U.S. patent application number 15/280306 was filed with the patent office on 2017-03-30 for semifluorinated compounds and their compositions.
The applicant listed for this patent is NOVALIQ GMBH. Invention is credited to Ralf GRILLENBERGER, Frank LOSCHER, Dieter SCHERER, Hartmut VOSS.
Application Number | 20170087100 15/280306 |
Document ID | / |
Family ID | 57047224 |
Filed Date | 2017-03-30 |
United States Patent
Application |
20170087100 |
Kind Code |
A1 |
SCHERER; Dieter ; et
al. |
March 30, 2017 |
SEMIFLUORINATED COMPOUNDS AND THEIR COMPOSITIONS
Abstract
The present invention is directed to compositions comprising
semifluorinated compounds and their use as medicaments for topical
administration to the eye.
Inventors: |
SCHERER; Dieter; (Laufen,
CH) ; GRILLENBERGER; Ralf; (Nurnberg, DE) ;
LOSCHER; Frank; (Schriesheim, DE) ; VOSS;
Hartmut; (Schriesheim, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NOVALIQ GMBH |
Heidelberg |
|
DE |
|
|
Family ID: |
57047224 |
Appl. No.: |
15/280306 |
Filed: |
September 29, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 27/02 20180101;
A61K 9/0048 20130101; A61F 9/0008 20130101; A61K 31/02 20130101;
A61K 9/08 20130101 |
International
Class: |
A61K 31/02 20060101
A61K031/02; A61K 9/00 20060101 A61K009/00; A61F 9/00 20060101
A61F009/00; A61K 9/08 20060101 A61K009/08 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 30, 2015 |
EP |
15187767.7 |
Oct 30, 2015 |
EP |
15192441.2 |
Claims
1. A composition comprising
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and
CF.sub.3-(CF.sub.2).sub.5-CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3.
2. The composition according to claim 1, comprising at least about
80 wt % of CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3.
3. The composition according to claim 1, comprising up to about 25
wt % of
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3.
4. The composition according to any preceding claim 1 comprising
about 97 wt % of CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3
and up to about 3 wt % of
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.-
sub.3.
5. The composition according to claim 1, being formulated as a
clear liquid solution.
6. The composition of claim 1, being substantially free of: (a) a
polymer, (b) a perfluorinated compound, and/or (c) a dissolved
pharmacologically active ingredient.
7. The composition of claim 1, having a dynamic viscosity of not
more than 10 mPas, and preferably not more than 4 mPas, at ambient
temperature and pressure.
8. A method of treating a disease or condition of a patient in need
of such treatment, comprising administering the composition
according to claim 1 to the patient.
9. The method according to claim 8, wherein the composition is
topically administered to a lacrimal sac, into a lower eyelid, to
an eye surface, or to an ophthalmic tissue.
10. The method according to claim 8, wherein the composition is
administered up to four times per day.
11. The method according to claim 8, wherein the disease or
condition to be treated is keratoconjunctivitis sicca or a symptom
or condition associated therewith, and/or Meibomian Gland
Dysfunction (MGD).
12. The method according to claim 8, wherein the composition is
administered to lubricate the eye surface.
13. The method according to claim 8, wherein the condition to be
treated is corneal damage.
14. A kit comprising a composition according to claim 1 and a
container for holding the composition, wherein said container
comprises a dispensing means adapted for topical administration of
the composition to a lacrimal sac, into a lower eyelid, to an eye
surface, or to an ophthalmic tissue.
15. The kit of claim 14, wherein the dispensing means comprises a
dropper dimensions such as to dispense droplets having a volume of
8 to 15 .mu.L.
16. The composition according to claim 1 consisting of about 97 wt
% of CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and up to
about 3 wt % of
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3.
17. The composition according to claim 3, being formulated as a
clear liquid solution.
18. The composition of claim 4, being substantially free of: (a) a
polymer, (b) a perfluorinated compound, and/or (c) a dissolved
pharmacologically active ingredient.
