COMPOSITION WITH DRUG MICRO-NANO PARTICLES OF AN ANTI-CANCER AGENT

Abstract

The present invention relates to a composition comprising a water-insoluble anti-cancer agent present as surface modified and unmodified drop particles in water, a method for producing such a composition, a lyophilizate of such a composition and such a composition for use in the treatment of cancer.

Claims

1-15. (canceled)

16. A composition comprising: (a) one or more water-insoluble anti-cancer agents; (b) one or more immunomodulatory agents chosen from curcumin, clofazimine, lutein, flavonoids, apigenin, hesperetin, aioene, arctigenin, β-carotene, Lycopene epigallocatechin-3-gallate, ginsan, glabridin and guinic acid; (c) one or more surfactants chosen from poloxamer, polysorbate, phosphatidylcholine, cholesterol or derivatives thereof, sorbitan fatty acid esters, vitamin E derivatives, polyvinyl alcohols, Macrogol glycerol ricinoleate, Polyoxyl-35-castor oil, Span, Macrogol 15 Hydroxystearate, Polyoxyl 15 Hydroxystearate and Polyethoxylated 12-hydroxystearic acid, lipoids and derivatives thereof, lipids, phospholipids, hydrogenated phospholipids, glycerophosphocholine, synthetic phospholipids, and sterols, (d) optionally, one or more solvents; (e) optionally, one or more coating materials; (f) water; and (g) optionally, one or more further pharmaceutically acceptable components, wherein the one or more anti-cancer agents form drop particles in component (f) of the composition, at least 80% of the drop particles have a particle size of ≤500 nm, component (a) and component (c) are in a weight ratio of 1:50 to 20:1 ((a):(c)).

17. The composition of claim 16, wherein component (a) and component (b) are in a weight ratio of 1:20 to 50:1 ((a):(b)).

18. The composition of claim 16, wherein component (b) and component (c) are in a weight ratio of 1:50 to 50:1 ((b):(c)).

19. The composition of claim 16 comprising component (d), wherein component (a) and component (d) are in a weight ratio of 1:50 to 20:1.

20. The composition of claim 16 comprising component (d), wherein component (c) and component (d) are in a weight ratio of 1:20 to 10:1.

21. The composition of claim 16 comprising component (e), wherein component (a) and component (e) are in a weight ratio of 0.5:1 to 500:1.

22. The composition of claim 16 comprising component (e), wherein component (c) and component (e) are in a weight ratio of 5:1 to 150:1.

23. The composition of claim 16, wherein at least 30% of the drop particles have a particle size of ≥250 nm and ≤300 nm.

24. The composition of claim 16, wherein the one or more anti-cancer agents of component (a) are anti-cancer agents for treating cancer types chosen from gastrointestinal cancer, gastric cancer, colorectal cancer, hepatobiliary or pancreatic cancer, appendix cancer, esophageal cancer, hepatocellular carcinoma, primary peritoneal cancer, ovarian cancer, endometrial cancer, prostate cancer, leukaemia, lymphoma, soft-tissue sarcoma, multiple myeloma, bladder cancer, lung cancer, thyroid cancer, Kaposi's sarcoma and tumours of embryonal origin.

25. The composition of claim 16, wherein the one or more anti-cancer agents of component (a) are chosen from cisplatin, doxorubicin, paclitaxel, oxaliplatin, and quercetin.

26. The composition of claim 16 comprising component (d), wherein the one or more solvents of component (d) are chosen from ethanol, acetone, ethyl acetate, chlorinated solvents, DMF, DMSO, acetic acid, methylated solvents, tetrahydrofuran, halogenated hydrocarbons, chloroform, dichloromethane, dioxanes, acetonitrile, polyethylene glycol, N-methylpyrrolidone, dimethylacetamide, and propylene glycol.

27. The composition of claim 16 comprising component (e), wherein the one or more coating materials of component (e) are chosen from celluloses, methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose, chitosan, carboxymethyl cellulose, polyvinyl alcohol, polyacrylic acid, polyvinylpyrrolidone, sodium alginate, pectin, carbomer, tragacanth, acacia, gelatin, starch, gellatinised starch, gums, gellan gum, xanthum gum, locust bean gum, acacia gum, hydrogels, folic acid, antibodies, dextran, and serum albumin.

