Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1~5834
The present invention relates to novel ophthalmic pre-
parations and a process for producing the same.
Eye lotions or ophthalmic ointments have heretofore
been widely used as ophthalmic preparations. Eye lotions, which
usually contain purified water as the hase ingredient, are not
easily spreadable over the cornea or become diluted with the ~ear
when applied to the eye, so that a large amount of the lotion
falls off the eyelids. Thus difficulties have been encountered
in causing the medicinal ingredient of eye lotions to be fully
retained on the eyelids or absorbed by the body.
Ophthalmic ointments, which contain vaselineor a mix-
ture of vaseline and liquid paraffin or purified lanolin as the
base ingredient, are not hydrophilic, are therefore liable to be
dislodged from the eyelids and unable to effectively adhere to
the cornea and the mucous rnembrane of the eye. Accordingly they
have the drawback of failing to fully release the active ingre-
dient therefrom, permitting only a small amount thereof to reach
the affected part for absorption. Additionally ophthalmic oint-
ments have another drawback that the oily base ingredient gives
the eyelids an unpleasant feel due to its stickiness when the
ointment is applied.
The present inventors carried out intensive research
to overcome these drawbacks and to provide highly effective
ophthalmic preparations which enable the mucous membr~ne of
the eye, the cornea and the like to fully absorb ophthalmic
drugs and found that preparations incorporating a carboxyvinyl
polymer to afford a specified viscosity produce outstanding
effects. Thus this invention has been accomplished.
According to the invention there is provided an
ophthalmic preparation in the form of a gel suitable for
application to the eye, which comprises a homogeneous mixture
of an aqueous solution of a carboxyvinyl polymer, havin~ a
il~5834
polymer concentration of 0.05 - 5.0~/O by weight, a water-
soluble basic substance, ~odium chloride, and a therapeuti-
cally effective amount of an ophthalmic drug, said gel having
a pH of 5 to 8 and a viscosity of 1,000 centipoises to 100,000
centipoises at 20C.
According to another aspect of the invention there
is provided a process for preparing the ophthalmic pre-
paration which comprises a) dissolving or dispersing said
ophthalmic drug in said aqueous solution of said polymer,
neutralizing said carboxyvinyl polymer with said basic
substance to a pH of 5 to 8 and introducing said sodium
chloride into the mixture, or b) neutralizing said aqueous
carboxyvinyl polymer solution containing 0.05 to 5%, by
weight, of said polymer with said basic substance to a pH
of 5 to 8, and introducing said ophthalmic drug and said
sodium chloride into the mixture, or c) admixing said
ophthalmic drug, aqueous carboxyvinyl polymer and basic sub-
: stance to form a mixture having a pH of 5 to 8, and intro-
ducing the sodium chloride to said mixture.
Carboxyvinyl polymers useful in this invention are
hydrophilic polymers polymerized predominantly from an
acrylic acid. Examples of such polymers are those commercially
available under the trademarks Carbopol 934, 940 and 941 and
manufactured by B. F. Goodrich Chemical Co., U.S.A.
- la
.~
S~334
Carboxyvinyl polymers have free carboxy groups.
The aqueou~ ~olution of such a polymer is acidic and ~orms
a consistent gel when neutralized with a base. Examples of
water-soluble basic substances useful in this invention for
neutralizing carboxyvinyl polymers are organic amines includ-
ing alkylamines such as methylamine, ethylamine and propyl-
amine; dialkylamines such as dimethylamine, diethylamine
and dipropylamine; trialkylamines such as trimethylamine,
triethylamine and tripropylamine; alkanolamines such as
methanolamine, ethanolamine and propanolamine, dialkanol-
amines such as dimethanolamine, diethanolamine, dipropanol-
amine and dibutanolamine; trialkanolamines such as tri-
methanolamine, triethanolamine, tripropanolamine and tri-
butanolamine; and trimethylolaminomethane. Inorganic
bases such as aqueous solutions of ammonia and alkali
hydroxides are also usable. Carboxyvinyl polymers, when
neutralized, give gels of substantially the same viscosity
irrespective of the kind of the
-2-
. . .
5834
basic substance used.
