Note: Descriptions are shown in the official language in which they were submitted.
Z593
Conventional sterilization methods for injectable solu-
tions or suspensions generally comprise the exposure of the per-
formed mixture to high temperatures or ionizing radiation suffi-
cient to kill any microorganisms present. This approach cannot
be used with materials that will be adversely affected by the
sterilizing conditions. Another approach is the sterile membrane
filtration system in which the solution is passed through a ster-
ile Millipore filter system. This technique can be cumbersome,
involved and expensive. soth approaches, however, fail to come
to grips with the problem associated with solutions which tend -
to decompose relatively rapidly thereby having an intolerably
low shelf life. Such materials as sodium ascorbate, for example,
are available in 50 ml vials containing 25% sodium ascorbate so-
lution (12.5 grams sodium ascorbate) preserved with sodium sulfite
and benzyl alcohol. When such materials are used, for example,
in the treatment of humans and animals in the manner described
by F. R. Klenner (J. International Acad. Prev. Med., vol. 1, No.
1, pages 49-65 (1974) and W. 0. Belfield et al (J. International
Acad. Prev. Med., vol. 2, No. 3, pages 10-26 (1975), and E.
Cameron et al, J. Internat. Res. Commun., vol. 1, No. 6, page 38
(1973), the sulfite produced adverse side effects resembling
those of beri-beri as a result of the reaction of the sulfite
with the patient's vitamin Bl. The manufacturer, upon request,
has produced vials without the sulfite but the manufacturer be-
lieves the shelf life is so short that they do not distribute
the product through normal channels. What is needed is an inex-
pensive means for sterilizing sensitive materials in the solid
state so that they can be stored for long periods and mixed with
sterile water immediately prior to use. This invention describes
such an approach.
It is accordingly an object of this invention to pro-
vide a simple economical method for sterilizing sensitive solid
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materials.
It is another object of this invention to provide a
sterile container of a sensitive solid material.
A further object of this invention is to provide steri-
lization with a non-toxic, volatile sterilizing agent that does
not have to be removed from the mixture before use, and in the
quantities employed for sterilization it would be normally meta-
bolized by the body without any unfavorable side effects on in-
jection.
These and other objects of this invention will be readi-
ly apparent from the following description. ~ -
According to this invention a stable sterile particulate
solid material is prepared by a simple, non-toxic, inexpensive
means in a convenient cheap disposable container. The container
and contents has a long shelf life and is capable of being simply
and rapidly used by the physician or nurse in the preparation of
fresh injectable solutions immediately before injection into the
patient.
The following description will be directed to the pre-
ferred embodiment of sodium ascorbate, but it should be recognizedthat the invention can be used with combinations of sodium ascor-
bate with other materials or with any other pharmaceutical mate-
rial (without the presence of sodium ascorbate), that is non-
reactive with ethyl alcohol.
Sodium ascorbate, for example, is rather unstable to
heat both in the dry state and in solution, so that the temper-
atures required for heat sterilization causes destruction and
loss of activity of the ascorbate. Sterilization by sterile mem-
brane filtration through a completely sterile system such as that
manufactured by the Millipore Corporation can be done, but is
limited to solutions. This is an expensive and time consuming
operation, especially if it is necessary to first get the sodium
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ascorbate into solution, membrane filter this solution and then
freeæe-dry the sterile solution under sterile conditions to ob-
tain a sterile dry powder for permanent shelf life stability in
the dry state in the sterile packaged product.
Another method of sterilization, by high energy radia-
tion, requires a tremendous investment in special equipment and
there is no data available on the effect of such high energy ra-
diation on an unstable material like sodium ascorbate as to loss
in activity and the shelf life stability of radiated ascorbate.
I have overcome all these objections to present custom-
ary sterilization procedures by the provision of a very simple,
elegant and inexpensive, non-toxic procedure for the low-tempera-
ture, vapor phase sterilization, which produces a stable parti-
culate material suitable for injection purposes, with no loss of
activity.
The principle of the method is to place a weighed charge
of, for example, sodium ascorbate (fine crystals preferred) into
a suitable sealable container (glass, plastic or other) and add
a quantity of ethyl alcohol sufficient to produce a high enough
concentration of alcoholic vapor to effectively kill and inactiv-
ate any viable microorganisms adhering to the sodium ascorbate
during the shelf-life storage time of the package containing it.
At the time the physician or nurse wants to prepare the solution
for injection, they either remove or penetrate the seal with a
sterile hypodermic syringe and add the required amount of sterile
water for injection needed for the preparation of the solution.
