American Tobacco
Flavor Enhanced Cigarettes and Cigars, Patent Application, Serial No. 550, 167
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United States Patent Office
1
2,952,585
IMMUNIZING AGAINST AND TREATMENT OF
DISEASES
John H. Heller, Wilton, Conn., assignor to New England
last|tufa for Medical Research, Rldgefield, Conn., a
corporation of Connecticut
No Drawing. Filed June 19, 1957, Ser. No. 666,/76
13 Claims. (CI. 167--78)
This invention relates to improvements in method and
means for immunizing mammals and birds against various
infections to which they are susceptible and for treating
mammals and birds for alleviating diseases,
It has long been known that immunity, for instance,
may be developed in nlammals and birds against various
toxins by introducing a corresponding toxoid into the
body. Numerous efl'cctive toxoids arc known and are
being successfully used. Various antigens and allergens,
hormones and therapeutic agents are also being success-
fully used in this way for the prevention and treatment
of various infections, diseases or dysfunctions.
Though various specifics arc known and in general use
for the treating of various conditions and for immuniz-
ing against them, frequently the effectiveness of the spe-
cific is of short duration, so that repeated treatment is
necessary, or else the agent must be administered in doses
of such size as to cause undesirable side-effects.
It is a purpose of my present invention to increase or
prolong the effectiveness of toxoids, antigens, antiallergic
agents, hormones, therapeutic agents and the like, in gen-
eral, in preventing or alleviating infections and diseases,
and to accomplish this with a materially reduced dosage
of the agent.
This purpose is accomplished by my present invention
in accordance with a new principle of depot medication
whe, chy there is induced significantly greater and longer
lasting immunity, and in accordance ~'ith which I ad-
minister the toxoid, or other selected agent, in a state of
adsorption in or on carbon black.
It has beeen gcnerally recogni?ed that a primary de-
fense of mammals and birds against infection is the retie-
uloendothelial system, commonly referred, to as the
RES, and so designated herein for brevity. The RES is
composed essentially of phagocytic cells, located primarily
in the liver, spleen and bone marrow, but to a laser (x-
tent scattered throughout most of the body as fixed :or
"wandering" cells. One of the functions of these cells
is .to clear the blood stream of bacteria, and other par-
ticdlate material, which may be present in the blood
stream or in the lymph system, by phagocytosis. Where
infectious foreign matter, bacteria for instance, enters the
body of a host, these phagocytic cells of the RES in some
way envelop and destroy the bacteria, thus rendering the
bacteria impotent. The development of antibodies against
the invading bacteria appears to be closely related to,
and a sequel of, this phagocytosis, in some way not fully
understood.
In the extensive study of the RES, it has been estab-
lished that where an appropriate aqueous suspension of
colloidal carbon black is in cctcd intravenously into a
host, this foreign particulate matter is quickly taken-up
from the blood stream by the phagocytic action of the
RE cells, i.e. the rcticulocndothelial cells of the RES.
The particles are phagocytized preferentially by RE cells
in the liver and by the spleen cells, as well as other loci,
according to particle size and electro-charge.
I utilize this selective phagocytic activity of the RE
2,952,585
Patented Sept. 13, 1960
i i it i i Jill i ill Jll Ill "--
2
cells toward carbon black to direct selectively an anti-
gun, toxoid, hormone therapeutic agent or the like to that
portion of the body where it is most effective by adsorb-
ing the antigen or the like in or on carbon black par-
ticles prior to their injection, so that the agent is con-
veyed by the carbon black particles directly to the RE
cells and is more quickly and more effectively taken up
by the ceils, together with the carbon black particles.
A major limiting factor in the development of any
new therapeutic agent is that the entire body must be
"drenched" with the substance so that the cells or organ
which one specifically desires to reach will have an ade-
quate amount. The side-effects, toxic or otherwise, of
"drenching" the entire body are a major limiting and
interdicting obstacle to the use of innumerable otherwise
useful agents.
Critical aspects of this invention are the particle size,
or range of particle sizes, the charge, adsorptivity, state
of aggregation of, and suspending agent for, the colloidal
carbon black. "[he adsorbed agent must not be too light-
ly adsorbed and hence lost before it reaches the RE cells,-
neither must it be too tightly adsorbed and hence un-
available for its function. Colloidal carbon black hav-
ing a particle diameter of from 1 to 100 millimicrons
(Paint, Oil and Chemical Review, vol. 115, No. g, page
22, April 10, 1952) is admirably suited as far as its range
of particle sizes is concerned.
In the previous investigations of the RES involving the
injection of colloidal carbon, difficulties have been ex-
perienced due to the accumulation of the carbon in the
lungs. Early experimenters used India ink as their source
of carbon black. It was not known until 1953 that the
shellac and other gums present in the ink were not toler-
ated by the body. By careful control of particle size,
by choice of original material and by ~ltracentrifuglng
and avoiding excessive agglomeration of the colloid in the
environment of plasma or other body fluids, I can avoid
any significant deposition of carbon black in the lungs
and selectively bring about its deposition largely in the
liver, spleen and bone marrow.
In the presently preferred aspect of the invention, the
carbon blafk having the toxoid, antigen or the like l~-
&~,~ the r~n is injected parenterally in suspension in a
physioio'g]~:al ~aque~ous~sus~nsion which must, of course,
be free from pyrogens which might cause shock, chills
or high fever. The colloidal suspension must be so pre-
pared that the particles retain an electro-negative charge
in the body fluids, and do not agglomerate significantly,
in the plasma, lymph or other body fluids. It is also es-
sential that the toxoid, antigen or the like be adsorbed in
or on the carbon black particles in such a way that it is
retained thereby until phagocytosis of the particle has
occurred. Various procedures may be employed in the
preparation of the colloidal suspension so long as de-
naturation of the antigen or the like is avoided by the
selected procedure.
It is essential that the adsorption force be sufficiently
great to prevent desorption en mute to the RE cells.
On the other hand, it must not be so great as to prevent
60 desorption once the particle is in the RE cell or, in/he
case of macmmolecules such as a protein, the adsorptive
force must not be so great as to uncoil or otherwise de-
nature the protein.
The size of the carbon black particles thereof may be
65 varied, depending primarily upon the location in the
body to which it is desired selectively to direct the agent.
They may be as small as 5 millimlcrons, or even 2
millimicrons. Usually the size of the largest particle
should not exceed about 80 millimicrons. I have found
70 that, where the particle size of the carbon black colloid
does not exceed this maximum, and excessive agglomera.
tion after injection is avoided, the carbon black Im no
10
15
go
~5
30
$5
4o
45
50
55
g,osg,585
3
noticeable toxic effect and may be administered in sur-
prisingly large amounts without ill effect on the host,
providing, of course, that the suspension used for intra-
venous injection is sterile, isotonic, and free from
pyrogens and other contaminants, as indicated above. 5
The colloidal carbon used in accordance with the pres-
ent invention, herein designated "carbon black" is not
to be confused with the various chars produced by de-
structive distilling of animal or vegetable matter. It is
produced by the pyrolysis of liquid or gaseous hydro- 10
carbons and is substantially free from mineral matter.
The proportion of the toxoid, antigen or the like ad-
sorbed on the carbon black may vary over a considerable
range and will usually be determined by the adsorptive
capacity of the particular carbon black for the particular 15
agent adsorbed. The amount of carbon black admin-
istered will, in large measure, depend upon the amount
of the agent adsorbed thereon. In general, the carbon
black having the agent adsorbed thereon or therein to be
administered by injection will be prepared in colloidal 20
suspension in a physiological isotonic solution. The sus-
pension may be administered in appropriate amounts,
usually proportionate to the body weight, by injection
intravenously, subcutaneously or intraperitoneally. It
may also be administered intramuscularly, or as a trans- 25
fusion, or intravenous feeding or by inhalation in a dry
powder form or aerosol.
The invention has been applied effectively, without
deleterious side-effects, to lower animals and birds and
is believed to be effective in the treatment of human be- 30
ings, though conclusive clinical evidence concerning the
latter is not presently available.
I,arge doses of carbon black have been injected intra-
venously into human beings with no toxic slde-effects.
But in my controlled testing of immunity, in which I 35
have used botulinum toxin, the most virulent protein
toxin known to man, I have carried out the tests on
lower animals, as is customary in this field of research,
before proceeding with tests on human beings. As will
be described below, protection of such lower animals by 40
the above-described methods has been obtain.ed.
For example, I have immunized mice against this
botulim, m infection, which is also a serious problem
with respect to duels, pheasants and other fowl, both
domestic and wild. 45
As previously noted, botulinum is recognized to be
one of the most toxic, deadly poisons known. Effective
botulinum toxioid has been prepared by treating the
botulinum toxin with formaldehyde. This toxoid has
been used effectively in accordance with the present in- 50
vention in developing in mice an immunity for this
deadly toxin.
More particularly, a suspension of carbon black, of a
particle size within the range of 18-25 millimicrons, and
having the botulinum toxoid adsorbed thereon, was pre- 5b
pared in a physiological solution and, at intervals one
week apart, 20-gram albino mice were twice injected in-
travenously with ~i0 cc. of the suspension containing 0.7
milligram of the carbon black having deposited thereon
70 micrograms of the protein toxoid. No ill effects 60
were apparent. One week following the last injection,
the mice were given ten 100% lethal doses of the
botulinum toxin without ill effect, while the controls
died within 30 minutes, showing that by this method
there was developed within the mice an effective ira- 65
munity for this deadly poison.
The size and potency of the injection should be varied
depending upon the weight of the mammal or bird
treated. Where a 20-gram mouse is immunized by ad-
ministering the toxoid protein in the customary manner, 70
i.e. not adsorbed on carbon black, 8.5 milligrams of the
toxoid would normally be required to establish compara-
ble immunity.
In the treating of wild fowl, e.g. ducks and pheasants,
care must be exercised to avoid domesticating them.
7~ venously.
4
For this reason, handling and confining of the fowl must
be reduced to a minimum. Preferably the immunizing
should be effected by a single handling. By my present
invention, this may be accomplished by a single injectieya
of the toxoid.
In the immunizing of pheasants, for instance, against
Clostridium botulinum, type C, the toxoid is with ad-
vantage adsorbed on carbon black and the fowl Injected
with an aqueous suspension thereof. To develop in a
4-pound fowl, for instance, a hotulinum immunity by
administering the toxoid in the conventional manner, re-
quires 275 milligrams of the toxo|d. In accordance with
my present invention, comparable immunity can be af-
fected by intravenously injecting the fowl with a suspen-
sion of carbon black, in the particle size range of 18-25
millimicrons, in physiological, isotonic solution, on which
there is adsorbed 1Ao0 that amount of the toxold.
The invention will be further illustrated by the fol-
lowing specific example of immunizing against botulinum
infection, it being understood that the invention is not
restricted to the particular aspects thereof illustrated.
Clostridium botulinum type C toxin is harvested from
a ten-day culture of CI. botulinum, type C, grown within
a cellophane dialyzing sack, the medium used being
cleared cornsteep liquor enriched with 6.5% glycerin and
0.1% CaCI2. The crude toxin is freed from the
organisms by centrifugatlon and subsequent filtration.
The toxin is then concentrated to ~Ao of its original value
by lyophilization. On dialysis of the concentrate, the
toxin is precipitated. The precipitate is dissolved in a
sterile sodium chloride aqueous solution (0.9%) and ad-
justed to pH 4.5 at which point the toxin flocculates.
This toxin so prepared contains a 2,000,000 MLD per
0.1 cc., or, for a 20-gram mouse, and is shown by chemi-
cal analysis to contain 0.1 rag. of protein nitrogen per ml.
To produce the toxoid, formaldehyde is added to the
toxin until the concentration of the formalin is 0.5%.
The toxin is then incubated at 37' C. for 10 days. After
that period, the resultant toxoid is tested in mice for
residual toxicity. If the mice survive injections of I mi.
of the undiluted toxoid daily for 4 days, the toxold is
ready for use.
A colloidal suspension of carbon black of a mean
particle size of 25 millimicrons and containing 90 mg.
of solid material per ml. is diluted with water to contain
20 mg. of solid per ml. An aliquot of the purified toxoid
is added to 5 times the volume of the carbon black sus-
pended at pH 6.8, at which pH the carbon black re-
mains in colloidal suspension. The mixture is then left
at 4° C. for 12 to 16 hours. The toxoid-carbon black
mixture is then adjusted to pH 2, causing the carbon
black agglomerates to drop out of the suspension. The
mixture is then centrifuged at 12,000 r.p.m, for 30
minutes (24,500 g.), and the resultant supernate is do-
canted and saved.
