U.S. patent application number 08/968463 was filed with the patent office on 2001-07-05 for polymeric delivery of radionuclides and radiopharmaceuticals.
Invention is credited to AVILA, LUIS Z, LEAVITT, RICHARD D.
Application Number | 20010006616 08/968463 |
Document ID | / |
Family ID | 24459139 |
Filed Date | 2001-07-05 |
United States Patent
Application |
20010006616 |
Kind Code |
A1 |
LEAVITT, RICHARD D, ; et
al. |
July 5, 2001 |
POLYMERIC DELIVERY OF RADIONUCLIDES AND RADIOPHARMACEUTICALS
Abstract
Locally deposited 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 structure may be employed to control
the rate of release. Standard radionuclides which have been used
for local radiotherapy may be used, such as radionuclides of
iodine, iridium, radium, cesium, yttrium or other elements.
Inventors: |
LEAVITT, RICHARD D,;
(BOSTON, MA) ; AVILA, LUIS Z; (ARLINGTON,
MA) |
Correspondence
Address: |
PATREA L. PABST
ARNALL GOLDEN & GREGORY
2800 ONE ATLANTIC CENTER
1201 W PEACHTREE STREET
ATLANTA
GA
303093450
|
Family ID: |
24459139 |
Appl. No.: |
08/968463 |
Filed: |
October 2, 1997 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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08968463 |
Oct 2, 1997 |
|
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08613904 |
Mar 11, 1996 |
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Current U.S.
Class: |
424/1.25 ;
252/625; 252/634; 424/1.11; 424/1.29; 424/1.33; 524/916; 600/1;
600/3; 600/4; 600/7; 600/8 |
Current CPC
Class: |
A61P 35/00 20180101;
A61K 51/0497 20130101; A61K 51/1213 20130101; A61K 51/06
20130101 |
Class at
Publication: |
424/1.25 ;
424/1.11; 424/1.29; 424/1.33; 600/1; 600/3; 600/4; 600/7; 600/8;
524/916; 252/625; 252/634 |
International
Class: |
A61N 005/00; A61M
036/14; A61K 051/00; A61M 003/00; A61M 036/00; C09K 003/00; C09K
011/04 |
Claims
We claim:
1. A method for local radiotherapy at a site in a patient,
comprising forming a polymeric depot at a site at which therapy is
to be administered, wherein the depot comprises one or more
radioisotopes in combination with a depot-forming biodegradable
biocompatible polymeric material.
2. The method of claim 1, in which the depot is a hydrogel.
3. The method of claim 1, in which the depot is a solid polymer
applied in a first fluent state and converted to a second less
fluent state upon application to tissue.
4. The method of claim 1 wherein the polymer is chemically coupled
to the radioisotopes.
5. The method of claim 1 wherein the polymer is conjugated to the
radioisotopes via a chelating agent coupled to the polymer.
6. The method of claim 1 wherein the depot comprises microspheres
comprising radioisotopes.
7. The method of claim 6 wherein the microspheres are biodegradable
at a different rate than the depot.
8. A composition for local radiotherapy, comprising one or more
radioisotopes in combination with a depot-forming material, wherein
the depot-forming material is a biodegradable, biocompatible
polymer and can be formed into a depot in vivo at a selected
site.
9. The composition of claim 8, in which the depot is a
hydrogel.
10. The composition of claim 8, in which the depot is a solid
polymer applied in a first fluent state and converted to a second
less fluent state upon application to tissue.
11. The composition of claim 8 wherein the polymer is chemically
coupled to the radioisotopes.
12. The composition of claim 8 wherein the polymer is conjugated to
the radioisotopes via a chelating agent coupled to the polymer.
13. The composition of claim 8 wherein the depot comprises
microspheres comprising radioisotopes.
14. The composition of claim 13 wherein the microspheres are
biodegradable at a different rate than the depot.
Description
BACKGROUND OF THE INVENTION
[0001] This relates to an improved method of local radiotherapy,
and devices and compositions for accomplishing local
radiotherapy.
[0002] 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.
[0003] 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.
[0004] 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
[0005] 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.
[0006] 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
[0007] 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.
