|Title of Invention||
A STERILE OPHTHALMIC DROP PREPARATION
|Abstract||The invention relates to a sterile ophthalmic drop preparation, especially a gel preparation, which comprises a two-phase carrier liquid or gel basis comprising a liquid aqueous and a liquid hydrophobic phase.|
|Full Text||The present Application is a divisional Application out of
I. P. Application No. 1431/CAL/96 dated August 9, 1996.
The invention relates to a sterile ophthalmic gel
preparation that can be applied in drop form, especially for use
as an artificial tear fluid and for the treatment of "dry eye",
as well as to a method for the production of such a gel
It has been known for some time to use aqueous preparations
to replace natural tear fluid and to treat "dry eye", which
aqueous preparations e.g. contain film-building materials based
on polyvinylalcohol (PVOH), polyvinylpyrrolidone (PVP), cellulose
derivatives or dextrane. An overview can e.g. be found in
sucker, Fuchs and Speiser, "pharmazeutische Technologie" 1978.
These are generally systems which only have one fluid or liquid'
phase, typically an aqueous solution of further components.
Where components are present which are difficult to dissolve in
water or which are water-insoluble, these are suspended as
solids, in finally divided form, in the aqueous phase.
In semisynthetic preparations, such as e. g. those based on
cellulose derivatives or dextrane, production is made more
difficult by the fact that such materials are difficult to
obtain free of insoluble components. One therefore has to incur
very high expenditure in preparing solutions from such
preparations which do not lead to eye irritation caused by
mechanical effects. Further, such preparations are very
difficult to sterilize, since they can only with great
difficulty, or not at all, be filtered to remove germs, and they
can also not be autoclaved without deteriation in quality.
Cellulose derivatives cannot be autoclaved without irreversible
changes in viscosity. Dextrane preparations are partly
decomposed by autoclaving.
Also polyvinylalcohol can only be sterilized by heating if a
very pure hydrolized form is employed since otherwise the PVOH
component is depolymerized. Since PVOH as well as PVP only
provide relatively little thickening effect, rather high amounts
of these components must be used to provide suitable
viscosities. This leads to a very high load of the
ophthalmological preparation with such materials, e. g. contents
of more than 10% in the case of PVOH.
It is already known from DE 34 40 352 and DE 43 03 818, and also
from US 5,252,318, to use polyacrylic acid and its derivatives,
such as e. g. Carbopol® 940 (obtainable from B. F. Goodrich
Company) as the gel basis for sterile ophthalmic gel drop
preparations. In US 5,441,732, which was only published after
the priority date of the instant application, a combination of
two specific gel components is disclosed, one of which is gelled
thermally, whereas the other is gelled by a change in pH.
Various cellulose derivatives are described as the thermally
reactive gel polymer, whereas polyacrylates, especially cross-
linked polyacrylates, are mentioned as polymers gelling in
dependance of the pH value. It appears that gel formation is
intended to only occur in the eye, by the pH change after
application to the eye. It is stated that these polymer mixtures
are to be used together with organic oils, wherein a
multiplicity of active agents can be dissolved. Vitamine A is
With respect to compliance, non-irritation, shelf life etc.,
very high standards must be met by ophthalmic preparations which
are to be used as film-forming preparations or lubricating
preparations. Especially where ophthalmic preparations must be
used for any extended period of time, which e.g. is regularly
the case in the treatment of "dry eye", even a temporary
irritation, such as a burning sensation in the eye is an
extremely unpleasant sensation, and is detrimental to any
extended therapeutical treatment. It is self-understood that in
the application of such ophthalmic preparations, impaired sight,
blurred view or other acute- irritations cannot be accepted.
In "dry eye" treatment, the use of vitamine A, generally in the
form of vitamine A palmitate, has proven to be effective. Thus,
gel drop preparations on Carbopol basis have been commercialized
(after the priority date of the instant application), which
besides other customary components contain vitamine A.palmitate.
These are one-phase gels with a continuous aqueous liquid phase,
and without any hydrophobic second liquid phase. These products
have a shelf life of about a year, when the vitamine A component
is provided in an excess of 40%. As trials have shown, the
vitamine A content decreases by about 20% over six months in
these preparations, so that at a 40% excess dosage, the
guaranteed minimum content is still present after one year.
Natural tear fluid comprises inter alia a fatty component which
comprises triglycerides and phospholipides. It has already been,
tried (WO 94/05298), to use triglycerides in synthetic tear
liquids, which was, however, only possible when an emulgator was
added, and the overall preparation was in the form of an
emulsion, for topical application to the eye. This has the
disadvantage that desirable residual amounts of natural tear
fluid in the eye are destroyed by the emulgator component.
