Low-density magnesia-alumina-silica (MAS) microparticles for radiotherapy and/or radioimaging

Abstract

This invention relates to low density radioactive magnesium-aluminum-silicate (MAS) microparticles for radiotherapy and/or radioimaging.

Claims

1. Microparticles for radio-imaging or radiation therapy in a mammal, comprising biologically compatible magnesia-alumina-silica glass microparticles, said microparticles containing at least one beta or gamma radiation emitting isotope distributed substantially throughout the magnesia-alumina-silica glass which emits an amount of beta or gamma radiation, the microparticles having a chemical durability such that subsequent to administration of the microparticles to the mammal, the microparticles will not release a significant amount of the radioisotope into the mammal's system wherein the glass microparticles comprise approximately 8-14 wt % MgO, 32-35 wt % Al.sub.2O.sub.3, and 47-52 wt % SiO.sub.2.

2. The microparticles of claim 1, wherein the microparticles have a density of about 3.0 g/ml or less.

3. The microparticles of claim 1 having a size range from about 20 to 200 um.

4. The microparticles of claim 2 having a size range from about 20 to 200 um.

5. The microparticles of claim 1 having a density of about 2.8.

6. The microparticles of claim 1 wherein the microparticles are microspheres.

7. The microparticles of claim 1 wherein the microparticles contain gallium-68 or fluorine-18 distributed substantially throughout the magnesia-alumina-silica glass.

8. A method of administering radioactive magnesia-alumina-silica glass microparticles to a patient in need thereof, comprising delivering by catheter to an artery that feeds an organ or a tumor of a patient a composition comprising the radioactive microparticles of claim 1, and a physiologically acceptable carrier.

9. The method according to claim 8 wherein the glass microparticles contain gallium-68 or fluorine-18 distributed substantially throughout the microparticles.

10. The method according to claim 8 wherein the microparticles have a density of about 3.0 g/ml or less.

11. The method according to claim 8 wherein the microparticles have a size ranging from about 20 to 200 um.

12. The method according to claim 10 wherein the microparticles have a size ranging from about 20 to 200 um.

13. The method of claim 8 wherein the microparticles are microspheres.

14. The method of claim 8, wherein the organ or tumor is selected from the group consisting of liver, spleen, brain, kidney, head & neck, uterine, and prostate.

15. A method of obtaining a radiologic image of an organ or tumor in a patient, comprising administering by catheter to an artery that feeds an organ or tumor of a patient a composition containing magnesium-alumina-silicate glass microparticles according to claim 1 in a physiologically acceptable carrier, and obtaining the radiologic image of the patient's organ or tumor.

16. The method of claim 15, further comprising wherein the radionuclide imaging technique is single photon emission computed tomography (SPECT).

17. The method according to claim 16 wherein the glass microparticles comprise gallium-68 or fluorine-18 distributed substantially throughout the microparticles.

18. The microparticles of claim 1 wherein the at least one beta or gamma radiation emitting radioisotope is Dysprosium-165.

19. The microparticles of claim 1 wherein the at least one beta or gamma radiation emitting radioisotope is Samarium-153.

20. The microparticles of claim 1 wherein the at least one beta or gamma radiation emitting radioisotope is Yttrrium-90.

21. The microparticles of claim 1 wherein the microparticles are microspheres having a particle size of from about 5 to about 75 micrometers.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) In accordance with the present invention, novel low density MAS microspheres and methods have been devised for use in the therapy and/or imaging of certain cancers and tumor bearing tissue. The invention contemplates a glass material having a stable element which can be activated by neutron irradiation to produce a beta or gamma radiation emitting isotope distributed substantially uniformly throughout the glass. Thus, these novel low density microspheres may be manufactured and sized before radioactivity is induced, thereby avoiding the necessity of either bonding a radioelement onto the microsphere surface, or adding radioisotopes to a high temperature melt and spheroidizing and sizing the particles while intensely radioactive.

