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2,407,412
Patented Sept. 10, 1946 .
UNITED STATES PATENT OFFICE
2,401,412
’
mum-zone SOLUTIONS
Douglas V. Frost, Waukegan, 111., assignor to Ab
bott Laboratories, North Chicago, Ill.,- a corpo
ration of Illinois
No Drawing. Application August 15, 1942,
Serial No. 454,919
10 Claims. (01. 167-81)
1
'2
The present invention relates to improved
I
therapeutic solutions and more particularly to
stabilized ribo?avin-nicotinamide solutions. The
7
Per cent w/v
Ribo?avin _____________________________ __ 0.10
preserlilt application is a congnuiiéignéiln-part of \
my p or application Serial
0.
,8
.
Ribo?avin is a naturally occurring representative of the polyhydyoxyisoauoxazine vitamins and
Nicotinamide __________________________ __ 5.00
5
.
c 'lll'he 320v;a?grg‘ggné?eagi?ggdwggegh??
sglustign i: comgllete. The solution is then cooled
its de?ciency 1s wldespread' Clinical symptoms
of _ polyhydroxyisoalloxazine de?ciency include
and su?lcient acidic material, such as hydrochlo
no acid added to adjust the pH to about 45
keratitis, cheilosis, vmydriasls, photophobia, etc. 10 to 66 ’
:'
Ribo?avin is only very slightly soluble in water
' '
'
and hypodermical administration in this form
11
necessitates the use of large volumes of liquid.
The natural solubility of ribo?avin in pure water
,
Ribo?avin
Per cent w/V
___
0.10
at 20' C., for example, is only about 0.013 per 15 Nicotinamidev ___________ -._. _____________ __ 5.00
cent and the administration of a good therapeu-
Thiamine hydrochloride _________________ __ 0.50
tic dose (10 mg.) at this temperature necessitates the injection of about 78 cc‘ 9f solution‘
The above ingredients are mixed with about
80 per cent‘ of the total volume of water required
In my co'pending related apphcati?“ Serial
in the formula and solution induced by warming.
No’ 416’757' which hats issued as Patent No‘ 20 When solution is complete the resulting solution
2’3.8§’261’.I ha"? descnbed 8' mephod for 50m‘
is allowed to cool and su?icient acidic material
bilizing ribo?avin by the formation of a ribo-
such
?avin-boron complex. These boron compositions
added to adjust the pH to about 4 to 5_0_ The
as monosodium dihydrogen
phosphate’
haw? proven highly Sa?SfF‘Ct-QW as .the-y employ
?nal solution is then made up by addition of
“.lmlmum .amounts of imectmn mm? and pro’ 25 chemically pure water. In certain cases, for ex
¥i1gg?ap€?tigald giggsu?gia?ggtgdgggggfm?on
of.
p
.
ample.
when preparing compositions containing
thiamm for oral administration the use of a pH
During the research work carried out on th1s
of 25 to 4 is preferred.
investigation I also discovered that nicotinamide
The present invention is not limited to the
and water soluble saltsof nicotinlc acid solubil- 30 above examples_ For example’ in place of the
ized polyhydroxyisoalloxazines Such as ribo?avinacidic materials described above other acidic buf
With continued investigation. including assay
fers which are not objectional for parenteral in
tests running over relatively long periods of time
jection, such as phosphoric acid, and the like
I discovered that these compositions possessed
may be used. In addition to thiamin, other vita
the desired physical stability but lacked the es- 35 mins, such as pyridoxine and salts of pantothenic
sential chemical. or physiological stability. Exacid, may also be added as desired. The follow
tensive tests, for example, showed ribo?avining example is illustrative
nicotinamide or -sodium nicotinate solutions to
be unsatisfactory for use after standing for sev-
m
Per cent w/v
eral weeks or months due to loss in vitamin po- 40 Ribo?avin _____________________________ __
tency.
.
Nicotinamide __________________________ __
0,3
10.0
The principal object of the present invention is
Thiamin hydrochloride _________ _-»_ _____ __
1.0 ,
to provide polyhydroxyisoalloxazine and partic-
Pyridoxine hydrochloride ________________ __
0.1
ularly ribo?avin solutions of desired concentra- 45 Calcium pantoihenate ------ 4- ---------- -_
1.0
tions characterized by both physical and physio-
Boric "Md
0-5
‘logical stability.
Other objects will be apparent as the detailed
The ribo?avin, nicotinamide and acid ingre
dients of this example are preferably ?rst mixed
description hereinafter proceeds.
