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Патент USA US3070509

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d?'mAgh
wtlnited grates iiiatent
Patented Dec. 25, 1952
2
1
10 mg. or more of vitamin K1 per ml. of solution can
readily be obtained. Furthermore, it has been found that
aeraasa
the solubilizing agent when administered parenterally in
FARENTERAL AQUEOUS SGELUTEGNS {BF FA?
SGLUELE Vi’i‘AlvtiiiNS
Eohn D. Mullins, lbansdaie, and Thomas J. Maceir, Glen
side, Pa, assignors to Merci; 8s (10., inc., Rahway, Ni,
concentrations suf?cient to provide useful aqueous paren
teral solutions of the oil-soluble vitamins is completely
innocuous, non-hemolytic and non-irritating to tissue.
These results were indeed very surprising and unexpected
in view of the difficulties encountered heretofore with
other polyoxyethylene compounds such as mentioned here
a corporation of New Jersey
No Drawing. Filed Sept. 19, 1%9, Ser. No. 56,701
13 Claims. (Cl. 161-58)
This invention relates to pharmaceutical formulations.
More particularly, it relates to stable aqueous vitamin
inabove.
compositions which are suitable for parenteral administra
tion.
in the aqueous compositions of this invention are those
generally classi?ed in the art as the fat-soluble or oily—
As previously indicated herein, the vitamins employed
vitamins, namely, vitamins A, D, E and K1. However,
The usefulness of the water-insoluble vitamins such as
although the natural form of these vitamins is preferred,
vitamins A, D, E and K1, hereinafter referred to as the
any other fat-soluble substance possessing the vitamin
oily vitamins or oil-soluble vitamins, in nutrition and for
activity of the above-mentioned vitamins may also be sat
the prevention and treatment of certain diseases is well
isfactorily employed. Included among such substances
known. In the past, these vitamins have been administered
are the fat-soluble esters of these vitamins; such as, for
orally in the form of tablets, pills, suspensions, emulsions
and the like. However, in many instances it is often 20 example, vitamin A palmitate, vitamin A acetate, vitamin
E acetate and the like, the fat-soluble derivatives of vita~
desirable to administer such vitamins parenteraily either
min K1, such as, for example, 2-methyl-3-phyty1-1,4~
intramuscularly or intravenously. Unfortunately, because
naphthoquinone, 2,3-0Xide and l-methyl-3-difarnesyl-1,4
of the virtual water-insolubility of the oil-soluble vitmins,
naphtho-quinone.
it has heretofore been necessary to employ emulsions of
these vitamins or to utilize aqueous solutions of water
soluble derivatives of these vitamins. However, as is well
known, the parenteral administration, particularly intra
venous injection, of an emulsion of a fatty material is
not without danger. Although aqueous solutions of water
soluble derivatives of these vitamins are somewhat more
desirable, they have the disadvantage that the derivatives
are not always equivalent in activity to that of the parent
substance. Furthermore, some of the oilesoluble vitamin
compounds do not form water-soluble derivatives which
may be satisfactorily employed parenterally.
25
The fat-soluble vitamins or fat-soluble substances
possessing the desired vitamin activity can be employed
singularly and in compatible combinations to provide
aqueous solutions having the properties or combination of
properties desired in various preparations for parenteral
administration.
The amount of fat'soluble vitamin or fat-soluble vita
min active substance in the aqueous compositions of this
invention will, of course, vary depending on the vitamin
or vitamin active substances employed, mode of adminis
tration as well as the treatment desired. However, in
More recently, attempts have been made to prepare
aqueous solutions which contained su?iciently high con
centrations of the oil-soluble vitamins and were suitable
general, those amounts which have heretofore been cus- _
a suitable agent which would effectively solubilize these
vitamins to the extent necessary for the preparation of
mentioned the condensation product of castor oil and
eth lene oxide. In general, it has been found that satis
satisfactory aqueous parenteral solutions and still be, in
the concentrations employed for this purpose, non-toxic,
substances are those condensation products which con
tomarily employed and found satisfactory for parenteral
administration may be used.
