Ophthalmic composition

The present invention is directed to an ophthalmic composition in the form of a topical aqueous solution consisting essentially of PA0 an ophthalmologically active agent, PA0 an ion sensitive, hydrophilic polymer in an amount a of 0.004 to 1.5% by weight, PA0 at least one salt selected from the group of inor ganic salts and buffers in a total amount of from 0.01 to 2.0% by weight, PA0 a wetting agent in an amount of 0 to 3.0% by weight, PA0 a preservative in an amount of 0 to 0.02% by weight, PA0 water, and optionally PA0 a pH regulating agent in an amount sufficient to give a pH of 4.0 to 8.0 to the composition, the ratio between salt and polymer components being such that the solution exhibits a viscosity of less than 1000 mPas. The composition contains a sufficient amount of polymer to provide for a controlled absorption of the drug into the eye, its viscosity having been reduced to provide for better handling characteristics.

BACKGROUND OF THE INVENTION 
The present invention relates to an ophthalmic composition in the form of a 
topical aqueous solution for human and veterinary use, as well as the use 
of the solution, especially for the treatment of glaucoma and ocular 
hypertension. 
It is well known to use polymers alone or in combination with other 
polymers for the preparation of ophthalmic pharmaceuticals and artificial 
tear compositions. The inclusion of the polymer aims at increasing the 
viscosity of the composition so as to provide for a longer contact time 
with the cornea of the eye, and, for example, in connection with 
ophthalmic drugs, to provide for a sustained release of the drug into the 
eye. 
For example, the U.S. Pat. Nos. 5,075,104 and 5,209,927 relate to an 
ophthalmic gel composition and an ophthalmic liquid composition, 
respectively. The first mentioned composition includes 0.25 to 8% by 
weight of a carboxy vinyl polymer (polymer of carbomer type), the latter 
0.05 to 0.25% by weight, resulting in viscosities of the compositions 
ranging from 15000 to 300000, or 10 to 20000, respectively. 
In the publication WO 93/17664 high viscosity, polymer containing 
ophthalmic compositions are disclosed containing, in combination, carboxy 
vinyl polymers of the carbomer type, and cellulosic polymers. According to 
this disclosure lower polymer concentrations can be used while still 
achieving the desired higher viscosity. A wide range for the concentration 
of polymers is given, the broadest range indicated being 0.05 to 3% by 
weight of carbomer, and 0.05 to 5.0% by weight of cellulose polymer. A 
similar two-polymer system is described in the WO-publication WO 91/19481, 
the system being such which gels when exposed to the pH and temperature 
conditions of the eye surface. In the said publication, an inclusion of up 
to 0.9% of salt is contemplated for the adjustment of the viscosity. 
There is also a number of publications relating to pharmaceutically active 
ophthalmic compositions containing various polymers, i.a. carboxy vinyl 
polymers, at various concentrations. As tonicity regulating agents, 
usually nonionic polyols are suggested so as not to interfere with the gel 
structure (WO 93/00887, WO 90/13284). In the publication Int. J. Pharm. 81 
(1992) 59-65 aqueous compositions containing timolol maleate and 0.6% 
polyacrylic acid (MW 250,000), as well as the salt of timolol base with 
0.6% polyacrylic acid are described, containing mannitol as tonicity 
regulator. The viscosity measured at low shear rates is indicated as being 
45 mPas. 
In the DE-patent specification 28 39 752 ophthalmic gel compositions are 
described containing carboxy vinyl polymers in an amount of 0.05 to 5.0% 
by weight and exhibiting viscosities of 1000 to 100,000 mPas. According to 
this disclosure, a small amount of sodium chloride from 0.001 to 0.5% by 
weight is added in order to prevent the gel from breaking down on the 
surface of the eye (see column 4, lines 41 ff). 
SUMMARY OF THE INVENTION 
The present invention is based on the discovery that the beneficial effect 
of ophthalmic compositions of the above type containing viscosity 
enhancing agents, is due to the concentration of the polymer present in 
the composition, rather than on the viscosity thereof. Thus the aim of the 
invention is to provide an ophthalmic composition with a sufficiently high 
concentration of polymer to control the formation of the polymer film on 
the cornea of the eye, but which composition is still fluid enough for 
ocular topical application. A further object of the invention is to 
provide an easy-to-use eye drop formulation with improved patient 
compliance. 
