AU2013202610A1 - Polymer Based Radionuclide Containing Particulate Material - Google Patents

Abstract

Abstract The invention relates to a particulate material having a diameter in the range of from 5 to 200 microns comprising a polymeric matrix and stably incorporated radionuclide, processes for its production and a method of radiation therapy 5 utilising the particulate material.

Description

P/00/011 28/5/91 Regulation 3.2 AUSTRALIA Patents Act 1990 ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Name of Applicant: Sirtex Medical Limited Actual inventor Bruce Nathaniel Gray Address for service is: WRAY & ASSOCIATES Level 4, The Quadrant I William Street Perth, WA 6000 Attorney code: WR Invention Title: Polymer Based Radionuclide Containing Particulate Material The following statement is a full description of this invention, including the best method of performing it known to me:- 1/2 .POLYMER BASED RAIONUCLIPE CONTAINING PARTICUJLATEh ATERI AL FIELD OF TIHE INVENTION 5 This invention relates to a particulate n-iaterial that composes a polymer, particularly a polymer and a radionuclide., to a riethod for the production thereof, and to methods for the use of this particulate materials In one particular aspect. this invention relates to microspheres which comprise a polymer and a radionuclide such as radioactive yttrium, and to the use of these microspheres in the 10 treatment of cancer in humans and other mammals. The particulate material of this invention is designed to be administered into the arterial blood supply of an organ to be treated, whereby it becomes entrapped in the small, blood vessels of the target organ and irradiates it. An alternate form of administration is to inject the polymer based particulate material directly into the target organ or a solid tumour to be treated. .5 The particulate material of the present invention therefore has utility in the treatment of various forms of'cancer an. rumours, but particularly inthe treatment of primary and secondary cancer of the liver and the brain. It is to be understood that the particulate material of the invention is not limited to radioactive mcrospheres, but may be extended to other radio active polymeric particles which are suitable for use in the treatment methods described 20 herein. BACKGRO UND 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 25 incorporated into sinall particles, seeds, wires and similar related configurations that can be directly implanted into the cancer. Whieu radioactive particles are administered into the blood supply of the target or'an, the technique has become known as Selective Itenal Radiation Therapy (SIRT). Generallydhe main. formi of applicatio-of SIRT-has been-its uscto treatcancers in the liver. There are many potential advantages of SIRT over conventional, external beam radiotherapy. 5 Firstly, the radiation is delivered preferentially to the cancer within the target organ. Scxondly, 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 particles that go to the cancerous part of the organ, as opposed to the healthy normal tissues. This has the effect of 10 preferentially increasing the radiation dose to the cancer while maintaining the radiation dose to the normal tissues at a lower level (Burton, MA. 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 15 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 nicrosiheres or small particles do not distribute evenly, aiid as a function of the absolute arterial blood flow, then they my accumulate in excessive numbers in some areas and cause fbcal areas of excessive radiation. It has been shown that microspheres of approximately 25-50 micron in diameter 20 have the best distribution characteristics when administered into the arterial circulation of the liver (Meade, V. et at; Distribution of different sized microspheres in experimental hepatic tumours. Europ. J, Cancer & Clin. Oncol 1987, 23:23-41). If the particles are too dense or heavy, then they will not distribute evenly in the target organ and will accumulated in excessive concentrations in areas that do not contain the cancer. It has 25 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 miicrospheres to kill the tumour cells. In contrast, lighter microspheres with a specific gravity Radiation Therapy; Distribution of radiation in the liver. Europl Cancer Clin, Oncol. 19S9, 25:1487-1491). For radioactive particulate material to be used successfilly for the treatment of cancer, the radiation emitted should be of high energy and short range. This ensures that the energy 5 emitted will be deposited into the tissues innediately around the particulate material and not into tissues which are not the target of the radiation treatment. In this treatment maode., it is desirable to have high energy but short penetration beta-radiation which will confmne the radiation effects to the immediate vicinity of the particulate material. There are many radionuclides that can be incorporated into microspheres that can be used for SIRT. Of 10 particular suitability for use in this form of treatment is the unstable isotope of yttrium (Y-90), Yttriur-90 decays with a half life of 64 hours, while emitting a high energy pure beta radiation. However, other radionuclides may also be used in place of yttrium-90 of which the isotopes of holmium, samariunm, iodine, iridium, phosphoius, rhenium are some examples. Ceramic particles have been produced that are either coated with or contain radionuclides. 15 However, the presence of other radioactive substances that are not required for the radiation treatment of the target tissue, has then unwanted and deleterious radiation effects may occur. It is therefore desirable to have particul ate material of such a composition that it only contains the single desired radionuclide. In the earliest clinical use of yttriuxn-90 containing microspheres, the yttriui w as incorporated 20 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. Attempts to incorporate other radionuclides such as hohniurm into resin or polymer based materials have resulted in leaching of the radioruicide 25 and this has resulted in severe conseqences for the patients that have been treated with the product. 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 yttcnn-90 distributed throughout the glass, has been developed (Intemational Patent Publication No. WO 86/03124). These microspheres are solid glass and contain the element vttrium-89 that can be activated to the radionclide yttrium-90 by placing the microspheres in a neutron beam. These glass microspheres have several disadvantages 5 including being of a higher specific gravity than is desirable and containing other elements such as almina and silica which are activated to undesirable radionuclides when placed in a neutron beam. Another approach has been focussed on the use of small hollow or cup-shaped ceramic particles or microspheres, wherein the ceramic base material consists or comprises yttria or 10 the like (International Patent Publication. No. WO 95/19841). These inicrospheres were developed to overcome the problem of high density associated with the solid glass microspheres described in International Patent Publication No. W086/03124. SUMMARY OF THE INVENTION 15 In on-te aspect the present invention provides a articulate material having a diameter in the ranC of from 5 to 200 microns comprising a polymeric matrix and a stably incorporated radionuclide. In another aspect, the invention provides a process for the production of a particulate material having a diameter in. the range of from 5 to 200 microns comprising the step of combining a 20 polyneric matrix and a radionuclide for a time and under conditions sufficient to stably incorporate the radionuclide in. the matrix to produce a particulate material having a diameter in the range of from 5 to 200 microns. hi another aspect, the present invention provides a method of radiation therapy of a patient, which comprises administration to the patient of a particulate material having a diameter in 25 the range of from 5 to 200 microns comprising a polymeric matrix and a stably incorporated radionuclide.