The solubilizing agent employed in the preparation
for parenteral administration, particularly intravenous in
jection. Toward this end, investigators have searched for 40 of the aqueous solutions of this invention is as previously
factory solubilizing agents for the fat-soluble vitamin
non-hemolytic and non-irritating to the tissue when ad— 45 tain from about 20 to about 40 moles of ethylene oxide
per mole of castor oil. However, castor oil-ethylene
ministered parenterally. Although many agents have been
oxide condensation products combining from about 30
tested for this purpose, none has been found which pro
to about 35 moles of ethylene oxida per mole of castor
vides a completely satisfactory solution of the problem.
oil are particularly effective and preferred. Such con
For example, polyoxyethylene ethers of lauryl alcohol
densation products may be ‘readily prepared in the man
have been proposed as solubilizing agents for vitamin K1.
ner described in German Patent No. 694,178, published
Although some solubilization of vitamin K1 is achieved
on July 27, 1940. A number of these products are avail
with this material, the degree of solubilization is consid
able commercially from the General Aniline and Film
erably less than is desired. in addition, this material,
Corporation
under the name “Emulphor,” e.g., Emul
even at relatively low concentrations, causes considerable
phor EL-62O and Emulphor Bis-719 and from the Proc
hemolysis when administeredintravenously. Other agents,
ess Chemicals Company under the name “Prosol” such
such as the polyethyleneglycol monoricinoleates and poly
as, for example, Prosol E-4329.
oxyethyiene sorbitan monooleates, while somewhat more
In the preparation of the aqueous solutions of this
effective solubilizing agents for vitamin K1, produce sig
invention, it is essential that the fat-soluble vitamin sub
ni?cant muscular irritation and hemolysis on parenteral
stance be ?rst dissolved in the solubilizing agent. After
administration.
solution is complete, water is then slowly added main
According to the present invention, it has now been
taining good agitation until the ?nal concentration of the
found that clear aqueous solutions of the oil-soluble vita
vitamin substance in the aqueous solution is obtained.
mins can be prepared by dissolving the oil-soluble vitamin
The amount of solubilizing agent employed will, of
in a solubilizing agent comprising the condensation prod
course, vary depending on such factors as the particu
uct of castor oil and ethylene oxide, and adding the result
lar fat-soluble vitamin substance or substances employed
ing mixture to water. Such compositions have the prop
and the concentration of vitamin or vitamin active sub
erties and characteristics which render them highly adapta
stance desired in the ?nal solution. However, in general,
bio for parenteral administration, particularly intraven
it has been found that satisfactory results are obtained
ous injection. Thus, it has been found that aqueous solu
when from about 5 mg. to about 25 mg. and preferably
tions containing relatively high concentrations of the oil
from about 7 mg. to about 15 mg. of the solubilizing
soluble vitamins can be prepared in the manner described
agent per mg. of vitamin is employed. Aqueous fat
above. For example, with vitamin K1 concentrations of
3,070,499
3
4.
soluble vitamin compositions prepared in the above man~
ner and containing from about 5% to about 25% of the
Example 3
An aqueous parenteral solution having the following
solubilizing agent (weight/volume) are highly satisfac
tory for parenteral administration. However, solutions
containing from about 7% to about 15% of the solubiliz
ing agent are preferred. It is to be noted that although
the above ranges represent practical limits, the ratio of
solubilizing agent to vitamin as well as the ?nal concen
composition is prepared according to the process of E):
ample 1:
Mg. per ml.
Vitamin A ________________________________ __ 7.5
Emulphor EL—620 __________________________ __
75
Distilled water, q.s.
tration of solubilizing agent in solution may be increased
Example 4
somewhat but some di?iculty will be encountered in ad 10
ministering such solutions parenterally because of in
An aqueous parenteral solution having the following
creased viscosity.
composition is prepared according to the process of Ex
The aqueous solutions of this invention are as men
ample 1:
tioned above highly suitable for parenteral administra
Mg. per ml.
tion, particularly intravenous injection. In such usage,
Vitamin D2 crystalline _______________________ __ 2.5
the solutions may, in addition to the above-mentioned
Emulphor EL—719 _________________________ __ 50
ingredients, contain other water-soluble ingredients, in
Distilled water, q.s.
cluding one o: more water-soluble vitamins, saline, glu
Emulphor EL*719 is the condensation product of
cose, dextrose and the like.
In addition, to guard against bacterial decomposition of 20 castor oil and ethylene oxide and contains about 40
moles of ethylene oxide per mole of castor oil.
the vitamin in solutions to be stored for prolonged periods,
it is desirable to incorporate a preservative in such solu
Example 5
tions.
Suitable preservatives include phenylethanol,
benzyl alcohol, benzalkonium chloride, methyl parabens
and methyl p-hydroxybenzoate. However, if the prepa
ration of these solutions is carried out under sterile con
An aqueous parenteral solution having the following
composition is prepared according to the process of Ex
ample 1:
Mg. per ml.
ditions and if the formulation is used immediately, the
addition of a preservative is not necesary.