According to the invention it has now been shown that by raising the 
concentration of the polymer over a value where the composition normally 
is a gel rather than a liquid and by simultaneously lowering the viscosity 
thereof, it is possible to obtain a desired beneficial effect of the 
active agent in the eye, while simultaneously reducing any discomfort in 
the patient's eye, as compared to the administration of a composition in 
gel form. The unbroken and even polymer film still being formed on the eye 
facilitates the binding and retaining of water on the surface of the eye, 
and thus provides for an additional wetting effect while providing for a 
better contact and thus a controlled absorption of active agent into the 
eye. 
The present invention thus provides an ophthalmological composition in a 
liquid, easy-to-use form which contains a sufficient amount of polymer to 
provide for both an increased and prolonged absorption of active agent 
into the eye. The invention thus makes it possible to treat e.g. glaucoma 
and ocular hypertension using a once-a-day-only or less frequent regimen 
for administering the ophthalmological active agent, and to lower the 
dosage clearly below the dosages presently in use. 
According to the invention we have shown that it is the amount of polymer 
in the composition, rather than the viscosity of the composition as such, 
which are important from the point of view of obtaining good absorption of 
drug into the eye. This is especially evident from the tests described 
below. In the FIG. 2 it is shown, for example, that by using the same 
amount of polymer, in compositions that have different viscosities, the 
compositions provide for substantially the same absorption. According to 
the state of the art one would, however, had expected the composition with 
the higher viscosity to provide for the higher absorption. 
More specifically, the object of the invention is an ophthalmic composition 
in the form of a topical aqueous solution consisting essentially of 
an ophthalmologically active agent, 
an ion sensitive, hydrophilic polymer in an amount of 0.004 to 1.5% by 
weight, 
at least one salt selected from the group of inorganic salts and buffers in 
a total amount of from 0.01 to 2.0% by weight, 
a wetting agent in an amount of 0 to 3.0% by weight, 
a preservative in an amount of 0 to 0.02% by weight, 
water, and optionally 
a pH regulating agent in an amount sufficient to give a pH of 4.0 to 8.0 to 
the composition, 
the ratio between salt and polymer components being such that the solution 
exhibits a viscosity of less than 1000 centipoise.

DETAILED DESCRIPTION OF THE INVENTION 
The ion-sensitive hydrophilic polymer to be used according to the invention 
contains acid groups, and is typically a carboxy vinyl polymer, or 
hyaluronic acid. Typical representatives of carboxy vinyl polymers are the 
polyacrylic acid polymers, known as carbomers. Carbomers are available at 
different molecular weights, typically ranging from e.g. 450.000 to 
4.000.000, and sold under the trade name Carbopol, e.g. Carbopol 907, 910, 
934, 934P, 940, 941, 971, 971P, 974, 974P, 980, and 981, preferably 
Carbopol 941 and 981. 
The polymer is preferably used in an amount of 0.01 to 0.8, more preferably 
0.01 to 0.4, and advantageously 0.04 to 0.4% by weight. 
According to the invention it has been established that it is favourable 
both from the view point of efficacy of the product in the target site, 
and of ease of application, to reduce the viscosity of the composition to 
a level of less than 1000 centipoise, suitably less than 500 centipoise, 
when measured at 25.degree. C. with a Brookfield LVDV-III type viscometer 
at a shear rate D of 1.1 s.sup.-1. This object is achieved by adding to 
the composition a salt and/or a buffer in the specified amount, preferably 
in an amount of 0.01 to 1.5% by weight. As viscosity decreasing salts and 
buffers, i.a. the following may be mentioned: sodium chloride, potassium 
chloride, sodium phosphates (monobasic and dibasic), sodium borate, sodium 
acetate, and sodium citrate, as well as their equivalents and mixtures 
thereof. In case no salts are added, a formulation with an unacceptably 
high viscosity is obtained.--It is to be noted that the composition 
according to the invention still exhibits favourable non-newtonian 
properties when applied to the eye surface, despite the addition of salts. 
