WO2024189275A1

WO2024189275A1 - A pharmaceutical composition for subcutaneous injection of anagrelide

Info

Publication number: WO2024189275A1
Application number: PCT/FI2024/050119
Authority: WO
Inventors: Dennie Van Den Heuvel; Katja IVANITSKIY; Mikael Maksimow
Original assignee: Sartar Therapeutics Oy
Priority date: 2023-03-15
Filing date: 2024-03-15
Publication date: 2024-09-19

Abstract

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

Description

A pharmaceutical composition for subcutaneous injection of anagrelide

FIELD

[0001] The present invention relates to the preparation of injectable, pharmaceutically applicable compositions. In particular, the invention is directed to formulations of anagrelide or 3 -hydroxy anagrelide as an active compound for use in the treatment of cancers or a myoeloproliferative disorder.

BACKGROUND

[0002] Anagrelide is an imidazoquinazoline, which was first disclosed in US 3,932,407, and was designated as a phosphodiesterase inhibitor. Anagrelide was originally developed as an inhibitor of platelet aggregation but subsequently found to have value as a platelet-lowering agent and also for the treatment of cancer types with phosphodiesterase 3A (PDE3A) expressing cells.

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

[0004] Although the prior art discloses anagrelide formulations suitable for pharmaceutical use, particularly for oral administration, low solubility of anagrelide to aqueous solutions is still a general challenge in the development of pharmaceutical compositions which comprise anagrelide and would be suitable for subcutaneous or intravenous administration.

SUMMARY OF THE INVENTION

[0005] The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body to achieve and then preferably maintain the desired drug concentration for a desired time. Regarding anagrelide, the most convenient and commonly employed route of drug delivery in the prior art has been by solid oral dosage forms, particularly tablets and capsules. In order to improve dosage palette of anagrelide, it is the aim of the present invention to provide a pharmaceutical formulation of anagrelide which is suitable for injections, such as subcutaneous and intravenous injections. These novel formulations are particularly advantageous for delivery of anagrelide for the treatment of cancers. [0006] The invention is defined by the features of the independent claims. Some specific embodiments are defined in the dependent claims.

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

[0008] According to a second aspect of the present invention, there is provided a pharmaceutical composition for subcutaneous injection comprising anagrelide, 3 -hydroxy anagrelide or a pharmaceutically acceptable salt thereof including the hydrochloride salt thereof in a solvent comprising a medium-chain triglyceride (MCT) oil, for use in the treatment of cancer, or a myoeloproliferative disorder, preferably thrombocythemia.

[0009] The present disclosure also provides methods for preparing these pharmaceutical compositions and dosage forms, and methods of treating subjects having cancer or a myoeloproliferative disorder utilizing the pharmaceutical compositions and dosage forms provided herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIGURE 1. Results of a single dose pharmacokinetic study of anagrelide in Sprague Dawley rats. Anagrelide plasma concentrations were measured after a single dose of i) 5 mg of anagrelide/kg p.o. (oral administration), ii) 7 mg of anagrelide/kg s.c. (i.e., a subcutaneous injection of one of the present novel formulations, SAR003), or iii) 35 mg of anagrelide/kg s.c. of SAR003 to male Sprague Dawley rats. Time curves (mean) of the measured plasma concentrations following the single doses are shown.

EMBODIMENTS

[0011] Anagrelide’s chemical name is 6,7-dichloro-l,5-dihydroimidazo[2,l-b]quinazolin- 2(3H)-one. However, the term "anagrelide" is used herein so that it covers nontoxic pharmaceutically acceptable acid addition salts of anagrelide. Thus, the term anagrelide encompasses all of such salts as well as the parent compound. Suitable salts of anagrelide include the hydrochloride, hydrobromide, hydroiodide, (lower)alkylsulfates, (lower)alkyl- and arylsulfonates, phosphate, sulfate, maleate, fumarate, succinate, tartrate and citrate salts. Anagrelide hydrochloride is a particularly preferred acid addition salt in this invention. 3 -hydroxy anagrelide is a well-known metabolite of anagrelide and can also be used as an active pharmaceutical ingredient in the present disclosure. Preparation of anagrelide is disclosed, e.g., in U.S. Pat. No. 5,391,737.