(2) Mas Glass

(3) In a preferred embodiment, the microparticle is manufactured from a Magnesia-Alumina-Silicate-type glass. In a preferred aspect, the magnesia-alumina-silica glass core has the approximate weight percent ranges of magnesia-alumina-silica comprising: MgO 8-14%; Al.sub.2O.sub.3 32-35%; and SiO.sub.2 47-52%.

(4) Cordierite, a magnesium aluminosilicate, is known for it's excellent thermal properties in industrial applications, and has also been reported to be useful as an antacid when administered as a fine powder, creating a gel-like coating and decomposing safely into magnesium products. Cordierite's chemical composition has been reported as MgO 8-14%; Al.sub.2O.sub.3 32-35%; SiO.sub.2 47-52%; sometimes FeO 0-9%; K.sub.2O 0.02-0.12%; Na.sub.2O 0.9-0.14%. As contemplated herein, the MAS glass will be substantially devoid of impurities.

(5) Manufacture of Microspheres

(6) The microspheres of the present invention may be prepared from a homogenous mixture of powders (i.e., the batch) that is melted to form the desired glass composition. The exact chemical compounds or raw materials used for the batch are not critical so long as they provide the necessary oxides in the correct proportion for the melt composition being prepared. For instance, if a SmY-MAS glass is being made, then samaria, yttria, magnesia, alumina, and silica powders could be used as the batch raw materials. The purity of each raw material is preferably greater than 99.9%. Note that the raw materials must be free of any neutron activatable impurities that would produce undesirable radiation.

(7) After either dry or wet mixing of the powders to achieve a homogeneous mixture, the mixture may be placed in a platinum crucible for melting. The crucibles containing the powdered batch are then placed in an electric furnace which is heated 1400.degree. to 1600.degree. C., depending upon the composition. In this temperature range, the batch melts to form a liquid which is stirred several times to improve its chemical homogeneity. The melt should remain at 1400.degree. to 1600.degree. C. till all solid material in the batch is totally dissolved, usually 2-8 hours being sufficient. When melting and stirring is complete, the crucible is removed from the furnace and the melt is quickly quenched by pouring the melt onto a cold steel plate or into clean water. This procedure breaks the glass into fragments, which aids and simplifies crushing the glass to a fine powder. The powder is then sized and spheroidized for use.

(8) Microsphere Size

(9) The microspheres of the present invention may be processed to have a size that is appropriate for the therapeutic application. The characteristics of the tissue in which the microspheres will be embedded generally dictate the appropriate size of the microspheres to be employed. Generally, microspheres having a size somewhere within the range of about 20 to 200 micrometers, or in other embodiments from about 5 to about 75 micrometers, are employed for therapeutic applications. In many cases it is preferred that the microspheres have a size somewhere within the range of about 5 to about 50 micrometers. For instance, in the treatment of liver cancer, it is preferred to employ microspheres having a size substantially within the range of about 20 to about 40 micrometers, more preferably 25-38 micrometers; microspheres of this size are small enough to be conveniently delivered to the liver through the hepatic artery but are too large to pass through the capillary bed of the liver.

(10) Where it is desired to use microspheres having a diameter in the range of about 20 to about 40 micrometers, and preferably about 25-38 micrometers, as for example in the treatment of liver cancer, it is preferred that the quenched and broken glass be first crushed to about minus 100 mesh particles using a mortar and pestle. The minus 100 mesh material is then ground using a mechanized mortar and pestle or ball mill, until it passes a 400 mesh sieve.

(11) Spheroidizing

(12) The particles are formed into glass microspheres by introducing the 400 mesh particles into a gas/oxygen flame where they are melted and a spherical liquid droplet is formed by surface tension. The droplets are rapidly cooled before they touch any solid object so that, their spherical shape is retained in the solid product.