The present nvention also provides fbr the use of particulate material having a diameter in the range of from 5 to 200 microns composing a polyrneric matrix and a stably incorporated radionuclide in the radiation therapy of a patient 5 DETAILE) DES(RIPT'fION OFTHE INVENTION As used herein, references to the radionuclide being stably incorporated into particulate material or polymeric matrix are to be understood as referring to incorporation of the radionuclide so that it does not substantially leach out of the particulate material under physiological conditions such as in the patient or in storage. In a preferred embodiment the 10 radionuclide is incorporated by precipitation into a polymeric matrix, The leaching of radionuclides from the polymeric matrix can cause non-specific radiation of the patient and damage surrounding tissue. Preferably the amount of leaching is less than 5%, more preferably less than 4%, 3%, 2%, 1% or 0.4%. One method of assessing leaching is by adjusting a sample to pH 7.0 and agitating in a water bath at 37c(" for 20 minutes, A 100 ptL 15 sample is counted for beta emission in a Geiger-IMIuller counter. Another representative 100 PL sample is filtered through a 0,22 gn filter and the filtrate counted for beta emission in the ieiger-M.uller counter. The per cent unbound radionuclide is calculated by: Fia-e (7w I 0=% UinboundRdinclide SamIpleCount The radionuclide can be. stably incorporated into the polymeric matrix by precipitating it as an 20 insoluble salt. Where the radionuclide used is yttrium-90 the yttrium is preferably precipitated as a phosphate salt. However the present invention also extends to precipitation of the radionuclide as other insohible salts including, for example, carbonate and bicarbonate salts. The radionuclide which is incorporated into the polymeric matrix in accordance with the present invention is preferably yttrium--90, but may also be any other suitable radionuclide 25 which can be precipitated in solution, of which the isotopes of holnmium, samarium, iodine, phosphorous, iridium and rhenium are some examples.