Preferably, the neutralization of carboxyvinyl polymers
with water-soluble basic substances is generally so adjusted that
the resulting preparation in the form of a gel has a pH close to
neutrality, i.e. of 5 to 8. It is desired that the preparation
have a pH value which is most favorable to the stability of the
drug to be incorporated therein. Accordingly the gel prepara-
tion of this invention should be adjusted to a pH o~ 5 to 8.
According to this invention, ophthalmic drugs are us-
able whether they are soluble or insoluble in water. Water-
insoluble drugs, when used, render the resulting gel preparation
turbid but will not precipitate in the preparation, so that the
preparation is applicable without any trouble. However, an auxi-
liary dissolving agent may be used to render the preparation
transparent or more effectively absorbable by the body. Alter-
natively the ophthalmic drug may be dissolved in a water-soluble
organic solvent first and then formulated into a preparation.
Examples of such water-soluble organic solvents are propylene
glycol, polyethylene glycol having a molecular weight of 300 to
400, etc., among which propylene glycol, which is widely usable,
is suitable. Furthermore, water-soluble basic substances may be
used also as solvents. Examples of auxiliary dissolving agents
are nonionic sur~actants including fatty acid esters of polyoxy-
ethylene sorbitan such as polyoxyethylene sorbitan monopalmitate
and polyoxyethylene sorbitan monostearate, polyoxyethylene alkyl
ethers such as polyoxyethylene lauryl ether, polyoxyethylene
cetyl ethër, polyoxyethylene stearyl ether, polyoxyethylene oleyl
ether and polyoxyethylene behenyl ether; and ben7,yl alcohol.
Ophthalmic drugs useful in this invention are those
nonionic and stable in preparations, namely in aqueous media.
Examples of ophthalmic drugs suitable for use in the gel prepara-
tions of this invention are prednisolone, cortisone~ hydrocorti~
1~5834
sone, hydrocortisone acetate, methylprednisolone, cortisone ace-
tate, cortisone caproate, dexamethasone, betamethasone, betame-
thasone valerate, betamethasone benzoate, dexamethasone acetate,
dexamethasone valerate, flumethasone, fluocinolone acetonide,
fluocinonide, flumethasone, prednisolone acetate, methylpredni-
solone acetate, triamcinolone, triamcinolone acetonide and like
adrenocortical hormones and derivatives thereof, chloramphenicol,
tetracycline, oxytetracycline, chlortetracycline, penicillin and
like antibiotics, vitamin B2, vitamin B6, vitamin B12, vitamin A,
vitamin E, vitamin D and like vitamins, boric acid, acrinol,
azulene, flavin adenine dinucleotide, allantoin, glutathione,
sulfa drugs, etc.
- According to the process of this invention, prepara-
: tions in the form of a gel are produced by dissolving or disper-
sing an ophthalmic drug in an aqueou3 carboxyvinyl polymer solu-
tion and uniformly mixing the.solution or dispersion with a water-
soluble basic substance which is added to the solution while
stirring to afford an adjusted pH of 5 to 8, or by admixing a
water-soluble basic substance with an aqueous carboxyvinyl poly-
mer solution while stirring to obtain a gel and adding an ophthal-
mic drug to the gel. The gel preparations obtained have a vis-
cosity of 1,000 to 100,000 centipoises at 20 C. Gels having a
iSCoQity of less than 1,000 centipoises are highly flowable like
conventional aqueous eye lotions and wi~l flow out of the body
as such or associated with the tear when applied, hence they are
undesirable. If the viscosity e~ceeds 100,000 centipoises the
: gels are too hard and are not fully collapsible when applied to
the mucous membrane of the eye, thus involving difficulties in
~: the release of the ophthalmic drug from the gel, adsorption of
~:,
:~ 30 the drug by the mucous membrane and absorption of-the drug by the
`. body.
. The gel preparations of this invention have a viscosity
5~34
widely ranging from 1,000 centipoises to 100,000 centipoises.
Preparations with a relatively low viscosity of from about 1,000
to about 10,000 centipoises have good flowability and ~an be
applied dropwise directly onto the mucous membrane around the
eyeball. On the other hand, relatively viscous preparations
having a viscosity of about 10,000 to about 100,000 centipoises
are less flowable, pasty and consistent than ointments and can
therefore be applied to the eyelids like conventional-ophthalmic
ointments to obtain medicinal results.
