WO1995016463A1

WO1995016463A1 - Radioactive compositions and their use for radiation ablation treatment

Info

Publication number: WO1995016463A1
Application number: PCT/US1993/008328
Authority: WO
Inventors: R. Keith Frank; Kenneth Mcmillan; Jaime Simon
Original assignee: The Dow Chemical Company
Priority date: 1992-09-23
Filing date: 1993-09-02
Publication date: 1995-06-22
Also published as: AU4846693A

Abstract

Radioactive polysaccharide compositions and the use of these compositions in a method for therapeutic radiation treatment, including rheumatoid arthritis, are disclosed.

Description

RADIOACTIVE COMPOSITIONS AND THEIR USE FOR RADIATION ABLATION TREATMENT

This invention relates to radioactive compositions containing a polymeric material and the use of these compositions in treating arthritis and other diseases.

Rheumatoid arthritis is a prevalent disease characterized by chronic inflammation of the synovial membrane lining the afflicted joint. Current treatment methods for severe cases of rheumatoid arthritis include the removal of the synovial membrane, e.g., synovectomy. Surgical synovectomy has many limitations including the risk of the surgical procedure itself, and the fact that a surgeon often cannot remove all of the membrane. The diseased tissue remaining may eventually regenerate, causing the same symptoms which the surgery was meant to alleviate.

Radiation synovectomy is radiation-induced ablation of diseased synovial membrane tissue accomplished by injecting a radioactive compound into the diseased synovium. Early attempts to perform radiation synovectomy were hampered by an instability of the radioactive compositions utilized and by leakage of such compositions from the synovium into surrounding healthy tissues. The instability of labile radionuclide complexes resulted in displacement of the radionuclide from the colloid complex and retention of the radionuclide in soft tissues. Significant leakage of the radioactive compound from the injection site exposed normal tissues to dangerous levels of radiation. Because of these limitations, new radiolabeled compositions were sought which would have minimal leakage.

U.S. Patents 4,752,464; 4,849,209 and 3,906,450 describe compositions comprising a radioactive colloid in which a radionuclide is entrapped within an iron hydroxide matrix. The radioactive colloids are useful in radiation ablation procedures, for example, ablation of a synovium in rheumatoid arthritis. However, the use of radioactive colloids may still result in significant leakage of radioactivity from a site of injection, e.g., a synovium, and into the surrounding normal tissues, exposing normal tissues to an undesirable amount of radiation. To compensate for the leakage, a radioactive metal having a short half-life, such as dysprosium- 165 (Dy-165) with a half-life of 2.3 hours has been proposed for use as the therapeutic radionuclide. Because of its short half-life, the majority of Dy-165 radioactivity decays before significant leakage can occur, thereby minimizing the dose of radiation to normal tissues.

The use of radioactive metals having a short half-life severely limits the utility of the therapeutic radiation procedure in two significant ways. First, radioactive compositions prepared with short half-life isotopes lose a significant amount of radioactivity because of decay during shipment to distant locations. Second, to achieve a therapeutic dose of a composition comprising a radioactive metal having a short half-life, large amounts of radioactive materials must be used. As a result, clinical personnel must handle large amounts of radioactive materials.

Therefore, there remains a need for a therapeutic radioactive composition which upon injection into a synovium, would remain at the site of injection, e.g., within a synovium, for a prolonged period of time. Prolonged retention at the site of injection would allow use of radionuclides having a longer half-life in therapeutic procedures, including radiation synovectomy, without fear of significant leakage from the site of injection and radiation 0 exposure to normal tissues.

It has now been found that when radioactive compositions prepared from radionuclides and polysaccharides are injected, for example, into a synovium, they are retained at the site of injection for a prolonged period of time, without significant leakage of ⁵ radioactivity. More specifically, the present invention provides a therapeutic radiation ablation treatment method comprising administering to a patient a therapeutical ly effective amount of a pharmaceutical composition comprising a radionuclide and a cellulose ether or a derivative thereof, wherein the cellulose ether has a molecular weight of 50,000 to 3 million daltons.