The sediment is resuspended in sodium phosphate buffer
solution at a pH of 6.8. The suspension becomes
colloidal again at this pH and does not sediment.
The above procedure of precipitating, separating and
resuspending is repeated three times. After each wash-
ing, the supernate is tested to determine the amount of
toxoid remaining in the supernate. Ordinarily the second
and third washings contain no toxoid. The final suspen-
sion of the carbon black adsorbed toxoid in the sodium
phosphate buffer at pH 6.8 is filtered through a clarifying
type sintered glass filter and analyzed for the amount of
toxoid present by measuring the amount of protein
present on the carbon black. The suspension is now
ready for injection.
Mode el administration o! the toxold
Two routes of administration are possible. The first
is conventional~intramuscularly. The second, since the
amount of carbon to be injected is innocuous, h intra.
At present, the recommended procedure with
9,952,585
5
botulinum toxoid is at least 6 injections over a period
of two to three weeks. But, since, in accordance with
my invention, the carbon black retains the adsorbed
toxoid and releases it gradually in the RES, two injec-
tions of 1 ml. each, spread one week apart will usually
be found sufficient.
By the intravenous route, the carbon black toxoid is
very rapidly taken up by the reticuloendothelial cells of
the liver and speen, thus forming a depot source of
antigenic material without the need for replenishing by
additional inoculation.
Te,st /or immunity in the immnnized mammals or birds
Two types of challenge may be used. One is by the
injection of graded lethal doses of the toxin into the
immuni.-,ed mammal or bird to determine the highest
dose they can tolerate. The second is by feeding the
mammals and birds graded amounts of toxin added to
their drinking water. The latter is believed to be a better
index of immunity since it involves the natural route of
botulinum intoxication. I claim:
I. As a composition of matter, colloidal carbon black
having adsorbed thereon an agent selected from the group
consisting of toxoids, antigens, anti-allergic agents,
hormones, natural and synthetic, and therapeutics.
2. As a composition of matter, colloidal carbon black
of a mean particle size within the range of 2-25 milli-
microns and having adsorbed thereon an agent selected
from the group consisting of toxoids, antigens, anti-
allergic agents, hormones, natural and synthetic, and
therapeutic,~.
3. A stable suspension, in physiological, isotonic solu-
tion, sterile and pyrogen free for intravenous injection, of
colloidal carbon black of a particle size within the range
of 2-25 millimicrons and having adsorbed thereon an
agent selected from the group consisting of toxoids,
antigens, anti-allergic agents, hormones, natural and syn-
thetic, and therapeutics.
4. ]'he st,spension of claim 3 in which the particle size
of the carbon black is within the range of 18-25 miUi-
' microns.
5. A stable suspension, in physiological, istonic solu-
tion, sterile and pyrogen free for intravenous injection,
of colloidal carbon black of a particle size within the
range of 18-25 millimicrons and having adsorbed there-
on an agent selected from the group consisting of toxoids,
antigens, anti-allergic agents, hormones, natural and syn-
thetic, and therapeutics, the liquid phase of the suspen-
sion being sttbstantially free from said agent.
6. A stable suspension, in physiological, isotonic solu-
tion, sterile and pyrogen free for intravenous injection,
of colloidal carbon black of a particle size within the
range of 18-25 millimicrons and having adsorbed thereon
an agent selected from the group consisting of toxoids,
antigens, anti-allergic agents, hormones, natural and svn-
6
thetic, and therapeutics, the liquid phase of the suspen.
sion being substantially free from said agent and the
carbon black particles with the agent adsorbed thereon
having electro-negatively charged surfaces.
5 7. A stable suspension, in physiological, isotonic solu-
tion, sterile and pyrogen free for intravenous injection,
of colloidal carbon black of a particle size within the
range of 18-25 miUimicrons and having botulinum toxoid
adsorbed thereon.
l0 g. A stable suspension, in physiological, isotonic solu-
tion, sterile and pyrogen free for intravenous injection,
of colloidal carbon black of a particle size within the
range of 18-25 millimicrons and having botulinum toxoid
adsorbed thereon, the liquid phase of the suspension being
15 substantially free from the toxoid.
9. In the method of administering toxoids, antigens,
anti-allergic agents, hormones, therapeutic and like agents
to mammals and birds, the steps of adsorbing the agent
on non-toxic colloidal carbon black particles, and intro-
20 ducing the agent into the body in the state of adsorption
on the carbon black.
10. The method of claim 9 in which the agent is ad-
sorbed on carbon black particles of a particle size within
the range of 18-25 millimicrons,
25 11. Method of conveying toxoids, antigens, anti-
allergic agents, hormones, therapeutic and like agents,
selectively, to the RE cells of mammals and birds which
comprises adsorbing the agent on non-toxoid colloidal
carbon black particles, suspending the particles in physio-
30 logical, isotonic solution and parenterally injecting the
suspension into the body.
12. The method of claim 11 in which the agent is ad-
sorbed on carbon black of a particle size within the range
of 2-25 millimicrons.
85 13. The method of immunizing mammals and birds
against bacterial toxin which comprises de-toxifying the
toxin, adsorbing the de-toxified toxin on carbon black
particles of a particle size within the range of 2-25 milli-
microns, suspending the carbon black particles having
40 the de-toxified toxin adsorbed thereon in the physiological
isotonic solution and parenterally injecting the resulting
colloidal suspension into the body.
References Cited in the file of this patent
45
UNITED STATES PATENTS
2,143,088 Rockwell .............. Jan. 10, 1939
2,897,115 Dullaghan .............. July 28, 1959
OTHER REFERENCES
50
Kato et al.: Internfl. J. Leprosy, vol. 23, No. 4, pp.
406-417, 1955 (as cited in April 1947, Biol. Abstr. 11462
and 11463).
Rossman: Ind. and Eng. Chem., vol. 35, No. 9, Sep-
55 temher 1943, pp. 972-976.
Wiegand: India Rubber World, December 1941, p. 270.
Development of Carbon Black: 1945, p. 90.
• ~ ~'te, ~'~
Id ~-" o~ _~, ."<.G"
~ .1,, ~:... .., ....
United States Patent O/t ce
2,787,579
Patented Apr. 2, 1957
I
2,787,S79
$HAFED ACTIVATED CARBON MEDICINAL
COATED WITH CARBOXYALKYL ETHER
Thonis Johannes van der Weel, Zandvoort, Netherlands,
assignor to N. V. Algemeene Norit MaatschappiJ,
Amsterdam, Netherlands, a corporation of the Neth-
erlands
No Drawing. Application June 15, 1953,
~rlal No. 361,869
Claims priori/y, application Netherlands June 17, 1952
4 Claims. (CI. 167---82)
' It is a well-known fact that gastric and intestinal dis-
turbances, nutritional poisonings and the like can be
successfully combated by means of activated carbon,
which to this end is often taken in the form of tablets,
such as the well-known medicinal Norit tablets.
Practical experience has shown, however, that these
tablets present some drawbacks. In the first place they
tend to give off powder, so that they blacken hands and
mouth. Furthermore the swallowing of these tablets
may be found to be difficult, especially for children.
This is, apparently, due to the adsorptive properties of
the activated carbon. In many cases the gullet veristalsis
is not capable of immediately conveying the tablet to the
stomach, so that the patient has the disagreeable feeling
that it "sticks halfway in his throat." With other tablets,
which are not composed of activated carbon, these draw-
backs are not encountered at all, or only to a very
slight degree.
The drawbacks in question have been met by dredging
the activated carbon, but it is, of course, undesirable to
add to a substance, whose activity is based on its surface-
active properties, extra large amounts of sugar.
According to the invention it is now possible to pro-
duce tablets, granules and similar moulded articles (which
for convenience sake will be called tablets hereinafter)
from activated carbon, which do not at all show the
above-mentioned drawbacks, by coating the tablets with
a thin film of carboxymethyl cellulose or of a similar
carboxyalkyl ether of cellulose. It appears that such a
film substantially entirely prevents the carbon particles
from giving off powder when ,one touches the tablets,
while as a result of the hydrophilic properties said film
will rapidly absorb water when the tablets are taken, so
that these will get a slippery surface and can easily pass
the throat and the gull©t.
The carboxyalkyl cellulose film may be very thin, and
in many cases its thickness is less than 0.01 ram. Very
good results can be obtained, for instance, by applying
on a carbon tablet of a normal size and of a weight of
e. g. 500 milligrams an amount of carboxymethyl cellu-
lose of e. g. 1-2 milligrams, which corre,ponds to a
thickness of a coating of about 0.003-0.006 nun. This
is a very favorable drcmnstance, as it is undesirable to
2
add considerable mounts of colloidal substances to the
activated carbon.
It is very surprising that it is thus possible to coat a
surface consisting of more or less porous, strongly ad-
sorptive carbon particles with an extremely thin film and
to obtain in this manner a "closed" surface, while unlike
the case of dredging, only very small amounts of foreign
substances are used and the adsorptive power does not
decrease in any respect.
10 The film can be applied by treating the finished tablets
with an aqueous solution of the carboxyalkyl cellulose,
preferably by spraying this solution on the tablets and
drying the latter, if necessary.
The carboxyalkylcellulose preferably used is carboxy-
15 methylcellulose. C.arboxyalkylcelluloses of a similar
character which may also be used according to the in-
vention are those which are soluble in water to a viscous
solution, e. g. carboxy ethyl cellulose and carboxy
propyl cellulose.
9.0 I claim:
1. A medicinal preparation comprising a shaped prod-
uct consisting essentially of activated carbon, said shaped
product being coated with a thin hydrophilic film to
substantially eliminate its tendency to give off carbon
25 particles upon contact with other surfaces, said film con-
sisting of water-soluble carboxyalkyl ether of cellulose
and being of a thickness of less than 0.01 ram., the
amount of said carboxyalkyl ether of cellulose being
such that the adsorptive properties of said carbon are
30 not materially decreased.
2. A medicinal preparation as defined in claim I,
wherein said carboxyalkyl ether of cellulose is carboxy.
methyl-cellulose.
3. A medicinal preparation as defined in claim 1,
35 wherein said film thickness is from about 0.003 to 0.006
mm.
4. A medicinal preparation comprising a shaped prod-
uct consisting essentially of activated carbon, said shaped
product being coated with a thin hydrophilic flint to sub-
40 stantially eliminate its tendency to give of/carbon par-
ticles upon contact with other surfaces, said film con-
sisting of carboxymethylcellulose and being of a thick-
ness of from about 0.003 to 0.006 ram., the amount
of said carboxymethylcellulose being such that the ad-
45 sorptive properties of said carbon are not materially
decreased.
50
t;5
References Cited in the file of this patent
UNITED STATES PATENTS
1,542,006 Sauer ................. June 16, 1925
1,552,549 Eicher ................ Sept. 8, 1925
2,196,768 Hlatt .................. Apr. 9, 1940
2,502,809 Vogelsang .............. Apr. 4, 1950
OTHER REFERENCES
Hollabaugh et al.: Ind. and Eng. Chem., October 1945,
p. 945.
T
.T
m
/
Patented Jan. 28, 1941
/
2,229,876
UNITED STATES PATENT OFFICE
2,229,876
MANUFACTURE OF A COMPLEX ADSORBATE
Ilenry A. Smith, Berkeley, Calif., assignor, by
mcsne assignments, to National Oil Products
Co., Harrison, N. J., a corporation of New
Jersey
No Drawing. Application August 13, 1937,'
Serial No. 158,953
6 Claims. (CI. 167--$1)
• •
This invention relates to the manufacture of a precipitates and floats to
the surface of the liquid,
vitamin adsorbate containing at least two vita- from whence it is readily
removed, dried and
rains which adsorbate is of a high plural vitamin ground.
potency per unit volume. The residual liquor, now
free from casein and
6. In manufacturing vitamin adsorbates contain- albumen, Is concentrated
for milk sugar recovery.
ing two or more vitamins, the usual practice is to Either before or after the
concentration step a
adsorb a vitamin on one adsorbent and then corn- preliminary vitamin G or
lactoflavln adsorbate
blne this with another adsorbent carrying an- can be secured.. For
,example, 40 pounds of
other vitamin. While the result is satisfactory fuller's earth is added to
1000 gallons of liquid
t0. in that a plural vitamin content is contained in prior to concentration.
