Note: Descriptions are shown in the official language in which they were submitted.
~063r~z3
Detai]ed D~scription
Pharmaceutical formulations intended for local
application, either therapeutically or cosmetically, to
healthy, in~ured or diseased skin or to mucous membranes
can be broadly grouped under the term "ointment". These
formulations are gels which can undergo plastic deformation
and which change their shape even under slight mechanical
stress due to pressure, shearing, rubbing or spreading and
adapt to the walls of the body cavities or to the shape of
the skin surfaces onto which they are applied. Their gel
nature im~arts to them dimensional stability, both when stored
in containers and at the point of application.
Among these ointments, hydrogels and emulsion
ointments of the "oil-in-later" type rsee M~nzel, Versuch
einer 3y~ema~ik der Saiben nacn gaieniscnen ~esicntspunkten
Pharm. Acta Helv. 28, 320 (1953)J occupy a special position
inasmuch as they can be easily washed off with water. Recause
of their high water content they can be rubbed onto the skin
easily with good penetration and, due to the evaporation of
water, produce a pleasant cooling effect.
The emulsion ointments are generally prepared by
machine. For example a typical procedure involves melting
the fat phase, adding the required amount of hot water and
the:l emulsifying the two phases with vigorous stirring, fre-
quently with the aid of emulsifier~ and emulsion stabilizers
such as thickeners or swelling agents. These latter com-
~k
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ponents are intended to prevent subsequent separation of the
emulsion. After cooling, medicaments, perfumes and preser-
vatives, for example benzyl alcohol, benzoic acid, sodium
benzoate, parahydroxybenzoic acid esters or sorbic acid,
ethereal oils and the like, can be added. These ready-to-use
ointments must then be packed in containers which are as air
tight as possible so that evaporation of the water is pre-
vented.
The hydrogels are a second type of hydrophilic oint-
ment and one to which the present invention is directed. They -
are generally prepared as follows: An anionic, crosslinked
carboxyvinyl poly~er, insoluble but extremely swellable in
water, having a high molecular weight of from about 860,000 to
about 1,000,000, is suspended in water. The rree acid groups
of the polymer are neutralized by the subsequent addition of a
base, such as, for example, sodium hydroxide soluti.on, potas-
sium hydroxide solution, a~monium hydroxide or triethanolamine.
During this neutralization, extensive thickening occurs and
an aqueous mucil~ge is produced. To these gels can now be
added the medicaments and lipophilic vehicle substances. As
in the case of the emulsion ointments described above, these
ready-to-use hydrogels have as their main constituent water
~nd they must therefore also be stored in tubes or other con~
tainers which close tightly. If not 80 packaged, the shelf
life, stability and useability of the formulation is greatly
restricted, both by evaporation of water and by possible mold
contamination. Since the main constituent of these ointment
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forwulations is water, the only packaging which is possible
in order to ensure that the finished product reaches the con-
sumer in a well-protected state is a relatively expensive
packaging in tightly closing tubes. This type of packaging
necessitates very large space requirements resulting in an
increase in the stock volume.
In addition, pharmaceutical agents which are sensi-
tive to moisture cannot be used in an ointment of this type
since stability is limited by the water which is present.
Finally, the consistency of these ointments cannot be adjustèd
by the ultimate user since it is determined by the manufacturer.
According to the present invention it has been found
that granules or powders which contain such anionic, cross-
linked carboxyvinyl polymer and an alkaline substance in which
either or both of the polymer and the alkaline substance are
coated with fats and/or emulsifiers, can be used to.prepare
ointments. These particulate solid compositions can also con-
tain an active ingredient such as a pharmaceutical or cosmetic
ingredient or alternatively, the compositions can be manufactured
free from any active ingredient, the active ingredient being
introduced into the composition when the granules or powder is
made up into an ointment. An essential constituent of the
granules or powder is the anLonic, crossli`nked carboxyvinyl
polymer which i8 insoluble but extremely swellable in water and
which has a high molecular weight of from about 860,000 to about
1~000,000. Generally, the required amount is from about 1% to
about 107., preferably 3% to 6%, based on the amount of granules
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or powder. -
The anionic carboxyvinyl polymer above does not pro-
duce a gel with water; on the contrary, gel formation occurs
only after an alkaline agent has been added. If such an
anionic carboxyvinyl polymer is introduced into water simul-
taneously with an alkali however, spontaneous clumping of
the polymer occurs. A homogeneous gel is then formed only
after some hours. This is also true when the pulverulent
carboxyvinyl polymer is introduced into an aqueous solution
of an alkalinizing age~t. However when the anionic carboxy-
vinyl polymer is coated with a thin protective film of an
emulsifier and/or lipophilic vehicle substances and the poly- -
mer is subsequently introduced into water, spontaneous clump-
ing in the presence of the alkaline agent is avoided. The
reverse is also possible. Thus the alkaline can be coated with
an emulsifier and/or lipophilic vehicle substances so as to -~
delay its immediate dissolution when introduced into water.
