U.S. patent number RE29,066 [Application Number 05/451,438] was granted by the patent office on 1976-12-07 for biodegradable radioactive particles.
This patent grant is currently assigned to Minnesota Mining and Manufacturing Company. Invention is credited to Roger L. Evans.
United States Patent |
RE29,066 |
Evans |
December 7, 1976 |
Biodegradable radioactive particles
Abstract
Particles, preferably substantially spherical particles having a
smooth outer surface and essentially void-free interior are
produced, consisting essentially of solid, cold-water insoluble
vehicle comprising a physiologically acceptable, parenterally
metabolizable protein or polysaccharide having dispersed therein a
water-insoluble carrier loaded with radioisotopes, which are
substantially non-leachable upon short term exposure to cold water.
Such particles can be administered parenterally for diagnostic
purposes, or for treatment with radioactive materials. On
administration in this way, they are broken down or solubilized by
the body fluids over a predeterminable period ranging from minutes
to several days, whereupon the radioisotopic material is excreted
from the body thus limiting exposure to the radiation.
Inventors: |
Evans; Roger L. (Sunfish Lake,
MN) |
Assignee: |
Minnesota Mining and Manufacturing
Company (St. Paul, MN)
|
Family
ID: |
24884246 |
Appl.
No.: |
05/451,438 |
Filed: |
March 15, 1974 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
717965 |
Apr 1, 1968 |
03663685 |
May 16, 1972 |
|
|
Current U.S.
Class: |
424/1.25;
250/303; 264/.5; 424/499 |
Current CPC
Class: |
A61K
51/1241 (20130101); A61K 2123/00 (20130101) |
Current International
Class: |
A61K
51/12 (20060101); A61K 043/00 (); A61K
009/14 () |
Field of
Search: |
;252/31.1R ;264/.5
;424/1,9,20,35,36 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Sebastian; Leland A.
Assistant Examiner: Nucker; Christine M.
Attorney, Agent or Firm: Alexander, Sell, Steldt &
DeLaHunt
Claims
What is claimed is:
1. Tiny free-flowing, unagglomerated radioactive particles of the
order of about one-half micron to 1 millimeter in largest
dimension, consisting essentially of a gelled vehicle of
physiologically acceptable parenterally metabolizable sol-forming
polysaccharide of the class consisting of glycogen, starch and
dextran or protein of the class consisting of albumin, gelatin and
hemoglobin having dispersed therein a physiologically acceptable
inorganic carrier for radionuclides, said carrier having solubility
product less than about 1.times.10.sup.-.sup.4, said carrier
containing a radionuclide and being present in said particles in
amount ranging from that which is at least adequate to contain said
radionuclide up to about 50% by weight based upon the weight of the
vehicle, and said particle being resistant to leaching of said
radionuclide when immersed in water at 37.degree. C. for at least
about 15 minutes.
2. Particles according to claim 1 which are substantially spherular
in form.
3. Particles according to claim 1, in which the vehicle is a
protein.
4. Particles according to claim 1, in which the vehicle is a
polysaccharide.
5. Particles according to claim 1, in which the carrier is a metal
salt.
6. Spherules according to claim 2, wherein the vehicle is albumin
and the carrier is a metal salt.
7. Spherules according to claim 2, in which the vehicle is a
polysaccharide and the carrier is a metal salt.
8. Spherules according to claim 2, in which the vehicle is albumin
and the carrier is ferric hydroxide.
9. Spherules according to claim 2, in which the vehicle is albumin,
the carrier is sodium iodide and the radionuclide is I.sup.131.
10. Spherules according to claim 2, in which the vehicle is
albumin, the carrier is ferric hydroxide and the radionuclide is
cerium.sup.144.
11. Spherules according to claim 2, in which the vehicle is
albumin, the carrier is technetium sulfide and the radionuclide is
technetium 99.sup.m.
12. Spherules according to claim 2, in which the vehicle is
glycogen and the carrier is ferric hydroxide.