When the ophthalmic preparations of this invention are
used, the tear collapses the gel to a liquid which can be readily
adsorbed by the mucous membrane and the cornea. Even viscous
gels turn to a liquid on application owing to a rapid reduction
in viscosity, so that the ophthalmic drug contained in the gel
will be absorbed by the mucous membrane of the eye and the cornPa
in intimate contact therewith. Whereas conventional eye lotions
are likely to be carried away with the tear, the preparations of
this invention are in the form of a gel, which breaks down to
assure the adsorption of the ophthalmic drug on the mucous mem-
brane of the eye or the like. Accordingly the preparations can
produce sufficient medicinal effects without being carried along
as such by the tear. Conventional ophthalmic ointments, which
contain vaseline, lanolin or like oleophilic base ingredient, will
not intimately attach to the mucous membrane of the eye, are very
likely to be carried away by the tear without allowing sufficient
absorption of the ophthalmic drug and give a sticky and uncomfor-
table feel to the eyelids. In contrast, the ophthalmic prepara-
tion of this invention, even when viscous, can be very easily
converted by the tear to a liquid which intimate~y attaches
to the membrane. Moreover the present preparations give no dis-
comfort to the patient since they are free from any oleophilic
base ingredient. With gel preparations of low viscosity, the
S834
mucous membrane of the eye intimately adsorbs and absorbs the
ophthalmic drug rapidly, while the gel takes a longer time for
breakdown with an încrease in viscosity, resulting in moderate
absorption of the drug and affording a sustained medicinal effect.
For this reason, a gel preparation of relatively low viscosity
is preferable when it is desired to rapidly achieve a medicinal
effect through efficient adsorption on the mucous membrane, where-
as a sustained effect is available for a prolonged period of time
with a gel preparation of relatively high viscosity. The visco-
10 sity, although somewhat dependent on the drug used, is governed
mainly by the concentration of the carboxyvinyl polymer. For the
formulation of gel preparations of specified viscosity, the car-
boxyvinyl polymer is used in the form of an aqueous solution
having a concentration of O.OS to 5.0% by weight. When the addi-
tion of some ophthalmic dru~ leads to a reduced viscosity, the
desired viscosity can be obtained with the use of an aqueous solu-
~ tion containin~ an increased amount of carboxyvinyl polymer.
S The preparation of this invention, when applied to the
eye, undergoes a marked reduction in its viscosity with break~
20 down of its gel form, presumably due to the presence of sodium
chloride in the tear. We found that the addition of a small a-
mount of sodium chloride or an aqueous solution thereof to the
ophthalmic preparation of this invention converts the gel to a
liquid with a great reduction of its viscosity. Directing atten-
tion to this finding, we conducted further research, which has
revealed that the addition of a small amount of sodium chloride
to the ophthalmic preparations of this invention delays the break-
.~ ~
-~ down of the gel when the preparation is applied to the mucous
~-~ membrane of the eye. Thus ophthalmic preparations containing so-
dium chloride are suitable when sustained effects are desirable.
;- In this case, it is preferable to use an increased amount of car-
boxyvinyl polymer to compensate for the reduction of viscosity
-- 6 --
,
. . .
5834
due to the addition of sodium chloride.
Although dependent on the kind of ophthalmic drug in-
corporated, the preparations of this invention, when containing
steroids or antibiotics for example, are remarkably effective
for the curing of various inflammatory diseases such as kerati-
tis, scleritis, blepharitis and iridocyclitis. They are also
useful for asthenopia (fatigue of the eyes), conjunctival injec-
tion (bloodshot eyes), prevention of ophthalmic diseases (after
swimming or when dust or perspiration has ingressed into the eye~,
inflammation of the eyes (snow blindness) caused by exposure to
ultraviolet rays or other rays! dacryocystitis (teary eyes), in-
flammation of eyelids (bleary eye), bacterial conjunctivitis,
replenishment of the tear and various other applications.
Given below are Examples of this invention, in which
the viscosities were measured at 20 C by a C-type viscosimeter
produced by Tokyo Keiki Co., Ltd., Japan.
Example 1
One gram of carboxyvinyl polymer (Carbopol 940) was
dissolved in 99 g of sterilized purified water to prepare a 1%
aqueous solution of carboxyvinyl polymer.