In a preferred embodiment the particulate rnaterial is a microsphere. The terrn microsphere is used in this specification as an example of a particulate material, it is not intended to limit the invention to mnicrospneres, as the person skilled in the art will appreciate that the shape of the particulate material while preferably without sharp edges or points that could damage the 5 patients arteries or catch in unintended locations, is not limited to spheres. Nor should the term microsphere be limited to spheres. Preferably the particulate material is substantially spherical. but need not be regular or symmetrical in shape. In a preferred embodiment the polyen.ric iatrix is partially cross linked. Preferably there is about 1% to about 20% cross link ing, preferably about 2% to 10% cross linking and more 10 preferably about 4% cross linking. in particular, the present invention provides a particulate material as described above in which the polymeric matrix is an ton exchange resil, particularly a cation exchange resin. Preferably the ion exchange resin comprises a partially cross linked aliphatic polymer, including polystyrene. One particularly preferred cation exchange resin is the styrene/divinylbenzene 15 copolymer resin commercially available under the trade name Aminex 50W-X4 (Biorad, Hercules, CA). However, there are many other commercially available cation exchange resins which are suitable. 'When 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 20 distribution within the target organ. If the small particles do not distribute evenly then they may accumulate in excessive numbers in some areas and cause focal areas oi excessive radiation. The particulate material is preferably low density, more particularly a density below 3.0 g/cc, even more preferably below 2,8g/cc, 2.5g/cc, 2.3g/cc, 2.2g/cc or 2.0 g/cc. The ideal particle for infection into- the-blood stream would have a very narrow size range with a SD of 25 less than 5%, so as to assist in even distribution of the microspheres within the target organ, particularly within the liver and would. be sized in the range 5-200 micron preferably 15-100 micron and preferably 20-50 micron, and most preferably 30-35 micron. It is also desirable to have the particulate material ianuffactured so that the suspending solution has a pH less than 9. If the pH is greater than 9 then this may result i irritation of the blood vessels when the suspension is injected into the artery or target organ Pree.-rably the pF is less than 8.5 or 8.0 and more preferably less than 7.5. The present invention particularly provides a method for the production of a radioactive 5 particulate material comprising a polymeric matrix as described above, characterised by the steps of: (i) absorbing a radionuclide onto an ion-exchange resin particulate material having a diameter in the range of 20 to 50 microns and a specific gravity of less than 2.5; and (ii) precipitating the radionuclide as an insoluble salt to stably incorporate the radionuclide 10 into the particulate material. In a preferred embodiment, the method of the present invention is carried out by firstly irradiating yttria yttriumm oxide) in a neutron beam to activate yttria to the isotope yttriu-i90. The yttrium-90 oxide is then solubilised, for example as yttriuma-90 sulphate solution. The ion exchange resin is preferably provided in the form of an aqueous slurry of microspheres of 15 ion exchange resin, having a particle size 30 to 35 microns, and the yttrium-90 sulphate solution is added to the slurry to absorb the yttriumr-90 into the ion exchange resin inicrospheres. Subsequently, the yttrium-90 is precipitated as a phosphate salt, for example by addition of tri-sodiunm phosphate solution, to stably incorporate the yttriurn-90 into the niicrospheres The particulate material may be combined with a solution of the radionuelide 20 or the salt of the radionuclide may be combined with the particulate matter, in a solution suitable for sohibilising the radionuclide. Alternate sources of yttrim-90 may be used in the production of these microspheres, For example, a highly pure source of yttrium-90 may be obtained by extracting yttrium-90 from a parent nuclide and using this extracted yttriurn-90 as the source of the soluble yttrium salt 25 that is then incorporated into the polymeric matrix of the microspheres. In order to decrease the pH of the suspension containing the microspheres for injection into patients the microspheres may be washed to remove any un-precipitated or loosely adherent radionuclide, The present invention provides a suspension of the required pH by precipitating the yttrium with a tri-sodium phosphate solution at a concentration containing at least a three fbd excess of phosphate ion, but not exceeding a 30-fold excess of phosphate ion, and then washing the. microspheres with de-i onised water, Another approach which ensures that the pl 5 of the microsphere suspension is in the desired range is to wash the resin with a phosphate buffer solution of the desired pH. The present invention also provides a method of radiation therapy of a human or other manmnalian patient that comprises administration to the patient of particulate material as described above. The person skilled in the art will appreciate the administration may be by any L0 suitable means and preferably by delivery to the relevant artery For example in treating liver cancer, administration is preferably by laparotomy to expose the hepatic artery or by insertion of a catheter into the hepatic artery via the femoral, or brachial artery. Pre or co-administration of another agent may prepare the turnour for receipt of the articulate material, for example a vasioactive substance, such as angiotension-2 to redirect arteiial blood flow into the tumour. 