation products relative to the amount of tasquinimod in the sample.

[0025] A further aspect is a process for manufacturing a pharmaceutical product comprising a pharma- ceutical effective amount of tasquinimod or a pharma- ceutical acceptable salt thereof, and pharma- ceutical acceptable excipients, said pharmaceutical product further comprising one or more compounds selected from N-methyl-4-(trifluoromethyl)aniline, 4-hydroxy-5-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, 4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one, and 3,3′-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one), said process comprising preparing a pharmaceutical composition comprising a pharma- ceutical effective amount of tasquinimod or a pharma- ceutical acceptable salt thereof, and one or more pharma- ceutical acceptable excipients, optionally processing the composition to obtain a pharmaceutical dosage unit, and evaluating the pharmaceutical product by a method defined herein.

[0026] A further aspect is the use of a compound selected from N-methyl-4-(trifluoromethyl)aniline, 4-hydroxy-5-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, 4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one, and 3,3'-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one) in a method or process as defined herein.

[0027] A further aspect is a compound represented by the formula

[0028] [ka]

[0029] or a salt thereof.

[0030] A further aspect is the use of a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of cancer.

[0031] A further aspect is a method of treating cancer by administering a pharmaceutical composition of the invention or a pharmaceutical dosage unit of the invention to a mammal in need of such treatment.

[0032] Further aspects and embodiments thereof will become apparent from the following description. [Brief description of the drawings]

[0033] [Figure 1] FIG. 1 is an HPLC chromatogram showing the elution order of compounds I-IV as defined herein, where ABR-221019 is compound I, ABR-221020 is compound II, ABR-221023 is compound III, and ABR-225865 is compound IV. [Diagram 2] FIG. 2 is an ESI mass spectrum of compound IV prepared in Example 1. [Diagram 3] FIG. 3 is the product MS spectrum of m / z 423 of compound IV prepared in Example 1. [Figure 4] FIG. 4 is a 1H NMR spectrum of compound IV prepared in Example 1. [Diagram 5] FIG. 5 is a 13C NMR spectrum of compound IV prepared in Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] Unless otherwise indicated or clear from the 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, definitions of some of the terms used herein are set forth herein below.

[0035] As used herein, and unless otherwise specified or clear from the context, the terms "degradation product" or "tasquinimod degradation product" or "degradation product as defined herein" and the like refer to one or more compounds derived from the degradation of tasquinimod in a pharmaceutical composition containing one or more excipients, said compounds being selected from N-methyl-4-(trifluoromethyl)aniline, 4-hydroxy-5-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, 4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one, and 3,3'-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one), and pharma- ceutically acceptable salts thereof.

[0036] As used herein, the term "effective" means effective to achieve a goal or desired purpose. Thus, for example, a "therapeutically effective amount," as used in the present disclosure, refers to an amount of a component sufficient to produce an indicated therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic reaction) commensurate with a reasonable risk-benefit ratio. The effective amount of a drug may vary depending on factors such as the condition, age, sex, and weight of the human or animal being treated.

[0037] The term "excipient" refers to a pharma- ceutically acceptable chemical compound known to those skilled in the art of pharmacy to aid in the administration of a drug. It is a compound that is useful in the preparation of pharmaceutical compositions and is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes excipients that are acceptable for veterinary and human pharmaceutical use. Exemplary excipients include encapsulating agents, sweeteners, flavoring agents, carriers, binders, fillers, diluents, disintegrants, anti-adhesives, and lubricants.

[0038] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur.

[0039] The term "pharmaceutical dosage unit" (or sometimes just "dosage unit"), as used herein, includes any device useful for administering a predetermined dose of a drug product to a patient, such as a capsule, tablet, sachet, microcapsule, etc.

[0040] "Pharmaceutically acceptable" means a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual in addition to the active compound of interest without causing clinically unacceptable biological effects or interacting adversely with any of the other components of the formulation in which it is contained.

[0041] Examples of pharma- ceutically acceptable salts include those containing (as counterion) an alkali metal ion, e.g., Li + , Na + Or K + or alkaline earth metal ions, e.g. Mg 2+ Or Ca 2+ or any other pharma- ceutically acceptable metal ion, e.g., Zn 2+ Or Al 3+ or pharmaceutically acceptable salts formed with organic bases such as diethanolamine, ethanolamine, N-methylglucamine, triethanolamine or tromethamine. Pharmaceutically acceptable salts may also include salts with inorganic or organic acids, such as hydrohalic acids (e.g., HCl) or carboxylic acids, such as acetic acid, succinic acid, tartaric acid, benzoic acid, and the like.

[0042] However, the tasquinimod referred to herein may have any degree of deuteration. In some embodiments, the tasquinimod has a degree of deuteration corresponding to the natural abundance of deuterium isotopes. In some other embodiments, the tasquinimod used herein is as described in WO2012 / 175541, see above in the present specification.

[0043] Depending on the type of product, which may be, for example, a composition containing tasquinimod for use in a tableting or encapsulation process, or a final tablet or capsule, the phrase "suitable for distribution," as used herein, may mean that the product is suitable for further processing required to obtain a useful drug product, such as an orally administrable capsule or tablet, or that the product is suitable for use by a patient. In other words, the method of evaluating a pharmaceutical product may be performed on a pharmaceutical composition containing tasquinimod or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier, as well as on a pharmaceutical dosage unit, such as a tablet or capsule, prepared by use of such a composition.

[0044] In the present context, the phrase "determining that a product is suitable for distribution", or a similar phrase that may be used herein, means that the product is believed to meet the selected requirement based on the determined amount of degradation products as defined herein in a sample of the product, optionally after stability testing. However, it should be noted that the product may also have to meet other requirements that are not evaluated in the manner described herein and are not considered herein. Thus, in the present context, "determining that a product is suitable for distribution" may mean that the product has been determined to meet the selected requirement, for example in terms of having sufficiently low levels of tasquinimod degradation products, but may not necessarily mean that the product also meets or has been determined to meet all other requirements that may be relevant in the pharmaceutical field.

[0045] As used herein, a "pharmaceutical product containing tasquinimod or a pharma- ceutically acceptable salt of tasquinimod" (sometimes simply referred to herein as a "pharmaceutical product" or "product") can be, for example, a pharmaceutical composition containing tasquinimod or a pharma- ceutically acceptable salt of tasquinimod in admixture with one or more excipients, or a capsule or tablet for oral administration containing such a composition. It is contemplated that a pharmaceutical product containing tasquinimod or a pharma- ceutically acceptable salt thereof as an active ingredient contains a therapeutically effective amount of said active ingredient. In accordance with the present invention, it has been found that a pharmaceutical product containing a therapeutically effective amount of tasquinimod or a pharma- ceutically acceptable salt thereof as an active ingredient also contains trace amounts of degradation products as defined herein.

[0046] The term "sample" refers to a portion of a product, usually a small portion taken for the purpose of testing the product, for example, for stability testing of the product. More specifically, in the present context, "sample" refers to a sample taken from a pharmaceutical product containing tasquinimod or a pharma- ceutically acceptable salt thereof and one or more excipients. The sample can be, for example, a portion of a powder composition, or multiple dosage units, such as capsules or tablets, containing the pharmaceutical composition.

[0047] Particularly in the presence of excipients in pharmaceutical compositions, tasquinimod has been shown to degrade to N-methyl-4-(trifluoromethyl)aniline and 4-hydroxy-5-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, which can then be decarboxylated to 4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one. Additionally, a dimeric impurity, 3,3'-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one, has been identified in pharmaceutical compositions containing tasquinimod. In the following, the compounds N-methyl-4-(trifluoromethyl)aniline, 4-hydroxy-5-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, 4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one, and 3,3'-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one) may be referred to as Compound I, Compound II, Compound III, and Compound IV, respectively.

[0048] The chemical names and structural formulas of compounds I-IV are shown in Table 1.

[0049] [Table 1]

[0050] The putative decomposition pathways leading to these compounds are illustrated herein below.

[0051] [ka]

[0052] In the drug product, compound I is formed along with compound II from the hydrolysis of tasquinimod. In the drug product stability test, the amount of compound I was observed to increase under any storage condition. Compound II is further decarboxylated to form compound III. However, in the drug product stability test, a slight increase in compound II was observed under any storage condition. This indicates that compound II is formed faster than it is decarboxylated to compound III.

[0053] Compound III is a decarboxylated species formed from the decomposition of Compound II. In drug product stability studies, the amount of Compound III was observed to increase under any condition.

[0054] In the drug product, compound IV is a dimer formed by two quinoline moieties, the amount of which was observed to increase under accelerated conditions. The mechanism of formation of compound IV in the drug product is unclear.

[0055] The amounts of compounds I-IV in the tasquinimod drug product were tested, and a chromatogram showing the elution order of compounds I-IV is shown in FIG. 1.

[0056] Table 2 lists the relative response factors used to convert the area % detected to weight % for each of compounds I-IV.

[0057] [Table 2]

[0058] Evaluation method Disclosed herein are methods comprising obtaining a sample of a pharmaceutical product containing tasquinimod or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier, and determining the amount of degradation products of tasquinimod in the sample, wherein the degradation products comprise one or more compounds selected from Compound I, Compound II, Compound III, and Compound IV, or pharma- ceutically acceptable salts thereof. Such methods are useful, for example, for evaluating pharmaceutical products containing tasquinimod or a pharma- ceutically acceptable salt of tasquinimod for the absence of excessive levels of tasquinimod degradation products therein.

[0059] Thus, in some embodiments, a method is provided for evaluating a pharmaceutical product containing tasquinimod or a pharma- ceutically acceptable salt of tasquinimod, the method comprising obtaining a sample of a pharmaceutical product containing tasquinimod or a pharma- ceutically acceptable salt of tasquinimod and a pharma- ceutically acceptable carrier, and determining an amount of degradation products of tasquinimod in the sample, wherein the degradation products comprise one or more compounds selected from compound I, compound II, compound III, and compound IV.

