Controlled local delivery of chemotherapeutic agents for treating solid tumors

Abstract

A method and devices for localized delivery of a chemotherapeutic agent to solid tumors, wherein the agent does not cross the blood-brain barrier and is characterized by poor bioavailability and/or short half-lives in vivo, are described. The devices consist of reservoirs which release drug over an extended time period while at the same time preserving the bioactivity and bioavailability of the agent. In the most preferred embodiment, the device consists of biodegradable polymeric matrixes, although reservoirs can also be formulated from non-biodegradable polymers or reservoirs connected to implanted infusion pumps. The devices are implanted within or immediately adjacent the tumors to be treated or the site where they have been surgically removed. The examples demonstrate the efficacy of paclitaxel and camptothecin delivered in polymeric implants prepared by compression molding of biodegradable and non-biodegradable polymers, respectively. The results are highly statistically significant.

We claim:  
     
       1. A chemotherapeutic composition comprising 
       a biocompatible synthetic polymeric matrix incorporating  
       an effective amount to inhibit tumor growth when released in vivo at the site of the tumor of a water insoluble, relatively lipid insoluble chemotherapeutic agent,  
       wherein the chemotherapeutic agent is incorporated into an released from a synthetic polymeric matrix by degradation of the polymer matrix or diffusion of the agent out of the matrix over a period of time of at least eight hours.  
     
     
       2. The composition of claim  1  wherein the chemotherapeutic acid is paclitaxel or a functionally effective derivative. 
     
     
       3. The composition of claim  1  wherein the chemotherapeutic agent is camptothecin or a functionally effective derivative. 
     
     
       4. The composition of claim  1  wherein the polymer matrix is biodegradable. 
     
     
       5. The composition of claim  4  wherein the polymeric matrix is formed  consists essentially of a hydrophobic polymer selected from the group consisting of polyanhydrides, polyhydroxy acids, polyphosphazenes, polyorthoesters, polyesters, polyamides, polysaccharides  copolymers and blends thereof. 
     
     
       6. The composition of claim  1  wherein the polymeric matrix is formed of ethylene vinyl acetate. 
     
     
       7. The composition of claim  1  further comprising additional biologically active compounds selected from the group consisting of other chemotherapeutics, antibiotics, antivirals, antiinflammatories, targeting compounds, cytokines, immunotoxins, anti-tumor antibodies, anti-angiogenic agents, anti-edema agents, radiosensitizers, and combinations thereof. 
     
     
       8. A method of administering to a patient in need of treatment of a solid tumor a water insoluble, relatively lipid insoluble chemotherapeutic agent comprising 
       administering at the site of the tumor an amount of the chemotherapeutic agent effective to inhibit growth of a solid tumor,  
       wherein the systemic administration of the same dosage of chemotherapeutic agent is not as effective to treat tumors or is not well tolerated by the patient, and  
       wherein the chemotherapeutic agent is incorporated into and released from a synthetic polymeric matrix by degradation of the polymer matrix or diffusion of the agent out of the matrix over a period of time of at least eight hours.  
     
     
       9. The method of claim  8  wherein the chemotherapeutic agent is paclitaxel or a functionally effective derivative. 
     
     
       10. The method of claim  8  wherein the chemotherapeutic agent is camptothecin or a functionally effective derivative. 
     
     
       11. The method of claim  8  wherein the chemotherapeutic agent is locally delivered by direct infusion to the tumor from a reservoir. 
     
     
       12. The method of claim  8  wherein the chemotherapeutic agent is locally delivered by implantation of a biocompatible polymer matrix incorporating the chemotherapeutic agent. 
     
     
       13. The method of claim  8  wherein the polymer matrix is biodegradable. 
     
     
       14. The method of claim  13  wherein the polymeric matrix is formed of a hydrophobic polymer selected from the group consisting of polyanhydrides, polyhydroxy acids, polyphosphazenes, polyorthoesters, polyesters, polyamides, polysaccharides,  copolymers and blends thereof. 
     