[0012] The term "medium chain triglyceride" or "MCT" refers to triesters of glycerol and C6-C12 fatty acids, examples of said fatty acids being caproic acid (Ce), caprylic acid (Cs), capric acid (Cio) and lauric acid (C12). The three fatty acid residues of the MCT can be the same or different, preferably there are two different fatty acid residues. Preferred medium chain triglycerides are caprylic/capric acid triglycerides (marketed as Stelliesters® MCT 65/35, 70/30, or 55/45, Crodamol® GTCC pharma, Miglyol® 810 N or 812 N, Neobee® M5 or 1053, and Captex INJ 8000 NP). Particularly preferable MCTs in the present disclosure are Miglyol® 810 N and 812 N with C8:C10 (caprylic acid:capric acid) ratios of 70:30 and 60:40, respectively.

[0013] The present disclosure is specially directed to a pharmaceutical composition for subcutaneous injection comprising anagrelide, 3 -hydroxy anagrelide or a pharmaceutically acceptable salt thereof including the hydrochloride salt thereof in a solvent comprising a mediumchain triglyceride (MCT) oil and optionally ethanol.

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

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

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

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

[0018] In another preferred embodiment, said medium-chain triglyceride oil comprises a triglyceride ester of caprylic (C8) and capric (CIO) fatty acids and glycerol.

[0019] In a more preferred embodiment, the medium-chain triglyceride oil comprises between 50% (w/w) and 80% (w/w) caprylic acid and between 20% (w/w) to 50% (w/w) capric acid or the medium-chain triglyceride oil comprises between about 50% (w/w) to 60% (w/w) caprylic acid and about 40% (w/w) to 50% (w/w) capric acid. [0020] In a most preferred embodiment, said medium-chain triglyceride oil has a C8:C10 (caprylic acid:capric acid) ratio of 70:30 or 60:40.

[0021] In another preferred embodiment, the composition of the present disclosure can be prepared for storage by mixing the active agent(s) having the desired degree of purity with optional physiologically acceptable carriers, preservatives, excipients, or stabilizers (Remington's Pharmaceutical Sciences, 22nd edition, Allen, Loyd V., Jr, Ed., (2012)), in any dosage form suitable. Said pharmaceutical composition may also be formulated for sustained-release, delayed- release, or timed-release, or said pharmaceutical composition is a blend of sustained-release and immediate-release formulations.

[0022] Daily doses of 1-10 mg anagrelide are preferred. Accordingly, the weekly dose of anagrelide can be 7-70 mg. However, the optimal interval and amount of doses can be determined empirically and is within the skill of the art.

[0023] In another preferred embodiment, said composition is to be administered by intravenous, intraperitoneal, subcutaneous, transdermal, or intramuscular administration.

[0024] In another preferred embodiment, the particle size of anagrelide, 3 -hydroxy anagrelide or a pharmaceutically acceptable salt thereof is less than 50 pm in diameter, preferably 45 pm, 40 pm, 35 pm, 30 pm, 25 pm, 20 pm, 15 pm, 10 pm, or 5 pm in diameter, or less than 45 pm, 40 pm, 35 pm, 30 pm, 25 pm, 20 pm, 15 pm, 10 pm, or 5 pm in diameter. In the present disclosure, particle sizes have been measured by the methods well-known for a person skilled in the art, preferably by a Malvern laser diffraction particle analyzer.

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

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

[0027] In an embodiment, the present disclosure is directed to a pharmaceutical composition as defined above for use in the treatment of cancer or a myoeloproliferative disorder, preferably thrombocythemia. [0028] In a preferred embodiment, the cancer treated is a soft-tissue sarcoma selected from the group consisting of: alveolar soft-part sarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), liposarcoma, leiomyosarcoma, malignant fibro histiocytoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, myxofibrosarcoma, undifferentiated and unclassified sarcomas, Ewing sarcoma, and synovial sarcoma.

[0029] In another preferred embodiment, the cancer treated is a bone, breast, cervical, colon, endometrium, gastrointestinal including GIST, head and neck, hematopoietic, kidney, liposarcoma, leiomyosarcoma, liver, lung, lymphoid, melanoma, ovarian, pancreas, prostate, soft- tissue sarcoma, thyroid cancer, or urinary tract cancer. In a more preferred embodiment, said cancer is known or has been tested to be susceptible to anagrelide. In another more preferred embodiment, said cancer comprises phosphodiesterase 3A (PDE3A) expressing cells.