[0060] It is noted that as used herein, and unless otherwise indicated or clear from the context, a reference to a compound selected from any one of compounds I, II, III, IV may also include salts thereof, preferably pharma-ceutically acceptable salts.

[0061] In some embodiments, a method is provided that includes obtaining a sample of a pharmaceutical product containing tasquinimod or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier, holding (storing) the sample for a period of time, and determining an amount of degradation products of tasquinimod in the sample, wherein the degradation products comprise one or more compounds selected from compound I, compound II, compound III, and compound IV.

[0062] Such methods are useful, for example, for evaluating pharmaceutical products containing tasquinimod or a pharma- ceutically acceptable salt of tasquinimod in terms of the chemical stability of the tasquinimod contained therein.

[0063] In some embodiments, methods are provided that include obtaining a sample of a pharmaceutical product containing tasquinimod or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier, optionally holding the sample at ambient temperature and relative humidity (RH) for a period of time, and determining an amount of degradation products of tasquinimod in the sample, wherein the degradation products comprise one or more compounds selected from Compound I, Compound II, Compound III, and Compound IV. Such methods may be used to assess the suitability of a pharmaceutical product containing tasquinimod or a pharma- ceutically acceptable salt of tasquinimod for distribution, for example, in terms of the chemical stability of tasquinimod contained therein and / or the absence of excessive levels of tasquinimod degradation products therein.

[0064] In some embodiments, the method includes determining whether a pharmaceutical product containing tasquinimod or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier is suitable for distribution. In some embodiments, a pharmaceutical product containing tasquinimod or a pharma- ceutically acceptable salt of tasquinimod is determined to be suitable for distribution only if a sample of the product contains about 5% w / w or less of degradation products of tasquinimod relative to the amount of tasquinimod in the sample.

[0065] Thus, in some embodiments, a method is provided that includes obtaining a sample of a pharmaceutical product containing tasquinimod or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier, optionally holding the sample at ambient temperature and relative humidity for a period of time, and determining whether an amount of degradation products of tasquinimod in the sample is about 5% w / w or less relative to the amount of tasquinimod in the sample, wherein the degradation products include one or more compounds selected from Compound I, Compound II, Compound III, and Compound IV.

[0066] "Keeping a sample at ambient temperature and relative humidity for a period of time" means that the sample is kept (stored) for a period of time, e.g. in a closed container, an open container, or in a suitable packaging material (e.g. a blister package), at a particular temperature or range of temperatures, e.g. room temperature (about 18-25°C) or higher (about 25-45°C), and at a relative humidity of e.g. 30-50%, or higher, e.g. 60-75% RH. The period of time can be, e.g., weeks, months, or years, e.g., 2 weeks to 5 years. Keeping or storing a sample for a period of time at a temperature and relative humidity may also be referred to herein as "stability testing."

[0067] In view of the above, in some embodiments, there is provided a method of evaluating a pharmaceutical product containing tasquinimod or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient, the method comprising obtaining a sample of the product, subjecting the sample to a stability test, and determining, at the end of the stability test, an amount of tasquinimod degradation products in the sample, wherein the tasquinimod degradation products comprise one or more compounds selected from Compound I, Compound II, Compound III, and Compound IV, or a pharma- ceutically acceptable salt of any one of these compounds.

[0068] In some embodiments, methods are provided for evaluating a pharmaceutical product containing tasquinimod or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient, the method comprising obtaining at least two samples of the product, determining an amount of tasquinimod degradation products in one or more of the product samples prior to any stability testing, subjecting one or more remaining samples of the product to stability testing, and then determining an amount of tasquinimod degradation products in the remaining one or more samples, the tasquinimod degradation products comprising one or more compounds selected from Compound I, Compound II, Compound III, and Compound IV, or a pharma- ceutically acceptable salt of any one of these compounds. Such methods may include comparing the determined amounts of tasquinimod degradation products in the different samples to evaluate the pharmaceutical product in terms of chemical stability of tasquinimod therein.

[0069] In some embodiments, the method may include obtaining multiple samples of the product, subjecting the multiple samples to stability testing for different lengths of time, e.g., 2 weeks, 1 month, 3 months, 6 months, etc., and determining the amount of tasquinimod degradation products in the samples subjected to the stability testing for the different lengths of time.

[0070] In some embodiments, the "pharmaceutical product" referred to herein is a batch of product, and the methods described herein can be used to assess the quality of the batch, e.g., in terms of the amount of tasquinimod in the batch compared to a target amount of tasquinimod (e.g., the dose strength of an intended dosage unit), the chemical stability of tasquinimod in the batch, and / or the amount of degradation products of tasquinimod in the batch.

[0071] In some embodiments, the method of evaluating a pharmaceutical product containing tasquinimod or a pharma- ceutically acceptable salt of tasquinimod is a method of determining whether the product is suitable for distribution. In some embodiments, the method of evaluating a pharmaceutical product is part of a method of determining whether the product is suitable for distribution, which may include determining whether other criteria are met, such as the absence of visible defects in the dosage unit (such as cracks or color differences), the absence of microbial contamination, etc., and in the case of a powder composition, the method may include determining whether the composition has suitable pharmacological-technical properties, such as flowability, bulk density, tapped density, Carr's index, moisture content, etc. Thus, in some cases, even if a pharmaceutical product is deemed suitable for distribution according to the evaluation criteria described herein, it may still occur that the product is not considered suitable for distribution for other reasons not taken into account by the method. Thus, in this context, "suitable for distribution" may refer to a situation in which a product is deemed suitable for distribution according to the results of the methods described herein, but may include a situation in which the product is deemed not suitable for distribution for some other reason.

[0072] In some embodiments, a product is considered suitable for distribution only if a sample of the product contains about 5% w / w or less of tasquinimod degradation products as defined herein relative to the amount of tasquinimod in the sample. In some of these embodiments, a sample may not contain more than about 2% w / w of any one of compounds I, II, III, and IV relative to tasquinimod.

[0073] Thus, in some embodiments, the method includes determining whether a sample of a pharmaceutical product containing tasquinimod or a pharma- ceutically acceptable salt of tasquinimod, optionally at the end of a stability study, contains about 5% w / w or less of tasquinimod degradation products, relative to tasquinimod, including one or more compounds selected from Compound I, Compound II, Compound III, and Compound IV, and pharma- ceutically acceptable salts thereof, and determining whether the sample contains about 2% w / w or less of any one of these compounds (i.e., none of these compounds are present in an amount greater than about 2% w / w).

[0074] In some embodiments, the method includes determining whether the sample contains about 2% w / w or less of tasquinimod degradation products, including one or more compounds selected from Compound I, Compound II, Compound III, and Compound IV, and pharma- ceutically acceptable salts thereof, relative to tasquinimod, optionally at the end of a stability study, and determining whether the sample contains about 0.5% w / w or less of any one of these compounds.

[0075] In some embodiments, the pharmaceutical product is a pharmaceutical composition containing tasquinimod or a pharma- ceutical acceptable salt of tasquinimod in admixture with one or more excipients, and a sample of the composition can be, for example, 100 mg to 100 g of the composition.

[0076] In some embodiments, the pharmaceutical product is a pharmaceutical dosage unit, e.g., a capsule or tablet for oral administration containing tasquinimod in admixture with one or more excipients, and the sample of said product can be one such dosage unit or a plurality of such dosage units, e.g., 1 to 100 capsules or tablets, or 1 to 50 capsules or tablets, or 1 to 20 capsules or tablets, or 1 to 10 capsules or tablets, or 1 to 5 capsules or tablets, e.g., at least 2, at least 3, at least 5, at least 10, or at least 20 capsules or tablets.

[0077] In some embodiments, the methods disclosed herein include storing (holding) a sample of the pharmaceutical product for a period of time, preferably under selected temperature and humidity conditions. The amount (or concentration) of tasquinimod and at least one of compounds I, II, III and IV in the sample can be preferably determined at or before the beginning of the storage period and at the end of the storage period. The selected storage conditions can include, for example, a temperature in the range of 20° C. to 40° C., and a relative humidity in the ambient atmosphere in the range of, for example, 30% to 75%, such as 25° C. and 60% RH, or 30° C. and 65% RH, or 35° C. and 70% RH, or 40° C. and 75% RH. The storage period can range, for example, from a few weeks to a few years. For example, the stability study period ("storage period") can be 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, 1 year, 18 months, 2 years, 3 years, 4 years or even 5 years or more. A shorter storage period may be selected by using a higher storage temperature and / or a higher relative humidity (RH). At the end of the storage period, the total amount of tasquinimod degradation products in the sample may be determined, for example, by HPLC.

[0078] In stability testing, the sample may be stored or held in a closed container or in an open container. In some embodiments, for example, when the pharmaceutical product is a dosage unit such as a capsule or tablet, the sample may be stored in a packaging material such as a blister package or a pharmaceutical glass or plastic jar or vial.

[0079] The method disclosed herein comprises determining the amount of one or more compounds selected from compound I, compound II, compound III and compound IV in a product sample. In some embodiments, the method comprises determining the amount of compound I, and optionally one or more of compounds II, III and IV. In some embodiments, the method comprises determining the amount of compounds I and II, and optionally one or both of compounds III and IV. In some embodiments, the method comprises determining the amount of compounds I, II and III, and optionally the amount of compound IV. In some embodiments, the method comprises determining the amount of compounds I, II, III and IV.

[0080] In some further embodiments, the method includes determining the amount of compound II, and optionally one or more of compound I, compound III, and compound IV, in the sample.