     
       15. The method of claim  8  wherein the polymeric matrix is formed of ethylene vinyl acetate. 
     
     
       16. The method of claim  8  further comprising administering radiation in combination with the composition. 
     
     
       17. The method of claim  8  further comprising administering with the chemotherapeutic agent additional biologically active compounds selected from the group consisting of other chemotherapeutics, antibiotics, antivirals, antiinflammatories, targeting compounds, cytokines, immunotoxins, anti-tumor antibodies, anti-angiogenic agents, anti-edema agents, radiosensitizers, and combinations thereof. 
     
     
       18. The method of claim  8  wherein the composition is in the form of micro-implants and are administered by injection or infusion. 
     
     
       19. The composition of claim  1  wherein the chemotherapeutic is released with linear or first order kinetics. 
     
     
       20. The composition of claim  5  wherein the chemotherapeutic agent is paclitaxel or a functionally effective derivative. 
     
     
       21. The composition of claim  5  wherein the chemotherapeutic agent is camptothecin or a functionally effective derivative. 
     
     
       22. The method of claim  8  wherein the chemotherapeutic is released with linear or first order kinetics. 
     
     
       23. The method of claim  14  wherein the chemotherapeutic agent is paclitaxel or a functionally effective derivative. 
     
     
       24. The method of claim  14  wherein the chemotherapeutic agent is camptothecin or a functionally effective derivative. 
     
     
       25. A chemotherapeutic composition comprising a chemotherapeutic agent incorporated into a synthetic polymeric biocompatible matrix releasing the chemotherapeutic by diffusion or degradation over a period of at least eight hours in an amount effective to treat brain tumors, wherein the chemotherapeutic agent is selected from the group consisting of carboplatinum, adriamycin, ternozolamide, vincristine, etoposide, cytokines, DNA or RNA including oligonucleotides, ribozymes, and guide sequences for ribozymes which inhibit translation or transcription of essential tumor genes  polynucleotides, and dacarbazine. 
     
     
       26. The composition of claim  25  wherein the composition further comprises an additional biologically active compound selected from the group consisting of other chemotherapeutics, antibiotics, antivirals, antiinflammatories, targeting compounds, cytokines, immunotoxins, anti-tumor antibodies, anti-angiogenic agents, anti-edema agents, radiosensitizers, and combinations thereof. 
     
     
       27. The composition of claim  25  wherein the compound is adriamycin. 
     
     
       28. The composition of claim  25  wherein the compound is carboplatinum. 
     
     
       29. The composition of claim  25  wherein the compound is a cytokine. 
     
     
       30. A method for treating brain  solid tumors comprising administering at a site in a patient in need of treatment a chemotherapeutic composition having incorporated into a synthetic polymeric biocompatible matrix releasing the chemotherapeutic by diffusion or degradation over a period of at least eight hours in an amount effective to treat brain  the solid tumors a chemotherapeutic agent selected from the group consisting of carboplatinum, adriamycin, ternozolamide, vincristine, etoposide, cytokines, DNA or RNA including oligonucleotides, ribozymes, and guide sequences for ribozymes which inhibit translation or transcription of essential tumor genes  polynucleotides, and dacarbazine. 
     
     
       31. The method of claim  30  further comprising administering with the chemotherapeutic composition an additional biologically active compound selected from the group consisting of other chemotherapeutics, antibiotics, antivirals, antiinflammatories, targeting compounds, cytokines, immunotoxins, anti-tumor antibodies, anti-angiogenic agents, anti-edema agents, radiosensitizers, and combinations thereof. 
     
     
       32. The method of claim  30  wherein the compound is adriamycin. 
     
     
       33. The method of claim  30  wherein the compound is carboplatinum. 
     
     
       34. The method of claim  30  wherein the compound is a cytokine. 
     
     
       35. The composition of claim  1  wherein the polymer matrix consists essentially of biodegradable polymers. 
     
     
       36. The composition of claim  1  wherein the water insoluble, relatively lipid insoluble chemotherapeutic agent is incorporated at a loading between ten and ninety percent by weight. 
     
