Pharmaceutical composition for anagrelide subcutaneous injection

Abstract

The present invention relates to a pharmaceutical composition for subcutaneous injection comprising anagrelide, 3-hydroxyanagrelide, or a pharmaceutically acceptable salt thereof, comprising a hydrochloride thereof, in a solvent comprising a medium chain triglyceride (MCT) oil and optionally ethanol. The invention also relates to methods for preparing these pharmaceutical compositions and dosage forms, and methods of treating subjects having cancer or myeloproliferative disorders using the pharmaceutical compositions and dosage forms provided herein.

Description

Technical Field

[0001] This invention relates to the preparation of injectable, pharmaceutically applicable compositions. In particular, this invention relates to the use of formulations containing anagrelide or 3-hydroxyanagrelide as the active compound for the treatment of cancer or myeloproliferative disorders. Background Technology

[0002] Anagrelene is an imidazoline, first disclosed in US 3,932,407 and classified as a phosphodiesterase inhibitor. Anagrelene was initially developed as a platelet aggregation inhibitor, but its value as a platelet-lowering agent was subsequently discovered, and it can also be used to treat cancer types with cells expressing phosphodiesterase 3A (PDE3A).

[0003] WO 2010 / 063824 relates to non-immediate-release anagrelide formulations. WO 02 / 058676 and US 2003 / 0158261 relate to extended-release anagrelide formulations with pH-independent release characteristics.

[0004] Although prior art discloses anagrelide formulations suitable for pharmaceutical use, particularly for oral administration, the low solubility of anagrelide in aqueous solutions remains a common challenge in the development of pharmaceutical compositions that include anagrelide and are suitable for subcutaneous or intravenous administration. Summary of the Invention

[0005] The goal of any drug delivery system is to deliver a therapeutic amount of drug to the appropriate site in the body to achieve and, preferably, maintain the desired drug concentration for the desired time. Regarding anagrelide, the most convenient and commonly used drug delivery route in the art is solid oral dosage forms, particularly tablets and capsules. To broaden the dosage form selection palette for anagrelide, this invention aims to provide a pharmaceutical formulation suitable for injection, such as subcutaneous and intravenous injections. These novel formulations are particularly advantageous for delivering anagrelide to treat cancer.

[0006] This invention is defined by the features of the independent claims. Certain specific embodiments are defined in the dependent claims.

[0007] According to a first aspect of the invention, a pharmaceutical composition for subcutaneous injection is provided, comprising anagrelide, 3-hydroxyanagrelide, or a pharmaceutically acceptable salt thereof in a solvent, said pharmaceutically acceptable salt comprising its hydrochloride salt, said solvent comprising medium-chain triglyceride (MCT) oil and optionally ethanol.

[0008] According to a second aspect of the invention, a pharmaceutical composition for subcutaneous injection is provided, comprising anagrelide, 3-hydroxyanagrelide, or a pharmaceutically acceptable salt thereof in a solvent, said pharmaceutically acceptable salt comprising its hydrochloride salt, said solvent comprising medium-chain triglyceride (MCT) oil, for use in the treatment of cancer, or myeloproliferative disorders, preferably thrombocytosis.

[0009] This disclosure also provides methods for preparing these pharmaceutical compositions and dosage forms, as well as methods for treating subjects with cancer or myeloproliferative disorders using the pharmaceutical compositions and dosage forms provided herein. Attached Figure Description

[0010] Figure 1 Results of a single-dose pharmacokinetic study of anagrelide in Sprague Dawley rats. Plasma concentrations of anagrelide were measured in male Sprague Dawley rats after the following single doses: i) 5 mg anagrelide / kg po (oral administration); ii) 7 mg anagrelide / kg sc (subcutaneous injection of SAR003, one of the novel formulations of this invention); or iii) 35 mg anagrelide / kg sc of SAR003. Time-time curves (mean values) of plasma concentrations measured after a single dose are shown. Detailed Implementation