13. Spherules according to claim 2, in which the vehicle is
glycogen, the carrier is ferric hydroxide and the radionuclide is
cerium.sup.144. .Iadd. 14. Tiny, free-flowing, unagglomerated
particles of the order of about one-half micron to one millimeter
in largest dimension adapted for containing radionuclides,
consisting essentially of a gelled vehicle of physiologically
acceptable parenterally metabolizable sol-forming polysaccharide of
the class consisting of glycogen, starch and dextran or protein of
the class consisting of albumin, gelatin and hemoglobin having
dispersed therein a physiologically acceptable inorganic carrier
for radionuclides, said carrier having solubility product less than
about 1.times.10.sup.-.sup.4, said carrier being present in said
particles in amount ranging from that which is at least sufficient
to bind radionuclides in the quantity used up to about 50% by
weight based upon the weight of the vehicle, and said particles
when administered parenterally in the animal organism, being broken
down and converted to soluble form. .Iaddend..Iadd. 15. Particles
according to claim 14, which are substantially spherical in form.
.Iaddend..Iadd. 16. Particles according to claim 15, in narrow size
range from about one-half to 60 microns in diameter.
Description
BACKGROUND OF THE INVENTION
(1) Field of the invention
It has heretofore been known to encapsulate natural products for
food or pharmaceutical use in proteinaceous materials, such as
gelatin and albumin, and even small spherical particles of such
encapsulated materials have been made, e.g. by processes such as
those disclosed in U.S. Pats. 3,137,631; 3,016,308; 3,202,731;
2,800,457 and the like. These prior art processes, however, either
produce capsular materials wherein a central core is surrounded by
a thin shell, e.g. albumin or gelatin; or, for purposes of
obtaining materials that can be handled, or stored under adverse
conditions, result in severe denaturization of the protein so that
its solubility and other properties are impaired. Such materials
are not suitable for parenteral administration in the animal
organism. Similarly, while the use of radioisotope-labeled
particulates parenterally in the animal body is known for
diagnostic and treatment purposes, the materials heretofore used
for such purposes have been relatively insoluble, very finely
divided irregular or spherical particles which, when used, lodge in
the body and remain there during substantially the entire life of
the radioisotope. Such particles, for example, are shown in U.S.
Pats. 3,334,050 and 3,147,225. While these are very useful for
certain purposes where long-continued radioisotopic treatment, for
example, is desirable and advantageous, there are other areas in
which their use is less desirable and in some instances may be
contra-indicated. Irregular macroaggregates of human serum albumin,
labelled with radionuclides, have been used for diagnostic
purposes. These materials cannot be prepared in narrow ranges of
particle size and are prepared in particulate form directly in the
solution in which they are to be used; they cannot be dried and
sized or otherwise treated, and then resuspended.
SUMMARY OF THE INVENTION
The present invention provides means to prepare certain
physiologically acceptable, parenterally metabolizable materials in
spherical form, in highly pure, undenatured condition so that these
can be administered parenterally as a solid without injury to the
organism, and containing dispersed therein in a carrier
radioisotopes which are useful for diagnostic, prophylactic and
treatment purposes. The invention also contemplates the provision
of a process for making such particles and their concomitant or
subsequent treatment to incorporate radioisotopes therein, and to
modify their solubility characteristics without bringing about
denaturization which would prevent their absorption in the
body.
Hereinafter, the material of which the particle, or matrix, in
which the radioactive material is dispersed, is termed the
"vehicle"; and the substance upon which the radioactivity is
absorbed is called the "carrier."
The particulate compositions of the invention comprise a
physiologically acceptable, solid, substantially water-insoluble
(at body temperature) vehicle which can be metabolized, or degraded
in a manner which does not form toxic residues, apparently by the
enzymes or other metabolic mechanisms in the parenteral body
fluids, such as blood, serum, plasma, lymph and the like. When so
metabolized or degraded, these substances are solubilized.
Dispersed in this vehicle is a relatively water-insoluble carrier
for radioisotopic ions, and this carrier is required to be
physiologically acceptable so as to be free from injurious toxic
effects when released in the body by the metabolic mechanisms which
solubilize the vehicle. The carrier further binds or contains the
radioisotopes, as by ion exchange, or by incorporating the
radioisotope ion as part of the carrier, e.g. as the anion or
cation of a salt.