To 7.5 g of the 1% aqueous solution of carboxyvinyl
polymer there were added 90.5 g of sterilized purified water, and
1.5 g of a solution prepared by dissolving 2 g of sodium hydro-
xide in 98 g of sterilized purified water was slowly added to
the mixture with full stirring. With continued stirring, the
solution became a gel, to which 0.5 g of chloramphenicol powder
was added. The mixture was vigorously stirred to give a prepara-
tion in the form of a gel containing 0~5% of chloramphenicol uni-
formly dispersed therein and having a pH of 7.0 and a viscosity
of 2,000 centipoises.
Example 2
To a mixture of 20 g of a 4% aqueous solution of car~o-
1~35i~33~
xyvinyl polymer and 74.8 g of sterilized purified water, 3.2 gof 10% aqueous solution of sodium hydroxide were added while
stirring. When thoroughly stirred, the mixture gave a consistent
gel, to which 2 g of chloramphenicol powder was added. The re-
sulting mixture was vigorously stirred, giving a gel preparation
containing 2% of chloramphenicol and having a pH of 6.95 and a
viscosity of 40,000 centipoises.
Example 3
Ten grams of a 1% aqueous ~olution of carboxyvinyl po-
lymer was added to an aqueous solution of 0.02 g of water-soluble
azulene (active component ofchamomile flower) in 87.98 g of
sterilized purified water. To the mixture, 2.0 g of 2% aqueous
colution of sodium hydroxide were added while stirring to produce
a gel preparation having a pH of 7.00 and a viscosity of 4,000
centipoises.
Example 4
A 0.05 g quantity of acrinol was dissolved in ~2.79 g
of sterilized purified water while heating on a water bath, and
the solution was cooled. To the solution, 14.3 g of a 1% aqueous
solution of carboxyvinyl polymer were added, and the mixture was
stirred. Subsequently 2.86 g of a 2% aqueous solution of sodium
hydroxide was added to the mixture. The resulting mixture was
thoroughly stirred, giving a gel preparation having a pH of 6.50
and a viscosity of 3,000 centipoises.
Example 5
2 g of boric acid were dissolved in 80.84 g of steri-
, lizedpurified water while heating on a water bath, and the solu-
tion was cooled. To this solution, 14.3 g of a 1% aqueous solu-
tion of carboxyvinyl pol~er were added and the mixture was
stirred. And then, 2.86 g of a 2% aqueous solution of sodium
hydroxide were added to the mixture. The resulting mixture was
thoroughly stirred, giving a gel preparation having a pH of 6.50
S834
and a viscosity of 3,000 centipoises.
Example 6
To 20 g of propylene glycol heated to about 70C on a
water bath, 0.05 g of butyric acid ester of riboflavin was dis-
solved, and the resulting solution was cooled. To this solution,
there were added 67.09 g of sterilized purified water and 10 g
of a 1% aqueous solution of carboxyvinyl polymer and the mixture
was thoroughly stirred. And then, 2.86 g of aqueous solution of
sodium hydroxide were added to the mixture. The resulting mix-
ture was thoroughly stirred, giving a gel preparation having a
pH of 80 00 and a viscosity of 5,000 centipoises.
Example 7
To 20 g of propylene glycol heated to about 70C on a
water bath, 0.1 g of butyric acid ester of riboflavin was dis-
solved, and the resulting solution was cooled. To this solution,
there were added 50.9 g of sterilized purified water, 25 g of 4%
aqueous solution of carboxyvinyl polymer and 4 g of 10% aqueous
solution of sodium hydroxide, and the resulting mixture was
thoroughly stirred to give a gel preparation having a pH of 6.99
20 and a viscosity of 50,000 centipoises.
Example 8
~o 25 g of propylene glycol heated to about 90C on a
water bath, 0.5 g of prednisolone was dissolved, and 60.1 g of
sterilized purified water and 12 g of 1% aqueous solution of car-
boxyvinyl polymer were added to the above solution. To the mix-
ture, 2.4 g of sodium hydroxide were added while stirring to give
a gel preparation having a pH of 7.10 and a viscosity of 2,200
centipoises.