[0011] The chemical name for anagrelide is 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one. However, the term "anagrelide" as used herein encompasses the non-toxic, pharmaceutically acceptable acid addition salts of anagrelide. Therefore, the term anagrelide includes all such salts as well as the parent compound. Suitable salts of anagrelide include hydrochloride, hydrobromide, hydroiodide, (lower) alkyl sulfates, (lower) alkyl sulfonates and aryl sulfonates, phosphates, sulfates, maleates, fumarates, succinates, tartrates, and citrates. In this invention, anagrelide hydrochloride is a particularly preferred acid addition salt. 3-Hydroxyanagrelide is a known metabolite of anagrelide and is also used as an active pharmaceutical ingredient in this disclosure. Preparation of anagrelide is disclosed, for example, in U.S. Patent No. 5,391,737.

[0012] The term "medium-chain triglycerides" or "MCT" refers to the combination of glycerol and C6-C6 glycerol. 12 Triesters of fatty acids, examples of which are hexanoic acid (C6), octanoic acid (C8), and decanoic acid (C9). 10 ) and lauric acid (C 12 The three fatty acid residues in the MCT can be the same or different, and preferably contain two different fatty acid residues. The preferred medium-chain triglyceride is caprylic / capric triglyceride (trade name: [omitted]). MCT 65 / 35, 70 / 30 or 55 / 45, GTCC pharma, 810N or 812N, M5 or 1053, and Captex INJ 8000NP). In this disclosure, a particularly preferred MCT is The C8:C10 (octanoic acid:decanoic acid) ratios of 810N and 812N are 70:30 and 60:40, respectively.

[0013] This disclosure particularly relates to a pharmaceutical composition for subcutaneous injection comprising anagrelide, 3-hydroxyanagrelide, or a pharmaceutically acceptable salt thereof in a solvent, wherein the pharmaceutically acceptable salt comprises its hydrochloride salt, and the solvent comprises medium-chain triglyceride (MCT) oil and optionally ethanol.

[0014] In a preferred embodiment, the solvent comprises at least 80%, 85%, or 90% (w / w) of the medium-chain triglyceride oil, more preferably at least 92%, 93%, 94%, 95%, or 96% (w / w) of the medium-chain triglyceride oil.

[0015] In another preferred embodiment, the solvent comprises at least 1% (w / w) of ethanol, preferably at least 3% (w / w) of ethanol.

[0016] In another preferred embodiment, the solvent comprises at least 94% (w / w) of the medium-chain triglyceride oil and at least 3% (w / w) of ethanol.

[0017] In another preferred embodiment, the medium-chain triglyceride oil comprises triglycerides of fatty acids having an aliphatic tail with 8-10 carbon atoms.

[0018] In another preferred embodiment, the medium-chain triglyceride oil comprises esters of caprylic (C8) fatty acids and decanoic (C10) fatty acids with glycerol triglycerides.

[0019] In a more preferred embodiment, the medium-chain triglyceride oil comprises 50% (w / w) to 80% (w / w) caprylic acid and 20% (w / w) to 50% (w / w) decanoic acid; or the medium-chain triglyceride oil comprises about 50% (w / w) to 60% (w / w) caprylic acid and about 40% (w / w) to 50% (w / w) decanoic acid.

[0020] In the most preferred embodiment, the C8:C10 (octanoic acid:decanoic acid) ratio of the medium-chain triglyceride oil is 70:30 or 60:40.

[0021] In another preferred embodiment, the compositions of this disclosure can be prepared by mixing one or more active agents of desired purity with optional physiologically acceptable carriers, preservatives, excipients, or stabilizers (Remington's Pharmaceutical Sciences, 22nd edition, Allen, Loyd V., Jr., Ed., (2012)) in any suitable dosage form for storage. The pharmaceutical compositions can also be formulated for sustained-release, delayed-release, or timed-release, or the pharmaceutical compositions can be blends of sustained-release and immediate-release formulations.

[0022] The preferred daily dose of anagrelide is 1-10 mg. Therefore, the weekly dose of anagrelide can be 7-70 mg. However, the optimal interval and dosage can be determined empirically, and this is within the scope of the art.