It is an important object of this invention to provide
ophthalmic preparations, especially gel preparations, which show
an improved shelf life, especially when containing sensitive
substances such as vitamine A and its derivatives.
It is a further important object of the invention to provide
such preparations which do not cause acute irritations and
impaired vision, especially when formulated for increased shelf
It is a further very important object of this invention to
provide such preparations which make it possible to use the
preparation repeatedly over an extended time period, and/or
enable extended duration in the eye after each individual
application without causing incompatibilities, lack of
compliance, irritation to the eye and other such problems.
The invention is based on various surprising findings.
According to the present invention there is provided a sterile ophthalmic drop
preparation, especially a corresponding gel preparation, /
wherein a two-phase carrier liquid or gel basis comprises a liquid aqueous phase and
a liquid hydrophobic phase, wherein the liquid hydrophobic phase comprises an
ophthalmologically acceptable organic oil.
On the one hand, it has surprisingly been found that relatively-
fast decomposition of vitamine A and its derivatives, especially
vitamine A palmitate, in artificial tear fluids and preparations
for "dry eye"' treatment can be dramatically reduced when the
preparation is in the form of a two component system with one
aqueous liquid phase and one hydrophobic liquid phase.
Especially it is preferred herein that the preparation has a
continuous aqueous phase wherein the hydrophobic liquid oil
phase is provided in the form of very finely divided droplets.
There is no easy explanation for this fact. Most probably,
oxygen and/or light are responsible for the decomposition of
vitamine A, and with respect to both, it should not make any
material difference whether the preparation comprises one or two
separate liquid phases. One would rather expect an increased
sensitivity with respect to oxygen and/or light in a solution of
the vitamine A component in tbe nydrophobic phase. -""^
Possibly, the simultaneous use of antioxidants, especially ,
vitamine E and its derivatives and most specifically viramine E
acetate has an influence in these preparations. In any case,
vitamine A is preferably used with such antioxidants in the
On the other hand, a further surprising effect of the invention
is that it makes it possible to prepare preparations with an
aqueous and a liquid hydrophobic phase which come very close to
the composition of natural tear liquid, and especially have a
corresponding content of triglycerides, without any necessity of
at the same time using emulgators. This is possible since
according to the invention, such preparations are in the form of
Basically, those ophthalmologically acceptable organic oils are
suitable as the liquid hydrophobic component of the inventive
two-phase preparations, especially gels, which can be dispersed
as droplets in an aqueous"ph"ase "in"the absence of_ emul^ators.
Examples are formed by fatty acid derivatives such as,
especially, fatty acid esters, triglycerides and pnthalic acid
esters. Triglycerides are presently specifically preferred,
especially the homogeneous or mixed triglycerides formed mostly
or totally from C8-C12 fatty acids. Especially, medium chain
triglycerides of the type defined in "Deutsches Arzneibuch"
(DAB) 10 (1993) are preferred. The acid component of these
triglycerides- is a mixture of at least 95% n-octanoic acid and
n-decanoic a'did; the remainder is formed by shorter chain fatty
Such medium chain triglycerides are made semi-synthetically from
the oil of the dry solid part of the endosperm of cocos
nucifera L., by hydrolizing the coco oil obtained from the
endosperm, fractioning the thus obtained fatty acids, and re-
esterification of the acids.
Such medium chain triglycerides are already in use as basic
substances for cosmetics, as adjuvants and carriers for
pharmaceuticals, and also for some foodstuffs. Very little is
known, however, about their potential uses and the limits of
such uses in ophthalmic preparations, although such medium chain
triglycerides have very well known beneficial properties.
Inventive preparations, especially on gel basis, with typical
contents between 0.1 and 3 weight-%, especially approximately
0.2 weight-% polyacrylic acid as the gel-forming agent in the
aqueous phase, contain typically between 0.5 and 10 weight-%,
especially approximately 1 weight-% of such medium chain
Inventive gel preparations preferably have a viscosity in the
range of approximately 2000 to 6000 mPas, at a pH value between
6 and 8. '
The inventive preparations preferably contain a preserving
agent, such as especially centrimid, benzalkoniumchloride or
thiomersal It is further preferred that such gel preparations
contain at least one isotonic agent, for which purpose sorbitol
is specifically suitable.
The especially preferred content of a vitamine A component,
especially vitamine A palmitate, is of the order of 500
international units per gram of the inventive preparation. The
vitamine A component is specifically preferred to be stabilized
with a small amount of at least one antioxidant, wherein
vitamine E and vitamine E acetate are specifically advantageous.