This mixture is agitated
the mixture, the mass is of a low vitamin potency for about 9.0 minutes and
then filtered, the filtrate
per unit volume, as can be readily appreciated, being returned to the
plant, where it goes Into the
because of the use of separate masses of adsor- next step, vacuum'
evaporation, for milk sugar
.. bent for each vitamin. I have dlscovered that production. The adsorbate
removed from th~
151 adsorbent materials selectively adsorb vitamins filter press is washed,
dried and ground in a ball
and that even though an adsorbent has practical- mill, this concentrate
containing approximately
ly exhausted its adsorbent capacity for a given 60 gamma of riboflavin per
gram.
vitamin, this adsorbent still has the capacity to Instead of the foregoing,
the liquid, free from
adsorb an appreciable quantity of another vita- casein and albumen, can be
concentrated in
20 rain. For example, I am able to successfully in- vacuum evaporators. Prior
to transportation of £0
corporate vitamins G and B~ on the same ad- the material to the milk
sugar crystallizer, the
sorbcnto thus reducing materially the unit volume material is contacted with
fuller's earth to secure
of the adsorbate, a first vitamin G
adsorbate. This process hos the
This selective adsorption enables a compound advantage that the color
of the subsequent sugar
U vitamin adsorbate to be manufsctured In which precipitated from the
liquid is improved, a whiter £5
the individual vitamins are present in selected sugar being obtained on
the first precipitation
values and at a'high unit volume potency. For when the fuller's earth
treatment follows the
example 1500 gamma of riboflavin (also termed concentration step.
lactoflavin and vitamin G) per gram can be It is also possible to"
recover the vitamin G by~
|0 placed on an adsorbate per gram thereof while a adsorption on fuller's
earth from the mother~30
.comparable high Bz value per gram can also be liquor obtained from the
lactose crystallizersl
placed on the adsorbate. The milk sugar when
delivered from the evapora-
As suitable adsorbent materials, I can use tors is in the form of a
heavy syrup. This ma-
fuller's earth, bentonite, and other adsorbent 'terial is transferred to
crystallizers in which the
$~l earths, _~ctivated carbon and the like. These sugar is slowly
crystallized. These crude crystals: U
materials operate-suecessfuliy in the liquid phase are separated from the
mother liquor in the cen-
and in the presence of water, trifuge. This mother
liquor is reconcentrated
Hereinafter I have disclosed the manufacture and again crystallized to
give as high a recovery
of an adsorbate containing lactoflavin and vlta- of sugar as is possible.
The mother liquor ob-
40 rain B~. Of course, any other vitamin which is tained by centrifuging the
raw crystals is of a 40
adsorbed on these materials can be substituted dark brown color
containing some sugar and the
.in place of these, these vitamins being mentioned minerals originally in the
milk and any addi-
as examples, tlonal salts added in the
proce~ of manufacture
A suitable source of lactoflavin is skim mtlk together with the vitamin
G contained in the
45 and its products. The lactoflavin manufacturing milk. It is possible to
treat this mother liquor 45
operation Of this invention includes precipitation with fuller's earth and
secure an adsorbate con-
of the casein from the skim milk by the addition raining up to 9.00--300
gamma of riboflavin'per "
of an acidifying medium as hydrochloric, sulfuric . grani,
i
or lactic acid. This causes casein coagulation, After the adsorbate has
been prepared by any
60 the casein being separated from the remaining one of the foregoing
processes, i~ should be 50
liquid, washed, dried, and ground for market, thoroughly washed to free
it from all occluded
Albumen is removed by adjtmting the pH of the milks, salts, or other form
contaminates picked up
remaining liquid to approximately 6.8, calcium in the process of
manufacture. The adsorbate
hydroxide being used for this, and the material may then be used wet as is,
or dried, ground and
65 thereafter Is brought to a boil. The albumen stored for future use.
/~6 ~li,
• .. " ~ !'~i
2
This adsorbate0 containing vitamin G, can be
treated with a liquid containing vitamin B~, or
any other water soluble vitamin which has the
property of being adsorbed on fuller's earth. The
5 resultant prodt.~ct is an adsorbate containing two
or more water soluble vitamins of the B complex.
To make an adsorbate containing vitamin G in
a higher concentration than is po~ible by ad-
sorption of riboflavin from crude substances by
I0 clay, the following method may be employed.
This enables a low potency adsorbate (50 to 250
gamma of riboflavin per gram) to be utilized in
Producing an adsorbate containing up to aP-
proximately 3000 gamma per gram. This rea-
l6 terial can be used as such or for making a com-
bination adsorbate by an additional adsorbate
with vitamin B, Be, etc.
The adsorbate is elutriated with a suitable
solvent such as 70% (60% to 90%) acetone, or
gO with pyridine; 250 pounds of the adsorbate con-
taining approximately 60 gamma of riboflavin,
for example, are mixed with 500 gallons of 70%
acetone in a ribbon type mixer. This mix is
preferably made by adding approximately 100
g~ gallons of acetone to the mixer; 250 pounds of
clay are then added, and the mix is agitated until
a uniform pasty consistency results. The balance
of the acetone is then pumped into the mixer,
after which it is agitated for two hours and then
30 filtered. The filtrate is pumped back to a feed
tank, and the cake is returned to the mixer.
The second extraction is made by adding 100
gallons of acetone to the mixer. Filter cake is
added slowly so that it is broken up in the mixer,
.~$; When the mix has a uniform pasty consistency,
the balance of the acetone (about 150 gallons)
is added and the mixture is agitated for two
hours. A filter aid as Filter-cell can be added
about 5 minutes before the material is pumPed
40 into the filter, to insure quick fltratlon. The
second nitrate is pumped to the feed tank and the
cake is discarded.
The acetone filtrate is then concentrated, in
the absence of light. The still is oPerated to first
45 drive off the acetone and then the water. When
the clutriate from the treatment of about 1000
pounds of the clay has been passed into the still,
it is concentrated down to as small a volume as
possible and drained into a receiving tank. The
O0 still is then washed down with water and the wash
is drained into the receiving tank. The ma~
terial In the receiving tank is now concentrated
under a vacuum to a volume of approximately 24
liters. The 24 liters is then filtered and the
05 filtrate adsorbed on fuller's earth, the 24 liters
requiring about 18Y~ pounds. The resulting earth
will contain approximately 1500 gamma of ella-
rain O per gram. A second adsorption made from
this liquid using 6 pounds of fuller's earth will"
00 give a potency of about, 100 gamma of vitamin O
per gram. Th~ clay is fl.nally separated from the
liquid by filtration after which it is air dried and
ground in a ball mill. Thereafter, the high po-
tency adsorbate may be used as is or may be
0~ treated with a solution of vitamin B~ or Be or
both to make a combination adsorbate,
For example: i00 pounds of rice bran, or an
equivalent amount of other cereal products con-
talning vitamin B~ (thiamine), is mixed with 500
~$ pounds of water. When thorough mixing has
been secured and sufficient time has.been allowed
for the thorough penetration of the material by
the water, the solid material is then separated by
passing the material through a suitable filte~
device. It is desirable to maintain the tempera-
ture at approximately 125° F. during the mixing
period.
The filtrate obtained from the mixture of bran
and water carries a suspended solid content of a 5
colloidal nature which is only difficultly sepa-
rated. In fact centrifuging and pH adjustment
are not effective and the only satisfactory way in
which the solids can be ©aimed to coalesce is by
heating. The solids are preferably removed be- 10
fore treatment with the adsorbent. The filtrate
is usually heated to a temperature between 60
and 100° C. Under these conditions the protein
and comparable material in suspension is caused
to coagulate and rise to the top of the liquid. 1~
The clear liquid can then be withdrawn from the
bottom of the tank, leaving a cake of coagulated
material. This clear liquid may now be tlsed as
a source of vitamins B~, Be, and the filtrate
factors. The cake of coagulated material may 20
either be washed to secure a better yield of vita-
min B complex or may be discarded.
The dried and ground adsorbate containing |'
laotofiavin is now contacted with the described
liquid containing vitamin B~. Be, and an absorp-
tion of B~ and Be occurs upon the adsorbate which
contains lactofiavin. Thereafter, this clay now
containing both vitamins adsorbed thereon Is
dried and ground. By suitably regulating the
amounts of vitamin B Per pound of adsorbate ~0
used, the amount of vitamin B~ adsorbed upon
the clay containing the lactoflavin can be regu-
lated to provide wherever varlation is desired.
I claim:
1. A method for producing a high potency vlta° $45
rain adsorbate of low bulk comprising adsorbing '"
on an adsorbent material a vitamin from a solu-
tion thereof, separating the adsorbent from the
solution, drying the adsorbent, adsorbing a second
vitamin on said adsorbent from a solution there- 40
of, seParating the adsorbent from the second
solution and drying the same toprovide a vitamin
adsorbate having at least two vitamins In an
amount greater than the vitamin content repre-
senting the saturation value of said adsorbent 45
with respect to' either one of the adsorbed vita- •
rains.
3. A method for producing a vitamin adsorbate
of high plural vitamin potency per unit volume
comprising adsorbing on an adsorbent material 50
vitamin G from a solution thereof, separating the
adsorbent from the solution and adsorbing vita-
min B thereon from a solution thereof to provide
an adsorbent material bearing vitamins B and G
in an amount greater than the vitamin content
representing the saturation value of said ad-
• sorbent with respect to either vitamins B or O.
• 3. A method for producing a vitamin adsorbate
of high plural vitamin potency per unit volume
comprising adsorbing on an adsorbent material 60
vitamin B from a solution thereof, separating the -
adsorbent from the solution and adsorbing vita-
min O thereon from a solution thereof to provide
an adsorbent .materl~l bearing vitamins B and G
in an amount greater than the vitamin content e~
representing the saturation value of said ad- '
sorbent with respect to either vitamins. B or O.
4. The process as setforth In claim 2 wherein
fuiler's earth is used as the adsorbent.
5. The process as set forth in claim 9. wherein ~O
bentonite is used as the adsorbent.
6. The process as set forth In claim 3 wherein
., bentonite is used as the adsorbent,
'HENRY A, SMITH.
---
Patented Sept. 29, 1936
Z,OSS,47S
UNITED
STATES PATENT OFFICE
M~4~S
Tm~TMimT OF FLUID
oxidizing szent in activated ee~tmn from aqueous
solutio~ I hsve tow~ that by such method s
high eoncentmtJon of oxidisi~ agent may be
obtained in the m~, such as to render it
hiZhly effective, and that the material is quail- J
fled to retain its effecttvonm for extended pe-
invention relates to the treatment of
fluids for modification or removal of sub~anees
carried in them, and to a new material and the
method of preparing same for such and other
5 tmeL
A general object of the invention is the pro-
vision of a new material having eharacteristies
qualifying it for industrial use in the oxidation,
sterilization or modification of fluids or of sub-
10 stances carried in them in suspension or solution.
Another object is the provision of a method for
treatment of fluids for oxidation, sterilization or
modification of them or their components.
8till another object is the prov~on of a rea-
l5 terial and method for the separation and re°
covery of solutes by oxidation.
Another object is the provision of a method
for the separation of oxldizl~ agents from
fluidL
~0 ~ another object is the provision of a new
oxidising material I~ceptlble of regeneration.
Other and further objects will be pointed out
or indicated hereinafter or will be apparent to
one skilled in the art upon an undemtsnd~
95 of the invention.
It is in many ~ces desirable to separate or
convert various oxidizable substances which are
carried in solution or in suspension in different
fluids. This may be desirable for the purpose
80 of freeing the fluid from such substances or for
the recovery of the mzlmtances themselves. For
-example, it may be desirable to free water from
iron or manganese carried in solution, or to sub-
Ject It to sterilizing trcatment for the Imrpose
85 of killing or incapacitating bacteria or other
micro-organisms which it may carry. Proce-
dures heretofore employed for such p~0 in
the treatment of water on a commercial or in.
dustrlal scale for example, involve the dosing of
40 the water, as with coagulants, precipltants and
bactericidal agents, as practiced for example in
the aluminum sulphate, lime and soda, and
chlorination metho~ In these various dosing
procedures, the success of the treatment and the
45 proper condition of the water are dependent upon
accuracy in the dosing and treatment, which ac-
curacy it is difficult to maintain. By utiliza-
tion of the present invention, all uncertalntiem
in and necessity for accurate dosage control are
50 obviated.
Described generally, the present invention coro-
t prises a new treating material consisting of acti-
rated carbon having an adsorbed oxidizing agent.