[0023] In another preferred embodiment, the composition is administered via intravenous, intraperitoneal, subcutaneous, percutaneous, or intramuscular administration.

[0024] In another preferred embodiment, the particle size of anagrelide, 3-hydroxyanagrelide, or a pharmaceutically acceptable salt thereof is less than 50 μm in diameter, preferably 45 μm, 40 μm, 35 μm, 30 μm, 25 μm, 20 μm, 15 μm, 10 μm, or 5 μm, or less than 45 μm, 40 μm, 35 μm, 30 μm, 25 μm, 20 μm, 15 μm, 10 μm, or 5 μm. In this disclosure, particle size is measured using methods well known to those skilled in the art, preferably using a Malvern laser diffraction particle size analyzer.

[0025] In another preferred embodiment, the particle size range of anagrelide, 3-hydroxyanagrelide, or a pharmaceutically acceptable salt thereof is 1-50 μm in diameter, more preferably 1-5 μm, 1-10 μm, 1-15 μm, 1-20 μm, or 1-25 μm in diameter, wherein preferably at least 90% or up to 90% of the total particles are within the above-mentioned size range.

[0026] In another preferred embodiment, the concentration of anagrelide, 3-hydroxyanagrelide, or a pharmaceutically acceptable salt thereof in the composition ranges from 0.5 to 200 mg / mL or 0.5 to 100 mg / mL, more preferably from 20 to 80 mg / mL, 20 to 60 mg / mL, 20 to 40 mg / mL, 0.5 to 20 mg / mL, or 0.5 to 5 mg / mL.

[0027] In embodiments, this disclosure relates to pharmaceutical compositions as defined above for the treatment of cancer or myeloproliferative disorders, preferably thrombocytosis.

[0028] In a preferred embodiment, the cancer being treated is a soft tissue sarcoma selected from the group consisting of: alveolar soft tissue sarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), liposarcoma, leiomyosarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, myxofibrosarcoma, undifferentiated and unclassified sarcoma, Ewing sarcoma, and synovial sarcoma.

[0029] In another preferred embodiment, the cancer being treated is bone cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, gastrointestinal cancer (including GIST), head and neck cancer, hematopoietic system cancer, kidney cancer, liposarcoma, leiomyosarcoma, liver cancer, lung cancer, lymphatic system cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, soft tissue sarcoma, thyroid cancer, or urinary tract cancer. In a more preferred embodiment, the cancer is known or detected to be sensitive to anagrelide. In another more preferred embodiment, the cancer comprises cells expressing phosphodiesterase 3A (PDE3A).

[0030] In embodiments, this disclosure relates to a method for treating a subject suffering from cancer or myeloproliferative disorders, preferably thrombocytosis, the method comprising the step of administering an effective amount of the pharmaceutical composition defined in this disclosure to the subject.

[0031] In an embodiment, this disclosure relates to a method for preparing a pharmaceutical composition as defined herein, the method comprising the steps of: mixing anagrelide, 3-hydroxyanagrelide, or a pharmaceutically acceptable salt thereof in solid form (preferably powder form) with a solvent comprising medium-chain triglyceride (MCT) oil, and stirring the mixture for at least 16 hours or at least 24 hours, preferably 16-48 hours, more preferably 16-24 hours, to prepare a homogeneous suspension with good resuspension properties.

[0032] In a preferred embodiment, the medium-chain triglyceride oil mixed with anagrelide, 3-hydroxyanagrelide, or a pharmaceutically acceptable salt thereof comprises between 50% (w / w) and 80% (w / w) caprylic acid and between 20% (w / w) and 50% (w / w) decanoic acid; or the medium-chain triglyceride oil comprises between about 50% (w / w) and 60% (w / w) caprylic acid and about 40% (w / w) and 50% (w / w) decanoic acid.