For some purposes, for example for appearance and storage purposes, the use 
of a buffering salt is preferred to the use of e.g. sodium or potassium 
chloride as the viscosity reducing agent. 
In case the active agent contains basic groups, such as amine groups, an 
additional beneficial effect is achieved when using polymers containing 
acid groups, such as carboxy groups, due to the ion exchange reaction or 
salt formation between the acidic polymer and the basic active agent. The 
increased retaining ionic forces between the polymer and active agent thus 
provides for improved delivery of the active agent. Due to the fact that 
the basic drug is well retained by the polymer, the dosage can be lowered 
and/or the daily number of administration of the drug can be reduced, if 
desired, without the loss of activity, and consequently the side effects 
can be reduced as well. 
The pH of the composition is suitably from 5.0 to 8, preferably from 6.5 to 
8.0. When using a base as the active agent, the pH of the composition can 
be regulated by the amounts used of acidic polymer and basic active agent 
respectively. However, if necessary, the pH of the composition may be 
adjusted also by adding an additional base or an acid, as the case may be, 
such as an alkali metal hydroxide, especially sodium hydroxide, or 
ammonium hydroxide, or e.g. hydrochloric acid. 
The ophthalmologically active agent is advantageously an antiglaucoma 
agent, a sympathomimetic agent, a sympatholytic agent, such as a 
.beta.-blocker, a carbonic anhydrase inhibitor, or an antibiotic, 
antiinflammatoric, antiallergic agent, etc., or a combination thereof. 
Preferably an agent active against glaucoma or effective in the treatment 
of increased intraocular pressure is used. 
As stated above, especially contemplated within the scope of the invention 
is the use of an amine group containing pharmaceutically active agent. 
Thus according to the invention, the eye drugs contemplated may contain a 
primary, secondary or tertiary amino group or organoammonium or amidine 
attached to a chain or a ring, or a nitrogen atom(s) can be a part in 
various basic heterocycles, such as imidazole, imidazoline, pyridine, 
piperidine or piperazine. Preferably an agent active against glaucoma or 
effective in the treatment of increased intraocular pressure is used. A 
particularly preferred group of compounds is comprised of .beta.-blocking 
agents having a secondary amine function such as betaxolol, carteolol, 
levobunolol, metipranolol, pindolol, propranolol and timolol, as such or 
in the form of their acid addition salts. An especially advantageous mode 
of the invention is such where timolol is used as its easily 
crystallizable S-timolol maleate or hemihydrate. 
Other typical examples of basic drug molecules useful in eye therapy in the 
advantageous mode of the invention include tobramycin and norfloxacin 
(antimicrobial, antibacterial), cyclopentolate, tropicamide, atropine, 
phenylephrine, metaoxedrine (anticholinergic, mydriatic), pilocarpine, 
carbacol, ecothiopate (cholinergic), adrenaline, dipivefrin, dopamine 
(adrenergic), naphazoline, tetryzoline (vasoconstrictor), verapamil, 
nifedipine (vasodilator), apraclonidine, clonidine, medetomidine 
(.alpha..sub.2 -agonist), sezolamide (carbonic anhydrase inhibitor), 
cetirizine (antihistamine), as such or in their acid addition, ester and 
prodrug forms. 
Especially contemplated in the invention is the use of a .beta.-blocking 
agent, such as S-timolol, as the only drug, or as combined with e.g. the 
base form of pilocarpine. 
The amount of active agent in the final composition may vary, such as 
between 0.001 to 5% by weight, usually however between 0.01 to 0.5% by 
weight, and typically between 0.1 and 0.5% by weight, especially in the 
case of S-timolol. 
According to an advantageous embodiment of the invention, the composition 
contains in addition, in order to enhance the wetting effect thereof, a 
wetting agent, preferably a polyhydric alcohol, such as glycerol. The 
amount of wetting agent is generally at the most 3.0%, such as of the 
order of 0.5 to 3.0% by weight. 