The invention also comprises a method of form-
55 lng such treating material by adsorption of an
rlods even when in Contact with liquids. Ttm,
material may be of granular, puiveruiemt or other
form ~ptinz it for suitable in~ of con-
tact with the fluids or other substances which 10
are to be treated. T'nk material, suitably
pared with an oxldistnz agent selected with ref-
erenco to the ecnteml~ted use or mal0mtanec to
be trested, will reset effectively with the con-
tempiated oxidisable substances canted in solu- 141
tion or in suspension in a fuid subjected to con-
ta~'t with the trestieG mtm'l~ Depending ms
the nature of the oxidim~e substance in the
fluid, it may unite with the trea~inZ material.
and thus be removed from the ~ or it may
reme~ in the fluid in Its oxidized ¢o~ditlo~ De-
pendinz upon the nsture of the o~ldizinZ ue~t
used in the prelmmtlon of the treatl~ material,
the latter may have sterfisin~ or b~zrlcidal
powers effective to kill or inc~actt~te micro-
ormmim~ in the treated fluid, or other powers
effective to modify substane~ contained In the
trested flu~L
• A more defied un~ of the inven-
tion may be had from the followinS specific ex- SO
smplec, which are presented merely by w~ of
liltmtmtlon, as they do not exhatmt the mnse of
particular applications of the invention.
The activated carbon used for preparation of
the treating material may be of vea~o~ kinds 85
now known. I have found an activated carbon
or char made from Texas l~zites, and marketed
under the trade-name 'q)areo", to prove gener-
ally effective and satl~s~zry. I have found
that in its fresh and activated Condition, and in 40
a~nular or pulvertdent form, this material will I
adsorb quantities of a number of oxldisl~ a~ente [
from aqueous solution, and with its adsorbed '[
content or loading or charge of the oxidiMng |
agent so acquired, will react subsequently with [1~
oxidizable or other substances carried in fluids, --
either in solution or in suspension and will re-
tain this power over an extended period of use
in treatment of liquids as well as pses. For
example, for preparation of the tnmting ma- 50
terial, a tenth-normal solution of potuslmn per-
manganate may be percolated thro~h a bed
of the activated carbon in sueh quantity that the
• carbon will acquire by adsorption an effective
charge or losdin~ of the ~ ~ Xn
1
9.
the concentration indicated, the solution may
be entirely decolorized and freed from the per-
manganate. The treating material thus formed
may be utilized for removal of iron and man-
6 ganese solutes from water by percolating the
water through a bed of the material. This may
be carried on in a cloced system, so that a pres-
sure head may be maintained on the treated
water./ The treating material may be regener-
10 ated periodically with a fresh solution of potas-
sium permanganate, with or without a prelimi-
nary removal of acquired manganese and iron
compounds by appropriate solvents.
By way of further example, a demonstration
15 of the effectiveness of the treating material Just
referred to may be made by passing through a
bed of the same an acid solution of ferrous sul-
phate, whereupon it will be observed that the
ferrous solute is oxidized to the ferric form. as
20 evidenced by a change in color of the solution
from blue to brown, and which may be confirmed
by suitable chemical analytical tests.
By way of further example, a treating mate-
rlal may be prepared by adsorption in activated
25 carbon of potassium dichromate from aqueous
solution, and upon the passing of a sulfuric acid-
, ethyl alcohol mixture through a bed of this ma-
~terial, there is an apparent conversion of the
| ethyl alcohol to acetaldehyde.
30/ As a further example of a treating material
"which may be employed for sterilizing effect,
~activated carbon may be charged with a bac-
tericidal oxidizing agent, such as iodine, by ad-
sor.ption from a suitable aqueous solution. Such
material possesses distinct germicidal powers,
and micro-organisms contained in the fluid sub-
Jected to contact with the material will be killed
or incapacitated by its action. As a variant of
such procedure for sterilization of a liquid, water
40 for example, the water maY be subjected to pre-
treatment with iodine in a concentration Such
as to effect ,sterilization, and the treated water,
after the desired contact period, may then be
passe~l through a bed of activated carbon, where-
45 in th~ iodine is removed from the water by ad-
sorpti0n.
In like fashion, by appropriate selection of the
oxidizing agent for preparation of the treating
material, the invention may be applied to the
50 treatment of other various particular fluids and
solutions. For example, to remove excess alka-
linity from water, a treating material may be
prepared by adsorption of an oxidizing agent
which is also an acid (e. g. nitric acid) in acti-
55 rated carbon, and the alkaline water passed
through a bed of such material. Thus water
which has been subjected to softening treat-
ment by the lime-and-soda process may be freed
Of its residual alkalinity. Tests have indicated
60 that regardless of the initial alkalinity of the
water, it may be effectively neutralized by this
treatment.
In certain industrial processes it is desirable
to free a gas from impurities which are reduc-
65 tng agents, sulphur dioxide, for example. My
treating material and process may be employed
to effect such result. By preparing the material
by adsorption of potassium permanganate in ac-
tivated carbon from a solution, and passing a
70 gas containing sulphur dioxide through a bed of
such material suitably moistened, large volumes
of the sulphur diOxide may be removed through
oxidation of the sulphur dioxide to sulphur tri-
oxide.
76 In instances where the oxidizable material
9j0§5~476
from the treated fluid unites with the treating
material, it may be recovered from the same by
appropriate treatment.
It is to be observed that an inherent advan-
tage of the present invention results from the 5
fact that it involves no proportioning of the oxi-
dizing agent to the material treated. Although
the actual amount of oxidizing agent actually
present may be greatly in excess of the require-
•ments of the oxidizable material or fluid in con- 10
tact with the treating material at any instant,
such excess does not become an addition to the
treated fluid, the amount supplied to the reac-
tion being automatically correct and controlled
by the reducing capacity of the substances which 15
are present "and which it is desired to oxidize.
Hence there is no possibility for overdosage un-
der any circumstances, or of insufficient dosage
so long as the treating material retains its oxi-
dizing power. Although, in the course of use, 20
the oxidizing effectiveness of the material may
become reduced, the material may be regenerat-
ed to restore that power by retreatment with
the oxidizing agent and, if necessary, by reacti-
vation as a preliminary to such additional ad° 25
sorption of the latter,
What I claim is:
1, A process for the treatment of a fluid con-
taining a sulfurous reducing agent, which com-
l~rlses submitting the fluid containing said sul- 30
furous reducing agent to contact with carbon
containing substantial quantities of an adsorbed
non-gaseous oxidizing agent, whereby to effect
a reaction between said sulfurous reducing agent
and said oxidizing agent. 35
2. A process for sterilizing an aqueous liquid,
which comprises contacting the liquid with car-
bon carrying a substantial qUantityof adsorbed
iodine.
3. A process for purifying fluids, which corn- 40
prises contacting said fluids with carbon carrying
a substantial quantity Of adsorbed iodine.
4. A process for treating a liquid cOntaining
a substance which will react with a water-soluble
oxidizing agent, which comprises contacting the 45
liquid with a water-soluble oxidizing agent ad-
sorbed in adsorptive carbon.
5. A process for treating a liquid COntaining a
reducing substance with a water-soluble oxidiz-
ing agent capable of reacting therewith, which 50
comprises contacting a water solution of said
oxidizing agent with adsorbent carbon tO the ex-
tent necessary to absorb a quantity of said ox-
idizing agent and to reduce the coneentrati0n of
said oxidizing agent in said solution, removing 55
said carbon from contact with said ~olution, and
then contacting the carbon containing said ad-
sorbed oxidizing agent with the liquid to be treat-
ed to liberate said o]/ldiziug agent onlY'to the ex-
tent necessary for the reaction with said reduc- 80
ing substance.
6. A process for treating a liquid containing
dissolved substances capable of being oxidized,
which comprises adsorbing a substantial quantity
of a non-gascous oxidizing agent in carbon and 65
from an aqueous medium, and contacting said
liquid with said carbon to effect a reactiOn be-
tween the oxidizable substance dissolved therein
and the oxidizing agent adsorbed in the carbon,
thereby removing from the carbon the amount of 70
oxidizing agent entering into the reaction with-
out physically displacing from the carbon the
portions of said oxidizing agent not entering into
the reaction.
7. The process which comprises adding to a 76
10
S,OSB~476
liquid an undetermined amount of a reducing
agent soluble therein, and then contacting said
liquid with carbon carrying a substantial quantity
of an adsorbed water-soluble oxidizing agent, said
quantity being in excess of that required for re-
action with the reducing compounds in the said
liquid~ whereby to react the reducing agent in
said liquid with the adsorbed oxidizing agent in
the carbon to remove from the carbon the amount
of the oxidizing agent entering into the reaction
without physically displacing from the carbon
the portion of said oxidizing agent which does
not enter into the reaction.
3
8. The method of treating a liquid containing
a dissolved quantity of an organic compound ca-
pable of being oxidized, which comprises contact-
ing said liquid with carbon containing a substan-
tial quantity of a water-soluble adsorbed non- 6
gaseous oxidizing agent to produce a reaction be-
tween said organic compound and said oxidizing
agent and to remove from the carbon only the
amount of said oxidizing agent necessary for said
reaction. 10
ABRAHAM SIDNEY BEI-IRMAN.
it~~
/
Patente'd June 15, 1926.
.., , r
1,589,081 f
UNITED STATES PATENT OFFICE.
RUDOLF ADLER~ OF CARLSBAD~ CZECHOSLOVAKIA.
ADSORPTIVE CHARCOAL FOR MEDICINAL I'URP0~ES.
N0 Drawing. Application £1ed ]~ebruary 25s 1921, ~erial No. 447s915, anti in Czechoslovakia December
5, 1919.
". Adsorptive charcoal for medicinal pur-
poses, in tim shape of compressed bodies of
powder, tablets, granules, pills and the like,
• is chiefly produced in the following way:
t "lhe charcoal is mixed with binding mate-
rials such as gelatinous substances, gums
and rosins, starch, dextrin, and the like,
and, after gradual granulation and compres-
• sion, is dried.
10 Practice, however, has shown that the
in the ceramic sense--represents tim thin-
ning substance. B~ the addition of large
quantities of charcoal shapes are obtained 4o
which are easily crumbled ll~l water or other
liquids, while on the other hand by the ad-
dition of small quantities of charcoal the
sh,qpes have greater durability.
• For pills, compressed bodies of powder, 45
and the like, in which a quick and 'complete
disintegration is desired in the mouth or in
charcoal preparations produced in this man- the digestive tract, and which, when sat-
net' have no action---or only little action-- nrated with water, are required to give a
,and it is found that under certain circum- "homogeneous suspension, the amount of t~0
stances, for example ,vith diabetic subjects, charcoal added would have to be consider-
1~ such prel)arations ha~e an injurious action, ably greater than in the production of flat j
It has now been found that charcoal prep- discs, cones, or sticks and the like, which are
]
arations Of excellent action can be obtained to_he recd. a_s ~lisinfvctants and_ o~~ [
if in place of the customary materials hith- bo_q.4j~ for introduction into wou-ii~s, and 1~
crto nsed for binding together the preferably K~,e therefore to retain their shape.
so finely divided charcoal, such materials are ']he plastic charcoal mas~s can, if re-i
employed which are t~ot, or o~,lv in ~ml)ara- qub'e~l~ before beitJg~]talWd~ Im ttdmi~ed with
I
lively ~mall qm.~titi,% s~d~orl~l by th(; cb~tr- oth(~J' medicated s.b.~tttt ¢(% if (hcue ~r(;
(o
coal. act at the same time as the adsorption char-
"6o
!: i¸
il :i
i)
I
it
(,
In this particular case, the masses retain In testimony whereof I have hereunto set
~5. their shape after drying. The durability of my hand. ' "
the formed shape is dependent upon the
quantity of the fine charcoal powder which-~- Da. RUDOLF ADLER.
Elastic clays, jelly-like silicates, gypsum" coal.
t:! :,
~t~ and the like have shown themseh'es as par- I claim as my invention:
~: ,:
ticularly suitable for this purpose. 1. A medicinal charcoal preparation in ........
"
l,~xample.--70 kg. of adsorption charcoal compressed body form consisting of a mix-
are mixed with 80 kg. of plastic clay, ture of powdered adsorptive chareoal, and an ~
j
kneaded with the addition of 70 litres of inorganic binding material,
t !
a0 water until a homogcneou.q mass is obtained 2. A medicinal charcoal preparation in
and then shaped in the tablet machine. The compressed body form consisting of a mix-
moist tablets are subsequently dried at a tern- ture of powdered adsorptive charcoal, and a
I:
perature of about 70°. - plastic clay. "
~0 ~, ~,
(
---
/
/
U ted States Patent
n , ,,, i i lllJ tl i
1
2,951,791
USE OF CALCIte1 SIIJCATE IN TABLET
COMPRESSING
Carl Louis Stearns, Orangebnrg, N.Y., 8s.slgnor to Ameri-
can Cyanamid Company, New Yorkj N.Y., a corpora-
tion of Maine
No Drawing. Filed Aug. 31, 11959, Ser. No. 836j939
2 Claims. (Ci.. 167----82)
This inventlon relates to the production of tablets of
therapeutic materials.