[0033] In another preferred embodiment, the anagrelide, 3-hydroxyanagrelide, or a pharmaceutically acceptable salt thereof mixed with the MCT oil has a particle size of less than 50 μm in diameter, preferably 15 μm or less. More preferably, the diameter is in the range of 1-50 μm, preferably 1-25 μm, wherein at least 90% or up to 90% of the total particles are within the mentioned size range.

[0034] In another preferred embodiment, the concentration of anagrelide, 3-hydroxyanagrelide, or a pharmaceutically acceptable salt thereof in the mixture ranges from 0.5 to 200 mg / mL or 0.5 to 100 mg / mL, more preferably from 20 to 80 mg / mL, 20 to 60 mg / mL, 20 to 40 mg / mL, 0.5 to 20 mg / mL, or 0.5 to 5 mg / mL.

[0035] It should be understood that the embodiments of the present invention disclosed herein are not limited to the specific structures, processes, or materials disclosed herein, but extend to equivalents recognized by those skilled in the art. It should also be understood that the terminology used herein is for describing specific embodiments only and is not intended to be limiting.

[0036] Throughout this specification, references to "one embodiment" or "implementation" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the invention. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing throughout this specification do not necessarily refer to the same embodiment.

[0037] As used herein, for convenience, multiple items, structural elements, constituent elements, and / or materials may be presented in a public list. However, these lists should be interpreted as if each member in the list were individually identified as a separate and unique member. Therefore, no single member in such a list should be construed as being factually equivalent to any other member in the same list, based solely on their performance within the common group, without any indication of the contrary. Furthermore, various embodiments and examples of the invention, along with alternatives to its various components, may be mentioned herein. It should be understood that such embodiments, examples, and alternatives should not be construed as factual equivalents of each other, but should be considered as separate and autonomous representations of the invention.

[0038] Furthermore, in one or more embodiments, the described features, structures, or characteristics can be combined in any suitable manner. Numerous specific details, such as examples of length, width, shape, etc., are provided in the following description to provide a thorough understanding of embodiments of the invention. However, those skilled in the art will recognize that the invention can be practiced without one or more specific details, or using other methods, components, materials, etc. In other instances, well-known structures, materials, or operations have not been shown or described in detail to avoid obscuring various aspects of the invention.

[0039] While the foregoing embodiments illustrate the principles of the invention in one or more specific applications, it will be apparent to those skilled in the art that various modifications, uses, and implementation details can be made without inventiveness and without departing from the principles and concepts of the invention. Therefore, it is not intended to be limiting except as set forth in the following claims.

[0040] The verbs “to comprise” and “to include” are used in this document as disclosure restrictions, neither excluding nor requiring the presence of features not listed. Unless otherwise expressly stated, the features recited in the dependent claims may be freely combined with each other. Furthermore, it should be understood that the use of “a” or “an” throughout this document, i.e., the singular form, does not exclude the plural form.

[0041] Experimental Section

[0042] Unless otherwise stated, all properties measured or determined experimentally herein were measured or determined at room temperature. Room temperature is approximately 25°C, unless otherwise stated.

[0043] Material

[0044] Several prototype formulations of anagrelide hydrochloride monohydrate (AGL.HCl.mhy or AGL) have been developed, with different solvents and combinations tested. Initial development of an injectable AGL formulation suitable for subcutaneous administration began with an AGL (free base) concentration of 90 mg / mL, which was subsequently adjusted to 60 mg / mL. Manually micronized AGL was primarily used, with a particle size distribution PSD d90 value of 26 μm, due to the preferred properties and behavior exhibited by this manually micronized AGL in the tested supports (see Table 1 below).

[0045] Table 1. PSD data provided for AGL batch FD 210126 (all batches manufactured by CPLSachse Berlin, Germany). The parameter d(v / 0.9) or d90 indicates that 90% of the total particles are smaller than the mentioned size.

[0046]

[0047] Example 1. Formulation development, step 1.

[0048] Table 2 below provides an overview of the prepared formulations and their observations.