[0081] In some further embodiments, the method includes determining the amount of compound II and compound III, and optionally one or both of compound I and compound IV, in the sample.

[0082] In some further embodiments, the method includes determining the amount of compound II, compound III and compound IV, and optionally the amount of compound I, in the sample.

[0083] In some further embodiments, the method includes determining the amount of compound III, and optionally one or more of compound I, compound II, and compound IV, in the sample.

[0084] In some further embodiments, the method includes determining the amount of compound III and compound IV, and optionally one or both of compound I and compound II, in the sample.

[0085] In some further embodiments, the method includes determining the amount of compound IV, and optionally the amount of one or more of compound I, compound II and compound IV, in the sample.

[0086] In some further embodiments, the method comprises determining the amount of compound I in the sample. In some further embodiments, the method comprises determining the amount of compound II in the sample. In some further embodiments, the method comprises determining the amount of compound III in the sample. In some further embodiments, the method comprises determining the amount of compound IV in the sample.

[0087] In some embodiments of the method for determining whether a pharmaceutical product containing tasquinimod is suitable for distribution, the product is determined to be suitable for distribution only if a sample of the product, optionally after stability testing (i.e., at the end of a selected stability testing period), contains about 5% w / w or less of tasquinimod degradation products as defined herein above. The step of determining that a product is suitable for distribution may also be referred to herein as "approving the product for distribution." In some embodiments, the method includes approving the product for distribution only if a sample of the product contains less than about 4.5% w / w of a tasquinimod degradation product as defined herein, or less than about 4.0% w / w, less than about 3.5% w / w, less than about 3.0 w / w, less than about 2.5% w / w, less than about 2.0% w / w, less than about 1.5% w / w, less than about 1.0% w / w, less than about 0.8% w / w, less than about 0.7% w / w, less than about 0.6% w / w, or less than about 0.5% w / w of said tasquinimod degradation products, relative to the amount of tasquinimod in the sample.

[0088] In some embodiments, the method includes approving the product for distribution only if a sample of the product, optionally after stability testing, contains less than about 2.0% w / w of compound I, less than about 1.5% w / w of compound I, less than about 1.0% w / w of compound I, less than 0.50% w / w of compound I, or less than about 0.25% w / w of compound I, relative to the amount of tasquinimod in the sample.

[0089] In some embodiments, the method includes approving the product for distribution only if a sample of the product, optionally after stability testing, contains less than about 2.0% w / w of Compound II, less than about 1.5% w / w of Compound II, less than about 1.0% w / w of Compound II, less than 0.50% w / w of Compound II, or less than about 0.25% w / w of Compound II, relative to the amount of tasquinimod in the sample.

[0090] In some embodiments, the method includes approving the product for distribution only if a sample of the product, optionally after stability testing, contains less than about 2.0% w / w of compound III, less than about 1.5% w / w of compound III, less than about 1.0% w / w of compound III, less than 0.50% w / w of compound III, or less than about 0.25% w / w of compound III, relative to the amount of tasquinimod in the sample.

[0091] In some embodiments, the method includes approving the product for distribution only if a sample of the product, optionally after stability testing, contains less than about 2.0% w / w of Compound IV, less than about 1.5% w / w of Compound IV, less than about 1.0% w / w of Compound IV, less than 0.50% w / w of Compound IV, or less than about 0.25% w / w of Compound IV, relative to the amount of tasquinimod in the sample.

[0092] In some embodiments, the method includes approving the product for distribution only if a sample of the product, optionally after stability testing, contains, relative to the amount of tasquinimod in the sample, (a) no more than about 5% w / w of tasquinimod degradation products as defined herein above, and (b) no more than about 2.0% w / w of any one of compounds I-IV, no more than about 1.5% w / w of any one of compounds I-IV, no more than about 1.0% w / w of any one of compounds I-IV, no more than 0.50% w / w of any one of compounds I-IV, or no more than about 0.25% w / w of any one of compounds I-IV.

[0093] In some embodiments, the method includes approving the product for distribution only if a sample of the product, optionally after stability testing, contains, relative to the amount of tasquinimod in the sample, (a) no more than about 4% w / w of tasquinimod degradation products as defined herein above, and (b) no more than about 2.0% w / w of any one of compounds I-IV, no more than about 1.5% w / w of any one of compounds I-IV, no more than about 1.0% w / w of any one of compounds I-IV, no more than 0.50% w / w of any one of compounds I-IV, or no more than about 0.25% w / w of any one of compounds I-IV.

[0094] In some embodiments, the method includes approving the product for distribution only if a sample of the product, optionally after stability testing, contains, relative to the amount of tasquinimod in the sample, (a) less than or equal to about 3% w / w of tasquinimod degradation products as defined herein above, and (b) less than or equal to about 1.5% w / w of any one of compounds I-IV, less than or equal to about 1.0% w / w of any one of compounds I-IV, less than or equal to 0.50% w / w of any one of compounds I-IV, or less than or equal to about 0.25% w / w of any one of compounds I-IV.

[0095] In some embodiments, the method includes approving the product for distribution only if a sample of the product, optionally after stability testing, contains, relative to the amount of tasquinimod in the sample, (a) less than or equal to about 2% w / w of tasquinimod degradation products as defined herein above, and (b) less than or equal to about 1.0% w / w of any one of compounds I-IV, less than or equal to 0.50% w / w of any one of compounds I-IV, or less than or equal to about 0.25% w / w of any one of compounds I-IV.

[0096] In some embodiments, the method comprises providing a sample of the product, optionally after stability testing, that, relative to the amount of tasquinimod in the sample, has (a) about 5% w / w or less of tasquinimod degradation products as defined herein above, and (b) about 2.0% w / w or less of Compound I, about 1.5% w / w or less of Compound I, about 1.0% w / w or less of Compound I, 0.50% w / w or less of Compound I, or about 0.25% w / w or less of Compound I; and / or about 2.0% w / w or less of Compound II, about 1.5% w / w or less of Compound II, about 1.0% w / w or less of Compound II, 0.50% w / w or less of Compound II, or about 0.25% w / w or less of Compound II, relative to the amount of tasquinimod in the sample. and / or approving the product for distribution only if it contains less than about 2.0% w / w of compound III, less than about 1.5% w / w of compound III, less than about 1.0% w / w of compound III, less than 0.50% w / w of compound III, or less than about 0.25% w / w of compound III, relative to the amount of tasquinimod in the sample; and / or less than about 2.0% w / w of compound IV, less than about 1.5% w / w of compound IV, less than about 1.0% w / w of compound IV, less than 0.50% w / w of compound IV, or less than about 0.25% w / w of compound IV, relative to the amount of tasquinimod in the sample.

[0097] In some embodiments, the method further includes determining an amount of tasquinimod in a sample of the pharmaceutical product relative to a target amount of tasquinimod in the pharmaceutical product, which can be a required dose strength of tasquinimod in a pharmaceutical dosage unit, e.g., 1 mg of tasquinimod / dose unit, or a corresponding amount of a pharma- ceutically acceptable salt of tasquinimod. For example, in some embodiments, the method includes storing a sample of the pharmaceutical product for a period of time, periodically determining the amount of tasquinimod in the sample, and comparing the determined amount of tasquinimod in the sample to the target amount of tasquinimod, which can be, for example, the amount of tasquinimod present in the dosage unit at the start of the storage period, or the intended dose strength. The process of preparing the product A further aspect is a process for preparing a pharmaceutical product comprising a therapeutically effective amount of tasquinimod or a pharma- ceutically acceptable salt of tasquinimod and a pharma- ceutically acceptable excipient, said process including the methods of evaluating the pharmaceutical product described herein.

[0098] In some embodiments, for example, a process for preparing a pharmaceutical product comprising tasquinimod or a pharma- ceutically acceptable salt of tasquinimod, the process includes mixing tasquinimod or a pharma- ceutically acceptable salt of tasquinimod with one or more excipients to obtain a pharmaceutical composition, optionally subjecting the pharmaceutical composition to further processing to obtain a dosage unit, e.g., a tablet or capsule, obtaining a sample of the product, and optionally subjecting the sample to a stability test, and and determining an amount of tasquinimod degradation products in the sample, wherein the tasquinimod degradation products comprise one or more compounds selected from N-methyl-4-(trifluoromethyl)aniline, 4-hydroxy-5-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, 4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one, and 3,3'-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one).

[0099] In some embodiments, the process includes determining whether a sample of the product contains about 5% w / w or less of a degradation product as defined herein relative to the amount of tasquinimod in the sample, and approving the pharmaceutical product for distribution if the sample contains about 5% w / w or less of a degradation product relative to the amount of tasquinimod in the sample.

[0100] In some preferred embodiments, the process includes determining the amount of a degradation product as defined herein in a sample of a pharmaceutical product containing tasquinimod, and approving the product for distribution only if the sample contains about 2% w / w or less of the degradation product relative to the amount of tasquinimod in the sample.

[0101] A process for preparing a pharmaceutical product comprising tasquinimod may include a process of synthesizing and isolating tasquinimod or a pharma- ceutically acceptable salt thereof, for example as described in any of the above publications, such as WO03 / 106424 and WO2012 / 004338, and then combining tasquinimod or a pharma- ceutically acceptable salt thereof with one or more suitable pharma- ceutically acceptable excipients to obtain a pharmaceutical composition containing tasquinimod or a pharma- ceutically acceptable salt of tasquinimod, and optionally then preparing a suitable pharmaceutical dosage unit containing said composition, such as an oral capsule or oral tablet.