[0030] In an embodiment, the present disclosure is directed to a method of treating a subject having a cancer or a myoeloproliferative disorder, preferably thrombocythemia, the method comprising a step of administering an efficient amount of the pharmaceutical composition as defined in this disclosure to said subject.

[0031] In an embodiment, the present disclosure is directed to a method for preparing the pharmaceutical composition as defined in this disclosure, the method comprising the step of mixing anagrelide, 3 -hydroxy anagrelide or a pharmaceutically acceptable salt thereof in a solid form, preferably in a form of powder, with a solvent comprising a medium-chain triglyceride (MCT) oil, and stirring the mix at least 16 hours or at least 24 hours, preferably 16-48 hours, more preferably 16-24 hours, in order to prepare a homogeneous suspension having a good re- suspensibility property.

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

[0033] In another preferred embodiment, the particle size of anagrelide, 3 -hydroxy anagrelide or a pharmaceutically acceptable salt thereof mixed with said MCT oil is less than 50 pm in diameter, preferably 15 pm or less than 15 pm. More preferably, in the range of 1-50 pm in diameter, preferably 1-25 pm in diameter, wherein at least 90% or up to 90% of the total particles are in the size range mentioned. [0034] In another preferred embodiment, the concentration of anagrelide, 3 -hydroxy anagrelide or a pharmaceutically acceptable salt thereof in said mix is in the range of 0.5 - 200 mg/mL or 0.5 - 100 mg/mL, more preferably in the range of 20 - 80 mg/mL, 20 - 60 mg/mL, 20 - 40 mg/mL, 0.5 - 20 mg/mL, or 0.5 - 5 mg/mL.

[0035] It is to be understood that the embodiments of the invention disclosed are not limited to the particular structures, process steps, or materials disclosed herein, but are extended to equivalents thereof as would be recognized by those ordinarily skilled in the relevant arts. It should also be understood that terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting.

[0036] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment.

[0037] As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary. In addition, various embodiments and example of the present invention may be referred to herein along with alternatives for the various components thereof. It is understood that such embodiments, examples, and alternatives are not to be construed as de facto equivalents of one another, but are to be considered as separate and autonomous representations of the present invention.

[0038] Furthermore, the described features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. In the following description, numerous specific details are provided, such as examples of lengths, widths, shapes, etc., to provide a thorough understanding of embodiments of the invention. One skilled in the relevant art will recognize, however, that the invention can be practiced without one or more of the specific details, or with other methods, components, materials, etc. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the invention.

[0039] While the forgoing examples are illustrative of the principles of the present invention in one or more particular applications, it will be apparent to those of ordinary skill in the art that numerous modifications in form, usage and details of implementation can be made without the exercise of inventive faculty, and without departing from the principles and concepts of the invention. Accordingly, it is not intended that the invention be limited, except as by the claims set forth below.

[0040] The verbs “to comprise” and “to include” are used in this document as open limitations that neither exclude nor require the existence of also un-recited features. The features recited in depending claims are mutually freely combinable unless otherwise explicitly stated. Furthermore, it is to be understood that the use of "a" or "an", i.e., a singular form, throughout this document does not exclude a plurality.

EXPERIMENTAL SECTION

Unless otherwise stated, properties that have been experimentally measured or determined herein have been measured or determined at room temperature. Unless otherwise indicated, room temperature is about 25 °C.

Materials

Several prototype formulations Anagrelide hydrochloride monohydrate (AGL.HCl.mhy or AGL) were developed, in which different solvents and their combinations were tested. The initial development of an injectable AGL formulation suitable for subcutaneous administration was started with an AGL (free base) concentration of 90 mg/mL, which was later adjusted to the 60 mg/mL. The manually micronized AGL with particle size distribution, PSD, value d90 of 26 pm was used mostly due to the preferred properties and behavior in the tested vehicles (see Table 1 below).

Table 1. PSD data of supplied AGL batch FD 210126 versions (all batches manufactured by CPL Sachse, Berlin, Germany). Parameter d(v/0.9) or d90 means that 90% of the total particles are smaller than the size mentioned.

EXAMPLE 1. Formulation development, step 1.

An overview of the prepared formulations and observations is presented in the Table 2 below.

Table 2: Batch overview with an AGL concentration of 90 mg/mL

From the first trials it was evident that the use of aqueous solvents should be limited. In the next experiments, AGL batch FD210126Z (d(90) 26 pm) was used in the different formulation vehicles as presented in the Table 3 below. The concentration of the AGL was also decreased to 60 mg/ml, as was originally planned for the use in a human product.

