U.S. patent application number 17/041758 was filed with the patent office on 2021-04-29 for pharmaceutical compositions comprising timolol.
The applicant listed for this patent is NOVALIQ GMBH. Invention is credited to Kirsten EICKHOFF, Bernhard HAUPTMEIER, Sonja KROSSER, Frank LOSCHER, Diana STREHL.
Application Number | 20210121471 17/041758 |
Document ID | / |
Family ID | 1000005343698 |
Filed Date | 2021-04-29 |
![](/patent/app/20210121471/US20210121471A1-20210429\US20210121471A1-2021042)
United States Patent
Application |
20210121471 |
Kind Code |
A1 |
LOSCHER; Frank ; et
al. |
April 29, 2021 |
PHARMACEUTICAL COMPOSITIONS COMPRISING TIMOLOL
Abstract
The present invention relates to pharmaceutical composition
comprising the beta 1(.beta..sub.1)-receptor blocker timolol and a
liquid vehicle comprising a semifluorinated alkane. The
pharmaceutical composition of the present invention may be useful
for topical administration, for example ophthalmic topical
administration and for use in the treatment of glaucoma, increased
intraocular pressure, ocular hypertension and/or a symptom
associated therewith.
Inventors: |
LOSCHER; Frank;
(Schriesheim, DE) ; KROSSER; Sonja; (Heidelberg,
DE) ; STREHL; Diana; (Heidelberg, DE) ;
HAUPTMEIER; Bernhard; (Schriesheim, DE) ; EICKHOFF;
Kirsten; (Aschaffenburg, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NOVALIQ GMBH |
Heidelberg |
|
DE |
|
|
Family ID: |
1000005343698 |
Appl. No.: |
17/041758 |
Filed: |
March 25, 2019 |
PCT Filed: |
March 25, 2019 |
PCT NO: |
PCT/EP2019/057429 |
371 Date: |
September 25, 2020 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/08 20130101; A61K
9/0048 20130101; A61P 27/06 20180101; A61K 31/5377 20130101 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61P 27/06 20060101 A61P027/06; A61K 9/00 20060101
A61K009/00; A61K 9/08 20060101 A61K009/08 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 28, 2018 |
EP |
18164563.1 |
Jul 25, 2018 |
EP |
18185436.5 |
Claims
1. A pharmaceutical composition comprising: (a) timolol and/or a
pharmaceutically acceptable salt thereof and (b) a liquid vehicle
comprising a semifluorinated alkane.
2. The pharmaceutical composition according to claim 1, wherein the
semifluorinated alkane has formula (II)
CF.sub.3(CF.sub.2).sub.n(CH.sub.2).sub.mCH.sub.3 (II), wherein n is
an integer from 3 to 7, and m is an integer from 4 to 7.
3. The pharmaceutical composition of claim 1, wherein the
semifluorinated alkane is selected from the group consisting of
1-perfluorobutyl-pentane
(CF.sub.3(CF.sub.2).sub.3(CH.sub.2).sub.4CH.sub.3; F4H5) and
1-perfluorohexyl-octane
(CF.sub.3(CF.sub.2)(CH.sub.2).sub.7CH.sub.3; F6H8).
4. The pharmaceutical composition of claim 1, wherein the timolol
and/or a pharmaceutically acceptable salt thereof is suspended in
the liquid vehicle comprising the semifluorinated alkane.
5. The pharmaceutical composition of claim 1, wherein the
concentration of timolol as free base is from about 0.3 to about
2.5% (w/v).
6. The pharmaceutical composition of claim 5, wherein the
concentration of timolol as free base is from about 0.5 to about
2.0% (w/v).
7. The pharmaceutical composition of claim 1, comprising timolol in
the form of timolol maleate.
8. The pharmaceutical composition of claim 4, wherein at least
about 90% of the suspended particles of timolol and/or a
pharmaceutically acceptable salt thereof have a size of not more
than about 15 .mu.m.
9. (canceled)
10. A method for the treatment of glaucoma, increased intraocular
pressure, ocular hypertension and/or a symptom associated
therewith, in a patient in need thereof, comprising administering
to said patient a pharmaceutical composition according to claim
1.
11. The method according to claim 10, wherein the composition is
administered to the eye of a subject up to four times daily.
12. The method according to claim 10, wherein the pharmaceutical
composition is administered in a dose volume per eye of from about
8 to about 15 .mu.l.
13. The method according to claim 10, wherein the semifluorinated
alkane is 1-perfluorohexyl-octane
(CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3, F6H8).
14. The pharmaceutical composition according to claim 1, further
comprising a co-solvent.
15. A kit comprising the pharmaceutical composition according to
claim 1 and a container for holding the pharmaceutical
composition.
16. The pharmaceutical composition of claim 5, wherein the
concentration of timolol as free base is from about 0.5 to about
1.5% (w/v).
17. The pharmaceutical composition of claim 7, wherein the
composition comprises the timolol maleate at a concentration of
from about 0.4 to about 3.4% (w/v).
18. The pharmaceutical composition of claim 17, wherein the
composition comprises the timolol maleate at a concentration of
from about 0.68% to about 2.1% (w/v).
19. The method according to claim 10, wherein the composition is
administered to the eye of a subject once daily.
20. The method according to claim 10, wherein the pharmaceutical
composition is administered in a dose volume per eye of from about
10 to about 12 .mu.l.
Description
BACKGROUND
[0001] The present invention relates to a pharmaceutical
composition comprising a) timolol and/or a pharmaceutically
acceptable salt thereof and b) a liquid vehicle comprising a
semifluorinated alkane. The pharmaceutical composition of the
present invention may be useful for topical administration,
especially ophthalmic topical administration.
[0002] Pharmaceutical compositions in liquid form represent one of
the preferred types of drug formulations. Certain routes of topical
administration, such as ophthalmic administration, typically
require the liquid form in order to provide for an efficient
delivery of the active ingredient and a patient-friendly mode of
use.
[0003] The simplest type of liquid formulation is a solution, such
as an aqueous solution of the active pharmaceutical ingredient. In
certain cases, however, the development of a more complex
formulation such as a suspension may be considered. For example, if
a drug substance is very poorly soluble in aqueous or other
biocompatible solvent systems, or if it is hydrolytically labile, a
simple solution may not be feasible or represent the best
choice.
[0004] Timolol belongs to a class of compounds named beta-blockers.
Timolol in its oral form is used to treat high blood pressure and
prevent heart attacks. In its ophthalmic form is used to treat
open-angle glaucoma.
[0005] Beta-blockers act by blocking beta-receptors at the level of
the ciliary body and by reducing the aqueous humour production,
thereby reducing the intraocular pressure (IOP). Two types of
topical beta-blockers are available for use in the treatment of
glaucoma: non-selective beta-blockers, which block both beta 1
(.beta..sub.1)- and beta 2 (.beta..sub.2)-adrenoceptors; and
cardio-selective beta blockers, which block only beta
1-receptors.
[0006] Timolol is a non-selective beta-adrenergic receptor
antagonist. Timolol, when applied topically to the eye, has the
action of reducing elevated, as well as normal, intraocular
pressure, whether or not accompanied by glaucoma. Elevated
intraocular pressure is a major risk factor in the pathogenesis of
glaucomatous visual field loss and optic nerve damage.
[0007] Increased intraocular pressure is a frequent disorder of the
eye which is often associated with optic nerve damage, in which
case the disease is glaucoma. In the absence of optic nerve damage,
the condition is referred to as ocular hypertension.
[0008] Normal intraocular pressure is usually defined as being in
the range from 10 to 21 mmHg. The pressure results predominantly
from the balance between the production rate and the drainage rate
of the aqueous humour in the eye. In addition, it is influenced by
the corneal thickness and rigidity. The intraocular pressure
typically fluctuates around about 15 to 16 mmHg with amplitudes of
up to 6 mmHg. For example, it usually decreases in the night due to
a decreased production of aqueous humour. It also responds to
various physiological factors such as exercise, heart rate,
respiration, fluid intake, as well as certain types of systemic or
topical drugs.
[0009] The aqueous humour is produced by the ciliary bodies of the
eye, from where it flows into the posterior chamber. The
composition of the aqueous humour is very similar to that of blood
plasma but differs from the latter by a lower protein content. Its
main constituents are water (99%), electrolytes (inorganic ions to
maintain the physiological pH), low amounts of albumin and
.beta.-globulins, ascorbate, glucose, lactate, and amino acids.
[0010] From the posterior chamber, the aqueous humour is
distributed via the pupil of the iris into the anterior chamber of
the eye. From here, it flows through the so-called trabecular
meshwork, which is a spongy tissue area lined by trabeculocytes
whose main function is to drain the humour into a set of tubes
called Schlemm's canal, from where the humour enters the blood
circulation. The humour flow from the trabecular meshwork into the
Schlemm's canal occurs via two different routes: either directly
via the aqueous vein to the episcleral vein, or indirectly via
collector channels to the episcleral vein by intrascleral plexus.
This trabecular outflow pathway accounts for the major fraction of
drained aqueous humour. In addition, there exists a second major
drainage pathway which is the uveoscleral outflow, which is
relatively independent of the intraocular pressure and normally
accounts for only 5 to 10% of the aqueous humour drainage in
healthy humans.
[0011] Ophthalmic timolol is available in the market as a solution
(liquid) and an extended-release (long-acting) gel-forming solution
(liquid that thickens to a gel when instilled in the eye). Timolol
eye drops are usually instilled once or twice a day, at evenly
spaced intervals, until pressure in the eye is controlled (about 4
weeks). Then it may be instilled once a day. Timolol gel-forming
solution is usually instilled once a day.
[0012] Timoptic.RTM. (timolol maleate ophthalmic solution) is
indicated in the treatment of elevated intraocular pressure in
patients with ocular hypertension or open-angle glaucoma.
