ACTIVE SUBSTANCE DELIVERY SYSTEM WITH DELAYED DELIVERY

Abstract

The present invention relates to an active substance delivery system, preferably an anti-cancer agent delivery system, for use in the treatment of cancer in a human subject, comprising one or more anti-cancer agents and optionally further active substances, both included in nano- and/or microparticles, 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 to the human subject an active substance delivery system, the active substance delivery system comprising: (a) particles comprising: (a.1) 50 to 98 wt.-%, based on the total weight of the particles, of a base substance consisting of: (a.1.i) one or more polymers selected from the group consisting of poly(lactic-co-glycolic acid) (PLGA), poly(lactide), poly(lactide-co-glycolide), poly(isobutylcyanoacrylate), poly(isohexylcyanoacrylate), poly(n-butylcyanoacrylate) poly(acrylate), poly(methacrylate), chitosan, alginate, gelatin, albumin, poly(methacrylate), poly(e-caprolactone), polylactic acid, poly(b hydroxyl butyrate), ethyl cellulose, polystyrene, poly(vinyl pyridine), poly(alkyl methacrylate), and poly(alkyl cyanoacrylate), and (a.1.ii) optionally, one or more lipids selected from the group consisting of glyceryl monostearate, glycerol mono-oleate, medium-chain triglycerides, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sorbitan monooleate, sorbitan trioleate, polyoxyethylene 20 sorbitan monostearate, polyoxyethylene 20 sorbitan mono palmitate, polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene 20 sorbitan mono oleate, propylene glycol monocaprylate, propylene glycol caprylate, propylene glycol monolaurate, oleoyl macrogolglycerides, linoleoyl macrogolglycerides, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, capryl alcohol, capri alcohol, lauryl alcohol, myristyl alcohol, palmityl alcoholl, stearyl alcohol, arachidiyl alcohol, behenyl alcohol, oleyl alcohol, cetostearyl alcohol, α-linolenic acid, myristoleic acid, palmitoleic acid, oleic acid, and linoleic acid; (a.2) 0.25 to 20 wt.-%, based on the total weight of the particles, of one or more anti-cancer agents; (a.3) optionally, 0.5 to 30 wt.-%, based on the total weight of the particles, of one or more surface coating material(s) selected from the group consisting of chitosan, carboxymethyl chitosan, cellulose, starch, polyethylene glycols (PEG), polyvinyl alcohols, polymers or block co-polymers (such as polyacrylic acid, poly-L-lysine, polytheylenimine or PDMAAm), dextran, albumin, and pullulan; (a.4) optionally, 1 to 10 wt.-%, based on the total weight of the particles, of one or more further active substances selected from the group consisting of immunomodulatory drugs, antibodies, viruses, adjuvants, and combinations thereof, and (a.5) 0.5 to 20 wt.-%, based on the total weight of the particles, of one or more stabilizers; wherein the average size of the particles is from 100 to 5000 nm, provided that when component (a.1.ii) is not present, the average size of the particles is from 400 to 5000 nm; and (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 anticancer agents of component (a.2) for at least 2 hours into a liquid medium that does not contain the one or more anticancer agents of component (a.2).

15. The method of claim 14, wherein the one or more anti-cancer agents of (a.2) are anti-cancer agents for treating gastrointestinal cancer, colorectal cancer, hepatobiliary or pancreatic cancer, appendix cancer, oesophageal 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, and Kaposi's sarcoma and tumours of embryonal origin.

16. The method of claim 14, wherein the one or more anti-cancer agents of (a.2) are chosen from cisplatin, doxorubicin, paclitaxel, and oxaliplatin.

17. 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 and the membrane is permeable to the liquid medium and the one or more anti-cancer agents (a.2) of the delivery system but not permeable to other constituents of the delivery system.

18. 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 2 hours.

19. The method of claim 14, wherein a single administration of the delivery system delivers 120 mg to 2500 mg of the one or more anti-cancer agents (a.2) 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.

20. 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.

21. 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.

22. The method of claim 20, wherein the delivery system is included in a mixture.

23. The method of claim 22, 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 particles.

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

25. A method for producing an anti-cancer delivery system comprising: (i) dissolving the one or more polymers (a.1.i) and optionally, the one or more lipids (a.1.ii), in a solvent, (ii) dissolving the one or more anti-cancer agents (a.2) in a solvent, (ii.a) optionally, dissolving the one or more further active substances (a.4), (ii.b) providing the one or more stabilizers of (a.5), (iii) mixing the solutions of (i), (ii), optional (ii.a), and (ii.b), (iv) providing a polyvinyl alcohol (PVA) solution, (v) adding the mixture of (iii) to the PVA solution of (iv) n to produce particles, (vi) optionally, evaporating the solvent of (i) and/or (ii), (vii) purifying the particles and subsequently dispersing the particles in a dispersant, (viii) coating the particles with one or more surface coating materials, and (ix) optionally, adding one or more further pharmaceutically acceptable components to the particles.