28. The composition of claim 16 comprising component (e), wherein at least 50% of the drop particles are coated with the one or more coating materials of component (e).

29. A method for producing the composition of claim 16 comprising: (i) providing the one or more water-insoluble anti-cancer agents of component (a); (ii) providing the one or more immunomodulatory agents of (b) (iii) providing the one or more surfactants of component (c); (iv) optionally, providing the one or more solvents of component (d); (v) optionally, providing the one or more coating materials of component (e); (vi) providing the water of component (f); (vii) optionally, providing the one or more further pharmaceutically acceptable components of component (g): (viii) mixing the components provided in (i)-(viii) and obtaining drop particles of the mixture by bead milling, high pressure homogenization, a microfluidic process, or a combination thereof.

30. A composition obtainable by the method of claim 29.

31. A lyophilizate of the composition of claim 16.

32. A method for treating cancer comprising administering the composition of claim 16 to a human subject.

33. The method of claim 32, wherein the composition is administered to the human subject by direct introduction into the abdomen and/or thorax.

34. The method of claim 33, wherein the composition is administered to the human subject by intraperitoneal administration, intravenous injection, oral administration, intramuscular, PIPAC, or combinations thereof.

Description

[0129] FIG. 1 depicts the mechanism of action of a composition according to the invention (B) versus a standard drug solution (A). The FIGURE shows a cross-section of the peritoneal cavity with the mesothelial layer (L1), the sub-mesothelial zone (L2) and the adipose and connective tissue including blood vessels (L3). For the standard drug solution (A) the formation of a thin film (A1) on the surface of the peritoneal cavity is shown. The composition according to the invention (B) includes smaller particles (B1), medium particles (B2) and larger particles (B3). The penetration of said particles into the tissue is indicated by the arrows below the particles.

[0130] Preferred embodiments and further aspects of the present invention also emerge from the attached patent claims and the following examples, wherein the present invention is not limited to these examples.

EXAMPLES

Example 1: Mixing and Homogenization by Microfluidic (Capillary) Process

[0131]

TABLE-US-00001 Ingredient [g] F1 F2 F3 F4 F5 F6 Paclitaxel 1 1 2 1 1 2 Clofazimine 1 2 2 1 2 2 Curcumin 2 2 2 2 2 2 Lutein 0 0 0 0 0 0 Quercetin 0 0 0 0 0 0 Tween 80 4 4 4 0 0 0 Poloxamer 0 0 0 4 4 4 DMSO 10 10 10 10 10 10 DMF 10 10 10 10 10 10 Water 72 71 70 72 71 70 Ingredient [g] F7 F8 F9 F10 F11 F12 Paclitaxel 1 1 2 1 1 2 Clofazimine 1 2 2 1 2 2 Curcumin 0 0 0 0 0 0 Lutein 2 2 2 2 2 2 Quercetin 0 0 0 0 0 0 Tween 80 4 4 4 0 0 0 Poloxamer 0 0 0 4 4 4 Ethanol 20 20 20 20 20 20 Water 72 71 70 72 71 70 Ingredient [g] F13 F14 F15 F16 F17 F18 Paclitaxel 1 1 2 1 1 2 Clofazimine 1 2 2 1 2 2 Curcumin 0 0 0 0 0 0 Lutein 0 0 0 0 0 0 Quercetin 2 2 2 2 2 2 Tween 80 4 4 4 0 0 0 Poloxamer 0 0 0 4 4 4 Ethanol 20 20 20 20 20 20 Water 72 71 70 72 71 70

[0132] The above indicated ingredients were provided and subsequently mixed and homogenized by a M-110EH-30 pilot scale machine (Microfluidic corp.) with a flow rate of 1 ml/min at a pressure of 800 bar to obtain the final product.