[0049] Table 2: Batch Overview of AGL Concentration at 90 mg / mL

[0050]

[0051]

[0052] Preliminary experiments clearly indicate that the use of aqueous solvents should be limited. In subsequent experiments, AGL batch FD210126Z (d(90) 26μm) was used in different formulation supports as shown in Table 3 below. Simultaneously, the concentration of AGL was reduced to 60 mg / ml, consistent with the initial planned concentration for human use.

[0053] Example 2. Formulation development, step 2.

[0054] In subsequent experiments, different amounts of ethanol were added to the previous formulations to dilute Miglyol 812N and obtain a lower viscosity suspension. These formulations were mixed at maximum speed using a magnetic rod, and observations were recorded after 2 hours and 48 hours of mixing.

[0055] A 60 mg / ml AGL suspension was prepared, and micronized and non-micronized AGL batches were tested. The results are shown in Table 3 below.

[0056] Table 3: Batch Overview of Ethanol Addition

[0057]

[0058]

[0059] In the tests conducted, it was noted that the non-micronized AGL.HCl.mhy dispersed uniformly in the suspension after 48 hours of mixing, with only occasional visible particle clusters. Flaky particles were observed under a microscope; however, no clusters were observed. 3% w / w ethanol allowed for a homogeneous suspension, with smaller, well-defined particles observed under a microscope. The formulation produced with 5% w / w ethanol appeared very similar to that produced with 6% ethanol. However, under a microscope, the particles appeared as larger clusters.

[0060] Example 3. Formulation development, step 3

[0061] In these trials, another MCT product, Miglyol 810N, was tested as a support for AGL, including both pure and ethanol-diluted forms. The formulation was mixed at maximum speed using a magnetic rod, and observations were recorded 2 hours and 24 hours after mixing.

[0062] A 60 mg / ml AGL suspension was prepared, and batches of micronized and non-micronized AGL were tested. The results for each batch are shown in Table 4 below.

[0063] Table 4: Batch Overview of Compositions Based on Miglyol 810N

[0064]

[0065]

[0066] Tests showed that Miglyol 810N could be used in its pure form as a support for micronized anagrelide batches (batch FD2101226Z2 (d(90) 15 μm)) because the suspension had no significantly larger agglomerates and was very homogeneous. Furthermore, when using micronized AGL batches, Miglyol 810N diluted with 5% ethanol appeared to shorten the mixing time. Adding unmicronized anagrelide batches to Miglyol 810N diluted with 6% ethanol showed support characteristics similar to those of Miglyol 812N diluted with 6% ethanol.

[0067] Example 4. Formulation development, step 4

[0068] In this experiment, Miglyol 810N was used as the loading medium to test three batches of AGL with different particle sizes. The formulation was mixed at high speed using a magnetic rod, and the results were recorded 24 hours after mixing.

[0069] Suspensions were prepared using AGL at concentrations of 60 mg / mL and 20 mg / mL. The composition of each batch is shown in Table 5.

[0070] Table 5: Batch Overview of Compositions Based on Miglyol 810N

[0071]

[0072]

[0073] After mixing with the magnetic rods overnight, all formulations exhibited a uniform, emulsion-like appearance with no visible lumps. Therefore, all suspensions were easily resuspended.

[0074] Example 5. Formulation development, step 5

[0075] AGL.HCl.mhy batch (FD210126Z2M05 (d(90) 5μm)) was obtained by JetPharma SA, Switzerland, after additional micronization. The formulation was prepared using Miglyol 810N in a manner similar to that described in the preceding examples. After 24 hours of mixing, the presence of agglomerates in the suspension was assessed by visual observation and microscopy.

[0076] The composition of each formulation is shown in Table 6 below.

[0077] Table 6: AGL formulations that provide d(90) 5 μm particle size after additional micronization

[0078]

[0079] After mixing for 24 hours, no clumps were observed, and the suspension was milky and uniform in appearance.