Suitable vehicles for the particulate compositions of the invention
are physiologically acceptable proteinaceous substances such as
albumin, gelatin, hemoglobin and the like; and polysaccharides,
such as starch, glycogen, dextran, etc.
The carrier can be loaded with radioisotopes by insoluble salt
formation, e.g. by forming silver iodide by reaction of silver
nitrate with hydriodic acid, a portion of which is HI.sup.131 ; or
by reacting barium chloride with a solution of sulfuric acid
containing a certain amount of S.sup.35 as sulfate ion. Another
method of introducing a radioisotope into a carrier is by ion
exchange or absorption, e.g. by absorbing Ce.sup.144 on ferric or
aluminum hydroxide.
Suitable carriers include, for example, hydroxides of iron,
chromium, aluminum and manganese; sulfates of barium, strontium and
calcium, and sulfides of zinc, copper, tin, nickel and cobalt.
Other metal salts which function usefully as carriers include
chromates, e.g. of barium; halides, e.g. of silver; and carbonates,
e.g. of calcium. These carriers have solubility product of the
order of 1.times.10.sup.-.sup.4 or less. The carrier is employed in
amount at least sufficient to bind the radioisotope in the quantity
used, but preferably is in excess thereof. Thus, up to about 50% of
carrier can be used, based on the weight of the vehicle. Preferably
about 1 to 10% of carrier is incorporated in the vehicle.
For use in diagnostic procedures or treatment requiring
radioisotopes to be directed to a particular locale within the
body, the vehicle is prepared in finely divided state, the sizes of
the particles being closely controlled by sorting techniques so as
to be in a narrow size range adapted to the specific use. Particles
thus segregated into narrow ranges can be from about 1/2 to 1000
microns in average diameter and preferably the size ranges chosen
do not vary more than about plus or minus 20% from the mean.
Preferably, spheroidal or essentially spherular particles are
employed as being more uniform and more easily controlled with
respect to radioisotope content and time of elimination from the
body. Spherules from 1/2 to 60 microns in diameter are most useful
for diagnostic purposes. Larger spherules, even up to 1 millimeter
in diameter, can be used for certain therapeutic purposes. Being
uniform in their dimensions, spheroidal or spherular particles are
more easily controlled with respect to radioisotope content and
time of elimination from the body. Particularly, they are preferred
because, by matching the diameter of the spherules to the size of
body passages, e.g. arteries, capillaries, etc., one can predict
their route through a healthy body and determine where they should
lodge with high accuracy.
To make the particles of the invention, a convenient method
consists in forming a sol by dispersing the vehicle, e.g. a
suitable protein or polysaccharide, in warm water, adding an amount
of finely divided carrier with bound radioisotope (which can
readily be an amount calculated to provide a desired level of
radioactivity for each gram of the product after drying), and
mixing until homogeneous, then causing the vehicle to gel as by
cooling or removing water, followed by drying. The dried material
can be comminuted by grinding or the like to form particles of the
size desired, grading by sieves or the like being entirely
feasible.
Preferably, however, the aqueous vehicle containing the carrier and
bound radioisotope is formed directly into tiny spheroids or
spherules by causing gelation to take place in that form. While
these gelled particles are prevented from coalescing, the water is
removed and the particles are dried to a free-flowing,
unagglomerated form.
When thus prepared, the essentially cold water-insoluble particles
can be washed to remove surface contamination by radioisotopes.
They can be subjected to heat treatment to modify their solubility,
and screened or otherwise graded to desired size range. They can be
soaked in water at 37.degree. C. for at least 15 minutes without
leaching out any radioactivity. In many cases they can be thus
treated for periods of hours or even days without disintegration or
loss of radioactivity. In physiological fluids such as blood serum,
however, they soon begin to be broken down and eventually are
completely solubilized.
Thus, for example, it has been found that by dispersing a solution
of albumin, e.g. by stirring into warm, inert fluid which is
immiscible with the solution of albumin and in which the albumin
itself is not soluble, small spherules of the albumin are formed.
