DELAYED DELIVERY OF ANTICANCER DRUGS

Abstract

The present invention relates to an anti-cancer delivery system with a delayed 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

1-14. (canceled)

15. An anti-cancer agent delivery system comprising: (a) one or more chemotherapeutic agents optionally dissolved in a solvent; and (b) a matrix surrounding the one or more chemotherapeutic agents, wherein the matrix is degradable in the human body and comprises: i) one or more surfactants; ii) one or more lipids; and iii) one or more fillers; wherein the matrix prevents release of more than 5 wt.-% of the one or more chemotherapeutic agents from the delivery system for at least 7 days when the delivery system is added to a liquid medium consisting of 50 vol. % of an artificial peritoneal dialysis fluid and 50 vol. % of saline.

16. The delivery system of claim 15, wherein the one or more chemotherapeutic agents are chosen from chemotherapeutic agents for treating gastrointestinal cancer, gynaecological cancer, prostate cancer, peritoneal metastasis, leukemia, lymphoma, a soft-tissue sarcoma, pseudomyxoma peritonei, a yolk sack tumor, a peritoneal cancer, multiple myeloma, breast cancer, bladder cancer, lung cancer, thyroid cancer, Kaposi's sarcoma.

17. The delivery system of claim 15, wherein the one or more surfactants are chosen from cationic surfactants, non-ionic surfactants, anionic surfactants, and a mixture thereof.

18. The delivery system of claim 17, wherein the one or more surfactants are chosen from macrogol glycerol ricinoleate, polyoxyl-35-castor oil, polysorbates, poloxamers, span, macrogol 15 hydroxystearate, polyoxyl 15 hydroxystearate, polyethoxylated 12-hydroxystearic acid, and a mixture thereof.

19. The delivery system of claim 15, wherein the one or more lipids is chosen from triglycerides, diglycerides, monoglycerides, phospholipids, lipoproteins, fatty acids, and a mixture thereof.

20. The delivery system of claim 15, wherein the one or more fillers are chosen from lactose, mannitol, lactulose, glucose, trehalose, xylose, sorbitol, sucrose and/or consisting of polymers such as carbopol polymers; polyethylenglycols, such as PEG 4000, preferably with a molecular weight of 600 g/mol or more; polyvinyl alcohols; polyvinylpyrrolidone; hydrocolloids, preferably carrageenan, chitosan or algenic acid; hydrogels; cellulose and its derivatives such as microcrystalline cellulose, cross-linked cellulose, non-ionic cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, carboxymethyl cellulose, cellulose ethers, anionic ether derivatives, starch, and a mixture thereof.

21. The delivery system of claim 15, wherein the matrix prevents release of more than 5 wt.-% of the one or more chemotherapeutic agents for at least 7 days and continues release for at least 30 days.

22. The delivery system of claim 15, wherein the delivery system comprises 0.01 to 70 wt. % of each of the one or more chemotherapeutic agents, based on the total weight of the delivery system.

23. The delivery systems of claim 15 incorporated into a mixture.

24. A method for treating cancer comprising administering an anti-cancer agent delivery system of claim 15 to an abdomen of a human.

25. The method of claim 24, wherein the one or more chemotherapeutic agents are chosen from chemotherapeutic agents for treating gastrointestinal cancer, gynaecological cancer, prostate cancer, peritoneal metastasis, leukemia, lymphoma, a soft-tissue sarcoma, pseudomyxoma peritonei, a yolk sack tumor, a peritoneal cancer, multiple myeloma, breast cancer, bladder cancer, lung cancer, thyroid cancer, Kaposi's sarcoma.

26. The method of claim 24, wherein the one or more surfactants are chosen from cationic surfactants, non-ionic surfactants, anionic surfactants, and a mixture thereof.

27. The method of claim 26, wherein the one or more surfactants are chosen from macrogol glycerol ricinoleate, polyoxyl-35-castor oil, polysorbates, poloxamers, span, macrogol 15 hydroxystearate, polyoxyl 15 hydroxystearate, polyethoxylated 12-hydroxystearic acid, and a mixture thereof.

28. The method of claim 24, wherein the one or more lipids is chosen from triglycerides, diglycerides, monoglycerides, phospholipids, lipoproteins, fatty acids, and a mixture thereof.

29. The method of claim 24, wherein the one or more fillers are chosen from lactose, mannitol, lactulose, glucose, trehalose, xylose, sorbitol, sucrose and/or consisting of polymers such as carbopol polymers; polyethylenglycols, such as PEG 4000, preferably with a molecular weight of 600 g/mol or more; polyvinyl alcohols; polyvinylpyrrolidone; hydrocolloids, preferably carrageenan, chitosan or algenic acid; hydrogels; cellulose and its derivatives such as microcrystalline cellulose, cross-linked cellulose, non-ionic cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, carboxymethyl cellulose, cellulose ethers, anionic ether derivatives, starch, and a mixture thereof.