EXAMPLE 2. Formulation development, step 2

In the next trial, ethanol in various amounts was incorporated in previous formulations to dilute Miglyol 812 N and obtain less viscous suspensions. The formulations were mixed with a magnetic bar at a maximum speed, and the observations were recorder after 2 hours, and after 48 hours of mixing.

Suspensions were prepared with an AGL concentration of 60 mg/ml, and both micronized and non-micronized AGL batches were tested. Results are presented in the Table 3 below. Table 3: Batch overview with added ethanol.

In the tests performed, it was noted that non-micronized AGL.HCl.mhy is homogeneously dispersed in the suspension after 48 hours of mixing, with occasional particle agglomerates visible. Flake like particles were observed under the microscope, however no agglomeration was noted. 3% w/w of ethanol allows to obtain a homogeneous suspension, and smaller and distinct particles were observed under the microscope. 5% w/w of ethanol seemed to produce a very similar formulation to the one where 6% of ethanol was used. Under the microscope, particles were grouped in large agglomerates.

EXAMPLE 3. Formulation development, step 3

In these trials, another MCT product Miglyol 8 ION was tested as a vehicle for the AGL both in a pure form and diluted with ethanol. The formulations are mixed with a magnetic bar at a maximum speed, and the observations were recorder after 2 hours, and after 24 hours of mixing. Suspensions were prepared with an AGL concentration of 60 mg/ml, and both micronized and non-micronized AGL batches were tested. The results of the respective batches are presented in the Table 4 below.

Table 4: Batch overview for Miglyol 810 N based compositions.

The tests showed that Miglyol 8 ION can be used in a pure form as a vehicle for the micronized Anagrelide batch (batch FD2101226Z2 (d(90) 15 gm), as the suspensions had no larger agglomerates and were quite homogeneous. Also, Miglyol 8 ION diluted with 5% ethanol seemed to shorten mixing time once the micronized AGL batch was used. Miglyol 8 ION diluted with 6% ethanol in which non-micronized Anagrelide batch was added, showed rather similar vehicle properties compared to Miglyol 812N diluted with 6% ethanol.

EXAMPLE 4. Formulation development, step 4

In this trial, Miglyol 8 ION was tested as a vehicle for three different batches of the AGL with a distinct particle size. The formulations were mixed with a magnetic bar at a high speed, and the observations were recorded after 24 hours of mixing.

Suspensions were prepared with an AGL concentration of 60 mg/ml or 20 mg/mL. The composition of the respective batches is presented in Table 5.

Table 5: Batch overview for Miglyol 810 N based compositions.

After overnight mixing with a magnetic bar, all formulations had a milky homogeneous appearance, and there were no lumps visible. All suspensions were therefore easy to resuspend.

EXAMPLE 5. Formulation development, step 5

AGL.HCl.mhy batch (FD210126Z2M05 (d(90) 5 pm)) was obtained after additional micronization by JetPharma SA, Switzerland. The preparation of the formulation with Miglyol 810 N was executed in a similar way as described in previous examples. After 24 hours of mixing the suspension was assessed visually for the presence of agglomerates, and under the microscope.

The composition of the respective formulation is summarized in Table 6 below.

Table 6: AGL formulation after extra micronization providing particle size of d(90) 5 pm.

After 24 hours of mixing, there were no agglomerates observed, and suspension had a milky and homogeneous appearance.

EXAMPLE 6. Formulation development, step 6

Anagrelide batch (CC-4001.0-03) was received from supplier ChemCon GmbH, Germany, with d90 8 pm. The preparation of the formulation was executed in a similar way as described in previous examples. After 24 hours of mixing the suspension was assessed visually for the presence of agglomerates, and under the microscope. A summary of the prepared formulations is demonstrated in Table 7 below.

Table 7. AGL formulation after extra micronization providing particle size of d(90) 8 pm.

Once the Miglyol 810 N oil was added to the AGL.HCl.mhy dry powder in formulation AGL.220531.04.01, there was a slight cake formation on the bottom of the vial observed, and the magnetic bar was stuck. After overnight mixing, some lumps were visible. After 24h of mixing, the suspension was free of any agglomerates.

EXAMPLE 7. A single dose pharmacokinetic study of anagrelide in Sprague Dawley rats.

