DELAYED AND SUSTAINED DELIVERY OF ANTICANCER DRUGS

Abstract

The present invention relates to an anti-cancer delivery system with a delayed and sustained release of one or more chemotherapeutic agent(s), a mixture for use in the treatment of cancer comprising such a delivery system and a method for producing such a delivery system.

Claims

1-13. (canceled)

14. A method for treating cancer in a human subject comprising administering an anti-cancer agent delivery system to the human subject, wherein the delivery system comprises: (a) nanoparticles comprising: (1) 0.05 to 15 wt.-%, based on the total weight of the nanoparticles, of one or more chemotherapeutic agents, (2) 75 to 99.9 wt.-%, based on the total weight of the nanoparticles, of one or more polymers chosen from natural polymers, synthetic polymers, and a combination thereof; and (3) 0.5 to 20 wt.-%, based on the total weight of the nanoparticles, of one or more surface coating materials chosen from chitosan, carboxymethyl chitosan, cellulose, starch, polyethylene glycols (PEG), polyvinyl alcohols, polymers or block co-polymers, dextran, albumin, surfactants, and pullulan; wherein the average size of the nanoparticles is from 100 to 350; (b) optionally, one or more further pharmaceutically acceptable components; wherein, in an in vitro assay, the delivery system prevents release of more than 5 wt.-% of the one or more chemotherapeutic agents of (a)(1) for at least 7 days into a liquid medium that does not contain the one or more chemotherapeutic agents of (a)(1).

15. The method of claim 14, wherein the one or more chemotherapeutic agents of (a)(1) are chemotherapeutic agents used against a cancer type 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, tumours of embryonal origin.

16. The method of claim 14, wherein the delivery system is enveloped in a membrane when added into the liquid medium of the in vitro assay, wherein the membrane is permeable to the liquid medium and the one or more chemotherapeutic agents of the delivery system but not permeable to the other constituents of the delivery system.

17. The method of claim 14, wherein the highest release rate of the one or more chemotherapeutic agents from the delivery system in the in vitro assay is not observed before 7 days.

18. The method of claim 14, wherein a single administration of the delivery system delivers 120 mg to 2500 mg of the one or more chemotherapeutic agents to the human subject and/or delivers 30 mg/m.sup.2 body surface to 250 mg/m.sup.2 body surface of the one or more chemotherapeutic agents to the human subject.

19. The method of claim 14, wherein the method treats a cancer type 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, tumours of embryonal origin.

20. The method of claim 14, wherein the method is performed with an assisting tool chosen from microneedles, spray devices, angio-injectors, and a combination thereof.

21. The method of claim 14, wherein the delivery system is included in a mixture.

22. The method of claim 21, wherein the mixtures comprises two or more different delivery systems and each of the two or more different delivery systems differ with respect to their respective one or more chemotherapeutic agents and/or with respect to their respective nanoparticles.

23. The method of claim 14, wherein the method prevents or delays cancer recurrence after a surgical tumor removal.

24. A method for producing an anti-cancer delivery system comprising: (i) dissolving PLGA in a solvent, (ii) dissolving one or more chemotherapeutic agents in a solvent, (iii) mixing the solutions of (i) and (ii) together, (iv) providing a polyvinyl alcohol (PVA) solution, (v) adding the mixture of (iii) to the PVA solution by injection to produce nanoparticles, wherein amounts of the mixture and the solution are such that a ratio of a least 1 ml of solution per 5 mg of the summed weight of PLGA and the one or more active substances is achieved, (vi) optionally, evaporating the solvent of (i) and/or (ii), (vii) purifying the nanoparticles and subsequently dispersing the nanoparticles in a dispersant, (viii) coating the nanoparticles with one or more surface coating materials, and (ix) optionally, adding one or more further pharmaceutically acceptable components to the nanoparticles.

25. The method of claim 24, wherein: the solvent of (i) and/or the solvent of (ii) comprises acetone, ethyl acetate, a chlorinated solvent, DMSO, a methylated solvent, tetrahydrofuran, a halogenated hydrocarbon, a dioxane, acetonitrile, or a combination thereof; and/or the PVA solution of (v) comprises water, ethanol, saline, or a combination thereof and/or the dispersant of (vii) comprises saline, glucose, a surfactant, a pH modifier, water, or a combination thereof.