Timoptic.RTM. is supplied as a sterile, isotonic, buffered aqueous
solution of timolol maleate in two dosage strengths. Each mL of
Timoptic.RTM. 0.25% contains 2.5 mg of timolol (3.4 mg of timolol
maleate). Each mL of Timoptic.RTM. 0.5% contains 5 mg of timolol
(6.8 mg of timolol maleate). As inactive ingredients, monobasic and
dibasic sodium phosphate, sodium hydroxide, water for injection and
benzalkonium chloride 0.01% as preservative are included.
[0013] The effects of timolol maleate on the intraocular pressure
in patients with chronic open angle glaucoma compared to
epinephrine or pilocarpine has been described in Drugs 1979
January; 17(1):38-55.
[0014] U.S. Pat. No. 6,335,335 B2 describes a method to promote
penetration of a beta blocker into the eye and to improve the
retention of the beta blocker in the ocular tissues by
incorporating a C3-C7 fatty acid into an eye drop containing the
beta blocker. Highly water soluble components find in the highly
hydrophobic corneal epithelium a barrier to the penetration of the
components into the eye. It is therefore necessary to instill the
eye drop containing the components in high dose or many times, so
that a sufficient amount of the components penetrates in the eye
tissues for lowering an intraocular pressure. However, in order to
separate from the systemic effect of the beta blocker, to get more
effect on lowering intraocular pressure and to get the prolonged
action of the beta blocker, it is preferable to promote penetration
of the drugs into the eye and to prolong retention of the drug in
the eye than to instill a high amount of the eye drop and instill
many times.
[0015] It is an object of the present invention to provide a novel
pharmaceutical formulation comprising timolol and/or a
pharmaceutically acceptable salt thereof, which can be useful as a
medicament, particularly for topical applications. It is a further
object of the present invention to find a treatment of increased
intraocular pressure, e.g. in association with open-angle glaucoma
or ocular hypertension, which overcomes at least one of the
limitations or disadvantages associated with prior art
formulations.
[0016] A further object of the present invention is to provide
liquid formulations of timolol and/or a pharmaceutically acceptable
salt thereof which is effective in decreasing intraocular pressure
at reduced target dosage compared to commercial timolol
solutions.
[0017] Further objects of the invention will become clear on the
basis of the following description, examples, and patent
claims.
SUMMARY OF THE INVENTION
[0018] In a first aspect, the present invention provides a
pharmaceutical composition comprising:
[0019] (a) timolol and/or a pharmaceutically acceptable salt
thereof, and
[0020] (b) a liquid vehicle comprising a semifluorinated
alkane.
[0021] In a second aspect, the present invention provides the
composition of the first aspect of the invention for use as
medicament, more specifically for the treatment of glaucoma,
increased intraocular pressure, ocular hypertension and/or a
symptom associated therewith.
[0022] In a further aspect, the present invention provides a method
for the treatment of glaucoma, increased intraocular pressure,
ocular hypertension and/or a symptom associated therewith,
comprising administering to the eye of a subject in need thereof a
pharmaceutical composition according to the first aspect of the
present invention.
[0023] In yet a further aspect, the present invention provides a
kit comprising the pharmaceutical composition according to the
first or second aspect of the invention and a container for holding
the pharmaceutical composition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] FIG. 1 is a graphical representation of the results of the
measurement of the in-vivo intraocular pressure study according to
Example 2 below in which a suspension of timolol at a concentration
of 0.5% (w/v) in 1-perfluorohexyl-octane (F6H8) is administered
once a day.
[0025] FIG. 2 is a graphical representation of the results of the
measurement of the in-vivo intraocular pressure study according to
Example 2 below in which a suspension of timolol at a concentration
of 1.37% (w/v) in 1-perfluorohexyl-octane (F6H8) is administered
once a day.
[0026] FIG. 3 is a graphical representation of the results of the
measurement of the in-vivo intraocular pressure study according to
Example 2 below in which a suspension of timolol at a concentration
of 0.5% (w/v) in 1-perfluorohexyl-octane (F6H8) is administered
twice a day.
DETAILED DESCRIPTION OF THE INVENTION
[0027] It has been found by the inventors that the composition of
the invention surprisingly overcomes several drawbacks of
previously known formulations of timolol.
In a first aspect, the present invention provides a pharmaceutical
composition comprising:
[0028] (a) timolol and/or a pharmaceutically acceptable salt
thereof, and
[0029] (b) a liquid vehicle comprising a semifluorinated
alkane.
[0030] The pharmaceutical composition according to the present
invention comprises as a first constituent (a) timolol and/or a
pharmaceutically acceptable salt of timolol. The compound timolol,
IUPAC name
(2S)-1-(tert-butylamino)-3-{[4-(morpholin-4-yl)-1,2,5-thiadiazol-3-yl]oxy-
}propan-2-ol, as used herein is of structural formula (a)
##STR00001##
[0031] with the chemical formula C.sub.13H.sub.24N.sub.4O.sub.3S
and molecular mass of 316.42 g/mol. Timolol is commercially
available in form of its free base ((S)-timolol base) as described
and shown by formula (Ia) above, as well as in the form of
pharmaceutically acceptable salts such as, for example timolol
maleate of formula (Ib), IUPAC name
(2S)-1-(tert-butylamino)-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]p-
ropan-2-ol maleate salt, molecular mass of 432.492 g/mol.
##STR00002##
[0032] Timolol free base can also be provided in form of
(S)-timolol base hemihydrate, as represented in formula (Ic) and
having chemical formula C.sub.26H.sub.50N.sub.8O.sub.7S.sub.2 and
molecular mass of 650.324 g/mol.
##STR00003##
[0033] The pharmaceutical composition comprises timolol and/or a
pharmaceutically acceptable salt of timolol, which means that the
composition may comprise timolol in form of its free base as, for
example shown in formula (Ia), either alone or in combination with
one or a mixture of different pharmaceutically acceptable salts of
timolol. Furthermore, the present pharmaceutical composition may
comprise timolol in form of a salt, such as timolol maleate of
formula (Ib) either alone or in form of a mixture with other
pharmaceutically acceptable salts of timolol as described
above.
[0034] In a preferred embodiment of the present invention, however,
the pharmaceutical composition of the present invention comprises
timolol in form of timolol maleate or (S)-timolol base hemihydrate.
In another preferred embodiment, the pharmaceutical composition of
the present invention comprises as component a) one selected from
timolol maleate and (S)-timolol base hemihydrate. Preferably, the
pharmaceutical composition of the present invention comprises as
component a) timolol maleate. More preferably, the pharmaceutical
composition of the present invention comprises as component a) the
levo-isomer of timolol maleate.
[0035] Preferably, the timolol and/or another pharmaceutically
acceptable salt of timolol as described above is present in the
pharmaceutical composition according to present invention in a
therapeutically effective amount. The term "a therapeutically
effective amount" as used herein refers to a dose, concentration or
strength which is useful for producing a desired pharmacological
effect.
[0036] As a second constituent (b), the pharmaceutical composition
according to the present invention comprises a liquid vehicle
comprising a semifluorinated alkane. Some of the key advantages of
the present invention are brought about by the presence of a
semifluorinated alkane in the composition, functioning as a liquid
vehicle for forming either a solution, dispersion or a suspension.
The term `semifluorinated alkane` as used herein means a compound
in which a perfluorinated linear or branched, preferably linear
hydrocarbon segment is attached to a linear or branched, preferably
linear hydrocarbon segment.
[0037] In preferred embodiments, however, the pharmaceutical
composition of the present invention or, more specifically, the
liquid vehicle of the pharmaceutical composition of the present
invention comprises a semifluorinated alkane of the general formula
(II)
CF.sub.3(CF.sub.2).sub.n(CH.sub.2).sub.mCH.sub.3 (II),
[0038] wherein the index n is an integer selected from 2 to 10, and
m is an integer selected from 2 to 10. Preferably, the liquid
vehicle of the pharmaceutical composition of the present invention
comprises a semifluorinated alkane of the general formula (II)
wherein the index n is an integer selected from 3 to 7, and m is an
integer selected from 4 to 7, more preferably wherein the index n
is an integer selected from 3 to 5, and m is an integer selected
from 4 to 7.
[0039] Accordingly, said semifluorinated alkane as used in the
composition of the present invention may preferably be selected
from CF.sub.3(CF.sub.2).sub.3--(CH.sub.2).sub.4CH.sub.3 (F4H5),
CF.sub.3(CF.sub.2).sub.3--(CH.sub.2).sub.5CH.sub.3 (F4H6),
CF.sub.3(CF.sub.2).sub.3--(CH.sub.2).sub.6CH.sub.3 (F4H7),
CF.sub.3(CF.sub.2).sub.3--(CH.sub.2).sub.7CH.sub.3 (F4H8),
CF.sub.3(CF.sub.2).sub.4--(CH.sub.2).sub.4CH.sub.3 (F5H5),
CF.sub.3(CF.sub.2).sub.4--(CH.sub.2).sub.5CH.sub.3 (F5H6),
CF.sub.3(CF.sub.2).sub.4--(CH.sub.2).sub.6CH.sub.3 (F5H7),
CF.sub.3(CF.sub.2).sub.4--(CH.sub.2).sub.7CH.sub.3 (F5H8),
CF.sub.3(CF.sub.2).sub.5--(CH.sub.2).sub.4CH.sub.3 (F6H5),
CF.sub.3(CF.sub.2).sub.5--(CH.sub.2).sub.5CH.sub.3 (F6H6),
CF.sub.3(CF.sub.2).sub.5--(CH.sub.2).sub.6CH.sub.3 (F6H7),
CF.sub.3(CF.sub.2).sub.5--(CH.sub.2).sub.7CH.sub.3 (F6H8),
CF.sub.3(CF.sub.2).sub.7--(CH.sub.2).sub.7CH.sub.3 (F8H8). More
preferably, said semifluorinated alkane may be selected from
CF.sub.3(CF.sub.2).sub.3--(CH.sub.2).sub.4CH.sub.3 (F4H5),
CF.sub.3(CF.sub.2).sub.5--(CH.sub.2).sub.5CH.sub.3 (F6H6),
CF.sub.3(CF.sub.2).sub.5--(CH.sub.2).sub.7CH.sub.3 (F6H8) and
CF.sub.3(CF.sub.2).sub.5--(CH.sub.2).sub.9CH.sub.3 (F6H10). Most
preferably, said semifluorinated alkane may be selected from
CF.sub.3(CF.sub.2).sub.3--(CH.sub.2).sub.4CH.sub.3 (F4H5) and
CF.sub.3(CF.sub.2).sub.5--(CH.sub.2).sub.7CH.sub.3 (F6H8).