(13) Just prior to spheroidizing, the 400 mesh powder is rescreened through a 400 mesh sieve to destroy any large agglomerates that may have formed during storage. The 400 mesh powder is then placed in a vibratory feeder located above the gas/oxygen burner. The powder is slowly vibrated into a vertical ceramic tube which guides the falling powder particles directly into the hot flame of a gas/oxygen burner. Any burner capable of melting 400 mesh particles of the particular glass composition being used is satisfactory. A typical rate for feeding the powder to the flame is 5 to 25 gm/hr with the described apparatus. The flame of the burner is directed into a metal container which catches the small glass beads as they are expelled from the flame. This container can be made of any metal which can withstand the heat of the burner and does not contaminate the glass. The container needs to be large enough so that the molten spheres can cool and become rigid before hitting any solid surface of the catcher container.

(14) Screening

(15) After spheroidization, the glass spheres are collected and rescreened. When the microspheres are intended to be used in the treatment of liver cancer, the fraction less than 30 and greater than 20 micrometers in diameter is recovered since this is the desirable size for use in the human liver. After screening, the 30/+20 microspheres are examined with an optical microscope and are then washed with a weak acid (HCl, for example), filtered, and washed several times with reagent grade acetone. The washed spheres are then heated in a furnace in air to 500.degree.-600.degree. C. for 2-6 hours to destroy any organic material.

(16) The final step is to examine a representative sample of the 30/+20 spheres in a scanning electron microscope to evaluate the size range and shape of the spheres. The quantity of undersize spheres (less than 10 micrometers in diameter) is determined along with the concentration of non-spherical particles. The composition of the spheres can be checked by energy dispersive x-ray analysis to confirm that the composition is correct and that there is an absence of chemical contamination. The glass microspheres are then ready for irradiation and subsequent administration to the patient.

(17) It is preferred that the microspheres be substantially spherical, i.e., there are no sharp edges or points that would cause the microsphere to lodge in a location other than that desired. In this context, elipsoidal and other similarly shaped particles that do not have sharp edges or points would be considered to be substantially spherical in shape. It is also preferred that the microparticles have a solid glass matrix throughout, and are not shells, e.g. microspheres containing a large gas bubble. It is preferred that solid microparticles are more robust, durable, and capable of withstanding radionuclide activation.

(18) In accordance with the present invention, the above processing steps are merely exemplary and do not in any way limit the present invention. Similarly, the present invention is not limited to glass microspheres having a size described above; the size of the microspheres of the present invention may be varied according to the application.

(19) Surface Area, Density

(20) The magnesium aluminosilicate microspheres of the present invention are particularly useful because they have a large surface area, pore structure, and low density. Generally, solid glass microspheres 25 to 20 microns in diameter will have a surface area of 30 m.sup.2/g to 50 m.sup.2/g. In one embodiment, it is contemplated that the microspheres of the present invention have a median surface area of at least 30 m.sup.2/g. In one embodiment, it is contemplated that the microspheres of the present invention have a median surface area of at least 50 m.sup.2/g. In another embodiment, it is contemplated that microspheres have a median surface area of at least 100 m.sup.2/g. In yet another embodiment, microspheres having a median surface area between about 50 and about 200 m.sup.2/g are contemplated as within the scope of the invention.

(21) It is contemplated as within the scope of the invention that the microspheres may be manufactured to have a density that is significantly lower than the 5 g/ml of prior art Yttrium microparticles. In this case, the microparticles of the present invention will preferably have density of 3.0 g/ml or less while maintaining the ability to deliver appropriately high levels of radiation to tissue. In one preferred embodiment, the present invention contemplates microparticles having a size range from about 25-38 um, a density of 3.0 or less, e.g. 2.8 g/ml, and either a .sup.177Lu (Lutetium-177) specific activity of 32 mCi per 10.sup.7 microparticles for imaging, a .sup.90y (Yttrium-90) specific activity of 162 mCi per 10.sup.7 microparticles for therapy, a .sup.153Sm (Samarium-153) specific activity of 12 mCi per 250,000 microparticles for imaging, or combinations of Lutetium-Yttrium, Samarium-Yttrium.