Production of an inventive sterile preparation, especially gel,
proceeds in a multistep method. In preparing the gel, a sterile
polyacrylic acid suspension is preferably obtained by the
procedure disclosed in DE 43 03 818, i. e. by autoclaving at
about 120°C, 1 bar excess pressure, and 20 minutes duration. In
parallel, an aqueous solution is prepared which contains the
preserving agent and the isotonic, i. e. preferably centrimid
and sorbitol. This aqueous solution is added to the autoclaved
polyacrylic acid suspension by sterile filtration, using
nitrogen as the pressurizing gas, or, in case, more simply using
pressurized air. Subsequently, careful neutralization is
achieved by adding sterile sodiumhydroxide solution, which
initiates gel formation. Once neutralization has been achieved,
there is no free base any more in the forming gel. The
hydrophobic liquid component, i. e. preferably the medium chain
triglyceride component, is then worked into the sterile gel
under antiseptic conditions. Stirring is maintained until
complete homogenization has been achieved. In the inventive
dispersion, the size of the thus obtained oil droplets is
maximal about 100 µm and is otherwise of the kind, which is
obtained in a conventional emulsion without the addition of
The sterile gel can now be confectioned in the customary
Otherwise, an active agent such as especially vitamine A
palmitate can be added to the thus formed sterile gel, in such a
fashion that the vitamine A component and the much smaller
amount of antioxidant, which is preferably also present, are
dissolved in neutral oil, followed by sterile filtration. The
sterile oil solution is then worked into the gel with stirring.
A comparable procedure is used when a preparation without gel
basis, e. g. a drop solution is to be prepared.
The gel forming agents used according to this invention are
preferably polyacrylic acids with a molecular weight of the
order of approximately 3 to 5 million. Specifically preferred
are the trade products such as Carbopol® polymeric acids as
obtainable from B. F. Goodrich Chemicals Co. Carbopol 980 NF® is
especially preferred. In the preparation, the concentration is
approximately 0.2 weight-%.
The neutralization necessary for gel formation is customarily
carried out using sterile diluted sodiumhydroxide solution,
whereby 1-N sodiumhydroxide solution is specifically
advantageous. However, also other inorganic bases or alkali
carbonates, or organic bases, such as amines, especially
triethylamine and diisopropylamine can be used.
The gels thus obtained have viscosities,in the range of
approximately 2000 to 6000 mPa;s_ at 20°C.
The preserving agent which is generally used according to this
invention, such as centrimid, benzalkoniumchloride or
thiomersal, is used in the customary concentration, i. e.
approximately 0.01 weight-% in the case of centrimid. The
isotoning agent, e. g. polyfunctional alcohols such as mannitol,
dextrose, glycerol, propylene glycol or, especially preferred,
sorbitol, are also used in customary concentrations. For
sorbitol, a concentration of approximately 4.85 weight-% is
The invention will now be further explained on the basis of two
A homogeneous suspension of 2000 kg polyacrylic acid (Carbopol
980 NF®) in approximately 375 kg water (pro injectionem) is
introduced, through a fibre removal filter with a pore size of
approximately 25 to 40 µm into a processing apparatus. This
suspension is then autoclaved under stirring at 121°C and 1 bar
excess pressure for 2 0 minutes, and is then cooled to room
temperature whereby ambient pressure is provided using a
sterilized air filter.
Meanwhile, approximately 964 kg water (pro injectionem) are
provided in a suitable vessel, and under stirring, 0.100 kg
centrimid and then 48.510 kg sorbitol are dissolved therein.
This solution is added to the already autoclaved pblyacrylic
acid suspension using a vapour sterilized membrane filter with a
pore size of 0.2 /on, and nitrogen as the pressurizing gas.
Subsequently, the apparatus is evacuated once or more to destroy
any foam that may have formed. ^
Now, 0.832 kg sodiumhydroxide are dissolved in approximately 20
kg water (pro injectionem) under stirring and sterile
conditions. The sodiumhydroxide is added by filtration through a
vapour sterilized membrane filter to the centrimid/sorbitol/
polyacrylic acid suspension, whereupon the remaining amount of
water (pro injectionem) is added. The gel thus formed is worked
by a homogenizer.
Then, the medium chain triglycerides are worked into the sterile
gel, being added through a sterile filter with a pore size of
0.2 /un, followed by stirring until complete homogenization has
been achieved. The pH value of the thus formed gel is
determined, which should be 6 to 8 at 20°C. The osmolality of
the inventive preparation is in the range of 260 to 32 0 mOsm/kg.
The gel formed in this fashion is then filled into 5 g polyfoil
tubes Under aseptic conditions.