19. The composition of claim 5, being substantially free of: (a) a
polymer, (b) a perfluorinated compound, and/or (c) a dissolved
pharmacologically active ingredient.
20. The composition according to claim 18, being formulated as a
clear liquid solution.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority to European Patent
Application Nos. 15187767.7 filed Sep. 30, 2015, and 15192441.2
filed Oct. 30, 2015, each of which are incorporated by references
in their entireties.
FIELD
[0002] The present invention is in the field of compositions
comprising semifluorinated compounds and their use in ophthalmic
administration.
BACKGROUND
[0003] Semifluorinated alkanes are compounds composed of at least
one non-fluorinated hydrocarbon segment and at least one
perfluorinated hydrocarbon segment. Linear, unbranched
semifluorinated alkanes of the general formula
CF.sub.3(CF.sub.2).sub.n(CH.sub.2).sub.mCH.sub.3, wherein n and m
are integers denoting the number of carbon atoms of the respective
segment are described for various applications, for example
commercially for unfolding and reapplying a retina, for long-term
tamponade as vitreous humour substitute (H. Meinert et al.,
European Journal of Ophthalmology, Vol. 10(3), pp. 189-197, 2000),
and as wash-out solutions for residual silicon oil after
vitreo-retinal surgery.
[0004] Semifluorinated alkanes of the formula
CF.sub.3(CF.sub.2).sub.n(CH.sub.2).sub.mCH.sub.3 are described in
other applications.
[0005] WO 2011/073134 discloses solutions of ciclosporin in a
semifluorinated alkanes of the formula
CF.sub.3(CF.sub.2).sub.n(CH.sub.2).sub.mCH.sub.3, optionally in the
presence of a co-solvent such as ethanol, wherein the
semifluorinated alkane functions as a liquid drug delivery vehicle
for ciclosporin for topical treatment of keratoconjunctivitis
sicca.
[0006] WO2014/041055 describes mixtures of semifluorinated alkanes
of the formula CF.sub.3(CF.sub.2).sub.n(CH.sub.2).sub.mCH.sub.3
(which may be alternatively expressed as
F(CF.sub.2).sub.n(CH.sub.2).sub.mH). These mixtures are described
to be ophthalmically applicable as tear film substitutes or for
treating patients with dry eye syndrome and/or meibomian gland
dysfunction.
[0007] A nomenclature which is frequently used for semifluorinated
compounds having linear and unbranched segments is FnHm, wherein F
means a perfluorinated hydrocarbon segment, H means a
non-fluorinated segment, and n and m define the number of carbon
atoms of the respective segment. For example, F3H3 is used for
perfluoropropylpropane,
CF.sub.3(CF.sub.2).sub.2(CH.sub.2).sub.2CH.sub.3, i.e.
1-perfluoropropylpropane.
[0008] Semifluorinated alkanes of formula
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
and compositions comprising
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
however have not been described, in particular for ophthalmic
applications. It is therefore an object of the invention to provide
compositions comprising such compounds, in particular in respect of
their use in compositions for use in ophthalmic applications.
SUMMARY OF THE INVENTION
[0009] In a first aspect, the invention relates to a composition
comprising CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3.
In particular, the invention relates to such compositions,
comprising at least about 80 wt % of
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3, and in another
aspect, to such compositions comprising up to about 25 wt % of
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3-
.
[0010] In another aspect, the present invention relates to
compositions comprising said compounds in the form of clear, liquid
solutions.
[0011] In still another aspect the invention provides the use of
composition comprising
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
for treatment of dry eye disease and/or Meibomian Gland Dysfunction
and any symptoms or conditions associated with these
conditions.
[0012] In a further aspect, the present invention provides a method
for treatment of dry eye disease and/or Meibomian Gland Dysfunction
and any symptoms or conditions associated thereof comprising
administering said composition topically to the lacrimal sac, into
the lower eyelid, to an eye surface or to an ophthalmic tissue.