[0102] Thus, the evaluation methods disclosed herein can be part of a process for preparing a pharmaceutical product as defined herein. For example, a process for preparing a pharmaceutical dosage unit, such as a capsule or tablet, for oral administration containing tasquinimod or a pharma- ceutically acceptable salt of tasquinimod can include preparing the dosage unit by conventional encapsulation or tableting of a pharmaceutical composition containing tasquinimod or a pharma- ceutically acceptable salt of tasquinimod, and subjecting a sample of the resulting capsule or tablet to the evaluation methods described herein to verify that the tablet or capsule meets the requirements in terms of maximum levels of undesired tasquinimod reactions or degradation products as defined herein.

[0103] A process for preparing a dosage unit, such as a capsule or tablet, containing a therapeutically effective amount of tasquinimod may include blending tasquinimod or a pharma- ceutically acceptable salt of tasquinimod with a filler, mixing a lubricant with the resulting blend, processing the resulting composition into a dosage unit, e.g., by tableting or encapsulating the composition, determining the amount of tasquinimod degradation products, as defined herein, in a sample of said dosage unit, and optionally measuring the amount of said dosage unit sample over a period of time, e.g., from 2 weeks to 5 years, or from 1 month to 24 hours. 5 years, or 1 month to 4 years, or 1 month to 3 years, or 1 month to 2 years, or 1 month to 1 year, or 1 month to 3 months, for example 3 months to 5 years, or 3 months to 4 years, or 3 months to 3 years, or 3 months to 2 years, or 3 months to 1 year, or 6 months to 5 years, or 6 months to 4 years, or 6 months to 3 years, or 6 months to 3 years, or 6 months to 2 years, or 6 months to 1 year, at a temperature of 25° C. to 40° C. and 60% to 75% RH, and determining the amount of tasquinimod degradation products as defined herein in the sample at the end of the storage period.

[0104] In some embodiments, multiple samples are obtained from one and the same pharmaceutical product and each sample is independently subjected to stability testing, e.g., at different lengths of time and / or different temperature and relative humidity conditions, whereby the amount of tasquinimod degradation products, as defined herein, is determined separately in each sample. Pharmaceutical Products Also provided herein is a solid pharmaceutical product comprising a therapeutically effective amount of tasquinimod or a pharma- ceutically acceptable salt thereof as an active ingredient, a pharma- ceutically acceptable excipient, and additionally comprising tasquinimod degradation products comprising one or more compounds selected from Compound I, Compound II, Compound III, and Compound IV, or pharma- ceutically acceptable salts of Compounds I, II, III, and IV. Preferably, in such a product, said tasquinimod degradation products are present in an amount of about 5% w / w or less relative to the amount of tasquinimod.

[0105] In such products, tasquinimod may be present in free base form or as a pharma- ceutically acceptable salt. Examples of pharma-ceutically acceptable salts include those that contain (as counterion) an alkali metal ion, such as Li + , Na + Or K + or alkaline earth metal ions, e.g. Mg 2+ Or Ca 2+ or any other pharma- ceutically acceptable metal ion, e.g., Zn 2+ Or Al 3+ or pharma- ceutically acceptable salts formed with organic bases such as diethanolamine, ethanolamine, N-methylglucamine, triethanolamine or tromethamine.

[0106] Such salts, as well as acid addition salts, for example with strong acids such as hydrohalic acids, may also be formed by decomposition products of tasquinimod.

[0107] Thus, herein, unless otherwise indicated or clear from the context, "taskinimod" and "taskinimod degradation products" should be understood to include both the free base and salt forms of the compound. In this regard, it is noted that any weight and % w / w specified herein of either taskinimod degradation products or taskinimod should be understood to refer to the non-salt (free base) form of taskinimod degradation products and taskinimod.

[0108] In some embodiments, the pharmaceutical product contains about 4.5% w / w or less of tasquinimod degradation products as defined herein relative to the amount of tasquinimod, e.g., about 4.0% w / w or less, 3.5% w / w or less, 3.0% w / w or less, 2.5% w / w or less, 2.0% w / w or less, 1.5% w / w or less, 1.0% w / w or less, 0.8% w / w or less, 0.7% w / w or less, 0.6% w / w or less, or 0.5% w / w or less of tasquinimod degradation products as defined herein relative to the amount of tasquinimod in the product.

[0109] Needless to say, it is preferred that as low an amount of tasquinimod degradation products as possible are present in the products of the invention. However, in some embodiments, the pharmaceutical product contains at least 0.01% w / w of tasquinimod degradation products as defined herein above relative to tasquinimod, for example at least 0.02% w / w, 0.03% w / w, 0.04% w / w, 0.05% w / w, 0.06% w / w, 0.07% w / w, 0.08% w / w, 0.09% w / w, or 0.10% w / w of tasquinimod degradation products as defined herein above relative to the amount of tasquinimod in the product.

[0110] In some embodiments, the pharmaceutical product is a composition containing a therapeutically effective amount of tasquinimod and one or more pharma- ceutically acceptable excipients, including fillers and / or lubricants. In some embodiments, the composition is a particulate composition or comprises a powder, for example as described in International Application No. PCT / EP2022 / 063887 (see above).

[0111] For example, the pharmaceutical product may be a composition containing about 0.1-2% by weight of tasquinimod and about 98-99.9% by weight of one or more pharma- ceutically acceptable excipients, such as about 0.2-1% by weight of tasquinimod and about 99-99.8% by weight of one or more pharma- ceutically acceptable excipients.

[0112] In some embodiments, the pharmaceutical product is a composition containing a therapeutically effective amount of tasquinimod and one or more pharma- ceutically acceptable excipients, such as a composition containing tasquinimod, a filler, and a lubricant.

[0113] In some embodiments, the pharmaceutical product is a composition containing tasquinimod and one or more pharma- ceutically acceptable excipients, such as a composition containing tasquinimod, pregelatinised starch as a filler, and hydrogenated vegetable oil as a lubricant.

[0114] In some embodiments, the pharmaceutical product is a pharmaceutical dosage unit, e.g., a pharmaceutical dosage unit for oral administration, such as a capsule or tablet. For example, the pharmaceutical product may be a dosage unit containing 0.25 mg to 2 mg of tasquinimod, e.g., 0.5 to 1.5 mg of tasquinimod, in particular 1 mg of tasquinimod (or a corresponding amount of a pharma- ceutically acceptable salt thereof), and one or more pharma- ceutically acceptable excipients, such as a filler and a lubricant.

[0115] In some embodiments, the pharmaceutical dosage unit is a tablet for oral administration. In other embodiments, the pharmaceutical dosage unit is a capsule for oral administration.

[0116] For example, the pharmaceutical product may be a capsule for oral administration, e.g., a hard shell capsule, containing 0.25 mg to 2 mg of tasquinimod, e.g., 0.5 to 1.5 mg of tasquinimod, in particular 1 mg of tasquinimod (or a corresponding amount of a pharma- ceutically acceptable salt thereof), and one or more pharma- ceutically acceptable excipients, such as a filler and a lubricant.

[0117] In some embodiments, the pharmaceutical product is a solid immediate release capsule containing about 100 to about 200 mg, e.g., about 150 mg, of powder composed of 0.1 mg to 2 mg of tasquinimod in combination with one or more pharma- ceutically acceptable excipients, e.g., pregelatinized starch as a filler and hydrogenated vegetable oil as a lubricant.

[0118] As noted herein above, in pharmaceutical products provided herein that are determined to be suitable for distribution, compounds I-IV are present in a total amount of about 5% w / w or less relative to the amount of tasquinimod in the product. Of course, in some cases, the amount of compounds I-IV in a pharmaceutical product containing tasquinimod may be extremely low, for example approaching or even below the detection limit.

[0119] In some embodiments, at least one of compounds I-IV is present in the pharmaceutical product in an amount of at least about 0.01% w / w relative to the amount of tasquinimod in the product, at least about 0.02% w / w, at least about 0.05% w / w, at least about 0.08% w / w, or at least about 0.10% w / w relative to the amount of tasquinimod in the product.

[0120] In some embodiments, a pharmaceutical product is provided that includes tasquinimod or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable excipient, and compound I, where compound I is present in the pharmaceutical composition in an amount of about 2.0% w / w or less relative to the amount of tasquinimod, or about 1.5% w / w or less, about 1.0% w / w or less, about 0.50% w / w or less, or about 0.25% w / w or less relative to the amount of tasquinimod. In some of these embodiments, compound I is present in an amount of at least about 0.01% w / w relative to the amount of tasquinimod in the product, at least about 0.02% w / w, at least about 0.05% w / w, at least about 0.08% w / w, or at least about 0.10% w / w relative to the amount of tasquinimod in the product.

[0121] In some embodiments, a pharmaceutical product is provided that includes tasquinimod or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable excipient, and compound II, where compound II is present in the pharmaceutical composition in an amount of about 2.0% w / w or less relative to the amount of tasquinimod, or about 1.5% w / w or less, about 1.0% w / w or less, about 0.50% w / w or less, or about 0.25% w / w or less relative to the amount of tasquinimod. In some of these embodiments, compound II is present in an amount of at least about 0.01% w / w relative to the amount of tasquinimod in the product, at least about 0.02% w / w, at least about 0.05% w / w, at least about 0.08% w / w, or at least about 0.10% w / w relative to the amount of tasquinimod in the product.

[0122] In some embodiments, a pharmaceutical product is provided that includes tasquinimod or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable excipient, and compound III, where compound III is present in the pharmaceutical composition in an amount of about 2.0% w / w or less relative to the amount of tasquinimod, or about 1.5% w / w or less, about 1.0% w / w or less, about 0.50% w / w or less, or about 0.25% w / w or less relative to the amount of tasquinimod. In some of these embodiments, compound III is present in an amount of at least about 0.01% w / w relative to the amount of tasquinimod in the product, at least about 0.02% w / w, at least about 0.05% w / w, at least about 0.08% w / w, or at least about 0.10% w / w relative to the amount of tasquinimod in the product.