[0040] An alternative nomenclature for the specified
semifluorinated alkanes as noted in parentheses below and as may be
further used herein, is based on the general formula FnHm, wherein
F means the linear perfluorinated hydrocarbon segment, H means the
linear non-fluorinated hydrocarbon segment and n, m is the number
of carbon atoms of the respective segment. For example, F4H5 may be
used to denote 1-perfluorobutyl-pentane or
CF.sub.3(CF.sub.2).sub.3--(CH.sub.2).sub.4CH.sub.3 (which may be
also, alternatively expressed as formula
F(CF.sub.2).sub.4(CH.sub.2).sub.5H), which has a linear
perfluorinated segment F with four carbons (n=4) and a linear
non-fluorinated hydrocarbon segment with five carbons (m=5).
Furthermore, F6H8 may be used to denote 1-perfluorohexyl-octane or
CF.sub.3(CF.sub.2).sub.5--(CH.sub.2).sub.7CH.sub.3 (which may be
also, alternatively expressed as formula
F(CF.sub.2).sub.6(CH.sub.2).sub.5H), which has a linear
perfluorinated segment F with six carbons (n=6) and a linear
non-fluorinated hydrocarbon segment with 8 carbons (m=8).
[0041] The pharmaceutical composition of the invention comprising
of "a" semifluorinated alkane is to be understood herein, as
comprising at least one semifluorinated alkane of Formula (II) as
described above. Optionally, however, the composition may comprise
of more than one, for example, a mixture of two or more
semifluorinated alkanes of Formula (II), i.e. of any one of the
semifluorinated alkane species as described above.
[0042] In a preferred embodiment, the pharmaceutical composition
according to the present invention comprises a semifluorinated
alkane of Formula (II) which is selected from
1-perfluorohexyl-octane
(CF.sub.3(CF.sub.2).sub.5--(CH.sub.2).sub.7CH.sub.3 (F6H8)) and
1-perfluorobutyl-pentane
(CF.sub.3(CF.sub.2).sub.3--(CH.sub.2).sub.4CH.sub.3 (F4H5)). In a
particular preferred embodiment of the present invention, the
semifluorinated alkane of Formula (II) is 1-perfluorohexyl-octane
(CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3, F6H8).
[0043] In yet a further embodiment, the liquid vehicle of the
pharmaceutical composition of the present invention may consist of
a semifluorinated alkane of Formula (II) as specified above. In
this context also, the term "a" semifluorinated alkane is to be
understood as at least one semifluorinated alkane, but may also
include the option of more than one, or a plurality of
semifluorinated alkane compounds. Accordingly, in one embodiment,
the composition may consist of more than one semifluorinated alkane
of Formula (II) as specified above.
[0044] In another embodiment, the pharmaceutical composition
according to the present invention may comprise (a) timolol and/or
a pharmaceutically acceptable salt thereof, and (b) a liquid
vehicle comprising or essentially consisting of a semifluorinated
alkane of general formula (II) as defined above, or a
semifluorinated alkane selected from any one, or combination of the
semifluorinated alkane compounds as defined above, and optionally,
(c) one or more excipients.
[0045] As used herein, the term "consists" and related terms
"consisting" or "consist" is to be understood as meaning that no
other features, other than those prefaced by the term are present.
In the context of compositions, if any other constituent or
component is present in the composition other than those prefaced
by such term, then it is present only in trace or residual amounts
such as to confer no technical advantage or relevance in respect of
the object of the invention, such as may be further understood by
the term `essentially" or "substantially" used in conjunction with
these terms (e.g. `essentially consisting of"). It is to be
understood that isomeric or olefinic impurities that originate from
synthesis of semifluorinated alkanes and that are present in only
trace or residual amounts, as these cannot be quantitatively
removed upon purification, and that do not confer any technical
advantage or relevance in respect of the object of the present
invention, do fall under the above definition of such other
constituent or component. In contrast, the term `comprising" or
related terms "comprises" or "comprise" in the context of the
present compositions, is to be understood as meaning that other
features, other than those prefaced by the term may be present in
the composition.
[0046] In a further embodiment, the liquid vehicle of the present
pharmaceutical composition as defined in any of the previous
embodiments described above, preferably comprises a semifluorinated
alkane or optionally, a mixture of semifluorinated alkanes in an
amount of at least 70% (w/w), 75% (w/w), 85% (w/w), 90% (w/w), 95%
(w/w), 98% (w/w), 98.5% (w/w), 99% (w/w), 99.5% (w/w), 99.8% (w/w)
or at least 99.9% (w/w) of a semifluorinated alkane or a mixture of
semifluorinated alkanes as described above, with respect to the
total weight of the liquid vehicle. In a preferred embodiment, the
liquid vehicle of the present pharmaceutical composition comprises
a semifluorinated alkane in an amount of at least 98% w/w.
[0047] In a further embodiment, the liquid vehicle of the present
invention essentially consists of 100% (w/w) of a semifluorinated
alkane or mixture of semifluorinated alkanes.
[0048] The term "% (w/w)" as used herein and unless indicated
otherwise refers to the amount of a component of a composition as a
weight percentage in relation to the total weight of the liquid
vehicle of the present pharmaceutical composition (with `w`
denoting weight).
[0049] In a particularly preferred embodiment, the liquid vehicle
of the pharmaceutical composition according to the present
invention comprises 1-perfluorohexyl-octane
(CF.sub.3(CF.sub.2).sub.5--(CH.sub.2).sub.7CH.sub.3 (F6H8)). In a
further preferred embodiment, the liquid vehicle of the
pharmaceutical composition of the present invention essentially
consists of 1-perfluorohexyl-octane (F6H8). It is understood that a
liquid vehicle essentially consisting of 1-perfluorohexyl-octane
may comprise in trace or residual amounts isomeric or olefinic
impurities (such as 2-perfluorohexyl-octane or
1-perfluorohexyl-octene) originating from synthesis of F6H8 which
cannot be quantitatively removed upon purification.
[0050] In further preferred embodiments, the liquid vehicle of the
pharmaceutical composition according to the present invention
comprises 1-perfluorobutyl-pentane
(CF.sub.3(CF.sub.2).sub.3--(CH.sub.2).sub.4CH.sub.3 (F4H5)). In a
further preferred embodiment, the liquid vehicle of the
pharmaceutical composition of the present invention essentially
consists of 1-perfluorobutyl-pentane (F4H5). It is understood that
a liquid vehicle essentially consisting of 1-perfluorobutyl-butane
may comprise in trace or residual amounts isomeric or olefinic
impurities (such as 2-perfluorobutyl-pentane or
1-perfluorobutyl-pentene) originating from synthesis of F4H5 which
cannot be quantitatively removed upon purification.
[0051] The liquid semifluorinated alkanes as described above are
chemically and physiologically inert, colourless and stable. Their
typical densities range from 1.1 to 1.7 g/cm.sup.3, and their
surface tension may be as low as 19 mN/m. Semifluorinated alkanes
of the RFRH type are insoluble in water but also somewhat
amphiphilic, with increasing lipophilicity correlating with an
increasing size of the non-fluorinated segment.
[0052] The liquid vehicle of the pharmaceutical composition
comprising a semifluorinated alkane as described above may also
comprise a further solubilizing agent, such as one or more solvents
or co-solvents. In specific embodiments, the liquid vehicle of the
present pharmaceutical composition may comprise a co-solvent,
preferably an organic co-solvent.
[0053] As used herein, the term "solubilizing agent" may denote a
compound or solvent or a co-solvent, preferably an organic solvent,
that is miscible with the semifluorinated alkane or the mixture of
different semifluorinated alkanes of the present liquid vehicle and
that enhances or facilitates the solubility, or the dispersability
of the active component timolol in the chosen liquid vehicle
comprising a semifluorinated alkane as described above.
[0054] Examples of potentially useful organic co-solvents include
glycerol, propylene glycol, polyethylene glycol, and ethanol.
However, the concentration of the co-solvent should preferably be
low relative to that of the semifluorinated alkane or
semifluorinated alkane mixture. The co-solvent comprised in the
liquid vehicle of the pharmaceutically composition according to the
invention may be ethanol. If an organic co-solvent such as ethanol
is used, it is recommendable to keep it at or below a level of
approximately 10% (w/w) or 5% (w/w) or even 3% (w/w) with regard to
the total weight of the liquid vehicle. Preferably, the content of
ethanol is from about 0.1 to about 2% (w/w), and more preferably
not more than about 1% (w/w) with regard to the total weight of the
liquid vehicle. In some embodiments, the liquid vehicle of the
present composition according to the invention, however, are free
of an organic co-solvent.
[0055] In other embodiments, the solubilizing agent, that may be
optionally comprised by the liquid vehicle of the present
pharmaceutical composition, may preferably be present in an amount
of up to 3% (w/w), or preferably of up to 2.5% (w/w) with respect
to the total weight of the liquid vehicle. In a preferred
embodiment, the liquid vehicle comprises a solubilising agent in
amounts as low as up to 1% (w/w), preferably up to 0.5% (w/w) with
respect to the total weight of the liquid vehicle. In another
preferred embodiment, the liquid vehicle further comprises a
solubilising agent in an amount of from about 2.5% to 0.5% (w/w),
preferably of from about 1% to 0.5% (w/w) with respect to the
weight of the liquid vehicle.