[0008] Polymers
[0009] 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.TM. 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.TM.), 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.
[0010] Degradable linkages in the polymers include esters,
orthocarbonates, anhydrides, amides and peptides, acetals,
phosphazane linkages, and Schiff base adducts. Examples of groups
forming suitable ester linkages include hydroxy acids, such as
lactic, 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.
[0011] 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.
[0012] 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 the tissue and on the condition to be treated. In many
applications, ethanol, isopropanol, mineral oil, vegetable oil, and
liquid silicones may be suitable.
[0013] The biodegradable polymer, and any solvent or adjuvant
included in the composition, must further be sufficiently
biocompatible for the purposes of the therapy. A biocompatible
material is one which arouses little or no tissue reaction to its
implantation, and where any reaction is of limited extent and
duration. The extent of irritation which is tolerable, or which
will be elicited, depends on the site of application. For example,
many polymers are minimally irritating on the skin, or within the
digestive tract, while only a few polymers are acceptable in the
peritoneum. Many materials of high biocompatibllity (minimally
irritating) are non-ionic and, after application, contain few
reactive or potentially reactive groups. Preferred examples of such
materials are poly(alkylene oxides), such as polyethylene glycols,
poloxamers, meroxapols and the like.
[0014] The depot formed by local deposition of an appropriate
biodegradable polymer, normally in combination with the radioactive
material at the time of deposition, will be structured to release
the radioactive material in a known and predictable manner during
biodegradation of the depot. The combined effects of radioactive
decay and of controlled release will determine the total energy
deposited into the target tissue. Numerous means are known for
controlling the release rate of a material from a depot. These
include diffusion of the material through a solid polymer;
diffusion of the material through pores in a polymer, or in a gel
formed from the polymer; burst release of a material on rupture of
a compartment; exposure of material to the environment due to
erosion of the polymer; slow dissolution of material from a solid
form which is maintained in place by the polymer; release of
diffusional restrictions on a material by degradation of a solid
polymer, a polymeric coating or a gel; release of a material from a
degradable linkage to a polymer, or to a carrier material contained
in or on a polymer; and de-binding of a reversible association
between a material and a polymer, or a carrier material contained
in or on a polymer. Combinations of such means may be used to
obtain an optimal release profile. For example, a small
radiolabelled molecule may be embedded in a degradable microsphere,
from which it is slowly released by a combination of diffusion and
degradation of the microspheres. The microspheres in turn are
restrained at the site of therapy by a polymeric gel formed in
situ, which itself provides minimal diffusion barriers and further
gradually degrades. Selection of the relative degradation rates of
the gel and of the microspheres will influence the total radiation
dose administered to the site of therapy. As used herein,
microspheres includes microparticles, microcapsules, liposomes,
lipid particles, and other formulations of similar size and
function.
[0015] Radioactive materials
[0016] Any radioactive material may be used. Standard radionuclides
which have been used for local radiotherapy may be used, such as
radionuclides of iodine, iridium, radium, cesium, yttrium or other
elements.
[0017] Preferred radioisotopes are those which have a particle
range in tissue which is concordant with the thickness of the layer
of tissue to be treated. Information on particle ranges is readily
available. For example, it is known that about 90% of the energy
from a .sup.14C (carbon-14) source will be absorbed in about the
first 70 microns of tissue, and similar distances will be found for
sulfur-35 and phosphorous-33, since their emitted particles are of
the same kind as .sup.14C (beta particles) and of similar energies.
More energetic beta particles would have a longer range, such as
those of phosphorous-32, which has a maximum range of about a
centimeter and thus can be used to treat thicker tumors, or blood
vessels having multi-millimeter thick medial layers. Very high
energy emissions, whether of beta particles or of other forms, are
generally less preferred because their emissions may exit from the
body, thereby causing shielding problems.
[0018] The radioisotope must be administered in a pharmaceutically
acceptable form The form must be biocompatible, as described above.