In the presence of carboxyvinyl polymers, this leads to gradual
thickening until a gel is prQduced without formation of lumps.
In addition to the alkaline agents mentioned above, ~ -
ammonium bicarbonate, potassium carbonate, hexamethylenetetra-
mine~ methylglucamine, lysine and glycine, and especially
sodium carbonate, are particularly suitable as alkaline agents.
Generally, the proportion of the alkaline agent is from about
1% to about 10% especially 2~ to 5%, of the amount of granules ;
or powder.
;~; A mixture of the anionic carboxyvinyl polymer and -
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ehe alkaline agent is, as noted above, not suitable for the
preparation of a non-clumping ointment preparation. Only
coating of at least of the ingredient of the mo1sture-sensitive
combination of carboxyvinyl polymer and the alkaline agent
with a thin hydrophobic film of an emulsifier and/or
lipophilic vehicle substance permits the immediate formation
of a smooth ointment from the granules or powder upon simply
stirring with water. Advantageously, the lipophilic vehicle
substance~ also provide a desirable slight lubrication
10 effect when the ointment is applied to the skin.
Emulsifiers include the "oil-in-water" type, such
as, for example, sodium stearate, sodium dioctylsulfosuccinate,
polyethylene glycol-400 stearate, polyoxyethylene-40 stearate,
sorbitan monolaurate, sorbitan monostearate, polyethylene
glycol sorbitan oleate, and the llk~. Sodium lauryl ~ulfate
has proved especially advantageous. Generally, the amounts
employed are from about 0.2% to about 3%, preferably 0.5% to
2%, based on the amount of granules or powdes.
Liquid hydrocarbons, such as liquid paraffin, and
20 liquid fats~ ~uch as triglycerides of caprylic to laurlc acid,
oleic acid decyl ester, cetyl alcohol and isopropyl myristate,
~; can be employed as the lipophilic vehicle substances. Solid
fats, such as for example, glycerol monostéarate and capric
to stearic acid triglycerides are preferred a~d partial gly- ~
ceride8 of palmitic to stearic acid with a monoglyceride con- -
tent of 40% to 90% are particularly suitable. These
latter ~noglycerides can be dispersed by stirring with
cold water and are therefore very suitable for the
gra~ules or powders of the prese~t in-
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invention. Generally, the amounts employed are from about
1% to about 30%, preferably 5% to 15%, based on the amount of
granules or powder.
It has also proved advantageous if additional agents
which increase the viscosity or which improve the disintegra-
tion are added to the granules or powders. Because of their
dissolving or swelling properties, these thickeners improve
the distribution of the granules or the powder in water.
Such substances include for example, potato starch, dextrin,
10 -lactose, sorbitol, glucose, colloidal silica, corn starch, -
mannit~ol and finely ground cellulose powder. me amounts used
are from about lOZ to about 90Z, preferably 20% to 80%, based
on the amount of granules or powder.
Granules, or a powder, for producing ointments can
be prepared in the following way: ~-
The anionic carboxyvinyl polymer with a molecular
`~eight of 860,000 to 1,000,000 is mixed intimately with a
medicament or a mixture of medicaments and one or more e~ten-
ders. m is powder mixture is then moistened thoroughly with
the emulsifier and/or one or more other lipophilic vehicle
substances dissolved in organic solvents, such as for example,
-~ carbon tetrachloride, chloroform~, methanol, ethanol, i~opropanol
or methylene chlor~de, or mixtures thereof. The solvents are
subsequently removed by evaporation. Depending on the degree
to which the dry mixture is comminuted, this produces granules
or a powder, to which onl~ an alkaline agent is still to be
; added.
.
~ Alternatively, the procedure described above is
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followed but the anionic carboxyv~nyl polymer and~or the
all~line ~gent is coated wlth an emulsifier andtor other
lipophilic vehicle substances.
If the use of organic solvents is not practicable,
a gel c~n be prepared in wa~er from the anionlc carboxyvinyl
polymer and an appropriate alkaline agent, all the necessary
additives, such as, if appropriate, a medicament, extenders,''
; an emulsifier ~nd a lipophilic vehicle substance, being in-
corporated into the gel. The mass is freed from water by sub-
sequent drying and'the dry product is brought to the desired
particle size.