[0056] In some embodiments, the solubilizing agent may be a liquid
excipient such as, for example, a further organic co-solvent as
described above and/or an oil selected from glyceride oils, liquid
waxes and liquid paraffin, or an organic solvent exhibiting a high
degree of biocompatibility.
[0057] Examples of potentially useful liquid excipients comprise
oily excipients which may be used in combination with one or more
semifluorinated alkanes and include triglyceride oils, mineral oil,
medium chain triglycerides (MCT), oily fatty acids isopropyl
myristate, oily fatty alcohols, esters of sorbitol and fatty acids,
oily sucrose esters or any other substance which is physiologically
tolerated by the eye. In one of the preferred embodiment, the
liquid vehicle comprises a solubilizing agent in form of a liquid
excipient. Further examples of potentially useful solubilizing
agents as used herein are organic solvents. Preferred organic
solvents include glycerol, propylene glycol, polyethylene glycol
and ethanol. In yet further preferred embodiments, the liquid
vehicle of the present pharmaceutical composition may comprise
ethanol as the solubilizing agent, preferably in an amount of up to
1% (w/w), more preferably of up to 0.8% (w/w) and most preferred of
up to 0.5% (w/w) with regard to the total weight of the liquid
vehicle of the present pharmaceutical composition.
[0058] The pharmaceutical composition of the present invention
comprises, as a constituent a), the active ingredient timolol
and/or a pharmaceutically acceptable salt thereof, preferably
timolol maleate, as described above. The present pharmaceutical
composition may comprise timolol and/or a pharmaceutically
acceptable salt thereof in an amount of from about 0.1% (w/v) to
about 10% (w/v), or from about 0.1% (w/v) to about 5% (w/v), or
from about 0.2% (w/v) to about 3% (w/v), or from about 0.2% (w/v)
to about 2% (w/v), or from about 0.5% (w/v) to about 2% (w/v), or
from about 0.5% (w/v) to about 1.5% (w/v).
[0059] In preferred embodiments, the present pharmaceutical
composition comprises timolol and/or a pharmaceutically acceptable
salt thereof, preferably timolol maleate or (S)-timolol
hemihydrate, most preferably timolol maleate, in a concentration
corresponding to a concentration of timolol free base of from about
0.5% (w/v) to about 2.0% (w/v), preferably from about 0.5% (w/v) to
about 1.5% (w/v).
[0060] In a preferred embodiment, the pharmaceutical composition of
the present invention comprises a) timolol maleate, preferably at a
concentration of from about 0.4 to 3.4% (w/v), more preferably of
from about 0.6 to about 3% (w/v), even more preferably of from
about 0.68 to about 2.7% (w/v), most preferably at a concentration
of from about 0.68% to about 2.1% (w/v).
[0061] Unless otherwise indicated, the term "% (w/v)" as used
throughout herein in connection with the present pharmaceutical
composition denotes the amount of a component of a composition as a
weight percentage in relation to the total volume of the
composition (with `w` denoting the weight and `v` denoting volume).
For example, 0.05% (w/v) may be understood as relating to 0.5 mg of
a component in 1 mL of the composition, and 0.1% (w/v) would
correspond to 1.0 mg of a component in 1 mL of the composition.
[0062] The active component timolol and/or a pharmaceutically
acceptable salt thereof, preferably timolol maleate or (S)-timolol
hemihydrate, more preferably timolol maleate as described above,
may be dissolved, dispersed or suspended in the liquid vehicle
comprising a semifluorinated alkane as described below.
Accordingly, the liquid pharmaceutical composition of the present
invention may be in the form of a solution, preferably a clear
solution or in form of a suspension.
[0063] In preferred embodiments, the pharmaceutical composition of
the present invention is provided in form of a suspension. A
suspension may be defined as a type of a dispersion, a dispersion
being a system having at least one continuous (or coherent) phase
and at least one discontinuous (or inner) phase which is dispersed
in the continuous phase. In a suspension, the dispersed phase is in
the solid state. Preferably, the suspensions useful for practising
the present invention are liquids, at least at physiological
temperature, which means that the continuous phase is a liquid.
Typically, the suspensions are also liquid at room temperature.
[0064] Preferably, the present invention provides a pharmaceutical
composition in which particles of timolol and/or a pharmaceutically
acceptable salt thereof, preferably timolol maleate or (S)-timolol
hemihydrate, more preferably timolol maleate, as the dispersed
phase are suspended in a liquid vehicle comprising a
semifluorinated alkane, for example, a semifluorinated alkane of
formula (II) as defined above as the continuous phase. Accordingly,
in preferred embodiments of the present invention, the timolol
and/or a pharmaceutically acceptable salt thereof is suspended in
the liquid vehicle comprising a semifluorinated alkane.
[0065] In further preferred embodiment, the particles of timolol
and/or a pharmaceutically acceptable salt thereof, preferably of
timolol maleate or (S)-timolol hemihydrate, more preferably timolol
maleate, are solid particles.
[0066] In further preferred embodiments, the pharmaceutical
composition of the present invention comprises timolol and/or a
pharmaceutically acceptable salt thereof suspended in the liquid
vehicle b), at a concentration corresponding to a concentration of
timolol free base of from 0.3 to 2.5% (w/v), preferably of from 0.5
to 2.0% (w/v), more preferably of from about 0.5 to 1.5% (w/v). For
example, considering that 1.3668 mg timolol maleate correspond to
1.0 mg timolol free base, in a preferred embodiment of the present
invention, component a) is timolol maleate suspended at a
concentration of from about 0.4 to about 3.4% (w/v), preferably of
from about 0.6 to about 3% (w/v), more preferably of from about
0.68 to about 2.7% (w/v), most preferably at a concentration of
from about 0.68% to about 2.1% (w/v).
[0067] The particle size of the timolol and/or pharmaceutically
acceptable salt thereof is preferably below about 100 m, which
means that most of the particles, e.g. at least about 90% thereof,
have a size below 100 .mu.m. Which type of particle diameter is
considered as particle size will depend on the method used for
particle size distribution, which in turn is selected to be
appropriate for the type of solid material and the approximate size
range. For example, laser diffraction or dynamic light scattering
(also known as photon correlation spectroscopy or quasi-elastic
light scattering) are appropriate methods for determining particle
sizes in the colloidal and low micron range, whereas sedimentation
analysis, sieve analysis or photoanalysis may be selected for
larger particle sizes.
[0068] In a further preferred embodiment, at least about 90% of the
suspended timolol and/or a pharmaceutically acceptable salt thereof
have a particle size of not more than about 20 .mu.m, preferably of
not more than about 15 .mu.m. In a most preferred embodiment, at
least 90% of the suspended particles of timolol and/or a
pharmaceutically acceptable salt thereof have a size lower than
about 10 .mu.m, more preferred have size lower than about 5 .mu.m.
Especially for ophthalmic administration, at least about 90% of the
suspended particles of timolol and/or a pharmaceutically acceptable
salt thereof have a size lower than about 20 .mu.m, preferably with
at least about 90% of the suspended particles having a size of not
more than about 15 .mu.m, more preferably of not more than about 10
.mu.m, most preferably of not more than about 5 .mu.m, as measured
by state-of-the-art particle size distribution techniques (e.g.
laser diffraction, dynamic light scattering).
[0069] The pharmaceutical composition comprising timolol and/or a
pharmaceutically acceptable salt thereof, preferably timolol
maleate, especially when suspended in a liquid vehicle comprising a
semifluorinated alkane, displays advantageous stability, especially
with regard to the size of the suspended particles. As known from
other pharmaceutical compositions in form of suspensions, the
suspended particles may aggregate, and depending on the forces by
which the particles attract each other, the aggregates thus formed
may be rather difficult to resuspend. A further problem associated
with that is that in suspensions having non-uniform particle sizes
there is a tendency for smaller particles to gradually dissolve,
whereas larger particles grow through the deposition of dissolved
material onto their surfaces (Ostwald ripening). In result, the
particle size distribution of a suspension may become broader over
time. Particles which grow beyond a certain size may be unsuitable
for the intended use; for example, they may occlude an injection
cannula or, in case of ophthalmic administration, irritate or even
damage the ocular surface.
[0070] In contrast to this, it was found that the pharmaceutical
composition of the present invention comprising timolol and/or a
pharmaceutically acceptable salt thereof, especially when provided
in form of a suspension, can be stored for prolonged periods of
time without significantly changing their particle size
distribution. Accordingly, the pharmaceutical composition of the
present invention comprising timolol and/or a pharmaceutically
acceptable salt thereof, preferably timolol maleate or (S)-timolol
base hemihydrate, more preferably timolol maleate, in form of a
suspension may be stored for extended periods of time, such as, for
example for up to 1 year, or up to 6 months, or up to 3 months, or
up to 2 months or up to 1 month without significantly changing
their particle size distribution of the suspended particles. In
exemplary embodiments, the present invention provides a
pharmaceutical composition comprising timolol and/or a
pharmaceutically acceptable salt thereof in form of a suspension,
wherein at least about 90% of the suspended particles of timolol
and/or a pharmaceutically acceptable salt thereof have a size of
not more than about 15 .mu.m, after three weeks of storage at room
temperature. The term room temperature as used herein is to be
understood throughout as a temperature in the range of 20 to
25.degree. C.
[0071] In another exemplary embodiment, the present invention
provides a pharmaceutical composition comprising timolol and/or a
pharmaceutically acceptable salt thereof in form of a suspension,
wherein at least about 90% of the suspended particles of timolol
and/or a pharmaceutically acceptable salt thereof have a size of
not more than about 10 .mu.m, after three weeks of storage at room
temperature.