[0123] In some embodiments, a pharmaceutical product is provided that includes tasquinimod or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable excipient, and compound IV, where compound IV is present in the pharmaceutical composition in an amount of about 2.0% w / w or less relative to the amount of tasquinimod, or about 1.5% w / w or less, about 1.0% w / w or less, about 0.50% w / w or less, or about 0.25% w / w or less relative to the amount of tasquinimod. In some of these embodiments, compound IV is present in an amount of at least about 0.01% w / w relative to the amount of tasquinimod in the product, at least about 0.02% w / w, at least about 0.05% w / w, at least about 0.08% w / w, or at least about 0.10% w / w relative to the amount of tasquinimod in the product.

[0124] The pharmaceutical product provided herein (e.g., pharmaceutical composition or pharmaceutical dosage unit containing such pharmaceutical composition) is preferably in solid form.In some embodiments, the pharmaceutical product is a pharmaceutical composition.In some embodiments, the pharmaceutical product is a pharmaceutical dosage unit, such as an oral capsule or tablet.

[0125] It is noted that tasquinimod and compounds I-IV can exist in either the non-salt form or the salt form. Unless otherwise indicated or clear from the context, any reference to tasquinimod or any one of compounds I-IV includes the non-salt and salt forms thereof, but any amounts provided herein should be understood to refer to the non-salt forms of tasquinimod and compounds I-IV. Use of pharmaceutical products As mentioned hereinabove, the therapeutic activity of tasquinimod in the treatment of various diseases has been previously demonstrated. It is believed that the pharmaceutical product provided herein will be 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 the pharmaceutical product provided herein for use in the treatment of cancer.

[0126] A further aspect is the use of the pharmaceutical composition provided herein in the manufacture of a medicament for the treatment of cancer.In some embodiments, the manufacture comprises preparing a capsule by encapsulating the pharmaceutical composition provided herein using encapsulation techniques well known in the art.In some other embodiments, the manufacture comprises preparing a tablet using tableting techniques also well known in the art. It should be noted that the selection of suitable excipients and manufacturing conditions is within the knowledge of a person skilled in the art, taking into full consideration the descriptions herein, and by referring to well-known texts, such as "Aulton's Pharmaceutics, The Design and Manufacture of Medicines", 6th Edition 2021, Editors: Kevin Taylor, Michael Aulton (paperback ISBN: 9780702081545, eBook ISBN: 9780702081569), Copyright: (Copyright) Elsevier, or "Remington, The Science and Practice of Pharmacy", 23rd Edition 2020, Editor: Adeboye Adejare, (hardcover ISBN: 9780128200070, eBook ISBN: 9780128223895), Copyright: (Copyright) Academic Press.

[0127] Another further aspect is a method of treating cancer by administering an effective amount of a pharmaceutical product provided herein to a mammal in need of such treatment.Preferably, the method comprises oral administration of a pharmaceutical dosage unit provided herein, such as an oral tablet or capsule.In an embodiment, the method comprises oral administration of a tablet provided herein.In an embodiment, the method comprises oral administration of a capsule provided herein.

[0128] 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, such as early or late stage. 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.

[0129] In some embodiments, the cancer is a blood cancer, such as leukemia, lymphoma, myelodysplastic syndrome, myeloproliferative neoplasm, or multiple myeloma. In some embodiments, the blood cancer is selected from leukemia and multiple myeloma. In some embodiments, the blood cancer is selected from leukemia, myelodysplastic syndrome, and myeloproliferative neoplasm.

[0130] 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.

[0131] The leukemia may 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.

[0132] 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 progress to myelofibrosis. Thus, in some embodiments, the pharmaceutical product provided herein is for use in preventing or reducing the progression of myeloproliferative neoplasms, such as essential thrombocythemia or polycythemia vera, to fibrotic stage.Thus, the term "myelofibrosis" as used herein 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.

[0133] 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 (such as certain non-muscle invasive bladder cancer, muscle invasive bladder cancer, and metastatic and urothelial bladder cancer), prostate cancer and renal cell carcinoma.In some embodiments, the cancer is bladder cancer.

[0134] For any subject, in medical treatment by use of the pharmaceutical products provided herein, dosage levels and frequency will generally be as determined by the treating physician, with due regard to factors such as the sex, age, weight and relative health of the subject to be treated, the selected route and form of administration, the additional use of other drugs, e.g., in combination therapy.

[0135] Generally, daily dosages ranging from 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, are contemplated. In some embodiments, tasquinimod is 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.

[0136] In some embodiments, the dosage may be gradually adjusted until optimal results are reached, so-called dosage titration. For example, dosage titration may include starting with a low daily dosage, for example 0.25 mg, and maintaining this dosage level for 1 or 2 weeks. If no significant side effects are observed that may contraindicate increasing the dosage, then the level may be increased to, for example, 0.5 mg / day for 1 or 2 weeks, after which a further increase may be contemplated to reach a daily dosage of 1 mg, etc. In such a manner, if any significant side effects occur after the dosage escalation, the dosage may again be reduced to the previous level. Possible side effects include those that may be commonly observed in this type of treatment, such as gastrointestinal disorders, fatigue, and flu-like symptoms, which are believed to be related to the dosage.

[0137] 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., every other day, once a week, etc. It is noted that when a pharma- ceutically acceptable salt of tasquinimod is administered, the equivalent dosage corresponds to the designated dosage of tasquinimod in the non-salt form (i.e., as the free base). The compound 3,3'-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one) A further embodiment is a compound having the structural formula:

[0138] [ka]

[0139] The compound 3,3'-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one), (Compound IV) or a pharma- ceutically acceptable salt of said compound.

[0140] Compound IV is useful, for example, in the evaluation methods described herein. Process for preparing 3,3'-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one) A further aspect is a process for preparing compound IV or a salt of said compound, said process comprising the step of allowing 4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one (compound III) to react (e.g., by slurrying) with paraformaldehyde in the presence of ethane-1,2-diamine and acetic acid in a solvent such as anhydrous (99%) ethanol.

[0141] In some embodiments, the process includes a step of obtaining compound III by subjecting 4-hydroxy-5-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (compound II) to a decarboxylation reaction.

[0142] In some embodiments, the process includes obtaining compound II by hydrolysis of the corresponding C1-C6 alkyl ester, or C1-C3 alkyl ester, such as methyl 4-hydroxy-5-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate.

[0143] In some embodiments, the process includes a step of converting the obtained compound IV into a salt thereof, for example an alkali metal salt, for example a salt with a metal selected from lithium, sodium, potassium, and the like. Use of a compound selected from compounds I, II, III and IV Compounds I, II, III, and IV are useful in the methods disclosed herein, e.g., as reference samples for analysis or to generate calibration curves, e.g., in methods for determining whether a pharmaceutical product containing tasquinimod or a pharma- ceutically acceptable salt of tasquinimod is suitable for distribution. Accordingly, some embodiments are directed to the use of any one or more of compounds I, II, III, and IV in the methods disclosed herein and in processes for preparing pharmaceutical compositions comprising tasquinimod to which such methods are applied.

[0144] In some embodiments, there is provided the use of Compound I in the methods described herein.

[0145] In some embodiments, there is provided the use of compound II in the methods described herein.

[0146] In some embodiments, there is provided the use of compound III in the methods described herein.

[0147] In some embodiments, there is provided the use of compound IV in the methods described herein. EXAMPLES

[0148] The invention is further illustrated by the following non-limiting examples.

[0149] Example 1 Synthesis of 3,3'-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one) Step 1: 4-Hydroxy-5-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid Methyl 4-hydroxy-5-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (40 g) was hydrolyzed with NaCl / H2SO4 in acetic acid to give 4-hydroxy-5-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (compound II) (23.7 g). Step 2: 4-Hydroxy-5-methoxy-1-methylquinolin-2(1H)-one Compound II (12 g) was heated in DMSO at 120° C. for 2 hours to give 4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one (compound III) (9.31 g, Mw 205.22). Step 3: 3,3'-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one) Compound III (3.0 g, 14.6 mmol) and paraformaldehyde (205 mg, 6.1 mmol, 90%) were slurried in 30 ml of anhydrous (99%) ethanol. To this slurry, ethane-1,2-diamine (21 μl) and acetic acid (80 μl) were added and the reaction mixture was refluxed. After 2 hours, the reaction mixture was diluted by addition of EtOH and filtered to give 3,3'-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one) (Compound IV) (2.6 g, Mw 422.43). The structure of Compound IV was determined by MS, NMR (Hz), NMR (Hz), δ 1.0-1.5 (methylenediamine ... 1 H NMR and 13 The structure was confirmed by C NMR, and the spectra are shown in Figures 2, 3, 4 and 5.

[0150] Example 2 Preparation and Evaluation of an Oral Capsule Containing 1 mg Tasquinimod A batch of oral capsules was prepared with a target dosage strength of 1 mg tasquinimod / capsule. The capsules were conventional solid immediate release capsules (hard gelatin, size 3 Coni-snap® capsules) with each capsule containing 154 mg of powder composed of tasquinimod (target weight 1 mg), pregelatinized corn-derived starch (Starch1500®) (150 mg), and hydrogenated vegetable oil (Sterotex®) (3 mg). The manufacturing process included a single-step blending procedure followed by filling the required amount of the blend into the capsule shells.

[0151] The resulting batch of capsules was evaluated by determining the amount of tasquinimod and the amount of compound III in a sample of capsules. The criterion selected for batch approval was that the sample capsules contained 1.0% w / w or less of compound III relative to the amount of tasquinimod. The sample capsules were found to contain 0.01% w / w of compound III relative to the amount of tasquinimod, which was determined to be 1.05 mg / capsule. Therefore, according to the criterion selected for approval, the batch of capsules was determined to be suitable for distribution.