(22) Radioisotopes

(23) In a preferred embodiment of the present invention, the constituent elements of the microspheres are chosen so that when administered to the patient, the microspheres may emit a therapeutic and/or diagnostic intensity and amount of radiation but will not emit a significant amount of unwanted beta or gamma radiation which could have a negative impact on healthy tissue surrounding the cancerous or tumor bearing tissue. In this regard, it is preferred that the constituent elements are MAS-samarium-yttrium, MAS-samarium, and MAS-lutetium.

(24) Diagnostic and/or Therapeutic

(25) In a preferred embodiment of the present invention, the radioisotopes/radionuclides are chosen so that when administered to the patient, the microparticles may emit either diagnostic radiation, therapeutic gamma radiation, or both. Although often many gamma emitters are diagnostic and beta emitters may be therapeutic, this is not necessarily always the case. Accordingly, it is within the scope of the invention to include any radioisotope that may provide diagnostic, therapeutic, or both types of functionality.

(26) The therapeutic radioisotope is chosen to deliver a therapeutic intensity and therapeutic amount of short-range radiation (e.g., a penetration of the tissue on the order of about several millimeters or less) but does not emit a significant amount of unwanted radiation which could have a negative impact on healthy tissue surrounding the cancerous or tumor bearing tissue.

(27) The diagnostic radioisotope is chosen to deliver a diagnostic intensity and diagnostic amount of longer-range radiation (e.g., capable of external detection) but does not emit a significant amount of unwanted radiation.

(28) Patient data such as age, gender, weight, and pre-existing conditions are considered when determining a radiotherapeutic and/or radiodiagnostic profile. Cancer data such as tumor size, tumor type, tumor location, degree of surgical intervention and success, vascular structures within and adjacent to the area being treated, and organ involvement are also considered when determining a radiotherapeutic and/or radiodiagnostic profile.

(29) The radioisotope Yttrium-90, which has a half-life greater than about two days and less than about 30 days is one particularly preferred therapeutic radioisotope which emits therapeutic beta radiation.

(30) For radioimaging, i.e. diagnostic, the radioisotopes Lutetium-177 (177-Lu) is particularly preferred.

(31) The present invention includes wherein the radioisotope is radiopharmaceutical grade and is selected from the group consisting essentially of, but not limited to: Actinium-225, Antimony-127, Arsenic-74, Barium-140, Bismuth-210, Californium-246, Calcium-46, Calcium-47, Carbon-11 Carbon-14, Cesium-131, Cesium-137, Chromium-51, Cobalt-57, Cobalt-58, Cobalt-60, Dysprosium-165, Erbium-169, Fluorine-18, Gallium-67, Gallium-68, Gold-198, Hydrogen-3, Indium-111, Indium-113m, Iodine-123, Iodine-125, Iodine-131 Diagnostic, Iodine-131 Therapeutic, Iridium-192, Iron-59, Iron-82, Krypton-81m, Lanthanum-140, Lutetium-177, Molybdenum-99, Nitrogen-13, Oxygen-15, Paladium-103, Phosphorus-32, Radon-222, Radium-224, Rhenium-186, Rhenium-188, Rb-82, Samarium-153, Selenium-75, Sodium-22, Sodium-24, Strontium-89, Thallium-201, Xenon-127, Xenon-133, Yttrium-90, and combinations, and mixtures thereof.

(32) Where combinations of radioisotopes are used with the microparticles or combinations of MAS microparticles with other microparticles are used to obtain a combination of radioisotopes, preferred combinations of radioisotopes include having one or more beta emitters along with one or more gamma emitters. Examples include but are not limited to Y-90/In-111, Y-90/Tc-99m, P-32/In-111, P-32/Tc-99m, Ho-166/In-111, Ho-166/Tc-99m, Sm-153/1n-111, and Sm-153/Tc-99m.