     
       37. The composition of claim  36  wherein the loading is between  10  and  50  percent by weight. 
     
     
       38. The composition of claim  37  wherein the loading is between  20  and  40  percent by weight.  
     
     
       39. The composition of claim  36  wherein the chemotherapeutic agent is paclitaxel or a functionally effective derivative.  
     
     
       40. The composition of claim  39  wherein the synthetic polymer is a hydrophobic polymer. 
     
     
       41. The composition of claim  40  wherein the polymeric matrix consists essentially of a hydrophobic polymer selected from the group consisting of polyanhydrides, polyhydroxy acids, polyphosphazenes, polyorthoesters, polyesters, polyamides, copolymers and blends thereof. 
     
     
       42. The composition of claim  1  wherein the chemotherapeutic agents is released in an effective amount over a period of at least one day. 
     
     
       43. The composition of claim  1  wherein the chemotherapeutic agent is released in an effective amount over a period of at least one week. 
     
     
       44. The composition of claim  1  wherein the chemotherapeutic agent is released in an effective amount over a period of at least one month. 
     
     
       45. The composition of claim  1  wherein the polymeric matrix comprises polymer degrading by bulk erosion. 
     
     
       46. The composition of claim  1  wherein the polymer matrix comprises polymer degrading by surface erosion. 
     
     
       47. The composition of claim  1  wherein the chemotherapeutic agent and the polymer forming the polymeric matrix are dissolved together in a solvent. 
     
     
       48. The composition of claim  1  wherein the polymeric matrix further comprises additives altering the properties of the polymeric matrix selected from the group consisting of fillers, spheronization enhancers, disintegrants, surfactants and binders. 
     
     
       49. The composition of claim  25  wherein the matrix is biodegradable. 
     
     
       50. The method of claim  30  wherein the matrix is biodegradable. 
     
     
       51. A chemotherapeutic composition comprising a compound selected from the group consisting of camptothecin, carmustine,  4 - hydroxycyclophosphamide, minocycline, carboplatin, taxol, methotrexate, and adriamycin in combination with a cytokine, wherein the compound or cytokine is encapsulated in a synthetic polymeric matrix.   
     
     
       52. The composition of claim  51  wherein the cytokine is selected from the group consisting of granulocyte- macrophage colony stimulating factor, interleukin  2 , tumor necrosis factor, interleukin  4 , interleukin  5 , interleukin  6 , and gamma interferon.   
     
     
       53. The composition of claim  51  wherein the compound is adriamycin and the cytokine is interleukin  2 . 
     
     
       54. The composition of claim  51  wherein the compound is carmustine and the cytokine is interleukin  2 . 
     
     
       55. The composition of claim  51  wherein the compound is taxol and the cytokine is interleukin  2 . 
     
     
       56. The composition of claim  52  wherein the compound and the cytokine are microencapsulated in a polymeric matrix. 
     
     
       57. The composition of claim  56  wherein the polymeric matrix is biodegradable. 
     
     
       58. The composition of claim  56  wherein the polymeric matrix is in the form of microspheres. 
     
     
       59. The composition of claim  57  wherein the polymer is selected from the group consisting of polyanhydrides, polyhydroxy acids, polyphosphazenes, polyorthoesters, polyesters, polyamides, copolymers and blends thereof. 
     
     
       60. The composition of claim  51  wherein the polymeric matrix is biodegradable. 
     
     
       61. The composition of claim  51  wherein the polymeric matrix is in the form of microspheres. 
     
     
       62. The composition of claim  25  wherein the polynucleotide inhibits translation or transcription of essential tumor genes and is selected from the group consisting of oligonucleotides, ribozymes, and guide sequences for ribozymes. 
     
     
       63. The method of claim  30  wherein the polynucleotide inhibits translation or transcription of essential tumor genes and is selected from the group consisting of oligonucleotides, ribozymes, and guide sequences for ribozymes.