1
_
-—-
-
-
together in about 80 cc. of water and solution
I have discovered that ribo?avin-nicotinamide 50 induced by warming. After solution the other
solutions may be physiologically stabilized by ad- .
‘ justing the pH value of the solutions to 2.6 to
6.6, and preferably from about 4 to 6.6. The fol- »
lowing examples will serve to illustrate the pres- _
ent invention.
'
ingredients are added and the resulting solution
then made up to 100 c0- by addition of distilled
Water- In this example. which has a pH of
about 4-5. the ratio is 033% ribo?avin t0 1.0%
55 nicotinamide. This represents a 50% increase
2,407,412
4
in ribo?avin over the ribo?avin-nicotinamide
ratio in Examples ‘1 and II. Increase in ribo
?avin was found possible by the discovery that
the other vitamin ingredients used in this ex
ample are characterized by valuable. additive
ribo?avin solubilizing effects. The solubilizing
action of boric acid is also effective in Example
.
salt formed between molecular. equivalents of
nicotinamide and hydrochloric acid, has 9. DH
of 2.0 and ‘has a low solubilizing capacity for
ribo?avin. Thus while the pH range which can
be used to obtain physiological stability is 2.6
6.6, the range which can be used to the greatest
advantage from the standpoint of both physi
ological and physical stability (high solubility)
falls roughly between pH 4 and pH 6.6.
The acidic solutions of the present invention
contain the ribo?avin in desired concentrations
and of utmost importance retain their physio
concentrations. I discovered, for example, that
logical potency over long periods of time. In
while 5 per cent nicotinamide solubilized 0.1 per
order to retain therapeutic potency in the present
cent ribo?avin at pH 5.0, 10 per cent nicotinamide
solubilized 0.28 per cent ribo?avin at pH 5 in 15 compositions the acidic material should be sum
cient tolower the pH not only below the alkaline
stead of 0.2 per cent as reported in early in
limit but also below the neutral point or pH ‘l’.
vestigations. I also discovered that 20 per cent, 30
Any acidic material which is substantially non
per cent, 40 per cent and 50 per cent nicotinamide
toxic at the concentration employed may be
at pH 5 solubilized about 0.6 per cent, 1 per cent,
1.6 per cent and 2.5 per cent ribo?avin, respec 20 used.
Tests show that alkaline ribo?avin nicotin
tively. These discoveries were unexpected for
amide solutions lose from about 33 to 100 per
early investigations with relatively low concentra
III.
.
During the research investigation in this ?eld,
I discovered that nicotinamide possessed unique
solubilizing effects when used in relatively high
tions of nicotinamide, i. e., up to 10 per cent as
cent of their ribo?avin potency on standing for
several months to a year at room temperatures.
illustrated above, had indicated that doubling
the percentage of nicotinamide merely doubled 25 Tests also show that neutral solutions lose from
about 15 to 30 per cent of their potency under
the percentage of dissolved ribo?avin. However,
similar conditions. While solutions of this lat
ter type having a pH of 'l or slightly below come
within. the range of usable compositions, experi
increased about 2.6, 6, l0, l6 and 25 times by
using 2, e, 6, 8 and 10 times, respectively, the 30 ments have demonstrated that such solutions
must be used shortly after preparation or, if
initial amount, i. e. 5 per cent, of nicotinamide.
stored, must be kept at refrigerated temperatures
The following example will serve to further il
in order to maintain the desired pharmaceutical
lustrate the present invention.
the above ?gures (which are given as % w/v)
show that the amount of ribo?avin solubilized is
stability.
,
The acidic solutions of the present invention
Per cent w/v 35 make it unnecessary to use the solutions within
Ribo?avin
___ 0.6
a relatively short time after preparation and also
Nicotinamide
20.0
make it unnecessary to keep the solutions under
The above ingredients are dissolved with heat
carefully controlled temperature conditions, i. e.
ing in water in the usual manner. When solu 40 below room temperature. In addition, as the
tion is complete about 0.2 per cent of a concen
acidic solutions are substantially free from physi
trated solution of hydrochloric acid is added to
ological deterioration, the present invention
bring the pH of the final solution to about 5.0.
makes it unnecessary in ordinary commercial
If desired, about 0.5 per cent boric acid may be
practice to run frequent ‘biological rechecks for
added as this ingredient in addition to its solu
such deterioration.
bilizing e?ects, has also been found to be an
The ribo?avin compositions solubilized by nico
excellent physiologically inert bacteriostatic agent
tinic acid salts are not stable under the 2.6-6.6
for use in the therapeutic solutions of the present
pH range employed in the above nicotinamide
invention.