As preservatives, e.g. benzalkonium chloride, benzyl alcohol, mercury 
salts, thiomersal, chlorhexidine or the like, as such or in combination. 
The amount of preservative usually lies in the range of 0 to 0.02% by 
weight. 
A preferred composition according to the invention in the form of an 
aqueous solution consists essentially of the following components (% 
being% by weight of the total composition): 
timolol in the form of its maleate salt or hemihydrate in an amount of 0.1 
to 0.5% by weight, calculated as the free base, 
polyacrylic acid in an amount of 0.04 to 0.4% by weight 
glycerol in an amount of 0.5 to 2.5% by weight 
sodium phosphates in an amount of 0.01 to 1.5% by weight, 
a preservative in an amount of 0 to 0.02%, 
water, and optionally 
a pH-regulating agent to give the composition a pH of 6.5 to 8.0, and 
wherein the viscosity of the solution is less than 800 centipoise. 
According to the invention, the term "consisting essentially of" is 
intended to mean that the composition contains only or essentially only 
the components listed in connection therewith. The compositions may, 
however, in addition, contain ophthalmologically acceptable additives and 
adjuvants of such type and amounts as to have no essential influence on 
the characteristics of the composition. 
The composition according to the invention is typically prepared in three 
stages. In the first step the polymer is dispersed in sterile water and 
sterilized by autoclaving. In the second step, the other ingredients, 
namely the active ingredient(s), inorganic salt(s), tonicity regulating 
agent(s), preservative(s) and any other additives, are dissolved in 
sterile water and sterilized by filtration on a filter (pore size e.g. 0.2 
.mu.m). In the third and last step the solution prepared in the two steps 
are combined aseptically and mixed until they form a homogenous solution 
with a low viscosity. The pH of the solution may be adjusted, if 
necessary, by adding a base or an acid. Thereafter the composition is 
packaged in multi- or unit dose form. 
The following examples illustrate the invention in more detail, without 
limiting the same. 
EXAMPLE 1 
The following composition was made: 
______________________________________ 
Composition (g) 
______________________________________ 
S-Timolol hemihydrate 2.56 
Carbopol 941 0.95 
Sodium phosphate monobasic 
0.08 
Sodium phosphate dibasic 
1.80 
Glycerol 23.0 
Benzalkonium chloride 0.06 
Water for injection to 1000 mL 
______________________________________ 
Carbopol 941 was dispersed in 300 mL sterile water at room temperature. The 
solution was sterilized in an autoclave. The autoclaved solution was 
cooled to room temperature (solution 1). Benzalkonium chloride, glycerol, 
sodium phosphate monobasic and dibasic and timolol hemihydrate were 
dissolved in 700 mL sterile water at room temperature and sterilized by 
filtration on a filter with a pore size of 0.2 .mu.m (solution 2). In the 
final step the solutions prepared in the two previous steps (solution 1 
and 2) were combined aseptically and mixed until they formed a homogenous 
low viscous solution. The pH of the solution obtained was 7.4 and its 
viscosity was 440 centipoise (D=1.1 s.sup.-1). Thereafter the solution was 
packed in traditional eye drop bottles. 
The viscosity vs. shear rate curve for the composition is shown in FIG. 1. 
It is to be noted that the shape of the curve shows still non-newtonian 
rheology despite the addition of salts. 
EXAMPLE 2 
The following composition was made: 
______________________________________ 
Composition (g) 
______________________________________ 
S-Timolol maleate 3.42 
Carbopol 941 2.00 
Sodium chloride 3.5 
Glycerol 15.0 
Benzalkonium chloride 
0.06 
Sodium hydroxide q.s. ad pH 7.5 
Water for injection to 1000 mL 
______________________________________ 
The solution was prepared according to the Example 1 except that the pH of 
the solution was adjusted to pH 7.5 by adding the sterile filtered sodium 
hydroxide solution. The viscosity of the solution was 430 centipoise 
(D=1.1 s.sup.-1). Viscosity vs. shear rate curve is shown in FIG. 1. 