Example 9
Into 20 g of propylene glycol heated to about 90C on
a water bath, 0.5 g of prednisolone was dissolved, and 50.5 g of
sterilized purified water and 25 g of 4% aqueous solution of car-
1~583~
boxyvinyl polymer were added to th~ above solution. To the mix-
ture, 4 g of a 10% aqueous solution of sodium hydroxide were
added while stirring to give a gel preparation having a pH of
6.80 and a viscosity of 43,000 centipoises.
E~ample 10
To 25 g of propylene glycol heated to about 90C on a
water bath, 0.5 g of hydrocortisone was dissolved, and 60.1 g of
sterilized purified water and 12 g of 1% aqueous solution of
carboxyvinyl polymer were added to the above solution while stir-
ring. To the mixture, 2.4 g of a 2% aqueous solution of sodium
hydroxide were added while stirring to give a gel preparation
having a pH of 7.10 and a viscosity of 2,200 centipoises.
Example 11
To 20 g of propylene glycol heated to about 90C on a
water bath, 0.5 g of hydrocortisone was dissolved and 50.5 g of
sterilized purified water and 25 g of 4% aqueous solution of car-
boxyvin~l polymer were added to the above solution while stirring.
To this mixture, 4 g of a 10% aqueous solution of sodium hydro-
xide were added while stirring to give a gel preparation having
20 a pH of 6.80 and a viscosity of 42,000 centipoises.
Example 12
~o 25 g of propylene glycol heated to about 90C on a
water bath, 0.1 g of dexamethasone was dissolved, and 60.5 g of
sterilized purified water and 12 g of a 1% aqueous solution of
carboxyvinyl polymer were added to the above solution while stir-
ring. To the mixture, 2.4 g of a 2% aqueous solution of sodium
hydroxide were added while stirring to give a gel preparation
having a pH of 7.05 and a viscosity of 2,200 centipoises.
Example 13
0.1 g of allantoin was dissolved in 76.7 g of steri-
lized purified water while heating gently, and to this solution,
20 g of a 4% aqueou~ aolution of carboxyvinyl polymer and 3.2 g
-- 10 --
~S834
of 10% aqueous solution of sodium hydroxide were added while
stirring, to give a gel preparation having a pH of 6.95 and a
viscosity of 40,000 centipoises.
Example 14
0.1 g of allantoin was dissolved in 90.9 g of steril~ed
purified water while heating gently, and to this solution, 7.5
g of 2 1% aqueous solution of carboxyvinyl polymer and 1.5 g of
a 2% aqueous solution of sodium hydroxide were added while stir-
ring to give a gel preparation having a pH of 7.00 and a visco-
sity of 2,000 centipoises.
Example 15
To 20 g of propylene glycol heated to about 70~C on a
water bath, 0.05 g of flavin-adenin-dinucleotide was dissolved
and the resulting solution was cooled. To this solution, 67.09 g
of sterilized purified water and 10 g of a 1% aqueous solution
of carboxyvinyl polymer were added while stirring. To this mix-
ture, 2.86 g of a 2% aqueous solution of sodium hydroxide were
added while stirring to give a gel preparation having a pH of
7.00 and a viscosity of 5,000 centipoises.
Example 16
To 20 g of propylene glycol heated to about 70C on a
water bath, 0.1 g of flavin-adenin-dinucleotide was dissolved,
and the resulting solution was cooled. To this solution, 50.9 g
of sterilized purified water and 25 g of a 4% aqueous solution
of carboxyvinyl polymer were added while stirring. To this mix-
ture, 4 g of a 10% aqueous solution of sodium hydroxide were
added while stirring to give a gel preparation having a p~ of
6.99 and a viscosity of 50,000 centipoises.
Example 17
~.0 g of boric acid were dissolved in 64.4 g of steri-
lized purified water while heating gently. After cooling, 12 g
of a 4% aqueous solution of carboxyvinyl polymer were added to
~583~
the above solution while stirring. To this mixture, 9.6 g of a
2% aqueous solution of sodium hydroxide were added in small por-
tions to give a gel preparation having a pH of 6.90 and a visco-
sity of 30,000 centipoises.
To the above gel, 12 g of a 1% aqueous solution of so-
dium chloride were added in small portions while stirring. The
viscosity of the gel was dropped. After stirring thoroughly, a
gel preparation having a pH of 7.00 and a viscosity of 3,000 cen-
tipoises was obtained.