[0013] In a yet further aspect, the present invention provides a
kit comprising compositions of the present invention held in a
container which comprises dispensing means adapted for topical
administration of the composition to the eye or ophthalmic
tissue.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 is a graph depicting the evaporation time of
compositions consisting of the compounds
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
as a function of the percentage of the latter compound in the
composition.
[0015] FIG. 2 is a graph depicting the refractive index determined
for compositions consisting of the compounds
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
as a function of the percentage of the latter compound in the
composition.
[0016] FIG. 3 is a graph representing results obtained from an Ex
vivo Eye Irritation Test (EVEIT) comparison of compositions of
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3,
a hyaluronic standard reference and 0.01% BAC positive control.
DETAILED DESCRIPTION OF THE INVENTION
[0017] In a first aspect, the invention relates to a composition
comprising CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3.
[0018] The compound
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
may also be referred to as 2-perfluorohexyloctane, based on the
hydrocarbon alkane as the root. This compound features a
stereocenter at the 2-alkyl position. As understood herein, the
general formula encompasses both enantiomers, enriched mixtures of
the two enantiomers, as well as the racemic mixture. The compound
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 may alternatively
be referred to as 1-perfluorohexyloctane, or F6H8, following the
nomenclature FnHm, wherein n is an integer representing the number
of carbon atoms of the linear, unbranched perfluorinated segment
and m is an integer representing the number of carbon atoms of the
linear, unbranched hydrocarbon segment.
[0019] Particularly preferred compositions of the invention are
those that comprise at least about 80 wt % of
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3. In other
embodiments, the compositions comprise of at least about 90 wt % or
at least about 95 wt % or at least 97 wt % of
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3. In another
preferred embodiment of the invention, the compositions comprise up
to about 25 wt % of
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3-
. In other embodiments, the compositions comprise up to about 10 wt
%, or up to about 5 wt % or up to about 3 wt % of the compound
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3.
[0020] As used herein, the term wt % refers to the weight of a
component as a percentage fraction of the weight of the composition
determined as a whole. The term about preceding a parameter such as
wt % includes the precise value as well as any value falling within
the degree of variability usually observed in the measurement and
determination of the parameter, including standard techniques and
equipment known in the art and field.
[0021] In a further preferred embodiment, the compositions of the
invention comprising of about 97 wt % of
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and up to about 3
wt % of
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3.
In yet a further embodiment, the composition may comprise of about
98 wt % of CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and up
to about 1 wt % of
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.su-
b.3.
[0022] The compositions comprising these semifluorinated alkanes as
defined above are preferably in the liquid form, and are preferably
formulated to be administered as a clear liquid solution. In this
context, clear means the absence of dispersed solid or liquid
particles which cause turbidity. In other words, such clear
solution is a purely monophasic liquid system, except that minor
and technically irrelevant amounts of particulate impurities may be
present.
[0023] In optional embodiments, the compositions may be formulated
to be administered as a gel, suspension, microemulsion, or a spray.
Preferably, the compositions are provided in sterile form.
[0024] Moreover, the composition is preferably formulated as a
liquid solution which exhibits a refractive index that is close to
that of water which is 1.333 at room temperature (RT). In a
particularly preferred embodiment, the refractive index of the
liquid solutions is in the range of from about 1.30 to about 1.35
at 20.degree. C., as determined by refractometer.
[0025] The compositions as defined above may also comprise further
excipients as required or as useful such as one or more acids,
bases, electrolytes, buffers, solutes, antioxidants, stabilizers,
and if required, preservatives. In one preferred embodiment, the
compositions as described herein are substantially free of water
and/or substantially free of a preservative, such as benzalkonium
chloride.