The speed of stirring, use of baffles and the like controls the
size of the particles obtained; empirical methods are used to
establish parameters of dispersion to yield spheroidal particles of
any particle size. Alternatively and preferably for continuous
production, tiny droplets of the aqueous liquid are injected
through a small orifice into a moving stream of the warm, inert
fluid. The water is removed from the albumin solution through the
medium of the warmed, inert fluid, which may be e.g. vegetable oil
or hydrocarbon solvents, so that dry, practically perfectly round,
free-flowing tiny spherules of albumin are obtained. These
spherules are from 1 to 500 microns or even up to a millimeter in
diameter and can be obtained through the process in very narrow,
pre-determined size distribution ranges. They are substantially
undenatured, and can be administered parenterally in the animal
organism. When so administered, it is surprisingly found that they
are readily broken down, probably by the enzymes in the body
fluids, and converted to soluble form.
The microspherules, e.g. of albumin, are made to contain
radioisotopes by incorporating the selected carrier with
radioisotopic material into the solution of albumin before it is
dispersed in the inert fluid. Alternatively, the vehicle is
prepared containing unlabelled carrier. These are treated with a
radionuclide solution. The spherules, while free from visible voids
or bubbles, apparently are porous enough to permit the radionuclide
to penetrate into the interior of the particle where it is absorbed
upon the carrier. This procedure is especially useful with
radionuclides with very short half-life; e.g. indium 113m, as the
absorption process requires a very short time and the particles can
be prepared in advance and treated with radionuclide immediately
before use. The radioisotopes cannot be leached from the resulting
radioactive spherules upon immersion in water for periods of time
of from about 15 minutes up to several days.
The albumin referred to herein is broadly any of the several
natural proteins which are so described. Such albumins include
those of egg, blood serum, milk and the like, as obtained from
various animal species. For the purposes of this invention, the
preferred albumins are animal albumins from serum, human serum
albumin, and in general, for eventual use in a given animal
organism, albumin obtained from the serum of that organism.
Polysaccharides work equally well in this process.
Spherules formed from sol-forming proteins do not shrink greatly
during drying; however, spherules formed from polysaccharides may
shrink up to 30% in diameter as they dry. Suitable allowance for
such shrinkage must therefore be made when particles of a
particular size are sought.
Suitable inert liquids for the process of making the spherules of
the invention include vegetable oils, for example, corn oil, olive
oil and the like; low melting animal fats; mineral oils,
particularly those having boiling points above about 150.degree.
C.; inert halogenated hydrocarbons, and the like. The function of
the inert liquid is to remove water from the protein and to cause
gelling, and it will be apparent that various solvents can be used
to accomplish this end.
The radioisotopes which can be incorporated into the spherical
particles of albumin include such materials as cerium-144,
iodine-131, yttrium-90, indium-114, indium-113, ytterbium-169,
technetium-99, and any other radionuclide which is capable of
existing in ionic form and of forming a salt or other solid
derivative. These are of course selected with respect to the type
and intensity of emitted radiation, to be adapted to the use for
which the particles are intended.
For use in diagnostic procedures, a suspension of the particles of
the invention, such as microspherules of albumin containing a
radionuclide, are suspended in a pharmaceutical extending medium
suitable for parenteral administration. This may be, e.g.,
physiological saline, or dextran or gelatin solutions. A quantity
of such a composition containing the desired amount of
radioactivity, e.g. one millicurie, is injected e.g. intravenously
into the animal body. The material thus injected circulates
throughout the body in the blood stream and, because of the
selected particle size, will lodge in a particular, predetermined
organ, e.g. the lung. Radiation detectors, or autoradiography, may
then be employed to visualize the organ. Because the microspherical
particles remain substantially intact for a short time in the
animal organism, a period of time ranging up to several days is
available for such diagnostic procedure. Thereafter, the body
enzymes begin to attack the vehicle, causing it to become
solubilized and absorbed. The radioisotopic material, or its decay
product, is, however, swept away from the localized area in the
blood stream and excreted, generally by the kidneys.
For therapeutic or prophylactic use, the products are administered
as described above except that the activity is usually much higher,
(e.g. 50 millicuries) and the biodegradability of the particles is
adjusted so as to retain the radionuclide until it has delivered
the energy required for these purposes.