Anagrelide plasma concentrations were measured after a single dose of i) 5 mg of anagrelide/kg p.o. (i.e., an oral dosing of anagrelide in 10 % ethanol solvent), ii) 7 mg/kg s.c. (i.e., a subcutaneous injection of the SAR003 formulation containing anagrelide in an MCT oil), or iii) 35 mg/kg s.c. of SAR003 to male Sprague Dawley rats. Time curves (mean) of the measured plasma concentrations following the single doses are shown in Figure 1. After the oral dosing of anagrelide plasma concentrations were detectable after up to at least 12 h and after the subcutaneous dosings plasma concentrations were still detectable up to at least 840 h and 1176 h post-dose for 7 and 35 mg/kg, respectively. Therefore, it can be concluded that the present novel pharmaceutical composition, which is suitable for subcutaneous injection of anagrelide, provides highly extended plasma exposure of anagrelide compared to corresponding oral dosing.

CITATION LIST Patent Literature

US 3,932,407

WO 2010/063824

WO 02/058676

US 2003/0158261

Claims

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

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

3. The pharmaceutical composition according to claim 1 or 2, wherein said 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 said solvent comprises at least 94% (w/w) of said 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 mediumchain triglyceride oil comprises triglycerides with fatty acids having aliphatic tails of 8-10 carbon atoms.

6. The pharmaceutical composition according to any one of claims 1-5, wherein said mediumchain triglyceride oil comprises a triglyceride ester of caprylic (C8) and capric (CIO) fatty acids and glycerol.

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

8. The pharmaceutical composition according to claim 6 or 7, wherein said medium-chain triglyceride oil has a C8:C10 (caprylic acid:capric acid) ratio of 70:30 or 60:40.

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

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

11. The pharmaceutical composition according to any one of claims 1-10, wherein said pharmaceutical composition is formulated for sustained-release, delayed-release, or timed- release, or said 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 the particle size of anagrelide, 3-hydroxy anagrelide or a pharmaceutically acceptable salt thereof is less than 50 pm in diameter, preferably 10 pm or less than 10 pm.

13. The pharmaceutical composition according to any one of claims 1-11, wherein the particle size of anagrelide, 3-hydroxy anagrelide or a pharmaceutically acceptable salt thereof is in the range of 1-50 pm in diameter, preferably 1-25 pm in diameter.

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

15. The pharmaceutical composition according to any one of claims 1-14 for use in the treatment of cancer or a myoeloproliferative disorder, preferably thrombocythemia.

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

17. The pharmaceutical composition for use according to claim 15, wherein said cancer is a bone, breast, cervical, colon, endometrium, gastrointestinal, such as GIST, head and neck, hematopoietic, kidney, liposarcoma, leiomyosarcoma, liver, lung, lymphoid, melanoma, ovarian, pancreas, prostate, soft-tissue sarcoma, thyroid cancer, or urinary tract cancer.

18. A method of treating a subject having a cancer or a myoeloproliferative disorder, preferably thrombocythemia, the method comprising a step of administering an efficient amount of the pharmaceutical composition according to any one of claims 1-14 to said subject.

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

20. The method according to claim 18, wherein said cancer is a bone, breast, cervical, colon, endometrium, GIST, head and neck, hematopoietic, kidney, liposarcoma, leiomyosarcoma, liver, lung, lymphoid, melanoma, ovarian, pancreas, prostate, soft-tissue sarcoma, thyroid cancer, or urinary tract cancer.

21. A method for preparing the pharmaceutical composition according to any one of claims 1-14, the method comprising the step of mixing anagrelide, 3 -hydroxy anagrelide or a pharmaceutically acceptable salt thereof in a solid form, preferably in a form of powder, with a solvent comprising a medium-chain triglyceride (MCT) oil, and stirring the mix at least 16 hours in order to prepare a homogeneous suspension having a good re-suspensibility property.

22. The method according to claim 21, wherein the particle size of anagrelide, 3 -hydroxy anagrelide or a pharmaceutically acceptable salt thereof is less than 50 pm in diameter, preferably 10 pm or less than 10 pm.

23. The method according to claim 21, wherein the particle size of anagrelide, 3 -hydroxy anagrelide or a pharmaceutically acceptable salt thereof is in the range of 1-50 pm in diameter, preferably 1-25 pm in diameter.

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

25. The method according to any one of claims 21-24, wherein the mix is stirred 16-24 hours.