[0026] In another embodiment of the present invention, the
composition as described above is substantially free of the
following: (a) a polymer (b) a perfluorinated compound, and/or (c)
a dissolved pharmacologically active ingredient which is not a
semifluorinated alkane. Such compositions are also preferably
formulated as clear liquid solutions. In another embodiment, the
composition as described in any of the embodiments herein may be
substantially free of a pharmacologically active ingredient, in any
form and which is not a semifluorinated alkane.
[0027] As understood herein, the term `substantially free` in
reference to a composition constituent refers to the presence of
said constituent in no more than trace amounts and that if present
in trace amounts the constituent provides no technical contribution
to the composition.
[0028] Examples of polymers which are preferably absent in the
compositions of the invention include silicone polymers
(polymerized siloxanes), polyether polymers and fluorinated or
perfluorinated derivatives thereof.
[0029] Examples of perfluorinated compounds, i.e. compounds in
which all the hydrogen atoms are replaced with fluorine, and which
are preferably absent in the compositions of the invention include
perfluoroalkanes such as perfluorodecalin, as well as halogenated
perfluoroalkanes such as perfluorooctylbromide.
[0030] The compositions of the invention are also substantially
free of a dissolved pharmacological active ingredient which is not
a semifluorinated alkane; as used herein, the term "pharmacological
active ingredient" refers to any type of pharmaceutically active
compound or drug, i.e. one that produces a pharmacological effect
and that may accordingly be useful in the prevention, diagnosis,
stabilization, treatment, or generally speaking, the management of
a condition or disease.
[0031] In a preferred embodiment, the composition according to the
present invention essentially consists of
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3.
Preferably the composition essentially consists of about 97 wt % of
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and up to about 3
wt % of
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3.
[0032] As used herein, the term "essentially consisting of" is
so-called closed language, meaning that only the mentioned
constituents are present. In contrast, the terms "comprise",
"comprises" and "comprising" are used herein as so-called open
language, meaning that further constituents may also be
present.
[0033] The compounds of the invention as well as the compositions
comprising these, even if free of other pharmacologically active
ingredients, however have beneficial therapeutic effects at the
site of administration.
[0034] The compositions as defined above are preferably formulated
to have a dynamic viscosity of not more than 10 mPas, and
preferably not more than 4 mPas, as determined under standard
ambient temperature and pressure (25.degree. C., 1 atm).
Preferably, the compositions have a dynamic viscosity of between 1
and 4 mPas. The viscosity of the compositions may be determined
using any standard viscometer device known in the art, such as a
glass tube or capillary viscometer.
[0035] The compositions as described herein may be used in medical
applications, in particular for use in ophthalmology, and in
particular in the topical administration to the eye, such as to the
lacrimal sac, into the lower eyelid, to an eye surface or to any
ophthalmic tissue or anatomy associated with the eye that may be
made available for topical administration.
[0036] It has been found that the compositions of the invention are
beneficial for use in the treatment of diseases and conditions
which would benefit from stabilization of the tear film and tear
film lipid layer and lubrication of the eye surface. Thus, the
compositions of the present invention are especially suited in the
treatment of dry eye disease (keratoconjunctivitis sicca) and/or
Meibomian Gland Dysfunction (MGD) and any symptoms thereof or
associated therewith.
[0037] Dry eye disease, also known as keratoconjunctivitis sicca,
can be distinguished into two categories, namely aqueous deficient
dry eye disease and evaporative dry eye disease. These conditions
are not necessarily mutually exclusive. Aqueous deficient dry eye
is typically observed in patients suffering from Sjogren syndrome,
or those suffering from a lacrimal gland insufficiency, lacrimal
duct obstruction or reflex hyposecretion. Evaporative dry eye
disease on the other hand has diverse root causes and is associated
with increased/abnormal evaporative loss of the tear film, for
example as a result of meibomian gland disorders, eyelid aperture
disorders, blinking disorders, or ocular surface disorders.
[0038] Symptoms of dry eye disease include dry, scratchy, gritty,
sandy or foreign body sensations in the eye; pain, soreness,
stinging or burning; itching, increased need for blinking, eye
fatigue, photophobia, blurry vision, redness and inflammation of
the eye tissue, excess mucus discharge and crusting/clotting,
contact lens intolerance, and excess reflex tearing.