(33) Particularly preferred radioisotopes include Indium-111 (radiodiagnostic gamma emitters), Lutetium-177 (being both a beta and gamma emitter), and Samarium-153 and Yttrium-90 (radiotherapeutic beta emitters).Radioisotopes have been used for imaging and function studies of the brain, myocardium, thyroid, lungs, liver, gallbladder, kidneys, bone, blood, and tumors. Indium-111 pentetreotide has been used in imaging of neuroendocrine tumors that overexpress somatostatin receptors and has become standard for localization of these tumors. This radioligand is internalized into the cell and can induce receptor-specific cytotoxicity by emission of Auger electrons. Lutetium-177 having both gamma and beta properties enables its use in imaging as well as treatment. It has a shorter radius of penetration that Y-90 which makes it an ideal candidate for radiotherapy of small tumors. Samarium-153 lexidronam (chemical name Samarium-153-ethylene diamine tetramethylene phosphonate, abbreviated Samarium-153 EDTMP, trade name Quadramet) is a complex of a radioisotope of the lanthanide element samarium with the chelator EDTMP. It has been used to treat cancer pain when cancer has spread to the bone. Once injected into a vein, it distributes throughout the body and localizes in areas where cancer has invaded the bone, allowing the beta particles (electrons) to destroy the nearby cancer cells. It is also commonly used in lung cancer, prostate cancer, breast cancer, and osteosarcoma. Yttrium-90 has been used in the treatment of various cancers including lymphoma, leukemia, ovarian, colorectal, pancreatic, and bone cancers, and in treatment of rheumatoid arthritis by radionuclide synovectomy.

(34) Although an attempt is made to provide an exhaustive list, it is well-known to nuclear medicine specialists that radioisotopes may be produced using a generator system, a thermal neutron reactor, a cyclotron, or fission produced. Accordingly, any radioisotopes with functional equivalents to those listed are intended to be encompassed wherever appropriate within the scope of the present invention.

(35) Tailoring Radioactivity

(36) The radiation dosage delivered through the use of the neutron activated microparticles upon administration to the patient can be varied by controlling the number of microparticles administered and by controlling the amount of radiation emitting isotope contained by the microparticles. The amount of radiation emitting radioisotope contained by the microparticles is affected by two factors: the amount of the neutron activatable isotope that will be converted to a radioisotope by irradiation, and the length of time of irradiation.

(37) Types of Cancers

(38) The microparticles of the present invention may be used in a variety of clinical situations, including but not limited to: selective internal radiation therapy for tumors of areas that have favorable vasculature, including the liver, spleen, brain, kidney, head & neck, uterine, and prostate. The microparticles may also be used for imaging, including a Liver/Spleen Scan-for tumors, cysts or hepatocellular disease; a Brain Scan-for tumors, trauma, or dementia; a Tumor Scan for malignant tumors or metastatic disease of the Kidney, Head & Neck, Uterine/Gynecological; and any Scan or Therapy having favorable vasculature for this approach.

(39) One radionuclide imaging technique contemplated as within the scope of the invention is single photon emission computed tomography (SPECT).

(40) Since most organs, besides the liver, have only one blood vessel that feeds it, administration may be performed by delivery to that main feeder artery and allowing the microparticles to lodge in the capillary bed since they are too large to move through the capillary. The liver may require a specialized delivery regimen, as exemplified below. In another embodiment, the vessel that feeds the tumor may be identified, and this artery is used to deliver the microparticles.

(41) Delivery

(42) The microspheres may be administered to the patient through the use of catheters either alone or in combination with vasoconstricting agents or by any other means of administration that effectively causes the microspheres to become embedded in the cancerous or tumor bearing tissue. For purposes of administration, the microspheres are preferably suspended in a medium that has a sufficient density or viscosity that prevents the microspheres from settling out of suspension during the administration procedure. Presently preferred liquid vehicles for suspension of the microspheres include polyvinylpyrrolidone (PVP), sold under the trade designation Plasdone K-30 and Povidone by GAF Corp, a contrast media sold under the trade designation Metrizamide by Nyegard & Co. of Oslo, Norway, a contrast media sold under the trade designation Renografin 76 by E. R. Squibb & Co., 50% dextrose solutions and saline.