In the pharmaceutical industry it is a well-known fact
that very few crystalline or powdered materials can be
compressed into suitable tablets on automatic tableting
equipment in their crystalline or powdered form. The
practice has developed of first preparing a granulation of
the material, because it is known that the grain-like struc-
ture thus formed is suitable for compression into tablets.
There are two weU-known methods of preparing a granu-
lation, namely, the wet granulating process, and the dry
granulating process which is also known as "slugging."
The method of preparing a granulation according to the
wet granulating process consists of moistening the dry
Powder, with or without the addition of an adhesive
substance, until the whole is converted into a crumbly
mass. The mass is then forced through a screen in order
to reduce the material to a grain-like structure of small
granules. The most commonly used moistening agent is,
of course, water although other solvents are well-known
for this purpose. It is also common practice to add a
substance such as gelatin, starch, or gum acacia in order
to assist in granulating the material.
The method of preparing a granulation according to the
dry granulating process consists of pre-eompressing the
dry powder into oversized tablets or "slugs." These over-
sized tablets or "slugs" are then broken into a granulation
of substantially uniform size.
The present invention is based on the discovery that the
addition of not less than about 20% hy weight of.cea~iu.m.-
silicate aerogel to crystalline or powdered materials ren-
it~rs'them ca~ble of being compressed directly into suit-
able tablets on automatic tableting equipment. The pres-
ent invention completely eliminates the necessity of first
preparing a granulation of crystalline or powdered ma-
terials before compressing them into tablets. In the
tableting art, the elimination of the necessity of first pre-
paring a granulation results in a host of economle ad-
vantages. Insofar as the wet granulating process is con-
corned, the wet mixing, drying, and screening operations
are eliminated. Insofar as the dry granulating process is
concerned, the pro-compression, breaking, and screening
operations are eliminated. In both cases, the amount of
equipment, labor and floor space needed is vastly re-
duced. Furthermore, since by praeticlng the present in-
vention a compressed tablet can be made eliminating all
but the steps of mixing and compressing, there results a
great saving of time.
The .present invention is not to be confused with the
1Jse of small amounts of calcium silicate aerogel as a lu-
bricant in tablet compressing. Lubricants are rarely used
in excess of 5% by weight in tablet compressing for the
purpose of preventing sticking in the die and promoting
the flow of powder in the hopper.
The calcium silicate aerogel that is used in practicing
the present invention is one of a number of commercially
available siliceous aerogels produced in either the vapor
phase or the liquid phase. It is an extremely porous, very
Of ce
2,951,791
Patented Sept. 6, 1950
2
light and relatively inert material which has a physical
structure which has been described as a tenuous web of
microscopic silica filaments. It has a bulk density rang-
ing from 6 to 15 pounds per cubic foot and a surface area
5 of the order of from 100 to 200 square meters per gram.
Particle sizes may range from 0.01 to 0.05 micron.
It is indeed surprising that the addition of other siliceous
aerogels, such as silica or silici¢ acid, to crystalline or
powdered materials does not render them capable of being
10 compressed directly into suitable tablets on automatio
tableting equipment.
Many materials which heretofore were exceedingly dif-
ficult to prepare in tablet form, such as, for example,
hexylresorcinol, may now be readily tableted by the prao-
15 tice of the present invention. In practicing the present
invention, it is only necessary that the crystalline or
powdered materials to be tableted are compatible with
the calcium silicate aerogel. The material to be tableted
may be mixed directly with the calcium silicate aerogel or
~0 it may be dissolved in a solvent and the resulting solution
may be mixed with the calcium silicate aerogel, after which
evaporation of the solvent is affected. Furthermore, the
maximum proportion of calcium silicate aerogel which
may be employed in practicing the present invention may
25 be very close to 100% by weight in the case of those
medicaments which are administered in small amount.
In practicing the present invention, lubricants such as
magnesium stearate, fillers such as starch, or disintegrators
such as polyvlnylpyrrolidone may be added to the mixture
80 of the calcium silicate nerogel and the crystalline or
powdered material prior to tableting on automatic tablet-
ing equipment.
The following examples are illustrative of th~ present
invention:
85 Example 1
In 200 parts of anhydrous ethyl alcohol was dissolved
200 parts of hexylresorclnol, and to the resulting solution
was added 1~0 parts of calcium silicate aerogel. After
40 thorough admixture, evaporation of the alcohol was
effected, and then 3.5 parts of magnesium stearate was
blended into the mixture. The resulting powder was
tableted in an automatic tableting machine whereby excel-
lent tablets were obtained.
Example 2
45
A mixture of 30 parts of 2.acetylamino-l,3,4-thiadi-
azole-5-sulfonamide, 26 parts of calcium silicate aerogel,
3 parts of starch, and 1 part of magnesium stearate was
prepared. The mixture was thoroughly blended and then
50 screened through a 60 mesh screen. The resulting powder
was tableted in an automatic tableting machine whereby
very good tablets were obtained.
Example 3
55- A mixture of 15.0 parts of ctdortetraeyeline hydro-
chloride, 10.5 parts of calcium silicate aerogel, 11.85 parts
of starch, and 0.15 part of magnesium stearate was pre-
pared. The mixture was thoroughly blended and then
screened through a 30 mesh screen. The resulting powder
60 was tableted in an automatic tableting machine whereby
excellent tablets were obtained.
What is claimed is:
1. The process of preparing tablets of therapeutic ma-
terials comprising the steps of mixing a non-granulated
active therapeutic material with not less than about 20%
135 by weight of calcium silicate aerogel having a particle size
of from about 0.01 micron to about 0.05 micron, and
forming the mixture thus obtained into tablets by com-
pression.
2. A therapeutic tablet consisting essentially of a non-
70 granulated active therapeutic material and not less than
about 20% by weight of calcium silicate aerogel h~vinf#
9,0B1,701
S
a particlo slze of from about 0.01 micron to about 0.05
micron.
Reference8 Cited in the file of this patent
UNITED STATES PATEN'~
2,059,811 8auez: .................. Nov. 3, 1936
2,768.899
2,868,655
5 533,625
Waldo .................. Oct. 30, 1956
Landerburg ............. Jan. 13, 1959
FOREIGN PATENTS
Great Britain ............ Feb. 7, 1941
•., • •
qL
.Q
2,143,0G8
,
!
UR]TED STATES PATENT OFFICE
1,14S,©$8
THEEAP~UTI0 AGENT
Oeor~ ~ ~o~n, ~atore, Ohio
NO Drawing. Application May 28, 195'/,.
Serial No. 145,884
9 Claims. (CI. 16'/--58)
This lnventlon relates to the~ral~utlc r,~en~and settling. Thief is what Is meant
by the term
more particularly to an agent t, dapted for l_ntra- "dispersed" as used in the
claims. These results
venous Injection for the purpose Of ads'~bing are accomplished by means of a
dispersing agent
b"h~Er]~l" toxins, stimulating phagocytosis, and or a protective agent alone, or
by a combination
5 activating ~lie-retlculo-endothellum system, of a dispersing ag6nt and
protective agent, or by I~
'~e Jn.tr~venous Injection of ch~rcoal or carbon means of an agent having
dispersing and protec-
Particles Is hot new. 'I~ae excellent adsorptive tlve properties. In using the
term "protective
powers of carbon are well. known and many at- agent", I Include, of course,
protective collolds~
tempts Imve been made In one way or another The use of these agents permits
fine grinding to
10 to use these advante.gcous qualltl~ of charcoal a much finer degree than can be
accomplished 10
In the treatment of human beings for the purpose without them, because they cause
eachel~artlcle
of removing a toxlc condition. The uses of char- to act as an entity. Thls
enables me to classify
coal for this purpose In the past have, however, the particles as to slze by
filtration, air separa-
been limited by reason of the fact that dangerous tlon, wet floatatlon, wet
classification or cen-
l~ results were apt to result from the action of the trlfuglng.
II~
carbon particles themselves. They might be As a car r!er I may use a large
number of sub- |
spicular in form ~ud cause puncturing of smaller stafig~--.-Examples of carriers
arc water, water
blood vcssels ]ea,.llng to the formatlbn of blood miscible solvents, saline
solution, and glucose.
clots and the llke. The size of the particles and Without limiting myself, I
prefer to use sterile
~0 their tendency to conglomerate has also caused double distilled water.
20
mechanical blockage of the blood vessels. Fur- Many dispersing agents are known
in the art;
thermore, dif~eulty has always been encountered among these are, by way of
example, the poly-
In passing the material through the bore of a merlzed organic salts of
sulphonlc acids of the
hypodermic needle. Another difficulty has been alkyl-aryl type, the alkylated
naphthalene sul-
due to the rapid sedamentatio~ of the carbon phonic acld type, and colloidal
dyes of various 25
particles In a very short space of time, par- types. Entirely without
limitation, I prefer to
tlcularly where the Injection is not made very " use Congo red, which is a
colloidal dye, and while
promptly after the syringe is filled, various amounts of a dispersing
agent may be
In vlew of these various difficulties It is an used, I have found it preferable
to use one per
object of my invention to provide a material cent of the Congo red by weight
of the carbon. 80
which may be tnjeeted intravenously where lndl- As a protective agent, or In some
Instances as a
cated with entire safety. Another object of my combination of dispersing agent
and protective
Invention Is to provide material which will be free agent, many materials may be
used. As examples,
flowing. In which the particles will not con- and without limitation, I may
employ dextrose,
~o" glomerate, in which sedimentation Is prevented ethylene glycol, trlethanolamlne,
gum acacia and ~15
or subste, ntlally reduced, m~d which will not cause others. I have found it desirable
to use a twenty-
clogging of hypodermic needles, or of the vasc~tlar five per cent solution of
dextrose in double dis-
syatem, tilled water. Some substances as
gum acacia,
Other objects of my Invention include the pro- for example, while they act
properly as protective
vision of a material e~ above outlined which wm agents have the objection that
they clog up the 40
be more efficient in c~rrylng out its pull~se, which pores of the carbon and thus
reduce its adsorptive
will be ~terlle and standardlr~d, powers; .~nd I therefore prefer
not to use such
These and other objects of my invention which ~ubstsncez.
will appear hereinafter to one s'kllled In the art An important feature of my
Invention resides
4 ~ or which will be poln~cd out, I accomplish by that in the size and form of the
carbon particles. The 45
composition of matter and by that process of particles must be small enough so
that they will
which I shall now describe an exemplary embodl- not produce mechanical
obstruction In the bore
ment. of the hypodermic needle or In
any part of the
Briefly, In the practice of my Invention, I pro- vascular system. The particles
must act as entl-
vide a sttspenslon of minute claa~lfled particles ties so that they will not
conglomerate and ball I~0
of actffatcd b~rbon (this includes carbon from up, and cause obstructions, as
above outlined.
any source) In dry form or ~!r~ some sort of a car- The particles must not have sharp
spicules or
tier. This suspenslou is such that each particle projections which might puncture
the Interior of
a blood vea~el and produce
ulceration or the like.
I~ ll~ventlon makes it possible
to prepare a sits- I~I~
2~
~0
4O
I50
• "~cts as an entity, and as a result, has Increased
fluidity or workability and a ~Ccrce~.ea. rf~te 91~
• 2 9,t48,088
pe~zsJon of carbon particles which will not be sub- of ways. Without limitation, I
prefer to stand-
Jeer to any of the objections discussed above. I ardize the agent on the per cent
concentration
have found it desirable to use no carbon particles of carbon or charcoal, the
number of particles
larger than a normal human red blood corpuscle, present in a unit weight or
volume, its adsorptive
5 and I prefer to use a suspension In which none capacity for certain dyes or
colors and bacterial ¢;
of the particles are larger than seven microns, toxins such as diphtheria toxin
or anaerobic
It Is possible by my invention to prepare suspen- autolysate of pneumococcus0 and
Its biological
slons in which none of the particles are larger activity.
than three microns, and, as a matter of fact. sus- I may In practice, after
sterilization, Introduce
10 pensions can be made in which the size of the "Merthiolate" or any other
germicide or anti- lO
maximum particles is even more minute, depend- septic Into the composition In
small quantities,
lng only on the fineness of grinding, such as 1:20,000
'.~Merthiolate". This Is a stand-
Another Important item Is that carbon or char- ard procedure In biological
products and is done
coal parUcles must bepurlfied an'd~'ctivated. I to inhibit the growth and
destroy any organisms
"preferto carryout this step i~9"t~ati'ng~tl~e~ar- which might accldently be
contaminated into the 15
bon or charcoal with hydrochloric acid and then material while withdrawing part
of the material
washing It free of the acid with double distilled with a hypodermic syringe, e. g.
when the needle
~vater.
is plunged through the rubber
cap. I]1
The purified carbon or charcoal is then dried The therapeutic agent
according to my tnven- !