15 Delivery of the particulate matter may be by single or nmiultiple doses, until the desired level of radiation is reached. Throughout this specification, unless the context requires otherwise, the word "comprise", and or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any ofher 20 integer or step or group of integers or steps. Further features of the present invention are more fully described in the following Examples. It is to be understood, however, that this detailed description is included solely for the purposes of exemplifying the present invention, and should not be understood in any way as a restriction on the broad description of the invention as set out above, 23 EXAMPI. 1 Ytrium (90Y) labelled microspheres are made in the for of a sterile, pyrog-n free suspension -9 of resin beads labelled with yttrium (90Y) phosphate. The resin beads consist of sulphuric acid groups attached to a styrene divinvlbenzene copolyier lattice, Yttrium oxide is irradiated to produce yttriunm-90 from the nuclear reaction Y-89 (ni, 7) Y-90. Yttriun-90 has a half life of 64 hours. The yttrium (90Y) oxide is then dissolved in 0.1M sulphuric acid with gentle heating and stirring to form a clear, colorless solution of yttrium (90Y) sulphate. Symmetrical microspheres of ion exchange resin (Aminex 50W-X4 cation exchange resin; supplied by 'Bio-Rad Cat # 147431 3 F) with a diameter of approximately 30 to 35 microns are added to water (Water for Injections BP) to forn a shuvy that is then transferred into a reaction 10 vessel. Yttrium (90Y) sulphate solution is added to the reaction vessel and the mixture stirred at a speed sufficient to ensure homogeneity to absorb the yttrium (90Y) solution into the resin based microspheres. Tri-sodium phosphate solution (1.25% w/v) is then added to the reaction vessel with further stirring to precipitate the radionuclide as yttrium (90Y) phosphate. The microspheres are then washed with a phosphate buffer solution until the pH- of the wash 15 solution is less than 9 and preferable less than 8.5. Following washing of the microspheres with water (Water for hIjection BP), the niicrospheres are resuspended and diluted (if necessary) with water (Water for Injections BP) to give a light brown suspensiort having an activity of 3000 NBq 0 10%. The resin-based yttrium microspheres produced by the above method have 0.01 -0.4% urbound 20 or unprecipitated 90Y when tested in the following leaching test: A 5 .L sample is diluted with water to 5 nL, adjusted to pH 7.0 and agitated in a water bath at 37"C for 20 minutes. A 100 p.L sample is counted for beta emission in a Geiger-MuI111er counter. Another representative 100 pL, sample is filtered through a 0.22 pm filter and the filitrate counted for beta emission in the Geiger-Muller counter. The per cent unbound 90Y 25 is calculated by: Fi-trateCoun --- <- ... 0 0 .;,- I,-u Unh)oiwY -10 IEXAMP iE 2 The effect of phosphate con centration in the precipitation solution, and the effects of washing with phosphate buffer on the pH of a rmicrosphere suspension are shown in the attached Figure 5 1 which sets out the results of a number of experiments. EXAMPLE 3 The technique of Selective Intemal Radiation Therapy (SIRT) has been described above. It involves either a laparotomy to expose the hepatic arterial circulation or the insertion of a catheter into the hepatic artery via the fermoral, brachial or other suitable artery. This may be 10 followed by the infusion of Angiotensin-2 into the hepatic artery to redirect arterial blood to flow into the ietastatic tumour component of the liver and away from the nonnal parenchyma. This is followed by embolisation of resin based yttrium-90 containing microspheres (produced in accordance with Example 1) into the arterial circulation so that they become lodged in the microcirculation of the tumour. Repeated injections of microspheres are made until the 15 desired radiation level in the nominal liver parenchyma is reached. By way of example, an amount of yttriumu-90 activity that will result in an infered radiation dose to the normal liver of approximately 80 Gy nmay be delivered. Because the radiation from SIRT is delivered as a series of discrete point sources, the dose of 80 Gy is an average dose with nany normal liver parenchymal cells receiving nmuch less than that dose. 20 The measurement of turnour response by objective parameters including reduction in tumour volume and serial estimations of serum carcino-embryonic antigen (CIJEA) levels, is an acceptable index of the ability of the treatment to alter the biological behaviour of the tumour