[0152] Example 3 Evaluation of an oral capsule containing 1 mg of tasquinimod The batch of capsules produced in Example 2 was evaluated by determining the amount of tasquinimod and the amount of compound III in a sample of the capsules. The criteria for approving the batch were therefore that the capsule samples of the batch contained 1.0% w / w or less of compound III relative to the amount of tasquinimod at the end of a one-month stability test. The stability test consisted of holding the capsules in open brown glass jars at 40° C. / 75% RH. At the end of the one-month stability test, the capsules contained 0.13% w / w of compound III relative to the amount of tasquinimod (1.04 mg / capsule). Thus, according to the criteria selected for approval, the batch of capsules was deemed suitable for distribution.

[0153] Example 4 Evaluation of an oral capsule containing 1 mg of tasquinimod A batch of capsules prepared in Example 2 was evaluated by the method as described in Example 3, except that the capsules were kept in open amber glass jars at 40° C. / 75% RH for 2 months. The criterion selected for batch approval was that at the end of the stability study, the sample capsules contained 1.0% w / w or less of compound III relative to the amount of tasquinimod. At the end of the 2-month stability study, the capsules contained 0.12% w / w of compound III relative to the amount of tasquinimod (1.04 mg / capsule). Thus, according to the criterion selected for approval, the batch of capsules was deemed suitable for distribution.

[0154] Example 5 Evaluation of an oral capsule containing 1 mg of tasquinimod A batch of capsules prepared in Example 2 was evaluated by the method as described in Example 3, except that the capsules were kept in open amber glass jars at 40° C. / 75% RH for 3 months. The criterion selected for batch approval was that at the end of the stability study, the sample capsules contained 1.0% w / w or less of compound III relative to the amount of tasquinimod. At the end of the 3-month stability study, the capsules contained 0.14% w / w of compound III relative to the amount of tasquinimod (1.00 mg / capsule). Thus, according to the criterion selected for approval, the batch of capsules was deemed suitable for distribution.

[0155] Example 6 Evaluation of an oral capsule containing 1 mg of tasquinimod The batch of capsules produced in Example 2 was evaluated by the method as described in Example 3, except that the capsules were kept in open amber glass jars at 40° C. / 75% RH for 6 months. The criterion selected for batch approval was that at the end of the stability study, the sample capsules contained 1.0% w / w or less of compound III relative to the amount of tasquinimod. At the end of the 6-month stability study, the capsules contained 0.16% w / w of compound III relative to the amount of tasquinimod (1.01 mg / capsule). Thus, according to the criterion selected for approval, the batch of capsules was deemed suitable for distribution.

[0156] Example 7 Preparation and Evaluation of an Oral Capsule Containing 0.5 mg Tasquinimod A batch of oral capsules (approximately 8000 capsules) was prepared with a target dosage strength of 0.5 mg tasquinimod / capsule. The capsules were conventional solid immediate release capsules (hard gelatin, size 3 (3 ml) Coni-snap® capsules) with each capsule containing 210 mg of powder composed of tasquinimod (target weight 0.5 mg), pregelatinized starch derived from corn (Starch1500®) (205.3 mg), and hydrogenated vegetable oil (Lubritab®) (4.2 mg). The manufacturing process included a three-step blending procedure: step 1) a first premix step involving mixing tasquinimod with a small portion of the fill in a small blender, step 2) a second premix step after addition of the lubricant and a second portion of the fill, and step 3) a final mix with the remaining fill in a tumble blender followed by filling the required amount of the blend into capsule shells.

[0157] The resulting batch of capsules was evaluated by determining the amount of tasquinimod and the amount of compound III in a sample of capsules. The criterion selected for batch approval was that the sample capsules contained 1.0% w / w or less of compound III relative to the amount of tasquinimod. The sample capsules were found to contain 0.03% w / w of compound III relative to the amount of tasquinimod, which was determined to be 0.498 mg / capsule. Therefore, according to the criterion selected for approval, the batch of capsules was determined to be suitable for distribution.

[0158] Example 8 Evaluation of an oral capsule containing 0.5 mg of tasquinimod The batch of capsules produced in Example 7 was evaluated by determining the amount of tasquinimod and the amount of compound III in a sample of the capsules. The criteria for approving the batch were therefore that a sample of the capsules of the batch contained 1.0% w / w or less of compound III relative to the amount of tasquinimod in the capsules at the end of a 3-month stability study. The stability study consisted of holding the capsules in a sealed amber glass jar at 40° C. / 75% RH. At the end of the stability study, the capsules contained 0.08% w / w of compound III relative to the amount of tasquinimod (0.493 mg / capsule). Thus, according to the criteria selected for approval, the batch of capsules was deemed suitable for distribution.

[0159] Example 9 Evaluation of an oral capsule containing 0.5 mg of tasquinimod The batch of capsules prepared in Example 7 was evaluated by the method as described in Example 8, except that the capsules were kept in closed amber glass jars at 40° C. / 75% RH for 6 months. At the end of the 6-month stability study, the capsules contained 0.14% w / w of compound III relative to the amount of tasquinimod (0.487 mg / capsule). Therefore, according to the criteria selected for approval, the batch of capsules was deemed suitable for distribution.

[0160] Example 10 Preparation and Evaluation of an Oral Capsule Containing 0.25 mg Tasquinimod A batch of oral capsules (6000 capsules) was prepared with a target dosage strength of 0.25 mg tasquinimod / capsule. The capsules were conventional solid immediate release capsules (hard gelatin, size 4 Coni-snap® capsules) with each capsule containing 150 mg of powder composed of tasquinimod (target weight 0.25 mg), pregelatinized starch derived from corn (Starch1500®) (146.75 mg), and hydrogenated vegetable oil (Lubritab®) (3.00 mg). The manufacturing process included a three-step blending procedure as described in Example 7, followed by filling the required amount of the blend into the capsule shells.

[0161] The resulting batch of capsules was evaluated by determining the amount of tasquinimod and the amount of compound III in a sample of capsules. The criterion selected for batch approval was that the sample capsules contained 1.0% w / w or less of compound III relative to the amount of tasquinimod. The sample capsules were found to contain 0.07% w / w of compound III relative to the amount of tasquinimod, which was determined to be 0.252 mg / capsule. Therefore, according to the criterion selected for approval, the batch of capsules was determined to be suitable for distribution.

[0162] Example 11 Evaluation of an oral capsule containing 0.25 mg of tasquinimod The batch of capsules produced in Example 10 was evaluated by determining the amount of tasquinimod and the amount of compound III in a sample of the capsules. Thus, the criteria for approving the batch was that a sample of the capsules of the batch contained 1.0% w / w or less of compound III relative to the amount of tasquinimod in the capsules at the end of a 3-month stability study. The stability study consisted of holding the capsules in a sealed amber glass jar at 40° C. / 75% RH. At the end of the stability study, the capsules contained 0.10% w / w of compound III relative to the amount of tasquinimod (determined to be 0.253 mg / capsule). Thus, according to the criteria selected for approval, the batch of capsules was determined to be suitable for distribution.

[0163] Example 12 Evaluation of an oral capsule containing 0.25 mg of tasquinimod A batch of capsules prepared in Example 10 was evaluated by the method as described in Example 11, except that the capsules were kept in a sealed amber glass jar at 40° C. / 75% RH for 6 months. The criterion for approving the batch was therefore that the sample capsules contained 1.0% w / w or less of compound III relative to the amount of tasquinimod in the capsule at the end of the 6-month stability study. At the end of the 6-month stability study, the capsules contained 0.10% w / w of compound III relative to the amount of tasquinimod (determined to be 0.247 mg / capsule). Thus, according to the criteria selected for approval, the batch of capsules was determined to be suitable for distribution.

[0164] Example 13 Preparation and Evaluation of an Oral Capsule Containing 0.25 mg Tasquinimod A batch of oral capsules (80000 capsules) was prepared with a target dosage strength of 0.25 mg tasquinimod / capsule. The capsules were conventional solid immediate release capsules (white, hard gelatin, size 4 Coni-snap® capsules) with each capsule containing 150 mg of powder composed of tasquinimod (target weight 0.25 mg), pregelatinized starch from corn (Starch1500®) (146.75 mg) and hydrogenated vegetable oil (Lubritab®) (3.00 mg). The manufacturing process included the same type of three-step blending procedure described in Example 7, followed by filling the required amount of blend into the capsule shells.

[0165] The resulting batch of capsules was evaluated by determining the amount of tasquinimod and the amount of compound III in a sample of capsules. The criterion selected for batch approval was that the sample capsules contained 1.0% w / w or less of compound III relative to the amount of tasquinimod. The sample capsules were found to contain 0.06% w / w of compound III relative to the amount of tasquinimod, which was determined to be 0.256 mg / capsule. Therefore, according to the criterion selected for approval, the batch of capsules was determined to be suitable for distribution.

[0166] Example 14 Evaluation of an oral capsule containing 0.25 mg of tasquinimod A batch of capsules manufactured in Example 13 was evaluated by determining the amount of tasquinimod and the amount of compound III in a sample of capsules. The criteria for approving the batch was therefore that the sample capsules contained 1.0% w / w or less of compound III relative to the amount of tasquinimod in the capsules at the end of a 3-month stability study. The stability study consisted of holding the capsules in a clear conventional blister pack at 40° C. / 75% RH. At the end of the stability study, the capsules contained 0.12% w / w of compound III relative to the amount of tasquinimod (determined to be 0.253 mg / capsule). Thus, according to the criteria selected for approval, the batch of capsules was determined to be suitable for distribution.