Example 18
To 25 g of propylene glycol heated to about 90C on a
water bath, 0. 5 g of prednisolone was dissolved, and to the re-
sulting solution 43 g of sterilized purified water and 11.5 g of
4% aqueous solution of carboxyvinyl polymer were added while
stirring. To this solution, 8 g of a 2% aqueous solut on of so-
dium hydroxide were added while stirring. A uniform gel having
a pH of 6.90 and a viscosity of 33,000 centipoises was obtained.
Subsequently, 12 g of a 1% aqueous solution of sodium
chloride were added in small portions to the above gel while
20 stir~ing to give a uniform gel preparation having a pH of 7.00
and a viscosity of 2,200 centipoises.
Example 19
To 61.7 g of sterilized purified water, 11 g of a 4%
carboxyvinyl polymer were added while stirring, and subsequently
8.8 g of a 2% aqueous solution of sodium hydroxide were added in
small portions while thoroughly stirring to give a ~el base hav-
iny a pH of 6.90 and a viscosity of 29~ 000 centipoises.
To the above gel base, 18 g of a 1% aqueous solution
of sodium chloride were added in small portions while stirring.
The viscosity of the gel base started to drop markedly by the
addition of an aqueous solution of sodium chloride. 0.5 g of
chloramphenicol powder was added to the above gel while stirring
- 12 -
33~
to give a uniform gel preparation having a pH of 7.00 and a vis-
cosity of 2,000 centipoises.
Examele 20
0.02 g of ~ater-soluble azulene was dissolved in 47.28
g of sterilized water, and to this solution, 11 g of a 4% aqueous
solution of carboxyvinyl polymer were added while stirring, and
then, 29.7 g of a 2% aqueous solution of triethanolamine were
added in small portions while stirring to give a uniform gel hav-
ing a pH of 6.90 and a viscosity of 28,000 centipoises.
12 g of an aqueous solution of sodium chloride were
added to the above gel in small portions while stirring, to give
a uniform gel preparation having a pH of 7.00 and a viscosity of
3,000 centipoises.
Example 21
0.02 g of vitamin B12 was dissolved in 90.98 g of
sterilized purified water, and to this solution 7.5 g of a 1%
aqueous solution of carboxyvinyl polymer were added while stir-
ring. Subsequently, 1.5 g of a 2% aqueous solution of sodium
hydroxide was added to give a uniform gel preparation having a
~0 pH of 7.Q0 and a viscosity of 2,000 centipoises.
Example 22
0.02 g of vitamin B12 was dissolved in 89.28 g of steri-
lized purified water, and to this solution 7.5 g of a 4% aqueous
solution of carboxyvinyl pol~mer were added while stirring. Sub-
sequently, 3.2 g of a 10% aqueous solution of sodium hydroxide
were added in small portions w~ile stirring to give a uniform gel
preparation having a p~ of 7.00 and a viscosity of 40,000 centi-
poises.
Example 23
0.1 g of allantoin was dissolved in 87.3 g of sterilized
purified w~ter while stirring, an~ to this solution, 7.5 g of a
1% a~ueous solution of carboxyvinyl polymer were added while stir-
- 13 -
. _
~5834
ring, and subsequently 5.1 g of a 2% aqueous solution of trie-
thanolamine were added in small portions while stirring to give
a uniform gel preparation having a pH of 7.00 and a viscosity of
~,000 centipoises.
Example 24
O.1 g of allantoin was dissolved in 53. 5 g of sterilized
purified water while heating gently. To this solution, 20 g of
a 4% aqueous solution of carboxyvinyl polymer were added while
stirring and subsequently 26. 4 g of a 2% aqueous solution of tri-
ethanolamine were added in small portions while stirring to givea uniform gel preparation having a pH of 6.95 and a viscosity of
40,000 centipoises.
Example 2 5
To 20 g of propylene glycol heated to about 70C on a
water bath, 0.05 g of flavin-adenin-dinucleotide was dissolved
and the solution was cooled. To this solution, 66.65 g of steri-
li-zed purified water and 10 g of a 1% aqueous solution of car-
boxyvinyl polymer were added while stirring to give a unifonm
solution. 3.3 g of a 2% aqueous solution of monoethanolamine
were added in cmall portions to the above solution, to give a
uniform gel preparation having a pH of 7.00 and a viscosity of
5,000 centipoises.