The form must also be capable of remaining at the site of
application for a controlled length of time, in combination with a
means for control of local delivery. For example, the radioisotope
could be in the form of an element, an inorganic compound, an
organic compound, or attached to a larger molecule, such as a
polymer. In the last case, incorporation could be into a backbone
group; as a side group, preferably covalently bonded; or as a
ligand, bound to a suitable binding group on the polymer. A binding
group could be a non-biological binding group, such as a chelator
for metal ions; or a biological group for binding, such as avidin
for biotin. Likewise, the polymer could be biological, such as a
protein, a polysaccharide or a nucleic acid; or it could be
synthetic, such as a polyalkylene glycol or a
poly(meth)acrylate.
[0019] Immobilization of Ions in a Gel
[0020] Radioactive ions can be directly immobilized in a gel. In
one embodiment, they may be locally converted to a low-solubility
salt form, for example by precipitation with an appropriate salt,
e.g., as calcium phosphate, or as a ligand on a polymer, or as a
cofactor bound to a biological molecule.
[0021] In a preferred embodiment, radioactive ions are immobilized
in a gel by chelation. A chelator can be covalently immobilized in
a gel. The covalently linked chelator (`host`) in turn can
immobilize the metallic ion (`guest`).
[0022] Polymerizable macromers or small molecules can be
synthesized bearing an appropriate chelator connected to the
backbone. An example of a suitable molecule would be one which has
one end(s) of the central backbone (e.g., a polyalkylene oxide,
such as polyethylene glycol (PEG) or polypropylene
oxide/polyethylene oxide (PPO/PEO)) bearing a chelator, optionally
attached through a spacer group such as a hydroxyacid. The other
end(s) of the PEG backbone would carry a polymerizable bond, with
or without spacer groups. This requires a backbone having two or
more functionalizable ends. The presence of the backbone is
optional; a chelating group could be directly coupled to a reactive
group, such as an acryl, allyl or vinyl group, which would
participate in the formation of a gel.
[0023] An example of a chelator (`host`) is the polyazamacrocycle
cyclam 1,4,8,11-tetra azacyclo tetradecane which is know to form
thermodynamically and kinetically stable complexes with Tc-99m
(`guest`), a metal ion used for medical applications.
[0024] An example of a guest is technetium-99m, a .gamma.-emitter
for clinical applications, which emits only .gamma.-radiation, has
a low radiation energy and a short half-life of only 6 hrs. Tc-99m
can be used for monitoring physiological changes using
scintigraphy, a highly sensitive .gamma.-radiation-based technique
used in most hospitals.
[0025] These chelator-bearing macromonomers can be delivered as
solutions and `gelled` in the target site using polymerizable
crosslinkers (e.g., PEG with acrylate endgroups linked to the PEG
by biodegradable spacers)). The degradation and other physical
property of the resulting hydrogel can be tailored to desired
specifications.
[0026] The significance of such a gel is that:
[0027] 1. Such hydrogels can be formed in situ and can bear a
.gamma.-emitter or other medically useful isotope for various
medical applications.
[0028] 2. Since databases for various chelators are available from
literature, it is straightforward to find an appropriate chelator
to selectively immobilize a particular metal ion within a
hydrogel.
[0029] 3. Other possible applications of the concept include
localized delivery or immobilization of medically useful nuclides,
localized delivery of physiologically beneficial (and therapeutic)
metal ions or other charged species.
[0030] Medical Applications
[0031] Applications of this technology include the local treatment
of tumors, cancer, and other unwanted growths (e.g., atheromae,
papillae); inhibition of scarring or healing to prevent excessive
scar formation or keloid formation; preservation of
surgically-created conduits, for example inhibition of healing over
of the sclera following a filtration procedure for glaucoma;
prevention of fibrosis and of capsule formation; and prevention of
restenosis following angioplasty.
[0032] Methods of Application
[0033] The local depot can be placed at the site to be treated by
any of several methods. For external application, a preformed depot
can be applied and secured by appropriate adhesives. An external
application would also require appropriate means for prevention of
migration of the radioactive material. For internal applications,
the depot-forming polymer, preferably in combination with the
radioactive material and any required excipients, accessory
materials, and drug delivery means, is typically administered in a
fluent form to the site of application by a delivery device, and
caused or allowed to solidify at the site. Delivery devices can
include percutaneous means such as catheters, cannulae, and
needles; or means applied through natural or surgically created
openings or through temporary openings, such as those created by
trocars, using syringes, brushes, pads, or brushes. Similar means
are used to apply any stimuli required to form the depot from the
fluid polymer material. For example, light may be brought to a
remote site via an optical fiber, or a device similar to a
laparoscope, to cause polymerization in a depot, or a chemical
could be applied by means similar to those used for the
depot-forming mixture.
