Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – Dissolving or eluting from solid or gel matrix
Reexamination Certificate
1997-10-02
2002-03-05
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
Dissolving or eluting from solid or gel matrix
C424S001290, C424S001330, C600S003000, C600S004000
Reexamination Certificate
active
06352682
ABSTRACT:
BACKGROUND OF THE INVENTION
This relates to an improved method of local radiotherapy, and devices and compositions for accomplishing local radiotherapy.
Radiation has been used for cancer therapy and to control local healing in areas as diverse as preventing excessive scar formation or reducing lymphoid infiltration and proliferation. More recently, radiation has been used to inhibit restenosis following coronary artery or peripheral artery angioplasty. Interstitial radiation by use of radioactivity incorporated into intravascular stents, delivery of radiation dose by use of catheters containing radioactive sources, and external beam radiotherapy have been used.
There are disadvantages to each of these approaches. When radiation is delivered by an extracorporeal beam, the usual problems of limiting the exposure only to those tissues intended to be affected are encountered. Moreover, doses must often be subdivided, requiring more than one visit to the hospital by the patient. If radiation is to be delivered by a catheter or other temporarily-installed medical device, then the rate of delivery of radiation from the device must be high. The active source will normally require careful shielding, even if relatively “soft” radiation, such as beta rays, is used. If administered in the same operation as balloon angioplasty or cardiac bypass, extra complications of an already complex and risky procedure are magnified. Delivery of radiation on a permanently implanted device, or a biodegradable device that necessarily is eroded over a long period of time because it also provides structural support, severely limits the choice of radioisotope because of the need to limit the total delivered dose to the tissue, while simultaneously providing sufficient initial dose to achieve the required effect. Moreover, repetition of the administration, if required, is not readily achieved.
The object of this invention is to provide an improved method for localized radiotherapy for the cure or alleviation of medical conditions.
SUMMARY OF THE INVENTION
Locally deposited biodegradable polymer depots are used as a vehicle for the immobilization and local delivery of a radionuclide or radiopharmaceutical. Radionuclides are incorporated in their elemental forms, as inorganic compounds, or are attached to a larger molecule or incorporated into the polymer, by physical or chemical methods. Ancillary structures may be employed to control, the rate of release. The depot is preferably made of a biodegradable material which is selected to degrade at a known rate under conditions encountered at the site of application. The depot is preferably fluent, or capable of being made fluent, so that it may be deposited at a site in a conforming manner by minimally invasive means. Examples of such materials are melted polymers which re-solidify at body temperature, and polymerizable materials which are polymerized at the site of deposition. The depot optionally is provided with means for controlling the rate of release of the radioactive compound. These means may include microparticles in which the radioactive compound is incorporated.
The use of the polymeric depots provides a way of immobilizing the source of energy from a radioactive source at a remote site within the body, which can be accessible by a less invasive surgical procedure, such as by catheter or laparoscopy. The duration and total dose of radiation can be controlled by a combination of choice of the radionuclide, control of the rate of degradation of the polymer, and control of the rate of release of the radionuclide from the depot. Following polymer degradation and/or release of the radionuclide, excretion from the body in urine and stool can be favored by administering pharmaceutical agents which favor excretion. For example, in the case of iodine radionuclides, excretion can be favored by blocking thyroid uptake of radioactive iodine or iodinated compounds by systemic administration of non-radioactive iodine compounds, such as sodium iodide or Lugol's solution.
DETAILED DESCRIPTION OF THE INVENTION
The polymeric depots provide a method of delivery of a radioactive agent to a local site of disease for treatment, such as for prevention of restenosis following angioplasty. The method has advantages over other methods of local radiation delivery in all applications, because the duration and intensity of the exposure can be altered by choosing radionuclides of differing physical half-life, and the biological half-life can be controlled by accelerating or retarding the rate of release of the radionuclide from the polymeric matrix. This provides a way to control local dosage of radiation without the need for physical removal of the implanted radionuclide. Radioactivity can thus be applied at any site in the body that is accessible by a less invasive procedure or catheter, for example, to a coronary artery or a tumor arterial supply. This also allows the application of interstitial, implanted radiotherapy while minimizing the exposure of the operator to radiation that is sometimes necessary when using other currently available methods of providing local radiotherapy.
Polymers
Polymers for forming the depot must be biodegradable, i.e., must dissolve into small molecules which can be removed by normal metabolic functions and/or excretion, under the conditions found at the site of application of the depot. In one aspect, the polymers may be slowly soluble under body conditions, for example, certain poloxamers, such as Pluronic™ F-68 (a polyethylene glycol-polyethylene oxide block copolymer marketed by BASF), which gel at body temperature and slowly dissolve over several days. In another aspect, the fluidity of the polymers is altered using temperature. For example, polymers can be melted by heating or by cooling (e.g., with Pluronics™), and applied to the site, where the polymer will re-solidify. Depot formation can also be caused by other known means of coacervation, such as complexation of polymers with ions (e.g., alginate with calcium), direct coacervation of polymers (e.g., polyglutamic acid with polylysine), and exsolvation of polymers by diffusional removal of non-water solvent molecules.
Degradable linkages in the polymers include esters, orthocarbonates, anhydrides, amides and peptides, acetals, phosphazene linkages, and Schiff base adducts. Examples of groups forming suitable ester linkages include hydroxy acids, such as lactic, 10 glycolic, hydroxybutyric, valerolactic and hydroxycaproic. Examples of anhydride-forming groups include oxalic, malonic, succinic, glutaric, adipic, suberic, azelaic sebacic, maleic, fumaric and aspartic. Examples of carbonate-forming compounds include trimethylene carbonate.
In another aspect, the polymers may be crosslinkable in situ. Crosslinking may be by any suitable chemical means. If chemically crosslinked, at least one of the polymer and the linkage formed must be biodegradable. Examples of biodegradable linkages include Schiff bases, anhydrides, disulfides, and acetals. Examples of other linkages, not necessarily biodegradable, include epoxy (oxirane) groups, urethanes, ester, ethers, amides, and sulfones. Linkages involving carbon-carbon double bonds may be formed by a variety of means, including the polymerization of ethylenically-unsaturated groups. These may include (meth)acryl, vinyl, allyl, styryl, cinnamoyl, and alkenyl groups. Such reactions can be initiated by thermal, chemical, radiative or photochemical means. It is known that most chemically crosslinkable groups and molecules will tend to crosslink in the presence of radioactive materials, and are preferably mixed with radioactive materials just before application.
In another aspect, the biodegradable polymer is dissolved in a solvent other than water (an “organic” solvent, broadly construed to include any biocompatible non-aqueous solvent) and deposited at the site, and precipitated as the organic solvent diffuses away from the site, forming a depot. The organic solvent must not cause undue damage to the tissue at the site. This will vary, depending on
Avila Luis Z.
Leavitt Richard D.
Focal, Inc.
Hartley Michael G.
Holland & Knight LLP
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