20 and ground, and Is then activated by the action of tlS-nby V!itue oths high
adsorptive qualities may
hydrogen passed through It while it is held at a also serve as a vehicle for
carrying other d~u~gs,"
temperature at approximately 300" F. These bacterial tox~lns,toxotds, Or
biological products ~|
steps may be accomplished by any of the well for Immunization purposes. In
this way much /t
known methods, higher doses may be given.
g~ A definite amount of the activated carbon Is It will thus be seen that I have
provided a 20
weighed out and mixed with the dispersing agent therapeutic agent which is
advantageous in the
and, if desired, with the protective agent in the adsorption of toxic materials,
whether bacterial
amount desired. By way of example, and without or from other sources, which
stimulates phago-
limitation, I prefer to use Congo red alone or cytosls and activates the
reticulo-endothelium
$0 dextrose alone, or a combination of.the two In system, and which is entirely
safe and which sO
amounts of one per cent of Congo red on the will not cause mechanical
difficulties; and that I
weight of the carbon or four hundred per cent have also shown an advantageous
process for pro-
of dextrose on the weight of the carbon or a corn- ducing a therapeutic agent.
blnation of both. This mixture is put in a mill It is to be understood that I am
not in any way
$5 and g~ound. This milling may be accomplished limited with regard to the
source or type of car- $5
dry, but I prefer to add double distilled water and bon or charcoal, and that
modifications may be
mill until the material is ground Satisfactorily. made without departing from the
spirit of my In-
I prefer to add enough water to make a six per ventlon and that I do not intend
to limit myself
vent concentration of the carbon. The milling is otherwise than as pointed out In
the claims which
40 continued until microscopic examination shows follow.
40
that most of the particles are of the desired fine- Having now fully described my
invention, what
~ess. The presence of the dispersing agent or the I claim as new and desire to
secure by Letters
protective agent or both permits a much finer Patent Is:--.
grinding than is otherwise possible, and Increases 1. The method of preparing a
carbon particle
45 the output of the mill. suspension for therapeutic
purposes, which In- 45
The next important step in my process is par- cludes the steps of making first
a concentrated
tlele slze classification. Thls can be accomplished, suspension of carbon particles,
then milling the
depending upon whether the milling was done wet mixture In the concentrated
state until no carbon
or dry, by one of the well known methods, such particle Is larger than a human
red blood cor-
150 as filtration, air separation, wet fioatatlon, wet puscle, then reducing the
concentration, dispers- t;0
classification or others. Without limiting myself, Ing. and sterilizing the
suspension.
I prefer to use the filtration method. 2. The method of preparing a
carbon particle
If the milling was done wet, sufficient double suspension for therapeutic
purposes, which In-
distilled water Is added either before or after cludesthe stepsof activating
thecarbon, grlnding
$5 particle slze classification, to bring the concen- it, mixing it wlth a substance
which will cause t;5
tratlon of the carbon or charcoal to that desired, the particles to be discrete and
retain their In-
I prefer to use concentrations of between one and dlviduallty so that they may act
as entities, mill-
three per cent; of course, if the milling has been ing the mixture to the desired
fineness, separat-
done in the dry state and it is desired to keep the lng out all carbon particles
larger than a human•
60 carbon particles In a dry state until an injection red blood corpuscle, dispersing,
and sterilizing the 60
Is to be given, then the double distilled water is
added to the carbon just before it is to be used suspension.
and thoroughly mixed at that time. 3. A therapeutic agent for
Intravenous lnJec-
The next step In my process comprises the tion adapted robe mixed with
waterimmedlately
65 sterilization of the agent. This may be done In prior to an injection,
comprising carbon particles 65
a number of ways, although I prefer to use heat. not larger than a human red
blood corpuscle, to-
Depending upon the type of protective agent, or gethcr With an agent which will
cause said par-
dispersing agent used, I either sterilize It In the ticles to be discrete and retain
their Individuality
Arnold for thirty to sixty minutes on three suc- so that they may act as
entities.
70 cesslve days, or in the autoclave at fifteen pounds 4. A therapeutic agent
comprising a dispersed 70
pressure for a period of twenty minutes. Sub- suspension of carbon particles
in a carrier, the
cultures are made as a control to be certain that size of said carbon particles
being not greater
the sterilization is complete, than a human red blood
corpuscle, and being pre-
The next step in my process consists in stand- dominantly 3 microns or over in
size.
?0 ardization which may also bc ~loae Ii~ a ntimber 5. A therapeutic agent according
to claim 4, T$
q
I~, 14,9s00~
In which the dispersing agent or carrier is a glu-
cose soluUon.
6. A therapeutic agent accordin~ to claim 4, in
which the dJsperslng agent is Congo red.
7. A filtered therapeutic agent 4according to
claim 4.
8. A therapeutic agent according to claim 4,
carrying an immunizing agent.
9. A sterile therapeutic agent comprising non-
3
spicular carbon particles not larger than a human
red blood corpuscle and predominantly 3 microns
or over in size in suspension in a carrier, said
particles being dispersed so that the cohesive
forces between the primary particles are reduced, 6
thus breaking up floes or agglomerates and forc-
ing said particles to be discrete and hence free to
act as entities.
GEORGE E. ROCKWEI~.
/
DEAR S. EDMONDS
%VI LLIS H. TAYLOR, JR.
H. MORTON .-~.I)AI~S
LESLIE ~.YOUNO
JAMES W. LAXST
DAYID WEILD, JR.
HAL E. SEAORAVES
THOMAS ~'. ]{EDDY, JR.
STANTON T. LAWRENCE, JR.
MERTON S NEILL
HAROLD A.T~VER
J. PJ~ILIP AI'~DEREOO
HUBERT O. MOORE, JR.
FRANK F. SCHECE
CLYDE C. METZOER
ROBERT MCKAY
S. LESLIE MISROCK
KEITH E. MULI2ENOER
CHAI~LES J. ~BRO~erl~
ROBERT J. KADEL
DAVID WEILD, ]IX
DAVID J. TOOMEY
CHARLES E. MCKENNEY
HARRY C. JONES, ~II
PENNIE, EDMONDS, MORTON, TAYLOR AND ADAMS
COUNSELLORS AT LAW
330 MADISON AVENUE
I~EW'~OI~K, N.Y. 10017
(S12) 086-8686
C~LE : PEHANGOLD
WASHINOTON OYJ~CE
]3JE NNSWLVA.N I t J~UILDINO
WASHINOTON, D. C. 20004
October 22, 1968
~LS SOCIATE S
~AYMOND ]~. CANFIELI)
AMHROSE A. ARNOLD
ARNOLD R. WORKMAN
HARRY R. S~kOE
JAMES O. POLEY
JOHN L. DOW~INO
CHARLES N. SHANE,JR;
~ILIP T. SHANNON
SIDNEY H, ]~RESNICK
]~ARRY D. REIN
JO"N T, RON~, IH
WILLIAM A.VICTOR
JONATRA~ A. MARS~LL
DERICK C. JANUARY
JEFFREY A. ROSEN
I~RA~E W. CUIFFO
ANN S. ~ISPKER
L~wZs S. REFT
JOSEPH J. C. RANALLI
" D. C. BAR ONLY
PX 18,254
Dr. Edward S. Harlow
The American Tobacco Company
P. O. Box 799
Hopewell, Virginia
RE: Use of Carbon in Therapeutics
Dear Ed :
As I explained to you on the phone last week, the
new classification relating to carbon in therapeutics has just
become available and our Searcher has looked at all patents
in this group. The idea of using active carbon as a carrier
for adsorbed therapeutic agent appears to be old.
The patent to Adler No. 1,589,081 (1926) describes
the use of "adsorptive" charcoal in pill form for internal
use. The patent does not clearly suggest the incorporation
of a therapeutic agent in the carbon and apparently is
concerned only with the activity of the carbon itself.
The patent to Behrman No. 2,055,475 (1936) dis-
closes active carbon containing an adsorbed oxidizing agent
for treating liquids. Although the patent does not mention its
use as a therapeutic agent, it does describe the adsorption
of iodine on the carbon.
-2-
The Smith patent No. 2,229,876 (1941) does
describe the use of activated carbon as an adsorbate
for two or more vitamins and thus contemplates a therapeutic
agent wherein carbon is used as a carrier for an adsorbed
therapeutic.
The van der Wee1 patent No. 2,787,579 (1957)
refers to pills made of activated carbon but does not
describe the adsorption of a therapeutic agent by the
carbon.
The Heller patent No. 2,952,585 (1960) is
concerned with the use of carbon containing an adsorbed
toxoid, antigen, or the like, which is injected intravenously.
Claim 1 of the patent defines a composition of matter compris-
ing carbon black having adsorbed thereon a variety of
medicaments including "therapeutics". The scope of this
claim would appear to dominate your concept and would
present a serious infringement problem unless you would
acquire the patent.
The Young patent No. 3,096,242 (1963) describes
a therapeutic composition to be taken internally and compris-
ing a vascodilator compound carried on activated carbon.
From a consideration of the aforementioned patents
it appears that the use of active carbon as a carrier for
a therapeutic agent, either in adsorbed form or otherwise,
is old and broadly unpatentably. However, there may be
something patentable in a specific composition if you wish to
go into this field.
Sincerely,
enc. (copy of each patent)
CC: C. F. Hetsko, Esq. (no enc.)
---
]DEA~ S. EDMONDS
~x LLI S H.TAYLOR, JI~.
JR. MORTO~ ADAMS
LEs~E B.YOUNO
JA~ES W. LAIST
DAVID "~VE ILD, JR.
HAL H. SEA@RAVES
TISOMAS r. REDDY, JR.
STANTON T. ~WRENCE, J~.
IVlE~TON S. NEILL
HAX~OLD A.T~vE~
J. PHILXP AIq'DEREO0
HUBERT G. MOORE, JR.
1Px~.I~K F. SC~ECK
CLT'DE C. METZOER
ROBERT MC]KAY
S. LESLIE ~ISROCK
~-~EITH E. ~BL~L~ENGER
CHARLES J. ~BRO~'N
Ro~E~r J. KA~EL
DAVID WEII~, III
DAVID J. Too~Y
C~A~L~S H. MCI~NNEY
HARRY C. JONES, Ill
PENNIE, EDMONDS, MORTON, TAYLOR AND ADAPTS
COUNSELLORS AT LAW
$80 MADISON AVENUE
NEwYoRK, N.Y. 10017
(2t2) 986-8686
CABLE : PENANC~)LD
WASHINOTON 0~C~
PENNSYLVANIA BUILDINO
~rASHINOTONs D. C. 20004
October 14, 1968
.JtSSOCIATES
RAYMOND B. CA~U'tELD
AMBROSE A, ARNOLD
ARNOLD R. WORKMAN
HARRY 11. SAOE
J~Es G. ]FoL~r
JOHN L DOWNINO
PHXXaP T. SHANNON
SIDNEY R. ][~RESN'~Clq
B~Y D. REIN
Jolter T. RON~, Ill
WXX~XAM A. VICTOR
Dzx~ucx, t C JA~ruA~
Jm~m_~Y A. ROSEN
F~x W. Ctrrr~
ANN S. Yxs~E~
I~wls S. REr~
Jos~P~, J. C. ~x
PX 18,254
Dr. Edward S. Harlow
The American Tobacco Company
P. O. Box 799
Hopewell, Virginia
RE: Use of Carbon in Therapeutics
Dear Ed:
Ten days ago while in Washington I checked
with our searcher on the use of carbon in therapeutics
and he told me that the patents had not yet been
returned by the Examining Division to the search room
for access by the public. He called me today to
report that over the weekend the patents in the carbon
sub-class had been returned to the stack and that he
was going through them now. I should have the results
by Wednesday and will report to you immediately.
Sincerely,
Merton S. Neill
~-~ OCT 17 ~6S ~,~!
Mr. C. ¢. Kera, Jr. Oetobor 2, 1968
it. IJ. Kerlov
EeferelLCOt
~J
WL
Telephone ConvorutLomwith Hr. Norton I~111 9/30/68.