Claims (16)

1. A particulate material having a diameter in the range of from 5 to 200 microns comprising a polymneric matrix and stably incorporated radionuclide. 2, The particulate material according to claim I wherein the radionuclide is incorporated by precipitation,

3. The particulate material according to claim I wherein the polymeric matinx is parti ally cross linked, 4, The particulate material according to claim 3 wherein the polymeric matrix conpises from about 1% to about 20% cross linking

5. The particulate material according to claim 4 vherein the polymeric matrix conmrises about 4% cross linking.

6. The particulate material according to claim 1 wherein the polymeric matrix is an ion exchange resin. 'The particulate material according to claim 6 wherein the polymeric matrix is a cation exchanwe resin.

8. The particulate material according to claim 6 wherein the ion exchange resin comrises a partially cross Iinkied aliphatic polymer.

9. The particulate material according to claim 6 wherein the ion exchange resin comprises a partially cross linked polystyTene.

10. The particulate material according to claim 9 wherein the ion exchange resin comprises polystyrene partially cross linked with divinyl benzene, it The particulate material according to claim 1, wherein the radionuclide is anr. isotope of yttrium, holmium, samarium, iodine, phosphorus, iridiumi or rhenium. -12~ 12, The particulate material according to claim 1, wherein the radionuclide is yttrmin-90.

13. The particulate material according to clain 1 being amicrosphere.

14. A particulate material having, a diarneter in the range of from 30 to 35 microns comriprising a copolymer comprised of styrene and divinyl benzene and precipitated ytirium-90

15. A process for the production of a particulate material according to claim I comprising the step of combining a polymeric matrix and a radionuclide in solution for a time and under conditions sufficient to stably incorporate the radionuclide in the matrix to produce a particulate material having a diameter in the range of from 5 to 200 microns.

16. A process according to claim 15 wherein the radionuclide is stably incorporated by precipitation into the polymeric matrix.

17. A process according to claim 15 wherein the radionuclide is yttriui-90.

18. A method of radiation therapy of a patient, which comprises administration to the patient of a particuliate material having a diameter in the range of from 5 to 200 microns comprsig a polymeric matrix and a stably incorporated radionuclide, 19 A method according to claim 18 wherein the radionuclide is yttrium-90. 20 A method according to claim 18 wherein the radiation therapy comprises treatment of a primary or secondary liver cancer.

21. Use of particulate material having a diameter in the range of from 5 to 200 microns comprising a polymeric matrix and a stably incorporated radionuclide in radiation therapy of a patient.

22. Use according to claim 21 wherein the radioumclide is yttrium-.90,

23. Use according to claim 21 wherein the radiation therapy comprises treatment of a primary or secondary liver cancer.