[0167] Example 15 Evaluation of an oral capsule containing 0.25 mg of tasquinimod The batch of capsules prepared in Example 13 was evaluated by the method as described in Example 14, except that the blister pack with the capsules was kept at 40°C / 75%RH for 6 months. The criterion for approving the batch was therefore that the sample capsules contained 1.0% w / w or less of compound III relative to the amount of tasquinimod in the capsule at the end of the 6-month stability study. At the end of the 6-month stability study, the capsules contained 0.24% w / w of compound III relative to the amount of tasquinimod (0.247 mg / capsule). Thus, according to the criteria selected for approval, the batch of capsules was deemed suitable for distribution.

[0168] Example 16 Preparation and Evaluation of an Oral Capsule Containing 1 mg Tasquinimod The general procedure of Example 13 was repeated to prepare capsules containing 1.00 mg of tasquinimod in combination with 146.00 mg of Starch 1500® and 3.00 mg of Lubritab® (i.e., a fill weight of 150 mg / capsule).

[0169] The resulting batch of capsules was evaluated by determining the amount of tasquinimod and the amount of compound III in a sample of capsules. The criterion selected for batch approval was that the sample capsules contained 1.0% w / w or less of compound III relative to the amount of tasquinimod. The sample capsules were found to contain 0.02% w / w of compound III relative to the amount of tasquinimod, which was determined to be 0.994 mg / capsule. Therefore, according to the criterion selected for approval, the batch of capsules was determined to be suitable for distribution.

[0170] Example 17 Evaluation of an oral capsule containing 1 mg of tasquinimod A batch of capsules prepared in Example 16 was evaluated by determining the amount of tasquinimod and the amount of compound III in a sample of capsules. The criteria for approving the batch was therefore that the sample capsules contained 1.0% w / w or less of compound III relative to the amount of tasquinimod in the capsules at the end of a 3-month stability study. The stability study consisted of holding the capsules in clear conventional blister packs at 40° C. / 75% RH. At the end of the stability study, the capsules contained 0.13% w / w of compound III relative to the amount of tasquinimod (determined to be 0.993 mg / capsule). Thus, according to the criteria selected for approval, the batch of capsules was determined to be suitable for distribution.

[0171] Example 18 Evaluation of an oral capsule containing 1 mg of tasquinimod The batch of capsules produced in Example 16 was evaluated by the method as described in Example 14, except that the blister packs with the capsules were kept at 40°C / 75%RH for 6 months. The criterion for approving the batch was therefore that the sample capsules contained 1.0% w / w or less of compound III relative to the amount of tasquinimod in the capsule at the end of the 6-month stability study. At the end of the 6-month stability study, the capsules contained 0.21% w / w of compound III relative to the amount of tasquinimod (determined to be 0.985 mg / capsule). Thus, according to the criteria selected for approval, the batch of capsules was determined to be suitable for distribution.

[0172] Example 19 Preparation and Evaluation of an Oral Capsule Containing 0.25 mg Tasquinimod A batch of oral capsules (200,000 capsules) was prepared with a target dosage strength of 0.25 mg tasquinimod / capsule. The capsules were conventional solid immediate release capsules (white, size 4 hard gelatin shell capsules) with each capsule containing 150 mg of powder composed of tasquinimod (target weight 0.25 mg), pregelatinized starch derived from corn (Starch1500®) (146.75 mg), and hydrogenated vegetable oil (Lubritab®) (3.00 mg). The manufacturing process included a three-step blending procedure as described in Example 7, followed by filling the required amount of the blend into the capsule shells.

[0173] The resulting batch of capsules was evaluated by determining the amount of tasquinimod and the amount of compounds I, II, III, and IV in a sample of capsules. The criterion selected for batch approval was that the sample capsules contained less than 5% w / w of compounds I-IV in total relative to the amount of tasquinimod. The sample capsules were found to contain less than 0.2% w / w of compounds I, II, III, and IV in total relative to the amount of tasquinimod, which was determined to be 0.244 mg / capsule. Thus, according to the criteria selected for approval, the batch of capsules was determined to be suitable for distribution.

[0174] Example 20 Evaluation of an oral capsule containing 0.25 mg of tasquinimod A batch of capsules prepared in Example 19 was evaluated by determining the amount of tasquinimod and the amount of each of compounds I, II, III and IV in a sample of capsules at the end of a 3-month stability study. The criterion for accepting a batch was therefore that a sample capsule contained a total amount of compounds I-IV of 5.0% w / w or less relative to the amount of tasquinimod in the capsule at the end of the 3-month stability study. The stability study consisted of holding the capsules in a water-impermeable blister pack at 25°C / 60% RH. At the end of the stability study, the capsules contained 0.06% w / w of compound I, less than 0.05% w / w of compound II, 0.10% of compound III and less than 0.05% w / w of compound IV relative to the amount of tasquinimod (determined to be 0.246 mg / capsule), i.e., less than 0.26% w / w of compounds I-IV in total relative to the amount of tasquinimod. Therefore, according to the criteria selected for approval, the batch of capsules was deemed suitable for distribution.

[0175] Example 21 Evaluation of an oral capsule containing 0.25 mg of tasquinimod The batch of capsules produced in Example 19 was evaluated by the method as described in Example 20, except that the blister pack with the capsules was kept at 25°C / 60%RH for 6 months. The criterion for approving the batch was therefore that the sample capsules contained a total amount of Compounds I-IV of 5.0% w / w or less relative to the amount of tasquinimod in the capsule at the end of the 6-month stability test. At the end of the 6-month stability test, the capsules contained 0.08% w / w of Compound I, less than 0.05% w / w of Compound II, 0.16% w / w of Compound III, and less than 0.05% w / w of Compound IV relative to the amount of tasquinimod (0.243 mg / capsule), i.e., less than 0.34% w / w of Compounds I-IV in total relative to the amount of tasquinimod. Thus, according to the criteria selected for approval, the batch of capsules was deemed suitable for distribution.

[0176] Example 22 Evaluation of an oral capsule containing 0.25 mg of tasquinimod The batch of capsules produced in Example 19 was evaluated by the method as described in Example 20, except that the blister pack with the capsules was kept at 25°C / 60%RH for 9 months. The criterion for approving the batch was therefore that the sample capsules contained a total amount of Compounds I-IV of 5.0% w / w or less relative to the amount of tasquinimod in the capsule at the end of the 9-month stability study. At the end of the 9-month stability study, the capsules contained 0.12% w / w of Compound I, less than 0.05% w / w of Compound II, 0.21% w / w of Compound III, and less than 0.05% w / w of Compound IV relative to the amount of tasquinimod (determined to be 0.243 mg / capsule), i.e., less than 0.43% w / w of Compounds I-IV in total relative to the amount of tasquinimod. Thus, according to the criteria selected for approval, the batch of capsules was determined to be suitable for distribution.

[0177] Example 23 Evaluation of an oral capsule containing 0.25 mg of tasquinimod A batch of capsules prepared in Example 19 was evaluated by the method as described in Example 20, except that the blister pack with the capsules was kept at 25°C / 60% RH for 12 months. The criterion for approving the batch was therefore that the sample capsules contained a total amount of Compounds I-IV of 5.0% w / w or less relative to the amount of tasquinimod in the capsule at the end of the 12-month stability study. At the end of the 12-month stability study, the capsules contained 0.11% w / w of Compound I, less than 0.05% w / w of Compound II, 0.26% w / w of Compound III, and less than 0.05% w / w of Compound IV relative to the amount of tasquinimod (determined to be 0.245 mg / capsule), i.e., less than 0.47% w / w of Compounds I-IV in total relative to the amount of tasquinimod. Thus, according to the criteria selected for approval, the batch of capsules was determined to be suitable for distribution.

[0178] Example 24 Evaluation of an oral capsule containing 0.25 mg of tasquinimod The batch of capsules prepared in Example 19 was evaluated by the method as described in Example 20, except that the blister pack with the capsules was kept at 25°C / 60%RH for 18 months. The criterion for approving the batch was therefore that the sample capsules contained a total amount of Compounds I-IV of 5.0% w / w or less relative to the amount of tasquinimod in the capsule at the end of the 18-month stability study. At the end of the 18-month stability study, the capsules contained 0.10% w / w Compound I, 0.05% w / w Compound II, 0.35% w / w Compound III, and 0.07% w / w Compound IV relative to the amount of tasquinimod (determined to be 0.245 mg / capsule), i.e., a total of 0.57% w / w Compounds I-IV relative to the amount of tasquinimod. Thus, according to the criteria selected for approval, the batch of capsules was determined to be suitable for distribution.

[0179] Example 25 Evaluation of an oral capsule containing 0.25 mg of tasquinimod The batch of capsules prepared in Example 19 was evaluated by the method as described in Example 20, except that the blister pack with the capsules was kept at 25°C / 60%RH for 24 months. The criterion for approving the batch was therefore that the sample capsules contained a total amount of Compounds I-IV of 5.0% w / w or less relative to the amount of tasquinimod in the capsule at the end of the 24-month stability study. At the end of the 24-month stability study, the capsules contained 0.13% w / w of Compound I, 0.05% w / w of Compound II, 0.41% w / w of Compound III, and 0.10% w / w of Compound IV relative to the amount of tasquinimod (determined to be 0.237 mg / capsule), i.e., a total of 0.69% w / w of Compounds I-IV relative to the amount of tasquinimod. Thus, according to the criteria selected for approval, the batch of capsules was determined to be suitable for distribution.

[0180] Example 26 Evaluation of an oral capsule containing 0.25 mg of tasquinimod The batch of capsules produced in Example 19 was evaluated by the method as described in Example 20, except that the blister pack with the capsules was kept at 25°C / 60%RH for 36 months. The criterion for approving the batch was therefore that the sample capsules contained a total amount of Compounds I-IV of 5.0% w / w or less relative to the amount of tasquinimod in the capsule at the end of the 36-month stability study. At the end of the 36-month stability study, the capsules contained 0.16% w / w of Compound I, 0.06% w / w of Compound II, 0.57% w / w of Compound III, and 0.15% w / w of Compound IV relative to the amount of tasquinimod (determined to be 0.237 mg / capsule), i.e., a total of 0.94% w / w of Compounds I-IV relative to the amount of tasquinimod. Thus, according to the criteria selected for approval, the batch of capsules was determined to be suitable for distribution.