Example 26
To 20 g of propylene glycol heated to about 70C on a
water bath, 0.1 g of flavin-adenin-dinucleotide was dissolved
and the solution was cooledO To this solution, 21.9 g of steri-
lized purified water and 25 g of a 4% aqueous solution of carbo-
xyvinyl polymer were added while stirring to give a uniform solu-
;~ tion. Then, 3.3 g of a 2% aqueous solution of monoethanolamine
were added while stirring in small portions to the above solutionto give a uniform gel preparation having a p~ of 6.99 and a vis-
cosity of 50,000 centipoises.
- 14 -
5834
Example 27
0.02 g of water-soluble azulene was dissolved in 83.23
g of sterilized purified water. To this solution, 10 g of a 1%
aqueous solution of carboxyvinyl polymer were added while stir-
ring and subsequently 6.75 g of a 2% aqueous solution of trie-
thanolamine were added in small portions while stirring to give
a uniform gel preparation having a pH of 7.00 and a viscosity of
4,000 centipoises.
Example 28
To 20 g of propylene glycol heated to about 70C on a
water bath, 0.05 g of butyric acid ester of riboflavin was dis-
solved and the solution was cooled. To this solution, 66.65 g
of sterilized purified water and 10 g of a 1% aqueous solution
of carboxyvinyl polymer were added while stirring, and then, 3.3
g of a 2% aqueous solution of monoethanolamine were added in
small portions while stirring to give a uniform gel preparation
having a pH of 8.00 and a viscosity of 5,200 centipoises.
Example 29
0.02 g of vitamin B12 was dissolved in 62.18 g of steri-
lized purified water, and to this solution. 11 g of a 4% aqueous
solution of carboxyvinyl polymer were added while stirring. Sub-
sequently, 8.8 g of a 2% aqueous solution of sodium hydroxide
were added in small portions to the above mixture giving a uni-
form gel having a pH of 6.90 and a viscosity of 29,000 centi-
poises.
To the above gel, 18 g of a 1% aqueous solution of so-
dium chloride were added while stirring in small portions to give
a uniform gel preparation having a pH of 7.00 and a viscosity of
2,000 centipoises.
Example 30
0.1 g of allantoin was dissolved in 43.2 g of sterilized
water while heating gently~ To this solution, 11 g of a 4%
- 15 -
5834
aqueou~ solution of carboxyvinyl polymer were added while stir-
ring, and subsequently, 29.7 g of 2~o aqueous solution of tri-
ethanolamine were added while stirring to give a uniform gel
having a pH of 6.90 and a viscosity of 28,000 centipoises.
To the above gel, 16 g of a 1% aqueous solution of so-
dium chloride were added in small portions while stirring to give
a uniform gel preparation having a pH of 7.00 and a viscosity of
2,000 centipoises.
Example 31
To 20 g of propylene glycol heated to about 70C on a
water bath, 0.05 g of flavin-adenin-dinucleotide was dissolved.
After cooling the solution, 41.95 g of sterilized purified water
and 12 g of a 4% aqueous solution of carboxyvinyl polymer were
- added while stirring, and then, 16 g of a 2% aqueous solution of
monoethanolamine were added in small portions to give a uniform
gel having a pH of 6.80 and a viscosity of 34,000 centipoises.
' To the above gel, 10 g of a 1% aqueous ~olution of so-
dium chloride were added w~ile stirring to give a uniform gel
; preparation having a pH of 7.00 and a viscosity of 5,000 centi-
poises.
Example 32
2 g of boric acid were dissolved in 83.96 g of steri-
lized purified water while heating gently on a water bath. After
cooling, 12 g of a 4% aqueous solution of carboxyvinyl polymer
were added to the above solution while stirring and then, 1.92 g
of lOYo aqueous solution of sodium hydroxide was added in small
portions w~ile stirring to give a uniform gel.
To the above gel, 0.12 g of sodium chloride was added
in small portions and the viscosity of the gel dropped substan-
tially. Stirring was continued to give a uniform gel preparationhaving a pH of 7.00 and a viscosity of 3,000 centipoises.
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3S834
Example_33
To 25 g of propylene glycol heated to about 90C, 0.5 g
of prednisolone was dissolved, and then, 61.28 g of sterilized
purified water and 11.5 g of a 4% aqueous solution of carboxy-
vinyl polymer were added while stirring.