[0080] Example 6. Formulation development, step 6

[0081] Anagrelene batch (CC-4001.0-03) with a d90 of 8 μm was obtained from the German supplier ChemCon GmbH. The formulation was prepared in a manner similar to that described in the preceding examples. After mixing the suspension for 24 hours, the presence of agglomerates in the suspension was assessed by visual observation and microscopic examination. A summary of the prepared formulations is shown in Table 7 below.

[0082] Table 7. AGL formulations that provide a particle size of d(90) 8 μm after additional micronization

[0083]

[0084] In formulation AGL.220531.04.01, when Miglyol 810N oil was added to AGL.HCl.mhy dry powder, a slight cake formation was observed at the bottom of the bottle, and the magnetic rod was stuck. After mixing overnight, some clumps were still visible. However, after 24 hours of mixing, there were no clumps in the suspension.

[0085] Example 7. Single-dose pharmacokinetic study of anagrelide in Sprague Dawley rats

[0086] Plasma concentrations of anagrelide were measured after administering the following single doses to male Sprague Dawley rats: i) 5 mg anagrelide / kg po (i.e., oral administration of anagrelide in 10% ethanol solvent); ii) 7 mg / kg sc (i.e., subcutaneous injection of SAR003 formulation of anagrelide contained in MCT oil); or iii) 35 mg / kg sc of SAR003. Figure 1 The figure shows the time curves (mean) of plasma concentrations measured after a single dose. Following oral administration, anagrelide plasma concentrations were detectable for at least 12 hours post-dose; and following subcutaneous administration, plasma concentrations remained detectable for at least 840 hours and 1176 hours for 7 mg / kg and 35 mg / kg, respectively. Therefore, it can be concluded that the novel pharmaceutical compositions of this invention suitable for subcutaneous anagrelide significantly prolong plasma exposure to anagrelide compared to corresponding oral administration.

[0087] Citation List

[0088] Patent documents

[0089] US 3,932,407

[0090] WO 2010 / 063824

[0091] WO 02 / 058676

[0092] US2003 / 0158261。

Claims

1. A pharmaceutical composition for subcutaneous injection, comprising anagrelide, 3-hydroxyanagrelide, or a pharmaceutically acceptable salt thereof in a solvent, wherein the pharmaceutically acceptable salt comprises its hydrochloride salt, and the solvent comprises medium-chain triglyceride (MCT) oil and optionally ethanol.

2. The pharmaceutical composition according to claim 1, wherein, The solvent comprises at least 90% (w / w) of the medium-chain triglyceride oil, preferably at least 94% (w / w) of the medium-chain triglyceride oil.

3. The pharmaceutical composition according to claim 1 or 2, wherein, The solvent comprises at least 1% (w / w) of ethanol, preferably at least 3% (w / w) of ethanol.

4. The pharmaceutical composition according to any one of claims 1-3, wherein, The solvent comprises at least 94% (w / w) of the medium-chain triglyceride oil and at least 3% (w / w) of ethanol.

5. The pharmaceutical composition according to any one of claims 1-4, wherein, The medium-chain triglyceride oil comprises triglycerides of fatty acids with an aliphatic tail having 8-10 carbon atoms.

6. The pharmaceutical composition according to any one of claims 1-5, wherein, The medium-chain triglyceride oil comprises esters of caprylic (C8) fatty acid and capric (C10) fatty acid triglycerides with glycerol.

7. The pharmaceutical composition according to claim 6, wherein, The medium-chain triglyceride oil comprises 50% (w / w) to 80% (w / w) caprylic acid and 20% (w / w) to 50% (w / w) decanoic acid; or the medium-chain triglyceride oil comprises about 50% (w / w) to 60% (w / w) caprylic acid and about 40% (w / w) to 50% (w / w) decanoic acid.

8. The pharmaceutical composition according to claim 6 or 7, wherein, The C8:C10 (octanoic acid:decanoic acid) ratio of the medium-chain triglyceride oil is 70:30 or 60:

40.

9. The pharmaceutical composition according to any one of claims 1-8 further comprises at least one of the following: a physiologically acceptable carrier, a buffer solution, an excipient, a preservative, and a stabilizer.