'
solutions. The solutions employing salts, such as
After discovering the importanceof pH control
the sodium, monoethanolamine, methyl gluca
in ribo?avin-nicotinamide solutions with regard
mine, etc. nicotinates must be maintained at a
to the physiological stability of ribo?avin, I made
pH of about 6 to 6.6.
the further discovery that pH control in the acid
It will !be understood that the present invention
pH range is essential to control of solubility or
is not limited to the above illustrative examples.
physical stability. For instance 5 per cent
55 All modi?cations of the present invention are in»
nicotinamide will solubilize about 0.1, per cent
tended to be covered by the following claims.
ribo?avin at about pH 4.3 and above, but as
I claim:
'
the pH is lowered by addition of acid a progres
1. A therapeutic composition comprising an
sive decrease in ribo?avin solubility occurs.
acidic aqueous solution containing at least about
Thus at about pH 4.05, 3.6, 3.2, 3.0 and 2.5, 5
60 1 mg. of ribo?avin per cc. and at least about 50
per cent nicotinamide will solubilize about 0.095
mg. of nicotinamide per cc. and a small amount
per cent, 0.07 per cent, 0.056 per cent, 0.044 per
of acidic material su?icient to maintain said so
cent and 0.032 per cent ribo?avin, respectively.
_ lutionvat a pH of 4 to 6.6.
Likewise, solutions of 10 per cent, 20 per cent
2. ,A therapeutic solution comprising an acidic
and 30 per cent nicotinamide were found to have ~ ‘aqueous solution containing more than 0.2 per
decreasing capacity to solubilize ribo?avin as the
cent ribo?avin and more than 10 per cent nico
pH was lowered below about DH 5. The decrease
tinamide, said solution having a pH of 4-6.6.
in solubilizing capacity of nicotinamide for ribo
3. Therapeutic compositions comprising acidic
?avin with decrease in pH is apparently related
aqueous solutions containing percentages of ribo
to salt formation between electropositive nicotin
?avin ranging from 0.2 per cent to 2.5 per cent
amide and electronegative acid anions. This ap 70 and nicotinamide ranging from 10 per cent to 50
percent respectively, said solutions having a pH
pears likely because the pH curve of electrometric
of 4-6.6.
'
titration of nicotinamide follows the ribo?avin
solubility curve closely. For example, a 10 per
5.5;The process of stabilizing an aqueous ribo
cent solution of'nicotinamide hydrochloride, the 75 ?avin-"nicotinamide solution which comprises ad
2,407,412
5
.
justing the pH of the solution by means of acidic
and stable for a time period of a year or so com
material to a value of about 4 to 6.6.
prising an aqueous solution containing ribo?avin
in excess of 0.013%; said solution containing also
nicotinamide to solubilize the ribo?avin; and
su?icient hydrochloric acid to adjust and main
tain the pH of the solution at values between 2.6
5. A stable therapeutic preparation compris
ing an aqueous solution having a pH of 4-6.6 and
containing ribo?avin and a solubilizing agent
consisting of nicotinamide. the nicotinamide be
ing present in amounts between 10% and 50%;
.the ribo?avin present being not. less than 2% of
the nicotinamide present.
6. A stable therapeutic preparation comprising 10
and 6.6.
_ 9. A therapeutic ‘composition for parenteral use
and stable for a time period of a year or so com
prising an aqueous solution containing ribo?avin
in excess of 0.013%; said solution containing also
nicotinamide to solubilize the ribo?avin; and
su?icient monosodium dihydrogemphosphate to
adjust and maintain the pH of the solution at
ing present in amounts between 30% and 50%;
the ribo?avin present being not less than 3.8% of 15 values between 2.6 and 6.6.
10. The process of stabilizing an aqueous ribo
the nicotinamide present.
?avin solution to prevent decomposition over a
'7. A therapeutic composition for parenteral use
an aqueous solution having a pH 01', 4-6.6 and
containing ribo?avin and a solubilizing agent
consisting of nicotinamide, the nicotinamide be
time period of a year or so, and to retain ‘the
and stable for a time period of a, year or so com
ribo?avin in solution for the same period, which
prising an aqueous solution containing ribo?avin
in excess of 0.013%; said solution containing also 20 comprises: adding nicotinamide to prevent pre
nicotinamide to solubilize the ribo?avin; and
su?‘lcient acidic material to adjust and maintain
the pH of the solution at values between 2.6 and
6.6.
cipitation; and preventing decomposition by the
addition of su?icient acidic material to maintain
the pH at about 4.5.
a
.8. A therapeutic composition for parenteral use 25
DOUGLAS V. FROST.
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