If, for ex~mple, 5 g of granules or a powder of this'
type are introduced into 45 g of wa~er while stirring 810wly~
an ointment which is immediately ready for use is formed witbin
1 to 2 minutes. Depending on the ratio of the granules or pow-
der to water, the consistency of such an ointment can be widely
varied as desired. Thus a relatively solid formulation is ob-
tained with 10 to 15% proportion of granules or powder, a rela-
; tlvely thin formulation with 6 to 8% proportion of granules or
powder and a lotion of low viscosity with 3 to 5% proportionof granules or powder.
It is possible to introduce a pharmaceutically active
-' compound into the ointment with the water so that the granules
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or powder serve as a general ointment ba~e in which both the
type of medicament(s) and concentration thereof cnn be varied
-~ by'the plt~sician or pharmacist.
An oint _nt formulation of this type can readily be
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1063~Z3
spread on and rubbed into the skin with any residues being
easily washed off.
This concept offers a number of advantages. Up to
a tenfold saving in space is achieved since the formulation is
made up to the volume for application only as needed. This is
especially important for example in the clinic, in the case of
an emergency, in military operations or in the veterinary field
when a large number ofpatientshave to be treated at once.
Relatively expensive packaging in tubes can be dispensed with
in favor of a cheaper packaging such as sachets. The granules
or powder for example can be sealed in an aluminium laminate.
Improved stability is realized in the case of moisture sensi-
tive active compounds. Thus ointments can be prepared with
agents which are not stable, or are stable for only a short
time, in an aqueous medium. Ointments of a thinner or firmer
~, consistency can be prepared as desired by using more or less
water. The physician, pharmacist or the user can thus ad~ust
the physical nature of the ointment. The formulation can be
prepared in any quantity, suitable either for a single hygienic
1 20 application or for several treatments.
The examples which follow are intended to illustrate
in more detail the granules or powder, according to the inven-
tion, or the preparation of ointments:
ExamPle 1
Granules for the preparation of a boric acid ointment
Five parts of an anionic carboxyvinyl polymer with
a mnlecular weight of 860,000 to 1,000,000 are suspended in
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300 parts of water and the suspensiDn is then thickened to
fonm a gel by adding 3 parts of potassium carbonate in 100
parts of water. A mixture of 20 parts of boric acid powder,
45 parts of corn starch, 10 parts of dextrin, 5.5 parts of
colloidal silica and 1.5 parts of sodium lauryl sulfate is
added gradually. After the solid constituents have been mixed
well, 10 parts of caprylic/lauric acid triglyceride are added.
The moist mass is then dried in a drier and brought to a suit-
able grain size by sieving.
When stirred with 45 parts of water, 5 parts of the
preparation produce a boric acid ointment which is suitable
for immediate use.
Example 2
Powder for the PreParation of boric acid ointment
Five parts of an anionic carboxyvinyl polymer with
a molecular weight of 86~,000 to 1,000,000, 1.5 parts of
sodium lauryl sulfate, 30 parts of boric acid powder, 35 parts
of corn starch, 11.5 parts of cellulose powder and 5 parts of
colloidal silica are mixed and then granulated with a solution
of 10 parts of sorbitan monostearate in methylene chloride.
After drying, the mixture i8 sieved through an extremely fine
sieve. 1.8 parts of lysine are moistened with a solution of
0.2 parts of oleic acid decyl ester in chloroform, dried and
sieved through an extremely fine sieve. The two mixtures are
then combined and mixed well.
When stirred with 45 parts of water, 5 parts of this
powder give a boric acid ointment which i~ ready for use.
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Example 3 1063~)~3
Granules for the Preparation of a burn ointment
Five parts of an anionic carboxyvinyl polymer with
a molecular weight of 860,000 to 1,000,000, 50 parts of sul- -
fanilthiocarbamide, 19.5 parts of glucose and 5 parts of col-
loidal silica are thoroughly mixed. A solution of 1.5 parts
of polyoxyethylene-40 stearate and 10 parts of palmitic/stearic
acid partial glyceride having a monoglyceride content of 90%
dissolved in 80 parts of methylene chloride i~ added. Granules
10 are formed which, after appropriate dry~ng, are brought to the
desired grain gize by sieving. Ten parts of glycine are then
added and mixed.
When stirred with 80 parts of water, 20 parts of
these granules give a burn ointment which can be u~ed at once.
Ex~ple 4
Granules for the preparation of an antimYcotic ointment
Ten parts of microfine clotri~azol, 5 parts of an
anionic carbo~gvinyl poly~er with a molecular weight of 860,000
to 1,000,000, 45 parts of corn starch, 20 parts of a water- -
20 soluble de~ctrin, 5.5 parts of colloidal silica and 1.5 parts
- of sodium lauryl sulfate are intimately mixed and then granu-
lated with a solution of 10 parts of palmitic/stearic açid
partial glyceride havil~g a monoglyceride contont of 60X in
40 parts of methylelle chloride and 40 part~ of methanol. The
solvent mi-cture i8 removed in a drier and the dry mixture i8
, ~
si ved to obtain granules of uniform size. Ttlree parts of
grou~d sodlu~ carbonate are then also mi~ced in. With 10 parts
- - 10 -
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1063~Z3of water, 2 parts of this mixture give an ointment which can
be applied at once.