To the above solution, 1.6 g of a 10% aqueous solution
of sodium hydroxide was added in small portions while stirring
to give a uniform gel. To this gel, 0.12 g of sodium chloride
was added in small portions while stirring to give a uniform gel
preparation having a pH of 7.00 and a viscosity of 2,200 centi-
poises.
Example 34
To a mixture of 86.56 g of sterilized purified water
and 11 g of a 4% aqueous solution of carboxyvinyl polymer, 1.76 g
of a 10% aqueous solution of sodium hydroxide was added while
stirring to give a uniform gel. And then, 0.18 g of sodium chlo-
ride was added in small portions while stirring to drop the vis-
cosity. Subsequently, 0.5 g of chloramphenicol powder was added
to the above gel, and the mixture was thoroughly stirred to give
a uniform gel preparation having a pH of 7.00 and a viscosity of
2,000 centipoises.
Example 35
0.02 g of water-soluble azulene was dissolved in 87.1 g
of sterilized purified water. To this solution, 11 g of a 4%
aqueous solution of carboxyvinyl polymer were added while stir-
ring. Subsequently, 1.76 g of a 10% aqueous solution of sodium
hydroxide was added in small portions while stirring to give a
uniform gel.
To the above gel, 0.12 g of sodium chloride was added
in small portions to drop the viscosity and to give a uniform gel
preparation having a pH of 7.00 and a viscosity of 4,000 centi-
poises.
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5834
Example 36
Allantoin was dissolved in 86.46 g of sterilized puri-
fied water, and to this solution, 11 g of a 4% aqueous solution
of carboxyvinyl polymer were added while stirring, and 1.76 g of
a 10% aqueouQ solution of sodium hydroxide was added in small
portions while stirring thoroughly to give a uniform gel. Subse-
quently, while stirring the a~ove gel, 0.18 g of sodium chloride
was added in small portions to drop the viscosity of the gel and
to give a uniform gel preparation having a pH of 7.00 and a visco-
sity of 2,000 centipoises.
Example 37
Into 20 g of propylene glycol heated to about 70C 0.05g of flavin-adenin-dinucleotide was dissolved. After cooling,
66.06 g of sterilized purified water and 12 g of a 4% aqueous
solution of carbo~yvinyl polymer were added to the above solution,
and 1.8 g of a 10% aqueous solution of sodium hydroxide was added
in small portions while stirring to give a uniform gel. Then,
0.09 g of sodium chloride was added in small portions while stir-
ring to give a uniform gel preparation having a pH of 7.00 and a
viscosity of 5,000 centipoises.
Example 38
Into 25 g of propylene glycol heated to about 90C 0.05
g of fluocinonide was dissolved. To this solution, 60.55 g of
sterilized purified water and 12 g of a 1% aqueous solution of
carboxyvinyl polymer were added while stirring thoroughly. And
; then, 2.4 g of a 2% aqueous solution of sodium hydroxide were
added to the above solution while stirring giving a gel prepara-
tion having a pH of 6.70 and a viscosity of 3,400 centipoises.
Example 39
Into 25 g of propylene glycol heated to about 90C 0.05
g of fluocinonide was dissolved. ~o this solution, 43.45 g of
sterilized purified water and 11.5 g of a 4% aqueous solution of
car~oxyvinyl polymer were added while stirring. To this solution,
- 18 -
li~5834
8 g of a ~O aqueous solution of sodium hydroxide were added while
stirring to give a uniform gel having a pH of 6.92 and a visco-
sity of 33,000 centipoises.
Subsequently, 12 g of a 1% aqueous solution of sodium
chloride were added in small portions to the above gel while stir-
ring to give a uniform gel preparation having a pH of 6.96 and a
viscosity of 2,200 centipoises.
Example 40
Into 25 g of propylene glycol heated to about 90C 0.05
g of fluocinonide was dissolved. To this solution, 45.95 g of
sterilized purified water and 25 g of 4% aqueous solution of car-
boxyvinyl polymer were added while stirring thoroughly. Then,
4 g of a 10% aqueous solution of sodium hydroxide were added to
the above solution while stirring thoroughly to give a gel pre-
paration having a pH of 6.75 and a viscosity of 41,000 centipoises.
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