EXAMPLE 3 
The following composition was made: 
______________________________________ 
Composition (g) 
______________________________________ 
S-Timolol hemihydrate 2.56 
Carbopol 981 1.4 
Sodium phosphate monobasic 
0.62 
Sodium phosphate dibasic 
2.85 
Glycerol 23.0 
Benzalkonium chloride 0.06 
Water for injection to 1000 mL 
______________________________________ 
The solution was prepared according to the Example 1. The pH of the 
solution obtained was 6.9 and the viscosity of the solution was 70 
centipoise (D=1.1 s.sup.-1). Viscosity vs. shear rate curve is shown in 
FIG. 1. 
EXAMPLE 4 
The following composition was made: 
______________________________________ 
Composition (g) 
______________________________________ 
S-Timolol hemihydrate 
1.02 
Carbopol 941 2.28 
Sodium phosphate monobasic 
1.55 
Sodium phosphate dibasic 
7.10 
Glycerol 20.0 
Sodium hydroxide q.s. ad pH 6.8 
Water for injection to 1000 mL 
______________________________________ 
The solution was prepared according to the Example 1. The pH of the 
solution was adjusted to pH 6.8 with a sodium hydroxide solution. The 
viscosity of the solution was 590 centipoise (D=1.1 s.sup.-1). 
EXAMPLE 5 
The following composition was made: 
______________________________________ 
Composition (g) 
______________________________________ 
S-Timolol maleate 6.84 
Carbopol 941 3.0 
Sodium phosphate monobasic 
0.59 
Sodium phosphate dibasic 
8.24 
Benzalkonium chloride 
0.1 
Sodium hydroxide q.s. ad pH 7.2 
Water for injection to 1000 mL 
______________________________________ 
The solution was prepared according to the Example 1. The pH of the 
solution was adjusted to pH 7.2 with sodium hydroxide and the viscosity of 
the solution was 270 centipoise (D=1.1 s.sup.-1). 
EXAMPLE 6 
The following composition was made: 
______________________________________ 
Composition (g) 
______________________________________ 
Clonidine (base) 1.25 
Carbopol 981 0.70 
Sodium phosphate monobasic 
0.04 
Sodium phosphate dibasic 
0.6 
Glycerol 23.0 
Benzalkonium chloride 0.06 
Water for injection to 1000 mL 
______________________________________ 
The solution was prepared according to the Example 1. The pH of the 
solution obtained was 7.0 and the viscosity was 540 centipoise (D=1.1 
s.sup.-1). 
EXAMPLE 7 
The following composition was made: 
______________________________________ 
Composition (g) 
______________________________________ 
Pilocarpine (base) 20.0 
Carbopol 981 3.0 
Sodium phosphate monobasic 
10.6 
Sodium phosphate dibasic 
0.53 
Glycerol 5.0 
Benzalkonium chloride 0.10 
Water for injection to 1000 mL 
______________________________________ 
The solution was prepared according to the Example 1. The pH of the 
solution obtained was 6.8 and the viscosity was 900 centipoise (D=1.1 
s.sup.-1). 
By leaving out from the formulations (Examples 1-3, 5-7) the benzalkonium 
chloride, corresponding unit-dose formulations were obtained. 
By adding to the formulations (Example 4) benzalkonium chloride 0.06 mg/ml, 
a corresponding multidose-formulation was obtained. 
Absorption of timolol into the rabbit eye (Study 1) 
An ophthalmic formulation (Example 1), which is a typical example of this 
invention, was instilled into a rabbit eye (n=6). The concentration of 
timolol in the aqueous humor was measured after 1/2 and 1 hours using 
HPLC. The reference product contained the same amount of Carbopol, timolol 
and preservative, benzalkonium chloride, but did not contain any inorganic 
salt(s). The viscosity of the reference product was much higher (7300 
centipoise, D=1.1 s.sup.-1). 
The timolol concentrations in the aqueous humor in rabbits are shown in 
FIG. 2. According to FIG. 2, the absorption of timolol in rabbits eye was 
equal despite the different viscosities.