Example 5
Powder for the Preparation of a nasal ointment
3.5 parts of an anionic carboxyvinyl polymer with a
nolecular weight of 860,000 to 1,000,000, 34 parts of glucose,
10 parts of dextrin, 10 parts of corn starch and 8 parts of
colloidal silica are mixed and granulated with a solution of
1 part of menthol, 5 parts of ethereal oil, 1 part of poly-
ethylene glycol sorbitan oleate, 4 parts of oleic acid decylester and 20 parts of capric acid/stearic acid triglyceride
in 60 parts of methylene chloride. The solvent is then removed
by gentle drying and the dry mass is sieved to give a fine pow-
der. 3.5 parts of methylglucamine are then admixed with this
powder.
When stirred with 9 parts of water, 1 part of this
powder produces a nasal ointment.
Example 6
Granules for the Pre~aration of an ointment for
haemorrhoids
Twenty parts of pulverized procaine hydrochloride,
1 part of water-soluble rutin, 5 parts of anionic carboxyvinyl
polymer having a molecular weight of 860,000 to 1,000,000,
54 parts of dextrin, 5.25 parts of colloidal silica and 1.5
parts of sodium lauryl sulfate are mixed intensively with one
another.
0.25 part of chamazulene and 10 parts of palmitic/
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stearic acid partial glyceride with a monoglyceride content
of 40X are dissolved ~n 75 parts of methylene chloride and
the powder mixture i8 granulated with this solution. After
drying the mixture, this is brought to a suitable grain size
and 3 parts of powdered sodium carbonate are mi~ed ~n.
When stirred with 9 parts of water, 1 part of the
granules gives a ready-to-use ointment for haemorrhoids.
E~ample 7
Granule~ for the preparation of a rheumatic ointment
About 3.5 parts of heparinoid (corresponding to
50,000 IU), 6 parts of an anionic carbo~vinyl polymer with
a molecular weight of 860,000 to 1,000,000, 44.2 parts of
dextrin, 20 parts of cellulose powder and 5.5 parts of col-
loidal silica are mi~ced well. Ten parts of glycerol mono-
stearate, 2 parts of sorbitan monostearate and 5 parts of
nicotinic acid benzyl ester are dissolved in 70 parts of
meth~lene chloride and the powder mixture is granulated with
this solution. After drying, the mixture i8 sieved to obtain
granules of a uniform size and 4 parts of potassium carbonate
20 are mixed in.
When stirred with 40 parts of water, 5 parts of these
granules give a rheumatic ointment which can be used immediately
and which spreads easily.
E~camPle 8
Powder for the preparation of an acne ointment
Four parts of finely powdered sodium carbonate are
mixed with 16 parts of corn starch and the mi~cture is thoroughly
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moistencd with a solution of 3 parts of sorbitan monolaurate
in 15 parts of chloroform. After the solvent has evaporated,
the dry mixture is sieved through an extremely fine sieve.
Four parts of an anionic carboxyvinyl polymer with
a molecular weight of 860,000 to 1,000,000, 10 part~ of hexa-
chlorophene powder, 3 parts of colloidal sulfur, 37 parts of
corn starch, 10 parts of water-soluble dextrin, 5 parts of
colloidal silica and 1 part of sodium lauryl sulfate are in-
timately mixed and granulated with a solution of 7 parts of
capric/stearic acid triglyceride in 40 parts of methylene
chloride. The moist mixture is dried and then finely powdered.
The two mixtures are combined and mixed well.
When stirred with 45 parts of water, 5 parts of this
powder ~ive an acne ointment which is ready for immediate use.
Example 9
Granules for the preparation of an acne ointment -
Five parts of an anionic carboxyvinyl polymer with
a molecular weight of 860,000 to 1,000,000, 3 parts of col-
loidal ~ulfur, 3 parts of very finely powdered salicylic acid,
5 parts of colloidal silica, 30 parts of mannitol, 30 parts of -
corn starch and 1 part of sodium lauryl sulfate are mixed in-
tensively and granulated with a solution of 5 parts of cetyl
alcohol and 15 parts of palmitic/stearic acid partial glycer-
ide with a monoglyceride content of 60% in 45 parts of methylene
chloride. After drying, the mixture i8 sieved and 3 parts of
hexamethylenetetramine are also admixed.
When stirred with 20 parts of water, 3 parts of these
granules give a ready-to-use acne ointment.
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