It will be apparent that the particular vehicle or carrier chosen
to prepare the particles of the invention which convey
radioisotopes into predetermined, temporary location in the body is
not critical. It is only necessary that the vehicle be
physiologically acceptable, capable of being prepared in
essentially insoluble form with respect to water at 37.degree. C.
for at least a short period, and capable of being metabolized or
degraded by body fluids to soluble form. Likewise, the carrier is
not critical so long as it is likewise essentially insoluble in
water and binds the radioisotope so as to prevent radioactivity
from being leached out of the particles when soaked in water at
37.degree. C. for a period of at least 15 minutes.
The following specific examples will more clearly illustrate the
specific embodiments of the invention. In these examples, all parts
are by weight unless otherwise specified. As a practical matter,
radioactive materials are in terms of their radiation level rather
than by exact weight and wherever radiation level is mentioned,
this is the exact amount of radionuclide used.
EXAMPLE 1
A solution was prepared containing 80 milligrams of ferric chloride
and about 1 milligram of cerium.sup.144 chloride (activity 5
millicuries) in .2 ml. of water. While stirring 10 percent aqueous
sodium hydroxide solution was slowly added until the pH of the
mixture was about pH 7-7.5. A gelatinous precipitate of ferric
hydroxide containing about 5 millicuries of radiocerium was formed.
This was washed by centrifugation and decantation with distilled
water.
The precipitate thus prepared was added to 4 ml. of a 25 percent
solution of human serum albumin in water. The mixture was carefully
stirred until homogeneous, avoiding the formation of bubbles. The
resulting mixture was then injected through a hypodermic needle
into about 1 liter of vegetable oil (cottonseed oil) which was
heated to about 30-50.degree. C. The rate of stirring determines
the ultimate size of the spherular material obtained. Using a
container which is greater in height than in diameter, with a 25
gauge hypodermic needle and stirring at about 500 r.p.m. with a
21/2 inches propeller-type stirrer, microspherular particles of
about 10 to 20 microns in diameter are obtained. Stirring is
continued while heating to 110.degree. C. until all of the water in
the microspheres is removed, as may be determined by removal from
the mixture of a small number of spheres to determine whether or
not they are still tacky. After removal of the water, the particles
are filtered away from the oil and washed with diethyl ether.
Microspherular particles of human serum albumin as a vehicle, with
radiocerium contained therein carried upon ferric hydroxide, are
obtained. The microspheres are about 10 to 20 microns in diameter
and are unagglomerated, free-flowing brown color.
The spherules thus obtained are washable in water at 37.degree. C.
When suspended in physiological saline solution, the spherules are
biodegraded and are 50% solubilized in less than a day after
injection into test animals.
Somewhat higher temperatures can be employed in the process,
accompanied by an increase in the time required for biodegradation.
Thus, for example, the oil is heated to 135.degree. C. and
maintained there for 40 minutes while stirring. Again,
free-flowing, unagglomerated particles of human serum albumin
containing radiocerium in ferric hydroxide carrier are recovered.
These are biodegraded and solubilized to the extent of 50% in about
one day.
Lower temperatures can be used for drying by heating at
subatmospheric pressures conveniently by using a water aspirator or
with a vacuum pump, reducing the temperature in proportion to the
reduction of pressure. Particles thus produced are biodegraded and
solubilized to the extent of 50% in less than a day.
Particles heated at 160.degree. C. are 50% solubilized in the
animal body in about 31/2 days; at 170.degree. C., in about 33/4
days; and at 190.degree. C., in over thirty days.
Similarly, when egg albumin is employed instead of human serum
albumin, spherular particles are obtained which closely resemble
the particles from human serum albumin.
A homogeneous mixture is made containing 0.1 g. of finely divided
radiobarium sulfate (S.sup.35, 0.5 millicurie) in 4 ml. of 25%
aqueous human serum albumin, and converted into spherules as
described above, drying at 110-130.degree. C. Free-flowing,
cream-colored radioactive spherules about 10-20 microns in diameter
are thus prepared.
In the same way, one millicurie of finely divided radio technetium
sulfide (Tc.sup.99m) is dispersed in 4 ml. of 25% aqueous human
serum albumin and formed into 10-20 micron spherules. The
radioactivity of the particles has a short half-life.