Hr. itoLll, Imvin8 discussod vith John Asbeorth some of tho epoeLfiest/mw
for f~icstioe of WL, /adtcatod a desire to t81~ vJ~h k, kvtd C. Los
of kusU. On, o£ the items oa vb/ch be vlshed tnfenmttoa uts freouss
of the pulp. Vo u88estod he contact Dr. Los but, usfortmwte17,
k. Lea us 8e~7 end he talked with John Betas. In the cevroe of the
¢ouvoruttoe the tkree rain dtfforn~es botvooa tbo Mskov~ Imtont 18d
the kust~t trostmeat mttoeo~ ere:
1, Ecust8 uses s 1see cook - ~bout six hours.
2. Stslho uNd It7 [eust, hey, sot ~ field dried. (Jlsk~ 90
to 100 days)
3. l~uote uses 57, stems.
lie lure to cheek into the stalks used In our WL fldlc~L~tLom to escort@in
tho leestk o5 ttw they mr, "field dried' m~ on11 Nr. Itei11 ea
gedeudsy, October 2. vhe8 he will hsve retraced hun Wuk/mstee.
jlMr. moill pixu, ix IhtshlJStem Tuosdey, to roviw at tbo lhmtmst Offieo,
ixfo~mstion relatLn8 to our ides of pstoetl~j the me of earbem as lm
edswhent md deleted relese4~ for p4ummee~leals, ere,
B|Iho
eel Dr. IP, It. Leaks
Copy made for John Ashworth
mucmcm~x
P.O. Iox T99
Ill,pin,oil, Va, 2M~
~st 2, 1968
Hr. Norton S. Neill
Penniep lgdscedsp Norton, Teylor and ~Sme
Counsellors st Lsw
330 Nodtoon Avenue
t/ev York, Nov York 10017
Dur Herr8
l~snk you for your letter of July 30 sad the copte8 of the
Kockwell and o! tho 8tosru pstonto vhteh Four gashtnston
sesrchers hod located.
We vtll plan to proceed to look into the tochetcst aspects
of us~ 8©ttvo carbon as s csrrtor of UedtMn~ts, If
the potent clssstfLcatt~n 8uboolsss mMtoMd Ln your
letter provides addttimutl pateate w vt11 be hePP7 to
revtev then tf 7o0 thtnk it sdvtsoble.
Sincerely,
E. 8. Ksrlov
MiM|lnJ DLrectot
ccs Hr. Arnold Ronoon
Lo881 l~psrtmont
f
DEAN S. EDMONDS
WILLIS H. TAYLOR, JR.
R. MORTON ADAMS
LESLIE B. YOUNO
JA~Es W. LAIST
DAYID WEILD, JR.
HAL ~. SEAORAVES
THOMAS ~'. REDDY, JR.
STANTON T. LAW~NCE, JR.
MERTON S. NEILL
]~,AROLD A .TR,~'VER
J. PHILIP ~kl~I)EREOO
HUBERT 0. MOORE, JR.
~'~ F, SCHECX
CLYD:E C. METZO~R
ROBERT MC~(AY
S. LESLIE I~ISROCX
I/~EITH ]q. MULLENOER
CHARLES d. BROWN
ROBErt J. I~D~L
DAVID WEILD, Ill
DAVID J. TOOMEY
CHARLES E. MCKENNEY
HARRY C. JONES, HI
PENNIE, EDMONDS, MORTON, TAYLOR AND ADAMS
COUNSELLORS AT LAw
330 MADISON _A~rENUE
NEWYORK, N.Y. 10017
(212) 986-8686
CABLE : PENANGOLD
WASHINOTON 0~CE
PENNSYLVANIA BUILDINO
WASHI~OTON, D. C. 20004
July 30, 1968
a~SOClATES
RAYMOND B. CANFIELI}
AMBROSE A. ARNOLD
ARNOLD R. ~)REMAN
HARRY R. SUaOZ
JAMES 0. ]FOLEY
JOHN L. Dow~INo
CRAR~S N. SHAW~,J~:
PHXLIP T. S~IANNON
SIDNEY R. BRE6NICK
BARRY D. REIN
Jo~N T. Ro~.~, HI
~I~AM ./~..VI CTOR
JONATHAN A. MARSHALL
DERICE C. JANUARY
JEP']FREY A. ROSEN
~RANK W. CUIFFO
ANN S, FISRER
LEWIS S. REFF
• D. C. BAR ONLY
PX 18254
Dr. Edward S. Harlow
The American Tobacco Company
P. 0. Box 799
Hopewell, Virginia
Dear Ed:
Last week I explained to you why we have been
so slow in reporting on the search you suggested by telephone
last March relating to the use of active carbon as a host
for medicaments to be taken internally. Our Washington
Office encountered an absence of any classification of
patents along this line, and several Examiners who were
interviewed gave little consolation until fairly recently
when one Examiner said that one of his classes was being
revamped and that there would be a sub-class on the uses
of carbon. As of the end of last week, July 25th, this
re-classified art has not been released, but I shall report
to you as soon as this is done. In the meantime, our
Washington searcher has reported to me on the art which
he has found to date. One is the patent to Rockwell No.
2,145,088 (1939) on the use of active carbon as a host
for therapeutic agents, the carbon to be injected intra-
venously. The only other patent of any pertinence is
that which issued to Stearns No. 2,951,791 (1950) on
the use of calcium silicate aerogel as a binding agent for
pill components. There is a possibility that this aerogel
might be considered an adsorbent material.
The only other prior art noted has been that
4
t
" t"
-2-
relating to chewing gum, but this I believe has no
bearing on your present concern.
A copy of each of the Rockwell and Stearns
patents is attached hereto.
~/Merton S. Neill
enclosures
cc: Arnold Henson, Esq. (no enc.)
~r
-B,
~Q
1
March 13, 1968
ADSORPTION OF VARIOUS SUBSTANCES INCLUDING THERAP~TIC
~ATERIALS ON CARBON AND OTHER ADSORBENTS FOR CONTROL~LEASE
Reference I: Telephone Conversation with C. F. Hetsko 3/12/68.
" 2: Letter to Arnold Henson from ESH dated 3/7/68.
Mr. Hetsko (Ref. i) approved approaching Mr. Neill concerning the
possibility of obtaining a patent on the subject conception.
He would appreciate correspondence and other relevant information
concerning this matter being forwarded to him as it accrues.
ESH:hc
IcX3DcX3mI~
~.0. Sex 799
Ropevoll. ¥LtSin~
J~Jrch 7. 1968
2386O
Nr. Arnold M~nson
Lepl kpsr ,sent
~he Amerlcsn Tobacco Company
:45 Pork Avenue
B~ York, New York 10017
Dear Arn~ !
As discussed Ln our con~ozoatton this mornluS, ve ~re interested in the
possibility of obteintus • patent in an area outside or beyond the
curr~t interest of our coepsny. Ms conceived this ld68 In 8 8eneral
way about 8 Fear 8So and early Le February defined Lt sore specifically.
Essentially it involves the use of activated carbon as 8 moans of
tntrodue£~ certain drubs, vitlmlns aa4 tim like into the tmmm.bo~y.
Thus the release of the druj Iteolf ~II be relatively slov end
therapeutic or uluLery levels can be controlled.
We are unaware of the previous use of urban for th£e purpox althoullb,
of course, vo are f~liar vith the "tins" pills and the encapsulation
principle by which they operate. If ve are able to obtain a patent
on thle i~ea. it could be very profLt2tble should the Cellpal~ ever ol~$e In
8ctivities related thereto! mlterutivsly, its ItcensinS utah, be
profLteble.
There is some ursency in ectilt8 since we are informed that the usa of
activated car~ for the 8deorption of toxic sebstenoes inJested by
children has been reported recently. Obviously, this recent work my
stimulate thinkins alerts the lines of our eoneeptLon.
Me vere u~ble to reachMert Meill since he 1o on vase, ten, but plan to
contact hinnnt week to dL|cuBsthLs Imtter. Your comMnte b~Ould be
appreciated.
Best tabards.
Sincerely,
CCl
Mr. J. n. J~rthy
VLee President -I~nufecture and Leaf
g. 8. lhurlo~
lfm~Sin8 Director
Legal
Patents ATC Applications
Cigarettes - Smokeless
U S Patent - General
CIGARETTE WITH COMPOSITE HEAT SOURCE
Background of the Invention
Cigarettes having heat sources other than, or in
addition to, the conventional tobacco rod are old. Heat
sources or fuel elements of carbon (British Pat. No.
956,544); ground tobacco composites, tobacco substitutes or
other combustible material have been proposed (U. S. Patent
No. 4,149,548). Fuel elements may be tandemly positioned to
the tobacco rod, filter or flavor-contalning section or
other section of the cigarette (U. S. Patent Nos. 3,169,535
and 4,340,072) or may be concentrically positioned relative
to one or more cigarette sections (U. S. Patent Nos.
2,863-,461 and 3,356,094).
Prior proposed cigarettes have not been found
satisfactory.
Summar7 of the Invention
Broadly, the present invention is a series of
tandemly arranged sections overwrapped and secured together
in part by a paper wrap having a thickness less than 0.4 mm
and preferably about 0.1-3 mm in thickness. The lighted end
includes a composite combustible fuel element which
generates heated gases including air, CO2 and water. The
remainder of the cigarette portions tandemly arranged from
the lighted end to mouth-end, in sequence are: a gas holding
and transport chamber, an aerosol chamber, a tobacco column.
and a filter element. The combustion element is a composite
of carbon, ash conditioner, binder and burn promoters.
It is a feature that the composite fuel element
is partially wrapped at its remote end with a metallic
material which functions to attach the element to the
remainder of the cigarette and also functions to transfer
-2-
heat generated as the fuel element burns so that the fuel
element extinguishes itself prior to a substantial burning
of the remainder of the cigarette that would permit the fuel
element to separate from the remainder of the cigarette.
It is a further feature of the cigarette that the
fuel element is composed of a mixture of materials and is
sized and shaped to burn throughout its length to produce a
desired volume of heated gases of selected temperature and
composition for delivery to and through the aerosol storage
chamber and through tobacco packed rod enclosure where
aerosol material and gases effect formation of the aerosols
and pick up flavors or flavors and nicotine for delivery to
the smoker.
Brief Description of the Drawings
Fig. 1 is an elevational view of the cigarette of
this invention sectioned for viewing its interior;
Fig. IA is a sectional view along line IA-IA;
Fig. 2 is a view similar to Fig. i during a
period in which the smoker is drawing on the cigarette;
Fig. 3 is an alternative embodiment including a
spool enclosure; and
Fig. 4 is a perspective enlarged view of the
spool enclosure.
Description of the Preferred Embodiment
In Figs. 1 and 2, cigarette i0 includes
combustion fuel element ii, gas holding and transport
chamber 12, aerosol-flavorant section 13 of chamber 12,
tobacco column 14 and mouth-end tip section 16. Chamber 12
-3-
and tobacco column 14 are defined by cardboard tube 20 with
separator 19. Tube 20 abuts fuel element ii at annular
surface 27 and filter 15 at annular surface 27a. Tip
section includes filter 15 and tipping paper 16a for
securing filter 15 to tube 20. Dimensions in millimeter
(mm) shown on Fig. 2 are preferred lengths for such portions
of the cigarette, it being understood that the dimensions
may be varied within the parameters of the present invention
as further described.
Combustion element ii is made of a mixture of
carbon, burn promoter, and ash conditioner. A binder of
carboxymethyl cellulose material performs the function of
maintaining the integrity of this mixture after forming into
the desired shape. These four materials can be combined
within the ranges shown in Table A below but a preferred
combination is of carbon:burn promoter:ash
conditioner:binder of 71:11:8:10.
Table A
Fuel Element Composition
Range Opt. Range Preferred
Binder 1.1% - 17% 5% - 12% 10%
(CMC)
Ash Conditioner 3.8% - 20% 5% - 10% 7.7%
(Fullers Earth)
Burn Promoters 0% - 14% 10% - 12% 11.5%
(KN03 + NaCI03
Carbon 49% - 95% 66% - 80% 70.8%
(Wood and Bone)
The burn promoter ensures a steady and even rate of burn of
the combustion element to provide a consistent quantity of
heat. The ash conditioner aids in forming an ash with a
color more consistent with regular cigarette ash.
-4-
While a combustion fuel element in accordance
with the present invention may have sufficient porosity to
pass limited quantities of heated gases with the combustion
element described above, gas passageways 17 are needed to
pass gasses in necessary volume at normal pressure drops
which gases include air, CO2, H20 and CO. Combustion
element Ii has lighted end 21 and remote end 22.
Gas chamber 12 functions to house and transport
hot gases of combustion from fuel element ii to flavorant-
aerosol chamber section 13 and onto tobacco column 14.