[0181] Example 27 Evaluation of an oral capsule containing 0.25 mg of tasquinimod The batch of capsules prepared in Example 19 was evaluated by the method as described in Example 20, except that the blister pack with the capsules was kept at 25°C / 60% RH for 48 months. The criterion for approving the batch was therefore that the sample capsules contained a total amount of Compounds I-IV of 5.0% w / w or less relative to the amount of tasquinimod in the capsule at the end of the 48-month stability study. At the end of the 48-month stability study, the capsules contained 0.16% w / w of Compound I, 0.06% w / w of Compound II, 0.79% w / w of Compound III, and 0.19% w / w of Compound IV relative to the amount of tasquinimod (determined to be 0.238 mg / capsule), i.e., a total of 1.2% w / w of Compounds I-IV relative to the amount of tasquinimod. Thus, according to the criteria selected for approval, the batch of capsules was determined to be suitable for distribution.

[0182] Example 28 Preparation and Multiple Evaluation of an Oral Capsule Containing 0.5 mg Tasquinimod A batch of oral capsules (200,000 capsules) with a target dosage strength of 0.5 mg tasquinimod / capsule was manufactured according to the procedure described in Example 19. The capsules were conventional solid immediate release capsules (white, size 4 hard gelatin shell capsules) with each capsule containing 150 mg of powder composed of tasquinimod (target weight 0.5 mg), pregelatinized starch derived from corn (Starch1500®) (146.5 mg), and hydrogenated vegetable oil (Lubritab®) (3.00 mg).

[0183] The resulting batches of capsules were subjected to multiple evaluations: the first evaluation involved determining the amount of tasquinimod and the amounts of compounds I, II, III, and IV in a sample of capsules immediately after production, such that the criterion selected for approving a batch for distribution was that the sample capsules contained 5% w / w or less of compounds I-IV in total relative to the amount of tasquinimod in a water-impermeable blister pack. Subsequently, eight further independent evaluations were performed to determine the amount of tasquinimod and the amount of each of compounds I, II, III, and IV in the samples of capsules at the end of 3, 6, 9, 12, 18, 24, 36, and 48 months of stability testing (by holding the capsules in water-impermeable blister packs at 25° C. / 60% RH), respectively, such that each time the criterion for batch approval was that the sample capsules contained a total amount of compounds I-IV of 5.0% w / w or less relative to the amount of tasquinimod in the capsule at the end of each stability period. Table 3 shows the amounts of compounds I-IV and tasquinimod in the capsules determined after manufacturing (i.e., at 0 months) and at the end of each stability period.

[0184] [Table 3]

[0185] The total amount of compounds I-IV was less than 5% w / w relative to the amount of tasquinimod in each sample capsule, and therefore each evaluation determined that the batch of capsules was suitable for distribution.

[0186] Example 29 Preparation and Multiple Evaluation of an Oral Capsule Containing 1.0 mg Tasquinimod A batch of oral capsules (200,000 capsules) with a target dosage strength of 1.0 mg tasquinimod / capsule was manufactured according to the procedure described in Example 19. The capsules were conventional solid immediate release capsules (white, size 4 hard gelatin shell capsules) with each capsule containing 150 mg of powder composed of tasquinimod (target weight 1.0 mg), pregelatinized starch derived from corn (Starch1500®) (146.0 mg), and hydrogenated vegetable oil (Lubritab®) (3.00 mg).

[0187] The resulting batches of capsules were evaluated multiple times as described in Example 28 and subjected to similar criteria to approve the capsules for distribution. Table 4 shows the amounts of Compounds I-IV and tasquinimod in the capsules determined after manufacturing (i.e., at 0 months) and at the end of each stability period.

[0188] [Table 4]

[0189] The total amount of compounds I-IV was less than 5% w / w relative to the amount of tasquinimod in each sample capsule, and therefore each evaluation determined that the batch of capsules was suitable for distribution.

[0190] Examples 30 to 46 Examples 30-46 are the same as Examples 2-18, respectively, except that the approval criteria were set at a maximum amount of Compound III relative to the amount of Tasquinimod of less than 0.5% w / w, and the capsules were deemed suitable for distribution according to the criteria.

[0191] Examples 47 to 57 Examples 47-57 are the same as Examples 19-29, respectively, except that the criterion for approval was a maximum total amount of degradation products relative to the amount of tasquinimod of less than 2.0% w / w. According to that criterion, the capsules were deemed suitable for distribution.

[0192] Examples 58 to 68 Examples 58-68 are the same as Examples 47-57, respectively, except that the approval criteria were further set at a maximum amount of each of Compounds I-IV less than 0.5% w / w relative to the amount of tasquinimod. According to the criteria, the capsules were deemed suitable for distribution.

Claims

1. A pharmaceutical composition comprising a therapeutically effective amount of tasquinimod, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition 【Chemical 1】 N-methyl-4-(trifluoromethyl)aniline, 【Chemical 2】 4-hydroxy-5-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, 【Chemical Formula 3】 4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one, and [Chemical Formula 4] 3,3'-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one), further comprises one or more compounds selected from these and their pharmaceutically acceptable salts, and the one or more compounds are present in a total amount of 5% w / w or less based on the amount of tasquinimod in the composition. A pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the one or more compounds are included in a total amount of 4% w / w or less based on the amount of tasquinimod in the composition. A pharmaceutical composition.

3. The pharmaceutical composition according to claim 2, wherein the total amount is 2% w / w or less based on the amount of tasquinimod in the composition. A pharmaceutical composition.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the composition contains the one or more compounds in an amount of 2% w / w or less for each based on the amount of tasquinimod in the composition. A pharmaceutical composition.

5. The pharmaceutical composition according to claim 4, wherein the amount of any one of the one or more compounds is 0.5% w / w or less based on the amount of tasquinimod in the composition. A pharmaceutical composition.

6. A pharmaceutical dosage unit for oral administration, comprising the pharmaceutical composition according to claim 1.

7. The pharmaceutical dosage unit according to claim 6, which is a capsule or a tablet.

8. The pharmaceutical composition according to claim 1 for use in the treatment of cancer.

9. The pharmaceutical dosage unit according to claim 6 or 7 for use in the treatment of cancer.

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

11. The pharmaceutical dosage unit according to claim 9, wherein the cancer is a blood cancer or a solid cancer.

12. The blood cancer is selected from multiple myeloma, lymphoma, myelodysplastic syndrome, myeloproliferative tumor, and leukemia, and 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 tumor (NET), and gastrointestinal pancreatic neuroendocrine tumor (GEP-NET). The pharmaceutical composition according to claim 10.

13. The blood cancer is selected from multiple myeloma, lymphoma, myelodysplastic syndrome, myeloproliferative tumor, and leukemia, and 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 tumor (NET), and gastrointestinal pancreatic neuroendocrine tumor (GEP-NET). The pharmaceutical dosage unit according to claim 11.

14. A method for evaluating a pharmaceutical product containing a therapeutically effective amount of tasquinimod or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, by obtaining a sample of the product and determining the amount of tasquinimod degradation products in the sample, wherein the tasquinimod degradation products are selected from N-methyl-4-(trifluoromethyl)aniline, 4-hydroxy-5-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, 4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one, and 3,3'-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one), and one or more compounds selected from their pharmaceutically acceptable salts.

15. The method according to claim 14, comprising the step of holding the sample at a temperature of 20°C to 40°C and a relative humidity of 30% to 75% for a period of 2 weeks to 5 years before determining the amount of the tasquinimod degradation products in the sample.

16. The method according to claim 14 or 15 for determining whether a pharmaceutical product is suitable for distribution, wherein the pharmaceutical product is determined to be suitable for distribution only when the sample contains 5% w / w or less of the degradation products relative to the amount of tasquinimod in the sample.

17. The method according to claim 16, wherein the pharmaceutical product is determined to be suitable for distribution only when the sample contains 2% w / w or less of the decomposition product relative to the amount of tasquinimod in the sample.

18. The method according to claim 14 for determining whether a pharmaceutical product is suitable for distribution, wherein the pharmaceutical product is determined to be suitable for distribution only when the sample contains 2% w / w or less of any one of the compounds relative to the amount of tasquinimod in the sample.

19. The method according to claim 18, wherein the pharmaceutical product is determined to be suitable for distribution only when the sample contains 0.5% w / w or less of any one of the compounds relative to the amount of tasquinimod in the sample.

20. A process for manufacturing a pharmaceutical product comprising a pharmaceutically effective amount of tasquinimod or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the pharmaceutical product further comprises one or more compounds selected from N-methyl-4-(trifluoromethyl)aniline, 4-hydroxy-5-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, 4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one, and 3,3'-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one), the process comprising preparing a pharmaceutical composition comprising a pharmaceutically effective amount of tasquinimod or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, optionally processing the composition to obtain pharmaceutical dosage units, and evaluating the pharmaceutical product by the method according to claim 14.

21. Use of a compound selected from N-methyl-4-(trifluoromethyl)aniline, 4-hydroxy-5-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, 4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one, and 3,3'-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one) in the method according to claim 14. Use of a compound selected from N-methyl-4-(trifluoromethyl)aniline, 4-hydroxy-5-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, 4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one, and 3,3'-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one) in the process according to claim 20.

23. Compound 3,3'-methylenebis(4-hydroxy-5-methoxy-1-methylquinolin-2(1H)-one) or a pharmaceutically acceptable salt thereof.

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