26. 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.

27. 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.

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 release of the one or more anti-cancer agents from the delivery system in the in vitro assay can be measured for at least 10 days.

30. 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 8 hours and the one or more anti-cancer agents from the delivery system in the in vitro assay can be measured for at least 90 days.

Description

[0147] FIG. 1 describes an exemplary particle according to the invention, wherein component a.1.ii) is not present.

[0148] FIG. 2 describes an exemplary particle with surface coating (A) according to the invention, wherein component a.1.ii) is not present.

[0149] FIG. 3 describes an exemplary particle with surface coating (A) according to the invention, wherein component a.1.ii) is present (B, grey lines).

[0150] 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

[0151]

TABLE-US-00002 Amount [mg] Ingredient A B C D E F G H I J PLGA 15 — — — 1 2 3 4 5 6 PCL — 50 30 40 — — — — — — Triglyceride — — — — 10 20 30 50 50 50 Paclitaxel 0.75 0.25 0.50 0.75 0.25 0.50 0.75 0.75 0.75 0.75 Acetone 3.5 — — — 1.5 2.5 3.5 — — — Polyvinylal- 0.8 1 1.2 1.2 0.5 1 1.2 1.2 1.2 1.2 cohol (PVA) Dichloro- — 1.5 2.5 3.5 — — — 1.5 2.5 3.5 methane Acetonitrile 0.5 0.15 0.30 0.50 0.15 0.30 0.50 0.15 0.30 0.50 Chitosan 2.7 1.5 2.1 2.7 — — — — — — Sodium algi- — — — — 1.5 2.1 2.7 1.5 2.1 2.7 nate Polysorbate 80 0.2 0.6 0.3 0.3 0.2 0.2 0.3 0.3 0.3 0.3 Water q.s.

[0152] PLGA or PCL (poly(e-caprolactone)) was provided and dissolved in acetone or dichloromethane. For some examples, also Triglyceride was provided. Additionally, paclitaxel was provided separately and dissolved in acetonitrile. All solutions were mixed together and added to an aqueous phase containing Polysorbate 80 as indicated.

[0153] 10 ml of a 2% polyvinyl alcohol (PVA) solution were prepared, wherein the polyvinyl alcohol was dissolved in water.

[0154] The mixture obtained above was added to the PVA solution by injection with a syringe pump with a constant rate as indicated below. Upon addition, particles, i.e. nano- and/or microparticles, were produced.

TABLE-US-00003 A B C D E F G H I J Injection rate 0.8 3 1.5 1.8 0.5 0.7 0.9 0.95 1 1.7 [ml/min]

[0155] Furthermore, the particles were coated with chitosan or sodium alginate. The particles were further purified by centrifugation at 15.000×g or other suitable technique like size exclusion chromatography at 20° C. The supernatant was removed and the pelleted particles were redispersed in 5-10 ml of water and 0.05-0.25 g of mannitol. In another approach, the pelleted particles were redispersed in 5 ml of water and were lyophilised using 0.05-0.25 g of cryoprotectant.

[0156] The particles had an average size (diameter) as indicated below:

TABLE-US-00004 A B C D E F G H I J Average parti- 500 3500 950 1200 278 320 600 758 870 980 cle size [nm]

Application Example 1: Release Profile

[0157] The compositions as in Example 1 were tested as follows:

[0158] 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 anti-cancer agent(s), however, not the delivery system or, respectively, the particles as such to pass. Therefore, the delivery systems or, respectively, the particles were enveloped. The enveloped delivery systems or, respectively, particles are each added to a separate medium mixture of 200 ml of artificial peritoneal dialysis fluid, which is warmed to 37° C. and continuously stirred at 100 rpm.

[0159] 2 hours, 5 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 90 hours, 120 hours, and preferably also 7 days, 10 days, 15 days, 30 days, 60 days and/or 90 days after the addition of the enveloped delivery systems, a sample of 2 ml of the medium is taken and replaced with fresh medium.

[0160] The content of Paclitaxel in the samples was analysed by applying HPLC. No content could be measured in the medium until 2 hours, thus, there was no release. However, at a later time, a release could be measured. A release until numerous days was measured.