(43) Treatment and/or Imaging of Liver Cancer

(44) The microspheres of the present invention may be used in the treatment and/or imaging of liver cancer by introducing a catheter into the hepatic artery and administering the radioactive microspheres. Preferably, the microspheres are suspended in a medium such as Plasdone K-30 or Metrizamide for purposes of administration. The particle density in the liver after administration is preferably optimized for treatment, imaging or both, depending on the medical isotope used. When administered in this manner, the microspheres become embedded in the capillary bed of the tumorous liver tissue rather than in normal liver, thereby delivering the radiation dosage primarily to the tumor. Vasoconstricting drugs may additionally be used to decrease hepatic artery flow to normal liver. Microspheres used in this treatment preferably comprise Y-90 because of their short-ranged radiation.

(45) Throughout this text, the term therapy and/or treatment means any effect which mitigates any damage or any medical disorder, to any extent, and includes treatment of damage itself as well as the control of damage. The term treatment means any amelioration of disorder, disease, syndrome, condition, pain or a combination of one or more thereof. Treatment of cancer refers to killing cancer cells.

(46) Radioactivity

(47) In accordance with a preferred embodiment, glass microspheres having a specific composition may have an activity of about 0.2 to about 0.6 Ci/gm of glass after irradiation. To achieve the desired level of activity, the microspheres are irradiated for an effective period. For instance, microspheres comprising about 40% by weight Y.sub.2O.sub.3 are irradiated in a nuclear reactor to a level of about 3 Ci/gm which requires about 75 hours of irradiation at 110.sup.14 neutrons/cm.sup.2 sec. Thus, by activating the microspheres to a level above the preferred administration range, decay of activity of the activated microspheres may occur during processing and shipment prior to administration to the patient and still permit administration within the preferred range of activity. If a glass microsphere containing Y-90 were used for the treatment of liver cancer, the specific activity required through irradiation would provide a half-life of 64 hours for Y-90, which defines the decay during transit and the time it remains active in the body.

(48) The following non-limiting example(s) merely helps to further illustrate the invention.

EXAMPLE 1

(49) A. Microsphere Preparation

(50) The glass compositions were prepared from reagent grade chemicals. Batches yielding 50 grams of glass were melted in platinum crucibles in an electric furnace at an appropriate temperature. A typical melting cycle required three hours for batch additions at 1000 degree C. (aluminosilicate) to 1500 degree C. (MAS glass) and three to four hours to refine the melt at the approximate melting temperature. The crucible containing the melt was quenched in 25.degree.C. water, after which the resultant glass fit was broken from the crucible and ground to 100 mesh. The 100 mesh glass powder was then slowly fed by a vibrating spatula into an oxygen/propane flame where surface tension pulled the molten particles into spheres. The flow rates of oxygen and propane were adjusted for each glass composition so as to yield the highest fraction of spherical particles. After spheroidizing, the microspheres were wet screened with deionized water, rinsed in acetone and dried.

(51) As various changes could be made in the above methods and products, without departing from the scope of the invention, it is intended that all matter contained in the above description or shown in any accompanying drawings shall be interpreted as illustrative and not in a limiting sense.

(52) Any references recited herein are incorporated herein in their entirety, particularly as they relate to teaching the level of ordinary skill in this art and for any disclosure necessary for the commoner understanding of the subject matter of the claimed invention. It will be clear to a person of ordinary skill in the art that the above embodiments may be altered or that insubstantial changes may be made without departing from the scope of the invention. Accordingly, the scope of the invention is determined by the scope of the following claims and their equitable Equivalents.