Example 2: Mixing and Homogenization by High Pressure Homogenization

[0133]

TABLE-US-00002 Ingredient [g] F1 F2 F3 F4 F5 F6 Paclitaxel 1 1 2 1 1 2 Clofazimine 1 2 2 1 2 2 Curcumin 2 2 2 2 2 2 Lutein 0 0 0 0 0 0 Quercetin 0 0 0 0 0 0 Tween 80 4 4 4 0 0 0 Poloxamer 0 0 0 4 4 4 Ethanol 5 5 5 5 5 5 Water 87 86 85 87 86 85 Ingredient [g] F7 F8 F9 F10 F11 F12 Paclitaxel 1 1 2 1 1 2 Clofazimine 1 2 2 1 2 2 Curcumin 0 0 0 0 0 0 Lutein 2 2 2 2 2 2 Quercetin 0 0 0 0 0 0 Tween 80 4 4 4 0 0 0 Poloxamer 0 0 0 4 4 4 Ethanol 5 5 5 5 5 5 Water 87 86 85 87 86 85 Ingredient [g] F13 F14 F15 F16 F17 F18 Paclitaxel 1 1 2 1 1 2 Clofazimine 1 2 2 1 2 2 Curcumin 0 0 0 0 0 0 Lutein 0 0 0 0 0 0 Quercetin 2 2 2 2 2 2 Tween 80 4 4 4 0 0 0 Poloxamer 0 0 0 4 4 4 Ethanol 5 5 5 5 5 5 Water 87 86 85 87 86 85

[0134] The above indicated ingredients were provided and subsequently mixed and homogenized by high pressure homogenization with 2 cycles at 200 bar, 2 cycles at 500 bar, 2 cycles at 1000 bar and subsequently 15 cycles at 1500 bar to obtain the final product.

Example 3: Grinding by Bead Milling

[0135]

TABLE-US-00003 Ingredient [g] F1 F2 F3 F4 F5 F6 Paclitaxel 1 1 2 1 1 2 Clofazimine 1 2 2 1 2 2 Curcumin 2 2 2 2 2 2 Lutein 0 0 0 0 0 0 Quercetin 0 0 0 0 0 0 Tween 80 4 4 4 0 0 0 Poloxamer 0 0 0 4 4 4 Ethanol 5 5 5 5 5 5 Water 87 86 85 87 86 85 Ingredient [g] F7 F8 F9 F10 F11 F12 Paclitaxel 1 1 2 1 1 2 Clofazimine 1 2 2 1 2 2 Curcumin 0 0 0 0 0 0 Lutein 2 2 2 2 2 2 Quercetin 0 0 0 0 0 0 Tween 80 4 4 4 0 0 0 Poloxamer 0 0 0 4 4 4 Ethanol 5 5 5 5 5 5 Water 87 86 85 87 86 85 Ingredient [g] F13 F14 F15 F16 F17 F18 Paclitaxel 1 1 2 1 1 2 Clofazimine 1 2 2 1 2 2 Curcumin 0 0 0 0 0 0 Lutein 0 0 0 0 0 0 Quercetin 2 2 2 2 2 2 Tween 80 4 4 4 0 0 0 Poloxamer 0 0 0 4 4 4 Ethanol 5 5 5 5 5 5 Water 87 86 85 87 86 85

[0136] The above indicated ingredients were provided and subsequently mixed and milled by bead milling at 6 passes using zirconia beads (0.2 to 0.4mm).

[0137] The obtained particles were coated by adding 0.18 g of hydroxypropylmethyl cellulose, in the 3rd stage of passage.

Example 4: Particle Size

[0138] The mean particle size of the compositions F1 to F18 of Example 3 was measured and found to be in the following ranges (indicated in nm):

TABLE-US-00004 F1 F2 F3 F4 F5 F6 F7 F8 F9 120- 220- 220- 200- 130- 220- 220- 240- 250- 250 270 310 240 250 280 280 280 350 F10 F11 F12 F13 F14 F15 F16 F17 F18 210- 230- 260- 200- 240- 250- 200- 240- 275- 260 250 320 260 290 320 50 290 350

Example 5: Lyophilisate

[0139] Compositions F13,14 to F18 of Example 2 were lyophilised by using mannitol as cryoprotectant. The freeze drying (Alpha 1-2 LDplus) was performed at a temperature of −70° C. and vacuum 0.09 mbar for 72 hours.