Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – Coated – impregnated – or colloidal particulate
Reexamination Certificate
2000-08-16
2003-03-25
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
Coated, impregnated, or colloidal particulate
C424S001110, C424S009100, C424S001370, C424S001330, C424S001650
Reexamination Certificate
active
06537518
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a particulate material which comprises small hollow or cup-shaped ceramic particles (hereinafter referred to as “microspheres”), to a process for the production thereof, and to methods for the use of this particulate material.
In one particular aspect, this invention relates to hollow or cup-shaped ceramic microspheres which consist of or comprise a radioactive material, and to the use of these radioactive microspheres in the treatment of cancer in humans and other mammals. In this aspect, the radioactive microspheres are designed to be administered into the arterial blood supply of the organ to be treated, whereby they become entrapped in the small blood vessels of the target organ and irradiate it. An alternate form of administration is to inject the radioactive microspheres directly into the tumour to be treated.
The particulate material of the present invention therefore has utility in the treatment of various forms of cancer and tumours, but particularly in the treatment of primary and secondary cancer of the liver and the brain. It is, however, to be understood that this invention is not limited to microspheres of radioactive material, and extends to microspheres of other ceramic materials which are suitable for use in the process described herein.
BACKGROUND OF THE INVENTION
Many previous attempts have been made to locally administer radioactive materials to patients with cancer as a form of therapy. In some of these, the radioactive materials have been incorporated into small particles, seeds, wires and similar related configurations that can be directly implanted into the cancer. In other approaches, the radioactive materials have been formulated into microspheres of regular size for injection into the arterial blood supply of the target organ. When radioactive particles or microspheres are administered into the blood supply of the target organ, the technique has become known as Selective Internal Radiation Therapy (SIRT). Generally, the main form of application of SIRT has been its use to treat cancers in the liver.
There are many potential advantages of SIRT over conventional, external beam radiotherapy. Firstly, the radiation is delivered preferentially to the cancer within the target organ. Secondly, the radiation is slowly and continually delivered as the radionuclide decays. Thirdly, by manipulating the arterial blood supply with vasoactive substances (such as Angiotensin-2), it is possible to enhance the percentage of radioactive microspheres that go to the cancerous part of the organ, as opposed to the healthy normal tissues. This has the effect of preferentially increasing the radiation dose to the cancer while maintaining the radiation dose to the normal tissues at a lower level (Burton, M. A. et al.; Effect of Angiotensin-2 on blood flow in the transplanted sheep squamous cell carcinoma.
Europ. J. Cancer Clin. Oncol.
1988, 24(8):1373-1376).
When microspheres or other small particles are administered into the arterial blood supply of a target organ, it is desirable to have them of a size, shape and density that results in the optimal homogeneous distribution within the target organ. If the microspheres or small particles do not distribute evenly, and as a function of the absolute arterial blood flow, then they may accumulate in excessive numbers in some areas and cause focal areas of excessive radiation. It has been shown that microspheres of approximately 25-50 micron in diameter have the best distribution characteristics when administered into the arterial circulation of the liver (Meade, V. et al; Distribution of different sized microspheres in experimental hepatic tumours.
Europ. J. Cancer
&
Clin. Oncol.
1987, 23:23-41).
If the microspheres or small particles do not contain sufficient ionising radiation, then an excessive number will be required to deliver the required radiation dose to the target organ. It has been shown that if large numbers of microspheres are administered into the arterial supply of the liver, then they accumulate in and block the small arteries leading to the tumour, rather than distribute evenly in the capillaries and precapillary arterioles of the tumour. Therefore, it is desirable to use the minimum number of microspheres that will provide an even distribution in the vascular network of the tumour circulation.
Similarly if the microspheres or small particles are too dense or heavy, then they will not distribute evenly in the target organ and will accumulate in excessive concentrations in parts of the liver that do not contain the cancer. It has been shown that solid heavy microspheres distribute poorly within the parenchyma of the liver when injected into the arterial supply of the liver. This, in turn, decreases the effective radiation reaching the cancer in the target organ, which decreases the ability of the radioactive microspheres to kill the tumour cells. In contrast, microspheres distribute well within the liver (Burton, M. A. et al.; Selective International Radiation Therapy; Distribution of radiation in the liver.
Europ. J. Cancer Clin. Oncol.
1989, 25:1487-1491).
For radioactive microspheres to be used successfully for the treatment of cancer, the radiation emitted from the microspheres should be of high energy and short range. This ensures that the energy emitted from the microspheres will be deposited into the tissues immediately around the microspheres and not into tissues which are not the target of the radiation treatment. There are many radionuclides that can be incorporated into microspheres that can be used for SIRT. Of particular suitability for use in this form of treatment are the unstable isotopes of yttrium (Y-90) and phosphorous (P-32), although other isotopes such as iodine can also be used. Yttrium-90 is the unstable isotope of yttrium-89 which can be manufactured by placing the stable yttrium-89 in a neutron beam. The yttrium-90 that is generated decays with a half life of 64 hours, while emitting a high energy pure beta radiation.
If the microspheres contain other radioactive substances that are not required for the radiation treatment of the target tissue, then unwanted and deleterious radiation effects may occur. It is therefore desirable to have microspheres of such a composition that they only contain the single desired radionuclide. In this treatment mode, it is desirable to have microspheres that emit high energy but short penetration beta-radiation which will confine the radiation effects to the immediate vicinity of the microspheres. For this purpose, yttrium-90 is the preferred radionuclide.
Therefore, the ideal microspheres for use in this treatment mode will have a low density relative to pure yttria, be in the size range of from 20-80 micron, and be stable so that no material leaches from the microspheres when administered into the body of a human or other mammalian patient.
In the earliest clinical use of yttrium-90-containing microspheres, the yttrium was incorporated into a polymeric matrix that was formulated into microspheres. While these microspheres were of an appropriate density to ensure good distribution characteristics in the liver, there were several instances in which the yttrium-90 leached from the microspheres and caused inappropriate radiation of other tissues.
In one attempt to overcome the problem of leaching, a radioactive microsphere comprising a biologically compatible glass material containing a beta- or gamma-radiation emitting radioisotope such as yttrium-90 distributed throughout the glass, has been developed (International Patent Publication No. WO 86/03124).
There have been several reports of clinical studies on the use of solid glass radioactive microspheres. In one report, ten patients with primary hepatocellular carcinoma were treated, however no patient had a complete or partial response (Shepherd, F. et al.,
Cancer,
Nov. 1, 1992, Vol.70, No.9, pp 2250-2254).
A further development in order to overcome the problem of leaching, was the production of light polymeric ion-exchange microspheres that did not
Baker & Botts L.L.P.
Sirtex Medical Limited
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