Where the addition of a preservative is desired, it is
normally not necessary to employ a preservative in an
amount in excess of 1.0% (weight/volume) of the com
position. With the more effective preservatives concen~
trations as low as 0.1% (weight/volume) are satisfac
tory.
Since the aqueous solutions of this invention are in
tended for parenteral administration, it will be under
stood that appropriate steps should be taken to insure
that the products are sterile and also that they are free
of pyrogens. In this connection, sterilization can be
Vitamin K1 _________________________________ __ 10
Emulphor EL-620 ___________________________ __ 70
Distilled water, q.s.
Example 6
An aqueous parenteral solution having the following
composition is prepared according to the process of Ex~
ample 1:
Mg. per ml.
Vitamin K2 _______________________________ __
10
Prosol E-4329 ____________________________ __ 100
Distilled water, q.s.
Example 7
readily effected by aseptic ?ltration. As for the control 40
of pyrogen content, this is best carried out by employing
An aqueous parenteral solution having the following
pyrogen-free components and carrying out the prepara~
composition is prepared according to the process of Ex
tion under esentially pyrogen-free conditions.
ample 1:
The following examples are included for the purpose
Mg. per ml.
of illustration and are not to be construed as any undue
VitaminE _________________________________ __ 50
limitation of the scope of the appended claims.
Prosol E~4329 _____________________________ -_ 250
Distilled water, q.s.
Example 1
An aqueous solution suitable for parenteral adminis
Example 8
tration and having the following composition is prepared
An
aqueous
parenteral
solution having the following
as follows:
composition is prepared as follows:
‘Mg. per ml.
Mg. per ml.
Vitamin K1 ________________________________ __ 5
Emulphor EL-620 __________________________ _. 7O
Distilled water, q.s.
The vitamin K1 is dissolved in the Emulphor EL-620.
Emulphor EL-62O is the condensation product of castor
oil and ethylene oxide and contains about 34 moles of
ethylene oxide per mole of castor oil. When the solu
Vitamin K1 _________________________________ __ 5
Emulphor EL-620 ___________________________ __ 70
Benzyl alcohol ______________________________ __ 9
Sodium chloride ____________________________ __
8
Distilled water, q.s.
The vitamin K1 is dissolved in the Emulphor EL—620.
tion is complete, water is added slowly maintaining good 60 When the solution is complete, water is added slowly
maintaining good agitation. When about 90% of the
agitation. The resulting solution is then sterilized by
required
volume is reached, the remaining ingredients
aseptic ?ltration under nitrogen pressure and subdivided
are added. The resulting solution is then diluted to
into suitable vials for immediate use.
volume, sterilized by aspetic ?ltration and subdivided into
Example 2
suitable vials.
An aqueous parenteral solution having the following
Example 9
composition is prepared according to the procedure of
Example 1:
An aqueous parenteral solution having the following
composition is prepared according to the process of
Mg. per ml.
Example 8:
Vitamin K1 oxide ___________________________ __ 10
70
Prosol E-4329 _____________________________ .. 50
Mg. per ml.
Distilled water, q.s.
Prosol E-4329 is the condensation product of castor
oil and ethylene oxide and contains about 30 moles of
ethylene oxide per mole of castor oil.
Vitamin A palmitate ________________________ __ 8.2
Emulphor EL-620 __________________________ __ 115
Phenylethanol
__________________ __‘ _________ __
Sodium chloride, to isotonicity.
Distilled water, q.s.
l0
aerator‘)
solution in an amount of from about 7 to about 15 milli
grams per milligram of said fat-soluble substance and said
aqueous solution containing from about 7 to about 15%
Example 10
An aqueous parenteral solution having the following
composition is prepared according to the process of Ex
ample 8:
Mg. per ml.
Vitamin E acetate __________________________ __
50
Prosol E-4329
____
250
Methyl Parabens __________________________ __ 1.5
Dextrose, to isotonicity.
(weight/volume) of said solubilizing agent.
8. A parenteral aqueous solution comprising a fat~
soluble substance having vitamin D activity and as a
solubilizing agent therefor a condensation product of
castor oil and ethylene oxide, said condensation product
containing from about 30 ‘to about 35 moles of ethylene
10 oxide per mole of castor oil and being present in said
Distilled water, q.s.
solution in an amount of from about 7 to about 15 milli~
grams per milligram of said fat-soluble substance and said
Various changes and modi?cations of the invention
aqueous solution containing from about 7 to about 15%
can be made, and to the extent that such variations in
(weight/ volume) of said solubilizing agent.
corporate the spirit of the instant invention, they are
9. A parenteral aqueous solution comprising a fat
intended to be included within the scope of the appended 15
soluble substance having vitamin E activity and as a solu
claims.