[0072] In contrast to some other suspensions known in prior art,
the pharmaceutical composition of the present invention when
present in the form of a suspension usually requires no surfactant,
or, if at all, only small amounts of surfactant, for its physical
stabilisation. This is a significant advantage as surfactants have
a substantial potential for irritation and local toxicity,
especially when administered to the eye or by injection. According
to one of the preferred embodiments, the pharmaceutical composition
of the invention is substantially free of surfactant. In a further
preferred embodiment, the total amount of surfactant or
surfactants, if more than one surfactant is incorporated, is not
more than about 5% (w/w), in particular not more than about 3%
(w/w), or preferably not more than about 1% (w/w), respectively,
with regard to the total weight of the final composition. In
further preferred embodiments, the amount is not more than about
0.5% (w/w), or not more than about 0.25% (w/w), respectively.
[0073] In this context, the semifluorinated alkanes as described
herein, although they possess some amphiphilic properties due to
their chemical structure which includes fluorinated and
non-fluorinated alkyl (or alkylene) groups characterised by
different degrees of lipophilicity, are not understood as being
within the scope of surfactants.
[0074] The surfactants which may be absent or only present in small
amounts include non-ionic, cationic, anionic, and zwitterionic
surfactants as commonly used as excipients in various types of
pharmaceutical compositions, e.g. as wetting agents, emulsifiers,
dispersing agents, solubilisers and the like. Examples of
surfactants which may be considered potentially useful include
tyloxapol, poloxamers such as Pluronic F68LF or Lutrol F68,
Pluronic L-G2LF and Pluronic L62D, polysorbates such as polysorbate
20 and polysorbate 80, polyoxyethylene castor oil derivatives,
sorbitan esters, polyoxyl stearates, lecithins, purified or
synthetic phospholipids, and mixtures of two or more thereof.
[0075] The pharmaceutical composition of the invention may further
comprise excipients in range of up to about 10% (w/v), more
preferably up to about 5% (w/v), even more preferably up to about
2% (w/v) such as, for example, non-fluorinated organic liquids, for
example in order to modify the properties of the liquid vehicle,
such as the viscosity. Such other liquid may be an oil selected
from glyceride oils, liquid waxes, and liquid paraffin, or an
organic solvent exhibiting a high degree of biocompatibility, or a
mixture of more than one liquid excipients.
[0076] Examples of potentially useful oily excipients which may be
used in combination with one or more semifluorinated alkanes as
described above may include triglyceride oils (i.e. soybean oil,
olive oil, sesame oil, cotton seed oil, castor oil, sweet almond
oil), mineral oil (i.e. petrolatum and liquid paraffin), medium
chain triglycerides (MCT), oily fatty acids, isopropyl myristate,
oily fatty alcohols, esters of sorbitol and fatty acids, oily
sucrose esters, or any other oily substance which is
physiologically tolerated by the eye.
[0077] The composition of the present invention may, of course,
comprise further pharmaceutical excipients as required or useful.
Potentially useful excipients include acids, bases, antioxidants,
stabilisers, synergists, colouring agents and thickening agents. In
a preferred embodiment, however, the liquid vehicle of the
pharmaceutical composition according to the present invention is
free of any excipients.
[0078] Furthermore, the invention provides a means of formulating
pharmaceutical compositions, preferably ophthalmic pharmaceutical
compositions comprising timolol and/or a pharmaceutically
acceptable salt thereof, preferably timolol maleate, which are
microbiologically stable. This is due to the fact that
semifluorinated alkanes as comprised by the liquid vehicle of the
present compositions and as described above are not normally prone
to microbial contamination. Hence, it is possible to formulate
preservative-free ophthalmic compositions which are better
tolerable for many patients, in particular patients suffering from
an ophthalmic disease or condition. The preservative-free
ophthalmic composition may be provided both in multi-dose or
single-dose format.
[0079] Accordingly, although the pharmaceutical composition of the
present invention may comprise a pharmaceutically acceptable
preservative, in a preferred embodiment, the pharmaceutical
composition of the present invention is free of a preservative.
This is especially useful when the composition of the present
invention is provided not only in dosage forms for single use
(single dosage forms), but especially in multiple dosage forms with
a plurality of doses.
[0080] In a further embodiment, water may also be present in the
pharmaceutical composition of the present invention, however,
preferably in small amounts of up 1.0% (w/w) or even of only up to
0.1% (w/w) or less, based on the final composition (final dosage
form). In a preferred embodiment, the pharmaceutical composition,
preferably the liquid vehicle of the pharmaceutical composition of
the present invention is essentially free of water, whereas the
residual water may be attributed to the potential residual water
content of the active ingredient timolol and/or a pharmaceutically
acceptable salt thereof, especially timolol maleate. The term
`essentially` as used herein means if present then in trace or
residual amounts such as to confer no technical advantage or
relevance in respect of the object of the invention.
[0081] For example, 1-perfluorohexyl-octane (F6H8) or
1-perfluorobutyl-pentane (F4H5) as preferred semifluorinated
alkanes in some embodiments of the present invention do not
comprise any water, or have a water content of no more than the
maximal solubility of water in 1-perfluorohexyl-octane or in
1-perfluorobutyl-pentane; for example 1-perfluorobutyl-pentane has
a water-content of less than 1.6.times.10.sup.-4 mg/ml as
determined by methods known in the art for moisture analysis, such
as Karl-Fischer titration methods.
[0082] In preferred embodiments, the pharmaceutical composition of
the present invention essentially consists of timolol maleate and a
semifluorinated alkane selected from 1-perfluorobutyl-pentane
(F4H5) and 1-perfluorohexyl-octane (F6H8). In further embodiments,
the pharmaceutical composition of the present invention essentially
consists of timolol maleate and 1-perfluorohexyl-octane (F6H8),
more specifically of timolol maleate suspended in
1-perfluorohexyl-octane (F6H8).
[0083] In exemplary embodiments, the pharmaceutical composition of
the present invention consists of from about 90 to about 99.99%
(w/w), more preferably from about 95 to about 99.9% (w/w), more
preferably from 97 to 99% (w/w) even more preferably from 98 to 99%
(w/w) of the liquid vehicle comprising a semifluorinated alkane as
described above, preferably a semifluorinated alkane selected from
F4H5 and F6H8, based on the weight of the final composition.
[0084] Liquid suspensions may be prepared by conventional methods.
The solid timolol and/or pharmaceutically acceptable salt thereof,
preferably timolol maleate or (S)-timolol-hemihydrate, more
preferably timolol maleate, may be suspended in the liquid vehicle
comprising the semifluorinated alkane. Alternatively, the particles
of timolol and/or pharmaceutically acceptable salt thereof,
preferably timolol maleate or (S)-timolol-hemihydrate, more
preferably timolol maleate, may be precipitated in situ by adding
a--typically organic--solution of the active ingredient (and,
optionally, one or more solid excipients) under controlled
conditions to the semifluorinated alkane-based vehicle.
[0085] Conventional grinding or milling methods using standard
equipment such as a ball mill, hammer mill, roller mill, colloidal
mill, jet mill, or the like may be used. If the particle size is to
be reduced after preparation of a suspension, ultrasonication as
well as various types of homogenisers may be used, such as colloid
mills or high-pressure homogenisers.
[0086] In a preferred embodiment, the particle sizes of timolol
and/or pharmaceutically acceptable salt thereof, preferably timolol
maleate or (S)-timolol-hemihydrate, more preferably timolol
maleate, when provided in form of a liquid suspension, are adjusted
by first combining the drug particles with a liquid vehicle
comprising or consisting of a semifluorinated alkane such as
described in any one of the above embodiments, followed by a step
of milling or grinding according to any of the above methods.
[0087] The pharmaceutical composition in suspended form in a liquid
vehicle comprising a semifluorinated alkane provides several
advantageous properties over conventional, aqueous or not
semifluorinated alkane-based formulations, especially with respect
to topical administration for ophthalmic use. For example, when
conventional perfluorinated compounds are used as liquid vehicles,
the suspensions tend to separate very rapidly by flotation of the
dispersed phase, or by its sedimentation, depending on the relative
densities of the dispersed phase and of the continuous phase. This
is accompanied by a rapid formation of particle aggregates which
may be dense and poorly re-dispersible. Rapid flotation or
sedimentation makes precise and reproducible dosing very
challenging, if not impossible. For example, if an ophthalmic
suspension settles very rapidly after shaking, the first dosing
from a full container, if not withdrawn immediately upon shaking,
will contain a lower-than-intended number of drug particles, unless
the container is held upside down, in which case more than the
intended quantity of drug particles will be dispensed. When the
same container is nearly empty and the last doses are dispensed,
the drug dose withdrawn per volume will be too high if it was low
in the beginning, and vice versa.
[0088] Moreover, aggregates may easily obstruct the dispensing
channels or openings of containers and thereby lead to erroneous
dosing. If dispensed from the container, they may cause irritation
of the conjunctiva or of the cornea, depending on their size, shape
and hardness.
[0089] In contrast, the semifluorinated alkane-based suspensions
comprising timolol and/or a pharmaceutically acceptable salt
thereof according to some embodiments of the invention remain
finely dispersed and homogeneous. If flotation or sedimentation
takes place, it occurs slowly, leaving sufficient time for the
patient to withdraw a dose after shaking the container. The
formation of large aggregates is not observed. After flotation or
sedimentation, the drug particles are easily re-dispersed by gentle
shaking, and appear to largely retain their original particle size
distribution. Preferably, the pharmaceutical composition of the
present invention is a suspension, wherein the particles of timolol
and/or a pharmaceutically acceptable salt, preferably timolol
maleate, are re-dispersible, for example by gentle shaking.