26. The method of claim 24 comprising the addition of the one or more further pharmaceutically acceptable components of (ix) to the nanoparticles, wherein the one or more further pharmaceutically acceptable components are chosen from carriers, polymers, surfactants, stabilizers, wetting agents, emulsifiers, antioxidants, pH influencing agents, disintegrants, recrystallization agents, fluxing agents, preservatives, solvents, salts fillers, binders, foamers, defoamers, lubricants, adsorbents for adjusting the osmotic pressure, and buffers.

27. The method of claim 14, wherein the one or more polymers of (a)(2) are chosen from poly(lactic-co-glycolic acid) (PLGA), poly(lactide), poly(lactide-co-glycolide), poly(isobutylcyanoacrylate), poly(isohexylcyanoacrylate), poly(n-butylcyanoacrylate) poly(acrylate), poly(mathacrylate), chitosan, alginate, gelatin, albumin, poly(methacrylate), poly(e-caprolactone), polylactic acid, poly(b hydroxyl butyrate), ethyl cellulose, polystyrene, poly(vinyl pyridine), poly(alkyl methacrylate), poly(alkyl cyanoacrylate), and a combination thereof.

28. The method of claim 14, wherein the delivery system is administered to the human subject by direct introduction into the abdomen and/or thorax.

29. The method of claim 14, wherein the one or more chemotherapeutic agents of (a)(1) is cisplatin, doxorubicin, paclitaxel and/or oxaliplatin.

30. The method of claim 14, wherein release of the one or more chemotherapeutic agents from the delivery system in the in vitro assay can be measured for at least 50 days.

Description

EXAMPLES

Example 1: Chemotherapeutic Agent

[0118]

TABLE-US-00002 Amount [wt.-%] Ingredient A B C D E F PLGA 5 10 15 1 3 20 Paclitaxel 0.5 0.8 0.8 0.1 0.35 0.9 Acetone 5 10 12.5 5 10 12.5 Acetonitrile 5 10 12.5 5 10 12.5 Chitosan 1 2 3 0.2 0.8 5 water q.s. 100

[0119] PLGA was provided and dissolved in acetone. Additionally, paclitaxel was provided separately and dissolved in acetonitrile. Both solutions were mixed.

[0120] 10 ml of a 2 % polyvinyl alcohol (PVA) solution were prepared, wherein the polyvinyl alcohol was dissolved in water.

[0121] The mixture obtained above was added to the PVA solution by injection with a syringe pump with a constant rate of 0.6 ml/min. Upon addition, nanoparticles were produced.

[0122] Furthermore, the nanoparticles were coated with chitosan. The nanoparticles were further purified by 30 min of centrifugation at 15.000 x g and at 20° C. The supernatant was removed and the pelleted nanoparticles were redispersed in 5 ml of water and 0.05-0.25 g of mannitol. In another approach, the pelleted nanoparticles were redispersed in 5 ml of water and were lyophilised using 0.05-0.25 g of cryoprotectant.

[0123] The nanoparticles had an average size (diameter) of 120 to 250 nm.

Application Example 1: Release Profile

[0124] The composition as in Example 1 was tested as follows:

[0125] 5 mL of the composition were added to a PVDF membrane with a pore size of approx. 0.01 μm, which allows the medium and the chemotherapeutic agent(s), however, not the delivery system or, respectively, the nanoparticles as such to pass. Therefore, the delivery systems or, respectively, the nanoparticles were enveloped. The enveloped delivery systems or, respectively, nanoparticles are each added to a separate medium mixture of 25 ml of artificial peritoneal dialysis fluid and 25 ml saline, which is warmed to 37 ° C. and continuously stirred at 80 rpm.

[0126] 5 days, 7 days, 10 days, 30 days, 60 days and 70 days after the addition of the enveloped delivery systems, a sample of 2 ml of the medium is taken and replaced with fresh medium.

[0127] The content of Paclitaxel in the samples was analysed by applying HPLC. No content could be measured in the medium until 5 days, thus, there was no release. After 7 days, a release could be measured, however, the release was lower than 5 wt.-%. The peak release was at day 30. A release until day 60 was measured.