EXAMPLE 2
Tiny spherical particles of albumin similar to those obtained in
Example 1 are also prepared as follows:
A solution containing 100 milligrams of ordinary, non-radioactive
sodium iodide in 8 ml. of water is mixed with 5 ml. of water
containing 5 millicuries of sodium iodide.sup.131. To this solution
is added 10 percent aqueous silver nitrate, with stirring, until an
excess of silver nitrate is present and no more silver iodide
precipitates. The precipitate is centrifuged down, the supernatant
liquid decanted, and washed with distilled water by repeatedly
suspending the precipitate in water and centrifuging, decanting the
supernatant liquid, until the washings are free from soluble silver
iodide. The precipitate is carefully mixed into 4 ml. of a 25
percent aqueous human serum albumin solution, avoiding the
incorporation of air bubbles, until the mixture is homogeneous. The
resulting albumin-silver iodide mixture is injected into warm corn
oil to form spherules, which are dried, as described in Example 1.
Brown, free-flowing, unagglomerated spherules about 10 to 20
microns in diameter, containing silver nitrate in which an amount
of radioactive iodine.sup.131 is carried are thus obtained.
Alternatively, 300 microliters of water containing 2 millicuries of
radioiodine.sup.131 as radioactive sodium iodide is mixed with 100
microliters of a 3 molar solution inactive sodium iodide as a
carrier. This solution is mixed with 4 ml. of 25% aqueous human
serum albumin. Vigorous stirring is used, avoiding bubble
formation. Continuing the stirring, 125 microliters of 3 molar
aqueous silver nitrate solution is slowly added. The solution
becomes primrose yellow in color as colloidal silver iodide is
formed.
The colloidal suspension of silver iodide in albumin thus formed is
made into microspherules as described in Example 1.
EXAMPLE 3
Radionuclide-free microspheres of albumin with ferric hydroxide are
made as described in Example 1, drying at 110-130.degree. C., but
leaving out the radiocerium chloride. These dry, free-flowing 10-20
micron spherules are readily loaded with radionuclides as
follows:
About one gram of the microspheres is added to a solution 5
millicuries of radiocerium chloride in 10 ml. of water. The mixture
is agitated gently for 10 minutes at 37.degree. C. After filtration
or centrifugation and washing over 60% of the radioactivity
originally present in the liquid is found to be firmly fixed or
absorbed in the spherules. Alternatively, ferric hydroxide is
prepared as a swollen gelatinous precipitate from ferric chloride
solution by carefully neutralizing it with dilute sodium hydroxide
solution. This precipitate is washed by centrifugation and
decantation with aliquots of water to remove excess alkali. Four
ml. of 25% aqueous human albumin is added to 0.1 gm. of the ferric
hydroxide (dry basis) and the system is carefully mixed until it is
homogeneous. This mixture is then formed into spherules as
described in Example 1.
After drying at 110-130.degree. C., the spherules are placed in a
solution of radioindium chloride with gentle agitation. Contact is
maintained until the desired amount of radioactivity has been taken
up by the beads. For example, in a solution originally containing
233,550 counts per minute of In.sup.114, 60% is taken up in 5
minutes, 79.5% in 2 hours.
An aqueous solution of sodium iodide is prepared containing 12.7
mg./ml. of iodide ion. To 1 ml. of this is added an excess of 10%
aqueous silver nitrate solution. The precipitated silver iodide is
washed to remove excess silver, and is mixed thoroughly with 0.5
ml. of a 25% aqueous solution of human albumin. The mixture is
formed into spherules and dried at 110-130.degree. C. as described
in Example 1.
After drying, the spherules are placed in a solution of radioactive
sodium iodide (I.sup.131) and gently agitated. Contact is
maintained until the desired amount of radioactivity has been taken
up by the spherules. For example, in a solution originally
containing 330,420 c.p.m., 99% is taken up in 10 minutes.