[0090] These properties of semifluorinated alkane-based suspensions
of timolol and/or pharmaceutically acceptable salt thereof result
in superior pharmaceutical quality and performance characteristics
for the use of timolol in for example the treatment of ocular
diseases. The level of convenience to the patient and/or health
care provider is greatly increased. More importantly, the dosing
accuracy, i.e. precision and reproducibility of dosing, is greatly
improved over other types of pharmaceutical suspensions. This will
bring about a more reliable therapeutic effect and a reduced risk
of adverse effects which result from overdosing.
[0091] A further surprising advantage of the presently
described-compositions in form of suspensions of timolol or and/or
a pharmaceutically acceptable salt thereof suspended in a
semifluorinated alkane is that they appear to form very small
droplets when dispensed from a dropper such as an eye dropper.
Without wishing to be bound by theory, it is believed that the
small droplet size is a result of an interplay of the
semifluorinated alkane's unique properties in terms of their
density, viscosity, and surface tension. In any case, it is
believed that for topical administration into an eye a small drop
or volume of administration is highly advantageous as the
capability of the lacrimal sac to accept and hold fluid is
extremely limited. In fact, it is very common that the
administration of a conventional eye drop formulation based on
water or oil immediately leads to a discharge of a substantial
fraction of the administered medicine as well as some tear fluid.
At the same time, there is a risk that some of the administered
dose will be taken up systemically via the nasolacrimal duct.
Hence, if an effective dose of an active ingredient can be
incorporated in a small volume of liquid which can be dispensed as
a very small droplet, this should also contribute to a
substantially increased dosing reliability and reproducibility,
thus enhancing the safety and effectiveness of the therapy.
[0092] A yet further advantage of the invention which is based on
the use of semifluorinated alkanes is that they can be designed or
mixed for an optimally adjusted evaporation behaviour after
administration. Thus, it is possible to formulate for example an
ophthalmic composition which delivers timolol or a salt thereof
efficiently to the eye in such a way that the liquid vehicles is
subsequently eliminated via evaporation. This is in sharp contrast
to oily or perfluorinated eye drop vehicles which do easily not
evaporate and thus form non-physiological residues at the site of
administration, e.g. in the lacrimal sac.
[0093] In a second aspect, the present invention provides the
pharmaceutical composition according to the first aspect of the
invention, namely pharmaceutical composition comprising:
[0094] (a) timolol and/or a pharmaceutically acceptable salt
thereof, and
[0095] (b) a liquid vehicle comprising a semifluorinated alkane for
use as a medicament.
[0096] The pharmaceutical composition including all embodiments
thereof as described above for the first aspect of the invention is
especially useful for the therapy or prevention of diseases or
conditions or any symptoms associated therewith related to an eye
of a subject, preferably to an eye of a human subject.
[0097] The pharmaceutical composition of the present invention may
be especially useful as an ophthalmic composition and may be
administered to the eye of a subject. More specifically, the
pharmaceutical composition of the present invention may be
administered topically to the eye of a subject, for example to the
eye lid, eye sac, eye surface and/or to an ophthalmic tissue of a
patient. Preferably, the pharmaceutical composition of the present
invention may be topically administered to an outer surface of an
eye of a patient or to an ophthalmic tissue which is readily
accessible by the patient or by another person administering the
pharmaceutical composition to the eye of the patient in need
thereof.
[0098] The present pharmaceutical composition, especially when used
as liquid of either low or higher viscosity (usually in the range
of 1 to 3.5 mPa s) may advantageously be administered in form of
drops or by spraying or by injection. Most preferably, however, the
liquid pharmaceutical composition of the present invention,
especially when provided in the form of a suspension, may be
administered as drops, more specifically as eyedrops to be
administered topically to the eye.
[0099] Depending on the extent of the disease, or whether or not
both eyes of the patient to be treated are affected, the drops or
eyedrops of the present ophthalmic pharmaceutical composition may
be administered to only one eye or to both eyes of the patient. The
present pharmaceutical composition may provide droplet sizes when
administered from conventional droppers, with a volume usually in
the range from about 5 to about 15 .mu.l. This small droplet size
usually facilitates the dropwise administration and, moreover,
facilitates precise dosage of the pharmaceutical composition of the
present invention. Accordingly, the pharmaceutical composition of
the present invention may be administered as single drops with a
volume of about 5 to 15 .mu.l per dose per eye, preferably with a
volume of about 8 to 15 .mu.l per dose per eye, more preferably
with a volume of about 9 to 12 .mu.l per dose per eye, even more
preferably with a volume of about 10 to 12 .mu.l per dose per eye
and most preferably with a volume of about 11 .mu.l per dose per
eye.
[0100] Depending on the need, the composition according to the
present invention may be administered once (qd), twice (bid),
three-times (tid) or four-times (qid) per day per eye. Preferably,
the composition according to the present invention is administered
up to two-times per day per eye. In a preferred embodiment, the
composition of the present invention is administered twice (bid)
daily. In a more preferred embodiment, the composition of the
present invention is administered once (qd) daily.
[0101] The pharmaceutical composition according to the present
invention is especially useful in the treatment of glaucoma,
increased intraocular pressure (IOP), ocular hypertension and/or a
symptom associated therewith.
[0102] The present invention provides stable liquid pharmaceutical
compositions, especially stable liquid suspensions comprising
timolol and/or a pharmaceutically acceptable salt thereof. These
compositions can be topically administered and allow the
administration of the active ingredient timolol in lower dosages
compared to known liquid formulations, thereby reducing the side
effects associated to the active ingredient and the additional
components of said known liquid formulations, in particular in the
treatment of glaucoma.
[0103] Based on this, the pharmaceutical composition for the use of
the present invention allows for a significant reduction of droplet
size and target dose volume as described above associated therewith
and therefore, as outlined above, for a significant reduction of
the total daily dose of timolol administered for use in the
treatment of glaucoma, increased intraocular pressure, ocular
hypertension and/or a symptom associated therewith. Accordingly, in
a preferred embodiment the present pharmaceutical composition for
use in the treatment of glaucoma, increased intraocular pressure
(IOP), ocular hypertension and/or a symptom associated therewith,
comprises timolol and/or a pharmaceutically acceptable salt
thereof, preferably timolol maleate, suspended in the liquid
vehicle comprising a semifluorinated alkane at a concentration
corresponding to a concentration of timolol free base of from 0.3
to 2.5% (w/v), preferably at a concentration of from 0.5 to 2.0%
(w/v), more preferably of from about 0.5 to 1.5% (w/v). In said
preferred embodiments, the liquid vehicle comprises or essentially
consists of a semifluorinated alkane, as defined by Formula (II) or
any one of the semifluorinated alkanes as defined above, such as a
semifluorinated alkane selected from 1-perfluorobutyl pentane or
1-perfluorohexyl octane. In further embodiments, the pharmaceutical
composition for the use according to the present invention may be
administered in a dose volume per eye of 10 to 12 .mu.l wherein the
timolol and/or a pharmaceutically acceptable salt thereof may be
suspended in the liquid vehicle in a concentration of at least 0.3%
(w/v), preferably of at least 0.5% (w/v).
[0104] In a preferred embodiment of the present invention, the
single dose of timolol as free base administered per eye is from
about 33 to about 280 .mu.g, preferably of from about 55 to about
220 .mu.g, more preferably of from about 55 to about 165 .mu.g,
most preferably of from about 55 to about 150 .mu.g. In a more
preferred embodiment, the pharmaceutical composition for use in the
treatment of glaucoma, increased intraocular pressure (IOP), ocular
hypertension and/or a symptom associated therewith comprises a)
timolol maleate suspended in a semifluorinated alkane, preferably
F6H8, wherein the dose of timolol, as a free base, administered per
eye is from about 55 to about 165 .mu.g, more preferably from about
55 to about 150 .mu.g.
[0105] In another embodiment, the pharmaceutical composition for
use in the treatment of glaucoma, increased intraocular pressure
(IOP), ocular hypertension and/or a symptom associated therewith,
may be administered to subjects concomitantly suffering from dry
eye disease and/or hypertension and/or cardiac related diseases.
Thus, the pharmaceutical composition for use in the treatment of
glaucoma, increased intraocular pressure (IOP), ocular hypertension
and/or a symptom associated therewith, is effective in not
exacerbating comorbidities such as dry eye disease and/or
hypertension and/or cardiac related diseases.
[0106] In another preferred embodiment, the pharmaceutical
composition for use in the treatment of glaucoma, increased
intraocular pressure (IOP), ocular hypertension and/or a symptom
associated therewith is effective in reducing side effects derived
from the treatment of glaucoma or ocular hypertension with
non-selective beta blockers at higher dosages, wherein said side
effects are exacerbation of chronic obstructive airways disease
and/or bronchospasm and/or dry eye symptoms.
[0107] In a third aspect, the present invention provides a method
for the treatment of glaucoma, increased intraocular pressure,
ocular hypertension and/or a symptom associated therewith,
comprising administering to the eye of a subject in need thereof a
pharmaceutical composition according to the first aspect of the
invention, namely a pharmaceutical composition comprising:
[0108] (a) timolol and/or a pharmaceutically acceptable salt
thereof, and
[0109] (b) a liquid vehicle comprising a semifluorinated
alkane.
[0110] Accordingly, the method according to this aspect of the
present invention comprises: [0111] providing a composition
comprising: [0112] (a) timolol and/or a pharmaceutically acceptable
salt thereof, and [0113] (b) a liquid vehicle comprising a
semifluorinated alkane, and [0114] topically administering said
composition to a surface of the eye of the subject, or the
patient.
[0115] It should be noted that for the method according to this
aspect of the invention all embodiments and preferred embodiments
as described above in connection with the other aspects of the
invention apply respectively. The subject, or patient in one
embodiment may be a human. In another embodiment, the subject may
be a veterinary subject or patient.