30. The method of claim 24, wherein the matrix prevents release of more than 5 wt.-% of the one or more chemotherapeutic agents for at least 7 days and continues release for at least 30 days.

31. The method of claim 24, wherein the delivery system comprises 0.01 to 70 wt. % of each of the one or more chemotherapeutic agents, based on the total weight of the delivery system.

32. The method of claim 24, wherein the administration is performed with an assisting tool chosen from microneedles, spray devices, angioinjectors, and a combination thereof.

33. The method of claim 24, wherein the treatment is carried out after surgical tumour removal and prevents or delays cancer recurrence after the surgical tumour removal.

34. The method of claim 24, wherein the delivery system is incorporated into a mixture that is administered to the abdomen of the human.

Description

EXAMPLES

Example 1

Low Shear Mixing

[0132]

TABLE-US-00002 Ingredient Wt.-% Carboxymethyl cellulose 5 Glyecryl behenate 30 Lactose 28 PEG 4000 29 Tween 80 5 water 2 Cisplatin 1 Sum 100

[0133] All the components are provided. 1000 mg of Cisplatin are dispersed in 29 g of PEG 4000 and 30 g of glyceryl behenate at 80° C. This solution was used as a granulating fluid for the mixture of 28 g Lactose, 2 g water and 5 g carboxymethyl cellulose under stirring at 500 rpm for 25 min to obtain granules with an average diameter of 0.1-0.5 cm.

Example 2

Fluid Bed Drying

[0134]

TABLE-US-00003 Ingredient Wt.-% Stearic acid 20 Lactose 30 Oxaliplatin 1 Mannitol 46 Poloxamer 188 2 Hydroxypropylmethyl cellulose 1 Water at 90 degree q.s. Sum 100

[0135] 1 g of Oxaliplatin, 2 g of poloxamer, 20 g of stearic acid, 1 g of hydroxypropylmethyl cellulose and 30 g of lactose are mixed in a fluid bed dryer to obtain mixture A. 46 g of Mannitol were dissolved in warm water and was sprayed on the dried mixture A till uniform granules are obtained. The complete process was carried out at an inlet temperature of 120° C. and an outlet temperature of 70° C.

Example 3

Granulation

[0136]

TABLE-US-00004 Ingredient Wt.-% Ethyl cellulose 47 Povidone 20 Palmitic acid 30 Poloxamer 188 2 Doxorubicin 1 Sum 100

[0137] 47 g of Ethyl cellulose, 20 g of povidone, 1 g of doxorubicin and 2 g of poloxamer are mixed. 30 g of Palmitic acid are melted at 50-80° C. and added to the mixture. All the components are subjected to hot melt extrusion at 90° C. to form pellets, which are then milled to a suitable smaller size.

Example 4

Spheronization

[0138]

TABLE-US-00005 Ingredient Wt.-% Hydroxypropylmethyl cellulose 15 Poloxamer 188 5 PEG 4000 45 Lactose 24 Oxaliplatin 1 Water 5 Ethanol 5 Sum 100

[0139] 15 g of Hydroxypropylmethyl cellulose, 5 g of poloxamer 188, 24 g of lactose and 1 g of Oxaliplatin are mixed in form of a powder. 5 g of water and 5 g of ethanol were added to the powder mixture to moisten the powder bed. 45 g of melted PEG 4000 at 80° C. were added and admixed to mixture. The mixture was immediately extruded using a Caleva extruder.

[0140] The extrudate is subsequently shaped into round granules by spheronization which was performed at 1500 rpm and at room temperature.

[0141] 88.5 g of granules are obtained.

Example 5

Crystal Mix 1

[0142]

TABLE-US-00006 Ingredient Wt.-% Povidone 2 Polysorbate 80 8 Lactose 20 Fully gelatinised starch 10 Triglyceride 20 PEG 4000 34 Paclitaxel 1 Water 5 Sum 100

[0143] 1000 mg of Paclitaxel are mixed into a powder bed of 2 g of povidone, 20 g of lactose and 10 g of fully gelatinised starch. 5 g of water at 50° C. and 8 g of polysorbate 80 were sprayed on the powder bed to moist the mass. In another beaker, 20 g of triglycerides are melted and used as granulating fluid (number-1). Simultaneously, 34 g of PEG 4000 are melted and used as a granulating fluid (number-2). In this way, the particles are attached and covered to each other either by a lipid or by PEG or a mixture thereof. The complete granulation process is performed at 1500 rpm.