Alternatively, a solution of 25% aqueous human serum albumin
containing 10% sodium chloride is converted into spherules as
described in Example 1, drying at 110-130.degree. C. One hundred
milligrams of these are suspended in 20 ml. of acetone and 1 ml. of
3 molar aqueous silver nitrate is added. The suspension is stirred
for half an hour at ambient or mildly elevated temperature. Then it
is filtered and washed thoroughly with water and acetone. The
spherules are again suspended in 10 ml. of acetone and 25
microliters of a solution containing 0.5 millicurie of ratioactive
sodium iodide (I.sup.125) are added. After contacting the spherules
with the radioactive solution for 17 hours, 99.75% of the
radioiodide has been absorbed as shown by radio-assay. The thus
labelled spherules are filtered off, washed with water and acetone
and dried in air.
Similarly, a solution of 25% albumin containing 0.6% silver nitrate
(dry weight basis) is converted into spherular particles in the
manner described in Example 1. One hundred milligrams of these are
suspended in 10 ml. of water at 18.degree. C.; 25 milliliters of an
aqueous solution containing 0.25 millicurie of radioactive sodium
iodide (I.sup.125) are added and the suspension is agitated for one
hour. Radio-assay then shows that 67% of the radioiodine has been
absorbed. The spherules are filtered off, washed with water and
acetone, and dried in air.
EXAMPLE 4
A solution is made by dissolving 1 gram of glycogen in 40 ml. of
water, mixing and stirring while avoiding incorporation of bubbles.
To this is added about 80 milligrams of ferric hydroxide containing
1 milligram (or about 5 millicuries) of radiocerium, as set forth
in Example 1. The mixture is dispersed in a stirred bath of
cottonseed oil which is kept at 65.degree. C. until all of the
glycogen dispersion has been introduced in the form of small
particles. Thereafter stirring is continued and the temperature is
raised to 105-110.degree. C. and maintained there until all of the
water has been removed from the particles.
The resulting particles, which are free-flowing, unagglomerated,
tiny spherules about 10 to 20 microns in diameter, dissolve rapidly
in water. To treat these particles to make them less soluble, they
are heated at 200.degree. C. in the dry form for 30 minutes.
Particles thus treated dissolve in physiological saline solution in
approximately 20 minutes. If heating in this manner is continued
for two hours, the particles dissolve in physiological saline
solution in about 30 minutes. However, no radioactivity is leached
from the particles if they are placed in water at 37.degree. C. for
15 minutes. If heated at 200.degree. C. for 13 hours, the particles
do not dissolve in physiological saline solution. The particles are
more rapidly solubilized in the body fluids than in physiological
saline solutions.
Substantially similar results are obtained if a solution of 1 gram
of starch phosphate in 10 ml. of water is employed, to which
radiocerium carried upon ferric hydroxide is added. The mixture is
dispersed into hot oil as set forth herein, and dried, to form
tiny, free-flowing, dry spherical particles of starch labelled with
radiocerium.
EXAMPLE 5
A solution of one gram of gelatin in 10 ml. of water was mixed with
precipitate of indium.sup.144 /ferric hydroxide made according to
Example 1. The mixing was continued until the system was
homogeneous, conveniently at ca. 60.degree. C. When mixing was
complete, the mixture was injected into a liter of rapidly stirred
cottonseed oil, also at ca. 60.degree. C. to disperse the gelatin
into tiny spherules. The temperature was raised to 110.degree. C.
and maintained there until the water was all evaporated. After
filtration and washing with ether, spherules of gelatin labelled
with radioindium were obtained, about 20-30 microns in diameter as
free-flowing, unagglomerated particles.
EXAMPLE 6
A convenient method for continuous production of spheroidal
particles is the following: Four parts of a 25% aqueous solution of
sodium chloride is thoroughly mixed with 40 parts of a 25% aqueous
solution of albumin. The mixture, at room temperature, is passed
through a No. 27 needle into a stream of cottonseed oil warmed to
about 50.degree. C., moving at the rate of about 12 feet per
minute. The albumin-containing mixture breaks up into droplets,
which are suspended in the oil. The stream of droplets-in-oil is
carried through a 50 ft. long tube, heated to ca. 115.degree. C.
This dries the droplets to microspherules of about 20-50 microns
diameter. The oil and dried spherules are run into a tube and after
cooling, they are collected, the oil being removed by filtration.
After warming again to about 50.degree. C., the oil is
recirculated.
Radioactive materials are incorporated into the spherules, when
required for use, by the process of post-loading described in
Example 3.
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