bilizing agent therefor a condensation product of castor
What is claimed is:
oil and ethylene oxide, said condensation product con
1. A parenteral aqueous solution comprising a fat
taining from about 30 to about 35 moles of ethylene oxide
soluble vitamin active substance and as a solubilizing
per mole of castor oil and being present in said solution
agent therefor a condensation product of castor oil and .
in an amount of from about 7 to about 15 milligrams per
ethylene oxide, said condensation product containing
milligram ‘of said fat-soluble substance and said aqueous
from about 20 to about 40 moles of ethylene oxide per
solution containing from about 7 to about 15%
mole of castor oil and being present in said solution in
an amount of from about 5 to about 25 milligrams per
(weight/volume) ‘of said solubilizing agent.
10. An aqueous parenteral solution having the follow
milligram of said fat-soluble vitamin active substance and 25
said aqueous solution containing from about 5 to about
ing composition:
I
Mg. per ml.
25% (weight/volume) of said solubilizing agent.
2. A parenteral aqueous solution comprising a fat
Vitamin K1
__.._10
soluble vitamin active substance and as a solubilizing agent
Condensation product of castor oil and ethylene oxide
containing about 34 moles of ethylene oxide per
therefor a condensation product of castor oil and ethyi 30
ene oxide, said condensation product containing from
mole of castor oil _..__; ____________________ __ 70
about 30 to about 35 moles of ethylene oxide per mole
Benzyl alcohol ______________________________ .. 9
of castor oil and being present in said solution in an
amount of from about 5 to about 25 milligrams per mil
ligram of said fat-soluble vitamin active substance and
said aqueous solution containing from about 5 to about
25% (weight/volume) of said solubilizing agent.
3. A parenteral aqueous solution comprising a fat
Sodium chloride
__
8
11. A parenteral aqueous solution comprising a fat
soluble vitamin active substance and as a solubilizing agent
therefor a condensation product of castor oil and ethylene
oxide, said condensation product containing from about
20 to about 40 moles of ethylene oxide per mole of castor
oil and being present in said solution in an amount suf
agent therefor a condensation product of castor oil and 40 ?cient to solubilize said fat-soluble vitamin active sub
soluble vitamin active substance and as a solubilizing
ethylene oxide, said condensation product containing from
stance.
about 30 to about 35 moles of ethylene oxide per mole of
12. A parenteral aqueous solution comprising a fat
castor oil and being present in said solution in an amount
soluble vitamin active substance and as a solubilizing agent
of from about 7 to about 15 milligrams per milligram
therefor a condensation product of castor oil and ethylenev
of said fat-soluble vitamin active substance and said 45 oxide, said condensation product containing from about
aqueous solution containing from about 7 to about 15%
20 to about 40 moles of ethylene oxide per mole of
(weight/volume) of said solubilizing agent.
castor oil and being present in said solution in an amount
4. A parenteral aqueous solution comprising a fat
of at least 5 mg. per mg. of said fat-soluble vitamin sub
soluble substance having vitamin K activity and as a
stance and said aqueous solution containing from about
solubilizing agent therefor a condensation product of 50 5 to about 25% (weight/volume) of said solubilizing
castor oil and ethylene oxide, said condensation product
agent.
containing from about 30 to about 35 moles of ethylene
13. The composition of claim 12 wherein the fat
oxide per mole of castor oil and being present in said
soluble substance is vitamin K1.
solution in an amount of from about 7 to about 15 milli
grams per milligram of said fat-soluble substance and said 55
aqueous solution containing from about 7 to about 15%
(weight/volume) of said solubilizing agent.
5. The composition of claim 4 wherein the fat-soluble
substance is vitamin K1.
6. The composition of claim 4 wherein the fat-soluble 60
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,5 18,230
2,879,205
Freedman et al _________ __ Aug. 8, 1950
McQuarrie ___________ __ Mar. 24, 1959
OTHER REFERENCE
'
7. A parenteral aqueous solution comprising a fat
Encyclopedia of Surface Active Agents, Sisley et al.,
soluble substance having vitamin A activity and as a
Chemical Publishing Co., Inc., New York, February 1959,
solubilizing agent therefor a condensation product of
page
293.
castor oil and ethylene oxide, said condensation product 65 Mima et al.: J. Pharm. Soc. of Japan, vol. 77, Novem
containing from about 30 ‘to about 35 moles of ethylene
ber 1957, pages 1201-1203.
oxide per mole of castor oil and being present in said
substance is vitamin K1 oxide.
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