[0116] In yet a further aspect, the present invention provides for
the use of the pharmaceutical composition according to the first
aspect of the invention, namely a pharmaceutical composition
comprising:
[0117] (a) timolol and/or a pharmaceutically acceptable salt
thereof, and
[0118] (b) a liquid vehicle comprising a semifluorinated alkane
[0119] for the manufacture of a medicament for the treatment of
glaucoma, increased intraocular pressure, ocular hypertension
and/or a symptom associated therewith. It should be noted that for
the manufacture of a medicament according to this aspect of the
invention, all embodiments and preferred embodiments as described
above in connection with the other aspects of the invention apply
respectively.
[0120] In yet a further aspect, the present invention provides a
pharmaceutical kit comprising the composition as described above in
connection with any aspect of the invention, namely a
pharmaceutical composition comprising:
[0121] (a) timolol and/or a pharmaceutically acceptable salt
thereof, and
[0122] (b) a liquid vehicle comprising a semifluorinated
alkane,
[0123] and a container adapted for holding the pharmaceutical
composition. Preferably, the container which contains the
pharmaceutical composition of the present invention further
comprises a drop dispenser or device adapted for administering the
pharmaceutical composition.
[0124] In specific embodiments of the kit according to this aspect
of the present invention, the container has a dispensing means such
as a dropping device adapted for topically administering the
composition to the eye of a subject or patient, more specifically
dispensing means for dropwise topical administration to a surface
of the eye of a subject or patient. In one of the preferred
embodiments, the dispensing means is adapted to dispense the
pharmaceutical composition dropwise in volumes of less than about
15 .mu.l per drop. In further embodiments, the dispensing means is
adapted to dispense drops having a volume of less than about 13
.mu.l, 12 .mu.l, or 11 .mu.l, respectively. In particular, drop
volumes of less than 12 .mu.l are presently considered very useful
in view of the limited holding capacity of one of the preferred
sites of administration, the front of the eye. For the avoidance of
doubt, such small droplet sizes are primarily enabled by the
incorporation of the semifluorinated alkane (or semifluorinated
alkanes) according to the invention, and common droppers for eye
drops which normally deliver aqueous drops of about 30 to 60 .mu.l
are capable of dispensing much smaller drops of semifluorinated
alkanes-based formulations.
[0125] In the kit according to this aspect of the invention, the
container may hold a single dose or a plurality of doses of the
present pharmaceutical composition comprising timolol and/or a
pharmaceutically acceptable salt thereof and a liquid vehicle
comprising a semifluorinated alkane as described above.
[0126] Furthermore, the kit according to this aspect of the
invention may further comprise instructions for use of the
container for dropwise topical administration of the composition to
a surface of the eye of a patient. The instructions or directions
for use preferably comprised by the kit according to this aspect of
the invention may be in any form suited to instruct the user how to
perform the topical administration to the affected eye of the
patient or subject. It may be in any readable or tangible form,
preferably in printed form or in any machine- or computer-readable
form preferably in form of a machine-readable optical label such
as, for example, a barcode or a QR-code. In a particularly
preferred embodiment the directions for use are provided in form of
an instruction leaflet, product or package insert or as an enclosed
label.
[0127] The following are numbered items comprised by the present
invention: [0128] 1. A pharmaceutical composition comprising:
[0129] (a) timolol and/or a pharmaceutically acceptable salt
thereof; [0130] (b) a liquid vehicle comprising a semifluorinated
alkane. [0131] 2. The pharmaceutical composition according to item
1, comprising a semifluorinated alkane of the formula (II)
[0131] CF.sub.3(CF.sub.2).sub.n(CH.sub.2).sub.mCH.sub.3 (II),
[0132] wherein [0133] n is an integer from 3 to 7, and [0134] m is
an integer from 4 to 7; [0135] or [0136] wherein [0137] n is an
integer from 2 to 10, and [0138] m is an integer from 2 to 10
[0139] 3. The pharmaceutical composition of item 1 or 2, wherein
the semifluorinated alkane is selected from the group consisting of
1-perfluorobutyl-pentane
(CF.sub.3(CF.sub.2).sub.3(CH.sub.2).sub.4CH.sub.3; F4H5),
1-perfluorohexyl-octane
(CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3, F6H8),
1-perfluorohexyl-hexane
(CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.5CH.sub.3, F6H6) and
1-perfluorohexyl-decane
(CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.9CH.sub.3, F6H10),
preferably one selected from the group consisting of
1-perfluorobutyl-pentane
(CF.sub.3(CF.sub.2).sub.3(CH.sub.2).sub.4CH.sub.3, F4H5), and
1-perfluorohexyl-octane
(CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3, F6H8). [0140] 4.
The pharmaceutical composition of any preceding item, wherein the
liquid vehicle comprises a co-solvent. [0141] 5. The pharmaceutical
composition of any preceding item, wherein the liquid vehicle
comprises at least 85% (w/w) of a semifluorinated alkane or a
mixture of different semifluorinated alkanes. [0142] 6. The
pharmaceutical composition of any preceding item, wherein the
liquid vehicle essentially consists of a semifluorinated alkane or
a mixture of different semifluorinated alkanes. [0143] 7. The
pharmaceutical composition of any preceding item, wherein timolol
and/or a pharmaceutically acceptable salt thereof is suspended in
the liquid vehicle comprising a semifluorinated alkane. [0144] 8.
The pharmaceutical composition of any preceding item, wherein
component a) is timolol maleate. [0145] 9. The pharmaceutical
composition of any preceding item, wherein the concentration of
timolol free base is from about 0.3 to about 2.5% (w/v). [0146] 10.
The pharmaceutical composition of any preceding item, wherein
component a) is timolol maleate suspended in b) the liquid vehicle.
[0147] 11. The pharmaceutical composition of any preceding item,
wherein the composition is essentially free of water and/or a
preservative. [0148] 12. The composition of any preceding item,
wherein the composition is free of further excipients. [0149] 13.
The composition of any preceding item, wherein the composition is
free of a surfactant. [0150] 14. The pharmaceutical composition of
any preceding item, comprising timolol in form of timolol maleate
and a semifluorinated alkane selected from 1-perfluorobutyl-pentane
(F4H5) and 1-perfluorohexyl-octane (F6H8). [0151] 15. The
pharmaceutical composition of any preceding items, wherein the
composition comprises a) timolol in form of timolol maleate and b)
1-perfluorohexyl-octane (F6H8). [0152] 16. The pharmaceutical
composition of any of item 7 to 15, wherein at least about 90% of
the suspended particles of timolol and/or a pharmaceutically
acceptable salt thereof have a size of not more than about 15 m.
[0153] 17. The pharmaceutical composition of any of item 7 to 16,
wherein at least about 90% of the suspended particles of timolol
and/or a pharmaceutically acceptable salt thereof have a size of
not more than about 15 m after three weeks of storage at room
temperature. [0154] 18. The pharmaceutical composition of any
preceding item for use as a medicament. [0155] 19. The
pharmaceutical composition for use according to item 18, for the
treatment of glaucoma, increased intraocular pressure, ocular
hypertension and/or a symptom associated therewith. [0156] 20. The
pharmaceutical composition for use according to item 18 or 19,
wherein the composition is administered to the eye of a subject.
[0157] 21. The pharmaceutical composition for use according to any
of items 18 to 20, wherein the composition is administered
topically to the eye of a subject. [0158] 22. The pharmaceutical
composition for the use according to any of items 18 to 21, wherein
the pharmaceutical composition is administered in a dose volume per
eye of from about 8 to about 15 .mu.l, preferably from about 10 to
about 12 .mu.l. [0159] 23. The pharmaceutical composition for the
use according to any of items 18 to 22, wherein the concentration
of timolol as free base is of from about 0.3 to about 2.5% (w/v),
preferably of from about 0.5 to about 2.0% (w/v), more preferably
of from about 0.5 to 1.5% (w/v). [0160] 24. The pharmaceutical
composition for the use according to any of items 18 to 23, wherein
timolol and/or a pharmaceutically acceptable salt thereof is
suspended in the liquid vehicle. [0161] 25. The pharmaceutical
composition for the use according to any of items 18 to 24, wherein
the composition is administered up to four times daily, preferably
the composition is administered twice daily, more preferably once
daily. [0162] 26. A method for the treatment of glaucoma, increased
intraocular pressure, ocular hypertension and/or a symptom
associated therewith, comprising administering to the eye of a
subject in need thereof a pharmaceutical composition according to
any one of items 1 to 17. [0163] 27. The use of a pharmaceutical
composition of any of items 1 to 17 for the manufacture of a
medicament for the treatment of glaucoma, increased intraocular
pressure, ocular hypertension and/or a symptom associated
therewith. [0164] 28. A kit comprising the pharmaceutical
composition according to any one of items 1 to 17 and a container
for holding the pharmaceutical composition. [0165] 29. The kit
according to item 28, wherein the container comprises a drop
dispenser for administering the pharmaceutical composition. [0166]
30. The kit according to item 29, wherein the container comprises
dispensing means for dropwise topical administration to a surface
of the eye of a patient, said dispensing means preferably being
adapted to dispense the composition dropwise in volumes of less
than about 15 .mu.l. [0167] 31. The kit according to any of item 28
to 30, wherein the container holds a single dose or a plurality of
doses of the composition of any of claims 1 to 17. [0168] 32. The
kit according to any of items 28 to 31, further comprising
instructions for use of the container for dropwise topical
administration of the composition to a surface of the eye of a
patient. [0169] 33. A method of treating glaucoma, increased
intraocular pressure, ocular hypertension or a symptom associated
therewith, the method comprising administering to an eye of a human
with glaucoma, increased intraocular pressure, ocular hypertension
or a symptom associated therewith, a composition comprising a)
timolol and/or a pharmaceutically acceptable salt thereof and b) a
liquid vehicle comprising a semifluorinated alkane, wherein timolol
and/or a pharmaceutically acceptable salt thereof is preferably
suspended in the liquid vehicle, wherein said method is
therapeutically effective in treating glaucoma, increased
intraocular pressure, ocular hypertension or a symptom associated
therewith. [0170] 34. The method according to item 33, wherein
component a) is timolol maleate and wherein the concentration of
timolol free base is of from about 0.3 to 2.5% (w/v), preferably of
from about 0.5 to 2.0% (w/v), more preferably of from about 0.5 to
about 1.5% (w/v). [0171] 35. The method according to any one of
items 33 to 34, wherein the composition target dose volume per eye
is from about 10 to about 12 .mu.l, preferably about 11 .mu.l.