[0034] Dose Control
[0035] The method provides three ways of controlling the total dose
delivered to a site, while simultaneously controlling exposure to
other areas of the body. First, the total amount of isotope can be
varied. Second, the half-life of the isotope can be selected; this
provides an upper limit of the applied dose. Third, the lifetime of
the radioisotope in the local delivery depot can be controlled.
[0036] For example, if the radioisotope is a macromolecule, then
the depot could be a gel, and the rate of release of the
macromolecule from the gel can be controlled by making the gel
sufficiently dense so that the macromolecule is released only as
the gel degrades. Such gels are known; for example, the gels
described by U.S. Pat. No. 5,410,016 to Hubbell et al. are
suitable.
[0037] If the radioisotope is a small molecule, rather than a
macromolecule, its rate of release can be controlled by embedding
it in a solid bioerodable material, such as polylactide,
polycaprolactone, a polyanhydride, or a polymerized biomaterial,
such as protein. Then the small molecule is released by a
combination of diffusion through the material, and erosion of the
material, each of which is adjustable.
[0038] Alternatively, the rate of release of a radioisotope may be
regulated by selecting the strength of interaction of the molecule
with its environment. For example, if both the molecule and the
depot are relatively hydrophobic, then the molecule will diffuse
out of the depot relatively slowly. If it is not practical to make
the depot hydrophobic, then the molecule can be included in more
hydrophobic microparticles, such as polymeric microparticles,
liposomes, emulsions, etc., which in turn are embedded within a
hydrophilic depot.
[0039] The present invention will be further understood by
reference to the following non-limiting examples.
EXAMPLE 1
[0040] Immobilization of a Radionuclide in an Interfacially
Deposited Gel
[0041] A radionuclide (.sup.125I or .sup.131I or other
radionuclide) is deposited in an interfacial hydrogel following
angioplasty, either coronary or peripheral, or intravascular stent
placement, or carotid artery stent, or an arterectomy. The
incorporated radionuclide is chosen to provide a total of exposure
of at least 1500 cGy to the arterial wall. The delivered dose is
adjusted by choosing the amount of incorporated radionuclide and is
further controlled by choosing a formulation of hydrogel with a
different persistence at the site of deposition. The duration of
exposure at the site of deposition can be controlled by adjusting
the biodegradable moieties of the hydrogel or by changing the
density of crosslink of the polymer at the site.
EXAMPLE 2
[0042] Local Radiotherapy from a Polymer Applied Via
Catherization
[0043] Local radiotherapy can be applied to any tumor which is
accessible by a vascular catheter. This technique is particularly
applicable to either highly vascularized tumors or tumors which
have a single dominant arterial vascular supply. This would provide
a method for treatment particularly applicable to renal cell
carcinoma, hepatoma, sarcomas, cancers of the head and neck, and
central nervous system tumors. In this example, radioactive
microspheres containing yttrium-90 are incorporated in a hydrogel
that is deposited in the artery supplying a tumor. The local tumor
volume in the area of deposition is radiated while the microspheres
are immobilized at the site of deposition. On degradation of the
hydrogel, the microspheres are released and redeposited in the
distal microcirculation, where they provide continued radiation
treatment. The exposure at the site of an initial deposition can be
regulated by controlling the rate of hydrogel degradation, either
by adjusting the biodegradable moieties in the hydrogel or the
density of crosslinking. The microspheres can be chosen for a
longer time of degradation or elimination of greater than 320
hours, when five half-lives of the implanted yttrium-90 have
expired and the vast majority of radioactive decay has
occurred.
[0044] Modifications and variations will be obvious to those
skilled in the art from the foregoing detailed description and are
intended to come with the scope of the following claims.
* * * * *