10. The pharmaceutical composition according to any one of claims 1-9, wherein, The composition is administered via intravenous, intraperitoneal, subcutaneous, percutaneous, or intramuscular administration.

11. The pharmaceutical composition according to any one of claims 1-10, wherein, The pharmaceutical composition is formulated for sustained release, delayed release, or timed release, or the pharmaceutical composition is a blend of sustained-release and immediate-release formulations.

12. The pharmaceutical composition according to any one of claims 1-11, wherein, Anagrelene, 3-hydroxyanagrelene or a pharmaceutically acceptable salt thereof, have a particle size of less than 50 μm in diameter, preferably 10 μm or less.

13. The pharmaceutical composition according to any one of claims 1-11, wherein, Anagrelene, 3-hydroxyanagrelene, or pharmaceutically acceptable salts thereof have a particle size ranging from 1 to 50 μm in diameter, preferably from 1 to 25 μm in diameter.

14. The pharmaceutical composition according to any one of claims 1-13, wherein, The concentration range of anagrelide, 3-hydroxyanagrelide, or a pharmaceutically acceptable salt thereof is 0.5–100 mg / mL.

15. The pharmaceutical composition according to any one of claims 1-14, for use in treating cancer or myeloproliferative disorders, preferably thrombocytosis.

16. The pharmaceutical composition for the use according to claim 15, wherein, The cancer is a soft tissue sarcoma selected from the group consisting of: alveolar soft tissue sarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), liposarcoma, leiomyosarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, myxofibrosarcoma, undifferentiated and unclassified sarcoma, Ewing sarcoma, and synovial sarcoma.

17. The pharmaceutical composition for use according to claim 15, wherein, The cancers mentioned are bone cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, gastrointestinal cancers such as GIST, head and neck cancer, hematopoietic system cancers, kidney cancer, liposarcoma, leiomyosarcoma, liver cancer, lung cancer, lymphatic system cancers, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, soft tissue sarcoma, thyroid cancer, or urinary tract cancer.

18. A method for treating a subject suffering from cancer or a myeloproliferative disorder, preferably thrombocytosis, the method comprising administering to the subject an effective amount of the pharmaceutical composition according to any one of claims 1-14.

19. The method according to claim 18, wherein, The cancer is a soft tissue sarcoma selected from the group consisting of: alveolar soft tissue sarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), liposarcoma, leiomyosarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, myxofibrosarcoma, undifferentiated and unclassified sarcoma, Ewing sarcoma, and synovial sarcoma.

20. The method according to claim 18, wherein, The cancers mentioned are bone cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, GIST, head and neck cancer, hematopoietic system cancer, kidney cancer, liposarcoma, leiomyosarcoma, liver cancer, lung cancer, lymphatic system cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, soft tissue sarcoma, thyroid cancer, or urinary tract cancer.

21. A method for preparing a pharmaceutical composition according to any one of claims 1-14, the method comprising the following steps: Anagrelene, 3-hydroxyanagrelene or a pharmaceutically acceptable salt thereof, in solid form, preferably in powder form, is mixed with a solvent comprising medium-chain triglyceride (MCT) oil, and the mixture is stirred for at least 16 hours to prepare a homogeneous suspension with good resuspension properties.

22. The method according to claim 21, wherein, Anagrelene, 3-hydroxyanagrelene or a pharmaceutically acceptable salt thereof have a particle size of less than 50 μm in diameter, preferably 10 μm or less.

23. The method according to claim 21, wherein, Anagrelene, 3-hydroxyanagrelene, or pharmaceutically acceptable salts thereof have a particle size ranging from 1 to 50 μm in diameter, preferably from 1 to 25 μm in diameter.

24. The method according to any one of claims 21-23, wherein, The concentration of anagrelide, 3-hydroxyanagrelide, or a pharmaceutically acceptable salt thereof in the composition ranges from 0.5 to 100 mg / mL.

25. The method according to any one of claims 21-24, wherein, Stir the mixture for 16-24 hours.

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