[0172] 36. The method according to any of items 33 to 35, wherein
the semifluorinated alkane is selected from F6H8 and F4H5. [0173]
37. The method according to item 36, wherein the semifluorinated
alkane is F6H8. [0174] 38. The method according to any one of items
33 to 37, wherein the composition is administered up to twice
daily, preferably once daily. [0175] 39. The method according to
any one of items 33 to 38, wherein the composition is substantially
free of water and of preservative.
DESCRIPTION OF THE DRAWINGS
[0176] FIG. 1 is a graphical representation of the results of the
measurement of the in-vivo intraocular pressure after
administration once a day of a suspension of timolol at a
concentration of 0.5% (w/v) in 1-perfluorohexyl-octane (F6H8)
versus a formulation of timolol in aqueous solution with a
concentration of 0.5% (w/v). The graph shows the chronological
progression of the mean intraocular pressure (IOP) as measured in
mmHg.
[0177] FIG. 2 is a graphical representation of the results of the
measurement of the in-vivo intraocular pressure after
administration once a day of a suspension of timolol at a
concentration of 1.37% (w/v) in 1-perfluorohexyl-octane (F6H8)
versus a formulation of timolol in aqueous solution with a
concentration of 0.5% (w/v). The graph shows the chronological
progression of the mean intraocular pressure (IOP) as measured in
mmHg.
[0178] FIG. 3 is a graphical representation of the results of the
measurement of the in-vivo intraocular pressure after
administration twice a day of a suspension of timolol at a
concentration of 0.5% (w/v) in 1-perfluorohexyl-octane (F6H8)
versus a formulation of timolol in aqueous solution with a
concentration of 0.5% (w/v). The graph shows the chronological
progression of the mean intraocular pressure (IOP) as measured in
mmHg.
Examples
[0179] The following examples serve to illustrate the invention;
however, these are not to be understood as restricting the scope of
the invention.
Example 1: Preparation of Timolol Suspensions
[0180] 109.34 mg of timolol maleate, CAS number 26921-17-5 (LKT
Labs; purity 99.5%) were introduced to a 25 mL vessel, filled with
stainless steel balls, diameter 2 mm. Afterwards, 8 mL of
1-perfluorohexyl-octane (F6H8) were added, the vessel was closed
and the milling was performed with a planetary ball mill (PM 100,
Retsch GmbH Germany) for 3 hours at 150 rpm with an interval of 10
minutes (with change of direction). After the milling, the thereby
formed suspension was transferred into a glass vial, shaken on a
Vortex shaker for a minimum of 30 seconds, and sealed. Considering
that 1.3668 mg timolol maleate correspond to 1.0 mg timolol free
base, a 1.0% (w/v) Timolol suspension (10 mg/mL) in F6H8 was
obtained.
[0181] Following the same procedure as described above, a 15 mg/ml
timolol suspension was prepared.
[0182] A suspension with the concentration 5 mg/mL was diluted out
of the 10 mg/mL stock suspension by diluting the suspension with
F6H8.
[0183] The 10 mg/mL timolol suspension was stored in a glass vial
at room temperature and the particle size distribution (PSD) was
determined by Laser diffraction (HELOS 2412, performed with a 50 mL
cuvette). Table 1 below shows the particle size distributions for
different Timolol suspensions after storage at room temperature
(RT).
TABLE-US-00001 TABLE 1 Conditions Formulation X.sub.50 (.mu.m)
X.sub.90 (.mu.pm) X.sub.99 (.mu.m) of storage Particle size by
laser diffraction (Helos H2412) performed with 50 mL cuvette and R2
lenses. (R2 lenses measurement range 0.25-87.5 .mu.m) 5 mg/mL
Timolol 6.02 10.37 15.53 2 days storage in F6H8 at RT 10 mg/mL
Timolol 5.80 10.23 15.83 3 days storage in F6H8 at RT 15 mg/mL
Timolol 6.35 11.25 16.53 3 days storage in F6H8 at RT Particle size
by laser diffraction (Helos H2412) with ultrasound treatment.
Performed with 50 mL cuvette and R1 lenses. (R1 lenses measurement
range 0.18-35 .mu.m) 5 mg/mL Timolol 3.22 3.94 4.18 2 days storage
in F6H8 at RT 10 mg/mL Timolol 3.18 3.92 4.17 5 days storage in
F6H8 at RT 15 mg/mL Timolol 3.15 3.89 4.17 5 days storage in F6H8
at RT
[0184] X.sub.50: median particle diameter determined on a
volumetric basis, i.e. 50% by volume of the particles are smaller
than the given diameter and 50% are larger.
[0185] X.sub.90: particle diameter corresponding to 90% of the
cumulative undersize distribution determined on a volumetric basis,
i.e. 90% of the particles have a diameter lower than the given
value Xo.
[0186] X.sub.99: particle diameter corresponding to 99% of the
cumulative undersize distribution determined on a volumetric basis,
i.e. 99% of the particles have a diameter lower than the given
value X.sub.99.
[0187] All Timolol suspensions in pure F6H8 with concentrations of
5 mg/ml, 10 mg/ml and 15 mg/ml, prepared by a ball milling process
as described above, showed an optical appearance, homogeneity of
the suspension and a suitability for re-homogenization of the
settled suspensions which were ranked positive for preclinical
studies in animal models.
Example 2: Measurement of Intraocular Pressure (IOP) in an Animal
Study
[0188] An animal study utilizing 8 normotensive dogs was carried
out in order to assess the pharmacodynamics of a composition
comprising Timolol and a semifluorinated alkane with regard to its
capability to lower the IOP (intraocular pressure) in comparison
with a commercial solution of Timolol which is administered in form
of an aqueous solution. The study setup and design was as
follows.
[0189] The dogs were selected for participation in the study based
on overall health, body weight, results of ophthalmic examinations,
response to IOP challenge, and the following criteria: [0190]
healthy, normal ocular surface; [0191] no invasive ocular
procedures for at least one month prior to the study; particularly
procedures involving the cornea or ocular anterior segment in
general; [0192] no topical or systemic corticosteroid treatment for
at least one month; [0193] washout from prior topical ocular study
medication commensurate with the typical washout period used for
clinical studies (at least one week)
[0194] The study was performed according to the plan as summarized
in Table 2 below. The topical ocular dose of the respective Timolol
aqueous solution or Timolol-suspension was administered to the
central or superior part of the cornea via a micropipette and
allowed to spread across the surface of the eye. After the dose was
administered, the eye was allowed to close naturally. Each animal
was restrained for approximately one minute to prevent rubbing of
the eyes.
TABLE-US-00002 TABLE 2 Target Dose Target Topical Ocular Level Dose
Dose Regime (.mu.g/eye) Volume Dose OD OS OD OS (.mu.L/eye)
Frequency Timolol 0.5% Timolol 150 55 11 (OS) QD for 8 (5 mg/mL)*
in F6H8 30 (OD) days (5 mg/mL) Target Dose Target Topical Ocular
Level Dose Dose Regime (.mu.g/eye) Volume Dose OS OD OS OD
(.mu.L/eye) Frequency Timolol 0.5% Timolol 150 150 11 (OD) QD for 8
(5 mg/mL)* in F6H8 30 (OS) days (13.7 mg/ mL) *aqueous solution OD:
right eye OS: left eye QD: once daily BID: twice daily
[0195] In a first study, as schematized in Table 2, a suspension of
Timolol (5 mg/mL) in F6H8 was administered to the left eye versus
an aqueous solution of Timolol (5 mg/mL), which was administered to
the right eye. The intraocular pressure (IOP) was measured at 0
(immediately pre-dose), 2, 4 and 6 hours post-dose on days 1, 2, 3,
6 and 7; at -1, 0 (immediately pre-dose), 1, 2, 4, 6, 24 and 48
hours post-dose on day 8 using a tonometer (TonoVet). Three
readings per eye were taken. The results are summarized in FIG. 1
showing the development of the mean intraocular pressure (IOP)
during treatment as described above.
[0196] In a second study, as schematized in Table 2, a suspension
of Timolol (13.7 mg/mL) in F6H8 was administered to the right eye
versus an aqueous solution of Timolol (5 mg/mL) which was
administered to the left eye. The intraocular pressure (IOP) was
measured at 0 (immediately pre-dose), 2, 4 and 6 hours post-dose on
days 1, 2, 3, 6 and 7; at -1, 0 (immediately pre-dose), 1, 2, 4, 6,
24 and 48 hours post-dose on day 8, using a tonometer (TonoVet).
Three readings per eye were taken. The results are summarized in
FIG. 2 showing the development of the mean intraocular pressure
(IOP) during treatment as described above.
[0197] In a third study, 11 .mu.l of a suspension of Timolol (5
mg/mL) in F6H8 were administered twice a day for 8 days to the left
eye versus 30 .mu.l of an aqueous solution of Timolol (5 mg/mL),
which was administered to the right eye. The intraocular pressure
(IOP) was measured at 0 (immediately pre-dose), 2, 4 and 6 hours
post-dose on days 1, 2, 3, 6 and 7; at -1, 0 (immediately
pre-dose), 1, 2, 4, 6, 24 and 48 hours post-dose on day 8, using a
tonometer (TonoVet). Three readings per eye were taken. The results
are summarized in FIG. 3 showing the development of the mean
intraocular pressure (IOP) during treatment as described above.
[0198] The compositions according to the present invention showed a
decrease of the intraocular pressure.
* * * * *