Chamber 12 preferably contains both an aerosol forming
material and a flavorant material. Thirdly, it may include
a nicotine or a nicotine supplying source material to
supplement the amounts of nicotine picked up as the gas
traverses the downstream tobacco column 14. Selectively,
one, two or more of such materials may be present in
aerosol-flavorant section 13.
Aerosol forming materials include triethylene
glycol, propylene glycol, i, 3-butylene glycol and glycerin.
Flavorants, or flavoring agents include vanillin,
coffee, chocolate, caffeine, menthol and other flavorants
known to the industry.
Fuel element ii and cardboard tube 20 are secured
together in an abutting relationship by a band of aluminum
or other conductive material band 18 adhered both to the
fuel element Ii and gas chamber section 12. In addition to
securing these portions of the cigarette in tandem
relationship, the aluminum band 18 conducts heat from fuel
element ii to section 12 and to the atmosphere surrounding
the cigarette. By causing such heat transfer by convection,
band 18 assists in termination of burning of element ii as
the coal reaches and engages band 18. Heat is conducted
-5-
from the fire cone by the conductive material 18 until the
cone is reduced below its burning temperature and
extinguishes itself.
Downstream of section 12, aerosol-flavorant
section 13 contains aerosol and/or flavorant materials unit
23 in any form suitable for storage and release by the
heated gases during ignition and smoking of the cigarette.
Flavorants in unit 23 may be located on heat stable
substrates, micro-encapsulated or in chemically combined
forms subject to thermal decomposition and availability to
the passing hot gases. Substrates of carbon, alumina or
glass wool have been found to be suitable. The temperature
of the gases supplied from fuel element II range between
100°C and 600°C. depending on the fuel element composition
and length; the number and size of ventilation passageways
17; burning rate and the pressure drop over the length of
the cigarette as created by the smoker.
The tobacco column 14 is composed of shredded
tobacco and, if desirable, tobacco substitutes having a
level of nicotine so that the heated gases will pick up a
desired amount of nicotine as the heated gases pass
therethrough on their way to the smoker.
A cardboard wrapper tube 20 surrounds the gas
chamber 12, aerosol-flavor chamber section 13, tobacco
column 14 and abuts mouth-end tip 16 at surface 27a. Tube
20 is made of cardboard or paper having a thickness range of
0.I mm to 0.4 mm.
Finally, with respect to Figs. 3 and 4, an
alternative third embodiment includes cigarette 10b having
an aerosol- flavorant-supply unit 29 in the form of a
plastic spool 31 having a hollow cylindrical body 32 and
-6-
lighted end piece 36 abutting fuel element llb and mouth-end
piece 34 abutting tobacco column 14b. An annular void 38 is
formed between the outside of spool body 32 and wrapper tube
26b. Glass wool, carbon or alumina fiber substrate 40b is
placed in a downstream portion of the interior 32a of body
32 for supporting aerosol material or flavorant material or
both.
Example 1
Twenty cigarettes were constructed in accordance
with Figure 4 having a fuel element consisting of the
following formulation:
Wood Carbon
Bone Carbon
CMC Binder
Potassium Nitrate
Sodium Chlorate
Fullers Earth
1.30 g
0.54
0.26
0.14
0.16
0.20
Ingredients from the above formula were mixed and made into
a paste using 1.6 ml H2OP, kneaded and rolled into a "rope"
and dried at i00~ C for 15 minutes. The rope was then
placed in a mold and pressed at i000 psi for 1 minute and
dried at i00~ C for 45 minutes. Four 1/16" diameter holes
are drilled through entire length of element.
The finished element is 15 mm long and 7 mm in
diameter. The fuel element was attached by means of a i0 mm
wide strip of aluminum foil to a cardboard sleeve 65 mm in
length containing a Teflon spool, 25 mm long, housing a i0
mm segment of glasswool that supports the aerosol material,
in the downstream end, thus creating a 15 mm void between
the fuel element and aerosol support. Tandemly arranged
downstream from the aerosol generating section within the
cardboard is a 40 mm segment of shredded tobacco material.
A 5 mm filter is attached to the mouth end of cigarette with
tipping paper, which completed an 85 mm smoking article.
0 ,
-7-
mg/CiEt
250
125
65
25O
125
65
25O
125
65
Aerosol transfer was measured on cigarettes
containing 250 mg, 125 mg and 65 mg aerosol, respectively.
The three levels of three different aerosol means were
tested, using 2 cigarettes per test and taking 8 puffs per
cigarette.
was used.
A 35 ml vilume and 2-second duration puff method
I. Glycerine - Propylene Glycol (i:i w/w)
Total of 2 Clgts. Total
w
mlg, mg, m~ Aerosol Transfer Aerosol
WP____M_M m20 ~ Pff Used, mg
21.5 4.9 8.5 4.9 500 13.4
21.0 3.7 8.0 6.8 250 14.8
23.3 4.3 9.2 5.2 130 14.4
2. Glycerine
15.2 3.4 9.6 500
12.9 3.1 8.7 - 250
10.6 1.8 5.0 - 130
3. Propylene Glycol
16.7 2.5 - 10.9 500
8.6 1.3 - 5.0 250
11.5 1.9 - 7.8 130
Total
Aerosol
Detected, mK
9.6
8.7
5.0
10.9
5.0
7.8
%
Transfer
2.7
5.9
ii.I
1.9
3.5
3.8
2.2
2.0
6.0
Wet particulate material.
-8-
Claims
I. A cigarette having a tobacco column and a combustible
element having a lighted end and having an end remote from the lighted
end for generating and supplying heated gas as its fire cone progresses
from the lighted end to the remote end comprising
(a) a heated gas storage and transport chamber tandemly
positioned adjacent the combustible element for
storing and transporting heated gas supplied from
the combustible element;
(b) an aerosol flavor material section immediately
downstream of the gas chamber having aerosol and/or
flavor materials located therein;
(c) a tobacco column having therein a second supply of
flavor materials including nicotine;
(d) a paper wrapper means having a thickness of between
about 0.1 nun and 0.4 mm wrapped around portions of
the gas storage and transport chamber, aerosol-
flavor section and tobacco column.
(e) a metallic band wrapped around portions of the
combustible element and the gas storage and
transport chamber which band causes the combustible
element to extinguish as the fire cone approaches
its remote end; and
(f) a low effeclency cellulose acetate filter plug
attached to the remote end of the tobacco column
with conventional tipping paper.
2. The cigarette of claim 1 having axial gas passageways
in the combustible element extending from the lighted end to the remote
end.
3. The cigarette of claim 1 in which the combustible
element, gas chamber, aerosol-flavor section and metallic band are
sized so that all measurable heat transferred to the aerosol-flavor
materials during smoking is received through convection as heated gases
-9-
flow from the remote end of the combustible element to the mouth-end of
the cigarette.
4. The cigarette of claim 1 in which the metallic band
has a width and thickness such that it dissipates heat away from the
cigarette as such heat is generated by the combustion of the
combustible element.
5. The cigarette of claim 2 in which the metallic band is
shaped and sized to be capable of dissipating a sufficient amount of
heat to extinguish the combustible element as the fire cone reaches the
end remote from the lighted end.
6. The cigarette of claim I in which the aerosol-flavor
material section has a glass wool, carbon or alumina substrate for
supporting aerosol and/or flavor generatingmaterials thereon.
7. The cigarette of claim 1 in which the gas storage and
chamber and aerosol-flavor sections are housed in a plastic spool
having a hollow cylindrical body for containing aerosol and/or flavor
generating materials.
8. The cigarette of claim 1 in which the aerosol-flavor
section is located a sufficient distance from the remote end of the
combustion element and a sufficient distance from the metallic band
that no significant amount of heat is conducted from the combustion
element or the metallic band to the aerosol and/or flavorant materials.
9. In a cigarette having a tobacco column, a tandemly-
arranged upstream aerosol generating section and a combustible element
for generating heated gases, the improvement in which (i) the
combustible element is composed of
a) carbon in range of 60 to 80%;
b) ash conditioner 5 to 10%;
c) burning promoters I0 to 12%; and
"o •
• °
-i0-
d) binder 5 - 12~
and in which (2) the combustion element and tandemly-arranged
downstream section are sufficiently insulated from one another so that
as the combustion element burns heat transfer to such downstream
section is by convection.
FIG. t
10
11 IA /
M 18"---,-----I~.I 27 13-.- ~,", ",,'-, 27n 16
--:-~_ L 12 ~. r: ----~.~ >,
23 16o)
1A
FIG
1A
17
0
FIG 2
10
/
/ ,, ~ ' ~ 20 16
18gI0 ~ 23 13 ,,-19 ( , "'1 J
.... ,--~ --- ~ .d-~--°- .... ~ ................ d
I- ........................ ==' - .......................... -I
e
FIG. 5
1~b 370 10b 3/.
31 38 ,~ v_ -
/x 36 /.,Ob - 14b
llb 29
F
REC~.a v~:.
AUG 5 1988
D~.:~~. OF,
#I'ES. ~. OSW.
., ~.-' ~"- ,M'", -
~,.. .; :: • •
,. -. 71.
•
/:i.:"I . • :
J ,
[DRAFT]
CIGARETTE WITH COMPOSITE HEAT SOURCE " "''
"-i:.i'i:~:"
Background of the Invention .....
• . ~~-
Cigarettes having heat sources ~ther than, or in
-.
addition to, the conventional tobacco rod are old. Heat "
sources or fuel elements of carbon (British Pat. No.
956,544); ground tobacco composites, tobacco substitutes or
other combustible material have been proposed (U. S. Patent '
No. 4,149,548). Fuel elements may be tandemly positioned tO
'~
the tobacco rod, filter or flavor-contalning section or " .... :-,,..
other section of the cigarette (U. S. Patent Nos. 3,169,535 •::
and 4,340,072) or may be concentrically positioned relative• .~S
to one or more cigarette sections (U. S. Patent Nos.
2,863,461 and 3,356,094). ::
Prior proposed cigarettes have not been found
satisfactory.
!
3o0..e o.)
-kt's p
.... ~..:~.> ~,
Summary of the Invention
Broadly, the present invention is a series of
tandemly arranged sections overwrapped and secured together
by a paper wrap havin~ a thickness less than 4 ~tm and
~"c:
=
~O~_-~UOOOI~ preferably about 1-3 mm in thickness. The lighted end
7m. Pv[O~L includes a composite combustible fuel element which
.x'~L O,1~4~4 generates heated gases including air, CO2 and water. The
• o O,~vt&4 remainder of the cigarette portions tandemly arranged from
-I-~\~d.- the lighted end to mouth-end, in sequence are: a gas holding :~
and tr~o~t~ch~_%e~nA~.~oI chamber)a4~ a tobacco
olumnt~ The combustion element is a composite of carbon; a4~ +.
?i +, -,
It is a feature that the composite fuel element
is partially wrapped at its remote end with a metallic
material which functions to attach the element to the
remainder of the cigarette and also functions to transfer
*, 2, t
-2-
L~. • .
Brief Description of the Drawings
~e/~kJ~ Fig. 1 is an elevational view of the cigarette of
~4~L~ this invention sectioned for viewing its interlor;
d.~uO'tn~ Fig. IA is a sectional view along llne IA-IA;
heat generated as the fuel element burns so that the fuel
element extinguishes itself prior to a substantial burning • : ~:j:!i;•.
of the remainder of the cigarette that would permit the fuel :/~i/i'~
element to separate from the remainder of the cigarette. ', :-
It is a further feature of the cigarette that the ~/~ :/~':
fuel element is composed of a mixture of materials and is " ::
sized and shaped to burn throughout its length to produce a~ -~
desired volume of heated gases of selected temperature and '?
composition for delivery to and through the aerosol storage• ~.
chamber and through tobacco packed rod enclosure where ~ ~ ;~"
aerosol material an~L~as~ effect formation of the aerosols ! : z
and pick up flavors ~and nicotine for delivery to the smoker.--'~J: ~
%
/~OUO S~OtO'&~----~ Fig. 2 is a view similar to Fig. I during a
~k~0~~bperlod in which the smoker is drawing on the cigarette;
-~A~O~~O~%~ Fig. 3 is an alternative embodiment of the
5e~A~ invention;
Fig. 4 is a second alternative embodiment
including a spool enclosure; and
Fig. 5 is a perspective enlarged view of the
• ./.~ -' . : ~i~" .
. . -k~
spool enclosure ....
,l
Descrlption of the Preferred Embodlment ~-~'~'~ tq~' "~.~ ~~
In Figs. 1 and 2, cigarette 10 includes k % ~ :"!~;:,~ili'•
combustion fuel element ii, gas holding and transport ;;~!i~