0 The present invention also provides a method of treating rheumatoid arthritis in an animal requiring such treatment, which method comprises administering to the animal an effective amount of a radionuclide sorbed to a cellulose ether or a derivative thereof, wherein the cellulose ether has a molecular weight greater then 25,000 daltons.

The use of a cellulose ether having a molecular weight of 50,000 to 3 million 5 daltons in the preparation of radioactive compositions allows the use of radionuclides having longer half-lives than previously used in radiation ablation procedures, while minimizing fear of significant leakage from the site of injection and radiation exposure to normal tissues.

The radioactive compositions of the present invention have a particular utility for ^υ therapeutic radiation ablation treatment methods to ablate diseased tissues, such as for the treatment of arthritis, particularly rheumatoid arthritis. The compositions are prepared by sorbing or chemically binding a radionuclide to one or more polysaccharides.

Suitable polysaccharides for use in the present invention are those to which a 5 radionuclide will bind without a substantial amount of leakage of the radionuclide from the polysaccharide when injected into the synovium of a patient. The use of the terms "bind" or "bound" to the polysaccharide means that a metal ion is sorbed to the polymer and remains associated with the polymer due to van der Waal's forces, hydrogen, ionic or covalent bonding.

To determine whether a polysaccharide will bind a radionuclide can readily be determined by those of ordinary skill in the art. For example, a polysaccharide can be mixed with a radionuclide in an aqueous environment in a pH range of 4 to 9 and the mixture than placed on a filter having a molecular weight cut-off sufficient to retain the polysaccharide on the filter. If the radionuclide is not bound to the polysaccharide, the radionuclide will pass through the filter and little or no radioactivity will be detected in association with the polysaccharide retained on the filter. Conversely, if bound, radioactivity will be detected in

10 association with the polysaccharide retained on the filter.

The polysaccharides for use in the present invention are also of sufficient molecular weight to prevent significant migration of the composition from the site of injection. While such factors as the secondary and tertiary structure of the polysaccharide will

15 affect the rate of migration of the composition away from the site of injection, the polysaccharides useful in the present invention generally have a molecular weight of 25,000 to 5 million daltons. Preferably, the molecular weight of the polysaccharide is 30,000 to 3 million daltons. More preferred are polysaccharides having a molecular weight of 50,000 to 2 million daltons. When the polysaccharide used in the present invention is a polymer having a size

^*^^υ distribution, the molecular weight refers to the average molecular weight (M_w) of the polymer. The molecular weight of a polysaccharide can be determined utilizing standard techniques known in the art, such as gel permeation chromatography, high pressure liquid chromatography or viscosity.

25 Polysaccharides useful in the present invention include, for example, fructan, levan, inulin, cellulose, xanthan, pectin, agar, and derivatives thereof. Preferred polysaccharides for use in the present invention are cellulose ethers and derivatives thereof which are capable of binding a metal ion. More preferred is the polysaccharide carboxymethylcellulose. The term polysaccharide includes modificationsthereof which do not

30 substantially alter the ability of the polysaccharide to sorb radionuclides or increase their migration away from the site of injection in a patient.

The polysaccharides for use in the present invention are commercially available or can be prepared using standard procedures in the art.

35 Examples of cellulose ethers for use in the present invention include such known cellulose ethers as methylcellulose, methylethyicellulose, hydroxypropyl methylcellulose. hydroxypropyl cellulose, hydroxyethyl methylcellulose and carboxymethylcellulose. Mixtures of such known cellulose ethers may also be used in the present invention.

Cellulose ethers useful in the present invention have an average molecular weight of approximately 50,000 to about 5 million daltons. Preferably, the molecular weight of the cellulose ethers is 75,000 to 3 million daltons, more preferably 75,000 to about 2 million daltons. -Cellulose ethers used in the present invention may be prepared by any of a number of known methods described, for example, in U.S. Patents 3,342,805; 3,388,082; 4,477,657; 4,410,693 and 4,820,813.

^■ O Preferably, the cellulose ether contains anionic constituents which may aid in binding a radionuclide. An example of such a cellulose being carboxymethylcellulose.