The sodium ascorbate quickly dissolves and the solution is ready
for injection into the patient or for further dilution for paren-
teral drip therapy. No attempt is made to remove the ethyl alco-
hol as the amount originally added is so small and harmless andwill be normally metabolized after injection into the patient,
with no deleterious side effects or toxicity. The patient is
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thus assured a perfectly fresh solution of the proper ascorbate
strength as the time between preparation and administration is so
short that no loss of ascorbate activity can take place.
The amount of ethyl alcohol required in this treatment
is very small and is easily calculated from the volume of the con-
tainer and the fact that 100 milligrams of ethyl alcohol (100%)
will produce approximately 50 milliliters of saturated vapor at
room temperature. If a 6 ounce (170 ml) container is used, then
about 360 milligrams of ethyl will be required to fill the con-
tainer with ethyl alcohol vapor. Less quantities than thatgiving 100% saturation, like 50% saturation, will also be effec-
tive, but I prefer to use an amount giving about 150% saturation.
Substantially larger amounts of ethyl alcohol beyond about 150%
are unnecessary and only add to the costs. The amounts of ethyl
alcohol needed are so small that they do not "wet" the powder,
with visible liquid in the interstices of the particulate mate-
rials. Besides, keeping the ethyl alcohol levels minimal is
desirable, to avoid unnecessary increases in the alcohol blood
levels of the patients. The adult blood volume is about 4 liters
so the ethyl alcohol added in the above example would produce an
insignificant rise of about 0.01% in the alcohol blood level.
The ethyl alcohol concentration in the alcoholic liquid
added to the dry particulate material is not critical, but should
be preferably high to avoid adding excessive water to the mixture
along with the alcohol. 100% or absolute alcohol may be employed,
but the less expensive azeotropic concentration of about 95%
ethyl alcohol is preferred. Lesser concentrations can be used
but require more liquid to generate the required vapor volumes.
The costs of the finished sterile product of this in-
vention will be low, being not much more than the costs of theraw materials and package, as there are no involved expensive
processing operations to produce sterility. This results in
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substantial savings to the patient in the cost of medical care.
Other materials like soluble vitamins, minerals or
other drugs that are required to be injected along with the ascor-
bate may be added to the sodium ascorbate in the package and the
ethyl alcohol added to the mixture before the package is sealed.
In this way the other additives for injection are sterilized at
the same time as the sodium ascorbate.
Sterile water "For Injection" is the preferred liquid
for dissolving the treated sodium ascorbate of this invention.
I have found that if this injectable grade of water is not avail-
able, particularly in veterinary medicine, boiled and cooled
distilled water or even plain tap water may be used for dilution,
without harmful effect on the patient.
The following are typical examples of the procedure of
this patent:
Example 1. Into a clean 6 ounce screw capped bottle weigh 15
grams of sodium ascorbate fine crystals. Add 360 milligrams of
ethyl alcohol (0.46 ml 95% ethyl alcohol), seal tightly and shake
vigorously to distribute the alcohol and permit rapid vaporiza-
tion throughout the sealed bottle. Allow to stand.Example 2. Weigh 30 grams of sodium ascorbate into a dry 1 liter
plastic parenteral bag. Add 600 milligrams of ethyl alcohol (0.8
ml of 90% ethyl alcohol) and mix thoroughly with the contained
powder. Fold the bag and store flat (to limit the internal vol-
ume) until ready to use. Dilute with 1 liter of sterile water
"For Injection", immediately before connecting to the patient.
This will produce a fresh sterile isotonic parenteral solution
of sodium ascorbate suitable for continuous intravenous drip ther-
apy.
Example 3. Weigh 20 grams of sodium ascorbate (fine crystals)
into a 100 ml sealable vial and add 300 milligrams of ethyl alco-
hol (0.48 ml 70% ethyl alcohol). Shake thoroughly and seal with
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a closure that can be sterily penetrated by a hypodermic needle.
Allow to stand. When ready for use, draw 100 ml of sterile water
for injection into a sterile hypodermic syringe. Penetrate the
cap with the hypodermic needle and add sufficient water to dis-
solve the sodium ascorbate by swirling, without removing the
hypodermic from the vial. When dissolved the solution is sucked
back into the hypodermic syringe, mixed and is ready for injec-
tion.
Example 4. 10 grams of sodium ascorbate (fine crystals) are
weighed into a 100 ml sealable vial and 300 milligrams of ethyl
alcohol is added (0.38 ml absolute alcohol) and the vial is
sealed and shaken as in Example 3 and is handled similarly.
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