0.6 g vitamine A palmitate and 0.03 g vitamine E acetate are
dissolved in 9.37 g neutral oil (Myritol 318®).
The solution is filtered through a 0.22 µm filter (Millipore®)
so that it is sterile.
10 g of the neutral oil solution are added to 990 g gel prepared
according to Example 1, and are worked into the gel using a wing
stirrer. After 20 minutes of stirring the ready product is
filled into 10 g polyfoil tubes. The gel corresponds to a
content of 500 international units vitamine A per gramm
preparation, at a 20% access.
A Carbopol gel is made according to Example 1; however, the
medium chain triglyceride component is not provided.
As according to Example 2, the gel of the Comparative Example is
provided with a corresponding content of vitamine A palmitate.
Samples of this vitamine A preparation without triglyceride
component are stored together with corresponding samples
according to Example 2, under standard conditions. After a total
of six months storage time, the vitamine A content in the
comparative samples without triglyceride component has fallen by
a total of 20%. In the samples according to Example 2, the
vitamine A content is found to be unchanged within the accuracy
1. A sterile ophthalmic drop preparation, especially a corresponding gel preparation,
wherein a two-phase carrier liquid or gel basis comprises a liquid aqueous phase and a liquid
hydrophobic phase, wherein the liquid hydrophobic phase comprises an ophthalmologically acceptable
2. Preparation as claimed in claim 1, wherein the preparation comprises the aqueous phase as the
continuous phase and the hydrophobic phase as droplets dispersed therein.
3. Preparation as claimed in claim 1 or 2, wherein the preparation is substantially, and preferably
completely, free of additional emulgator substances.
4. Preparation as claimed in any one of claims 1 to 3, wherein the aqueous phase contains at least
one polymeric gel-forming component, especially a polyacrylic acid or polymeric acrylic acid
derivative in an amount sufficient for providing gel properties to the preparation.
5. Preparation as claimed in claim 4, wherein the preparation contains between 0.1 and 3 weight-
%, especially approximately 0.2 weight-% polyacrylic acid.
6. Preparation as claimed in any one of claims 1 to 5, wherein the hydrophobic phase comprises
an oil that can be dispersed, and stays dispersed, as droplets in an aqueous phase without additional
7. Preparation as claimed in claim 6, wherein the oil comprises at least one fatty acid derivative,
one triglyceride and/or one phtalic acid ester.
8. Preparation as claimed in claim 7, wherein the oil comprises a triglyceride, especially a medium
chain triglyceride, and especially preferred a mixed triglyceride component substantially or completely
formed by C8-C12 fatty acids.
9. Preparation as claimed in claim 7 or 8, wherein the oil comprises a medium chain triglyceride
such as herein described.
10. Preparation as claimed in any one of claims 7 to 9, wherein the preparation comprises between
0.5 and 10 weight-%, especially approximately lweight-% medium chain triglycerides.
11. Preparation as claimed in any one of claims 1 to 10, wherein the preparation has viscosity in the
range of approximately 2000 to 6000 mPas.
12. Preparation as claimed in any one of the preceding claims, wherein the preparation has a pH
value of 6 to 8.
13. Preparation as claimed in any one of the preceding claims, wherein the preparation contains at
least one ophthalmic active agent in a therapeutically efficient amount, selected from vitamin A
component, especially vitamin A palmitate and specifically preferred in combination with an
antioxidant such as vitamin E or vitamin E acetate, wherein the preparation contains between 0.5 wt-%
and 10 wt-% of medium chain triglycerides as the liquid hydrophobic phase.
14. Preparation as claimed in any one of the preceding claims, wherein the preparation contains a
preserving agent and, in case, an ascertaining agent.
15. Preparation as claimed in claim 14, wherein the preserving agent is centrimid,
benzalkoniumchloride or thiomersal, and the isotoning agent is, in case, sorbitol.
16. A sterile ophthalmic drop preparation, especially a corresponding gel preparation, substantially
as hereinbefore described with reference to the foregoing examples.
The invention relates to a sterile ophthalmic drop preparation, especially a gel
preparation, which comprises a two-phase carrier liquid or gel basis comprising a liquid
aqueous and a liquid hydrophobic phase.
|Indian Patent Application Number||485/CAL/2001|
|PG Journal Number||22/2011|
|Date of Filing||29-Aug-2001|
|Name of Patentee||DR. GERHARD MANN CHEMISCH-PHARMAZEUTISCHE FABRIK GMBH|
|Applicant Address||BRUNEBUTTELER DAMM 165-173, 13581 BERLIN(SAPNADAU)|
|PCT International Classification Number||A61K 9/06|
|PCT International Application Number||N/A|
|PCT International Filing date|