Generally, a specific cellulose ether is prepared by the formation of an alkali cellulose by the addition of sodium hydroxide to a slurry of cellulose floe in a diluent. The alkali 15 cellulose is then reacted with an appropriate alkylating agent or agents under pressure. Thereafter, the slurry is neutralized and the product is extracted, dried, and ground. For preparing carboxymethylcellulose, the alkali cellulose is reacted with sodium chloracetate.

A description of suitable cellulose ethers which can be used in the present invention can be found in Handbook of Water-Soluble Gums and Resins, ed. R. L. Davidson,

20 pub. McGraw-Hill (1980), alkyl and hydroxyalkylalkylcellulose (Chapter 3), carboxy¬ methylcellulose (Chapter 4), hydroxyethylcellulose (Chapter 12) and hydroxypropylcellulose (Chapter 13).

Radionuclides useful in the present invention include those having therapeutic ^■" efficacy, for example, in radiation ablation therapies such as radiation synovectomy.

Preferably, the radionuclides are rare earth class metals and other beta emitting metals with half-lives of from 2 hours to 7 days. Examples of such metals include hoi mium (Ho- 166), samarium (Sm-153), rhodium (Rh-105), lutetium (Lu-177), indium (ln-1 15m), dysprosium (Dy-165), yttrium (Y-90), lanthanum (La-140), gadolinium (Gd-159), ytterbium (Yb-175), 30 rhenium (Re-186), (Re-188) and scandium (Sc-47). More preferred are the radionuclides

Ho-166, Sm-153, Re-186, Re-188, Rh-105, Lu-177, ln-1 15m, and Dy-165. Most preferred are the radionuclides Ho-166 and Sm-153.

The respective radionuclides can be produced by methods known in the art. For 35 example, in a nuclear reactor, a nuclide is bombarded with neutrons to obtain a nuclide with additional neutrons in its nucleus. For example: Ho-165 + neutron = Ho-166 + gamma

Typically, the desired radionuclide can be prepared by irradiating an appropriate target, such as a metal oxide. Another method of obtaining radionuclides is by bombarding nuclides with particles in a linear accelerator or cyclotron. Yet another way of obtaining radionuclides is to isolate them from fission product mixtures.

Binding of the radionuclide to the polysaccharide can be accomplished by exposing the metal to an aqueous suspension to the polymer at a pH of 3 to 12, preferably 4 to

9.

The pharmaceutical formulations of the present invention contain radioactive metals sorbed to a polysaccharide in a physiologically-acceptable carrier. In one embodiment, a pharmaceutical formulation of the present invention comprises as an active ingredient a radionuclide sorbed to a cellulose ether or a derivative thereof, associated with one or more acceptable carriers or excipiants. Examples of suitable physiologically-acceptable carriers include aqueous carriers such as phosphate buffered saline, glycols or saline. The pharmaceutical formulations can be administered to a patient for therapeutic treatment by methods known in the art, e.g., intravenously or by injection. For example, a radionuclide- carboxymethylcellulose formulation may be prepared in saline and injected into a joint for radiation synovectomy.

The formulations of the present invention are in solid or liquid form containing as an active ingredient a chelate sorbed to a polysaccharide or a radioisotope sorbed to a polysaccharide. These formulations may be kit form such that the various components are mixed at the appropriate time prior to use. Whether premixed or as a kit, the formulations usually require a pharmaceutically-acceptable carrier.

The quantity of the radioactive composition administered to the patient will depend upon several factors including the specific radionuclide, its specific activity and emissions, the particular type of therapeutic treatment, e.g., type of injection site, duration of therapy desired, and type of disease being treated, and the amount of radioactivity desired at the site of injection.

A therapeutic dosage of radioactivity is that which is sufficient, when administered to a patient, to achieve the therapeutic radiation ablation result. For example, a therapeutic dosage is the amount sufficient, when injected into the synovium of a patient, to ablate the synovial membrane. In general, the therapeutic dosage will be that which delivers approximately 5 Gy to 1 ,500 Gy. A more preferred dosage is that which delivers from about 20 Gy to about 500 Gy to the site of injection. Gy is Greys wherein 1 Gy equals 100 rads.