[0144] 95.6 g of crystals are obtained.

Example 6

Crystal Mix 2

[0145]

TABLE-US-00007 Ingredient Wt.-% Mixture 1 triglyceride 20 Paclitaxel 1 Water 49 lactose 20 Tween 80 5 Polyvinyl alcohol 5 Mixture 2 Glyceryl behenate 20 Phospholipid 2 Cisplatin 1 Poloxamer 1 Mannitol 27 Water 49

Mixture 1:

[0146] 1 g of Paclitaxel was dissolved in 20 g of triglycerides in one beaker and at 80° C. to obtain phase A. In another beaker, 5 g of tween 80 and 5 g of polyvinyl chloride were dissolved in 49 g of water and 20 g of lactose were dispersed therein at 80° C. to obtain phase B. Phase B is added to phase A under stirring at 1500-2000 rpm for 5 min and the solution is immediately cooled in an ice bath for 30 min and subsequently centrifuged to obtain a pellet.

Mixture 2:

[0147] 1 g of Cisplatin and 2 g phospholipids were dissolved in 20 g of glyceryl behenate in one beaker and at 80° C. to obtain phase A. In another beaker, 27 g of mannitol and 1 g poloxamer were dissolved in 49 g of water at 80° C. to obtain phase B. Phase B is added to phase A under stirring at 1500-2000 rpm for 5 min and the solution is immediately cooled in an ice bath for 30 min and subsequently centrifuged to obtain a pellet.

[0148] The pellets obtained from mixture A and mixture B were homogeneously mixed by vortexing and subsequently lyophilised to obtain a crystal mix. This method is used for preparing an anti-cancer agent delivery system of two different anti-cancer agents which can be administered simultaneously.

Example 7

Melt Casting

[0149]

TABLE-US-00008 Ingredient Wt.-% Hydroxypropylmethyl cellulose 20 Mannitol 8 Ethanol 30 Glycerol 10 Triglyceride 5 Poloxamer 1 Cisplatin 1 Water 25 Sum 100

[0150] 1 g of Cisplatin is dissolved in 25 g of water, and mixed with 1 g of poloxamer and 30 g of ethanol. Subsequently, 10 g of glycerol was added and the mixture was stirred at 1000 rpm for 10 min. To this solution, 20 g of HPMC were added and the mixture was warmed to 80° C. Further, 5 g triglycerides were added. A film is casted on casting belt and was cut in suitable size.

[0151] 94 g of the solidified product are then taken from the mould.

Example 8

Lipid Nanoparticles

[0152]

TABLE-US-00009 Ingredient Wt.-% Cetyl palmitate 15 Phospholipid 1 Oxaliplatin 1 Water 76 Poloxamer 188 1 mannitol 5 Polyvinylpyrrolidone 1 Sum 100

[0153] 1 g of Oxaliplatin was dissolved in 15 g of cetyl palmitate and mixed with 1 g of phospholipid in a beaker and at 85° C. to obtain mixture A. In another beaker, 1 g of poloxamer 188, 1 g of polyvinylpyrrolidone and 5 g of mannitol were dissolved in 76 g of water at 80° C. to obtain mixture B. Phase B is added to phase A under stirring at 1500-2000 rpm for 5 min.

[0154] The warm emulsion mixture is then passed through a high-pressure homogeniser either at 3 cycles at 1000 bar or 3 cycles at 1200 bar or 3 cycles at 1500 bar, according to the desired particle size. Upon homogenisation, the warm emulsion is immediately cooled in an ice bath for 30 min.

Application Example 1: Release Profile

[0155] Composition A was prepared according to Example 1.

[0156] Composition B was prepared according to Example 4.

[0157] Composition C was prepared according to Example 8.

[0158] Composition D was prepared according to Example 5.

[0159] The obtained delivery systems (compositions A-D) were enveloped with a PVDF membrane with a pore size of approx. 0.1 μm, which allows the medium and the chemotherapeutic agent(s), however, not the delivery system as such to pass. The enveloped delivery systems 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.

[0160] 5 days, 7 days, 10 days, 30 days, 60 days and 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.

[0161] The anti-cancer agent content in the samples was analysed by applying HPLC.

[0162] For all compositions, no anti-cancer agent content could be measured in the medium until 5 days, thus, there was no release. After 7 days, a release could be measured for compositions B, C and D. For composition B, however, the release was lower than 5 wt.-%.

[0163] The peak release of composition A, B and C was between 30 and 60 days. The peak release of composition D was around day 10. A release until day 30 was measured for all compositions. A release until day 60 was measured for compositions A, B and C.