The invention will be further clarified by a consideration of the following examples, which are intended to be purely exemplary of the present invention.

General Experimental

All centrifuging steps were performed at 4,700 rpm with a Clay-Adams Safetyhead centrifuge obtained from Becton-Dickinson, Piscataway, NJ.

The radioisotopes Ho-166 and Sm-153 were obtained from the University of Missouri Research Reactor, Columbia, MO.

Example 1 Preparation of Sm-153-Carboxymethylcellulose

To 8 mL of water was added 100 mg of carboxymethylcellulose (CMC) (average

MW of 110,000, polydispersivity of 18.5, viscosity of 400 to 800 centipoise, obtained from the Sigma Chemical Co., St. Louis, MO). The solution was purged with nitrogen for ten minutes.

To a 300 μL aliquot of the CMC solution was added 25 μL of a Sm- 153 solution (0.00126 M in 0.04 N HCI) and 50 μL of a sodium acetate solution (1.0 M). The pH was adjusted to between 5 and 6 and the mixture allowed to sit at room temperature for one hour. The mixture was placed on a microconcentrator having cellulose membrane with a 100,000 molecular weight cut-off (Centricon™ 100, trademark of Amicon Division of W.R. Grace Co.) and then 1 mL of water was added. The microconcentrator was centrifuged for one hour, and the filtrate placed in a counting vial. The filter was washed twotimes by the addition of 0.5 mL of water followed by centrifugation. The filtrate from each wash was placed in separate counting vials. The filter was then inverted and placed in the centrifuge for 2 to 3 minutes. The retentate (the material remaining on the filter) was placed in a counting vial. The retentate (approximately 250 μL) contained approximately 98 percent of the total radioactivity, . indicating efficient binding of the metal to the CMC. The retentate was brought to a total of about 0.75 mL by the addition of 0.5 mL water.

A 200 μL volume of the Sm-153-carboxymethyl-cellulose was injected into the synovium of a knee joint of an anesthetized rabbit. The syringe was disconnected from the needle, which was left in the joint, and the needle washed with 0.5 mL of 0.85 percent saline. The needle was then removed. The knee joint was stabilized and placed under a 3 inch Nal gamma detector (Canberra, Meriden, CT). The radioactivity was monitored for more than one hour. The data gathered over this time span, and corrected for radioactive decay, showed no evidence of leakage of radioactivity from the knee joint.

Other embodiments of the invention will be apparent to those skilled in the art from a consideration of this specification or practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the following claims.

Claims

C l a i m s :

1. A therapeutic radiation ablation treatment method comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a radionuclide sorbed to a cellulose ether or a derivative thereof, wherein the cellulose ether has a molecular weight greater than 25,000 daltons.

2. The method of Claim 1 wherein the patient is suffering from rheumatoid arthritis.

0 3. The method of Claim 1 wherein the cellulose ether has a molecular weight of greater than 50,000 daltons.

4. The method of Claim 1 wherein the carboxymethylcellulose has a molecular weight of 75,000 to 3 million daltons.

^■^ 5. The method of any one of Claims 1-4 wherein the cellulose ether is carboxymethylcellulose.

6. The method of Claim 5 wherein the radionuclide is Sm-153, Ho-166, Lu-177, La- 140, Gd-159, Yb-175, In- 155m, Y-90, Sc-47, Re-186 or Re-188.

20

7. The method of Claim 6 wherein the radionuclide is Ho-166 or Sm-153.

8. A formulation which comprises as an active ingredient a radionuclide sorbed to a cellulose ether or a derivative thereof associated with one or more acceptable carriers or excipiants, wherein the cellulose ether has a molecular weight greater than

²⁵ 25,000 daltons.

9. A method of treating rheumatoid arthritis in an animal requiring such treatment, which method comprises administering to the animal an effective amount of a radionuclide sorbed to a cellulose ether or a derivative thereof, wherein the cellulose ether has

30 a molecular weight greater then 25,000 daltons.

35