[0039] Meibomian Gland Dysfunction (MGD) refers to a condition
where the meibomian glands do not secrete enough oil or when the
oily secretions are of poor or abnormal quality. Often, the oil
gland openings may become plugged up or obstructed so that less oil
is secreted from the glands. The oil is secreted from the glands
can be granular (crusty) or otherwise abnormal, and can cause
irritation to the eye and eye tissues. In the early stages,
patients are often asymptomatic, but if left untreated, MGD can
cause or exacerbate dry eye symptoms and eyelid inflammation. The
oil glands become blocked with thickened secretions. Chronically
clogged glands eventually become unable to secrete oil, which may
result in permanent changes in the tear film and dry eyes.
[0040] Symptoms of Meibomian Gland Dysfunction include dryness,
burning, itching, stickiness/crustiness, watering light
sensitivity, red eyes, foreign body sensation, chalazion/styes or
intermittent blurry vision.
[0041] In a preferred embodiment, the compositions of the invention
as described above are used for the topical ophthalmic treatment of
evaporative dry eye disease and or Meibomian Gland Dysfunction
(MGD), and for the treatment or prevention of any one of the
symptoms or conditions associated thereof. In another embodiment,
the compositions as described herein may be used as a lubricant of
the eye surface, so as to ameliorate one or more of the symptoms
associated with dry eye disease and to wet the eye surface.
[0042] In another preferred embodiment of the invention, the
compounds and compositions thereof as described above are used for
the topical ophthalmic treatment of corneal damage. Thus, said
compounds and compositions are actively supporting the corneal
healing process of corneal damage, such as corneal erosions.
[0043] In further embodiments, the treatment of the above described
conditions (e.g. corneal damage) and diseases, and their associated
symptoms, also as described above is preferably carried out by a
method of administering to a patient in need thereof, an effective
amount of a composition as described above, comprising
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3,
for example wherein the composition comprises up to about 25 wt %
of
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3.
[0044] The advantages of the compounds and compositions described
above in the context of their use according to the present
invention, are believed to relate to their properties which are
particularly suited for ophthalmic applications. The close
proximity of the refractive indices of the compounds of the
invention to that of water, means that there would be no or minimal
impact of a patient's vision subsequent to administration, unlike
ophthalmic compositions based on oily carriers which can confer
blurry vision on administration. The generally low viscosity and
low surface tension and in particular their high wetting and
spreading capabilities of these compounds also ensures that they
are rapidly accommodated and adapted on administration over the
surface of the eye.
[0045] As will be made clearer in the examples below, it was found
that the compositions of the invention are biocompatible and
exhibit no apparent cytotoxic effects. Moreover, it has been
established that these compositions are not only well tolerated in
the eye and has no impact on visual acuity, but also provide a
beneficial effect in terms of lubrication of the eye and
stabilization of the tear film, in the form of relief in symptoms
of patients having mild to moderate symptoms associated with dry
eye disease. Patients with dry eye disease and/or dysfunctional
meibomian glands often express opaque and thicker meibum which can
lead to an abnormal lipid layer in the tear film. Without wishing
to be bound to theory, it is believed that the physico-chemical
attributes of the compounds featured in the compositions of the
invention may play a role in stabilizing the lipid layer of the
tear film, such as by solubilization of certain lipid components or
improving the fluidity of the lipid layer, as well as provide a
lubricating effect on the eye
[0046] In a further aspect, the present invention provides a method
for treatment of dry eye disease and any symptoms or conditions
associated thereof comprising administering the compositions of the
present invention topically to the lacrimal sac, into the lower
eyelid, to an eye surface or to an ophthalmic tissue. Preferably,
said compositions can be administered to the eye or eye tissue up
to four times per day.
[0047] Furthermore, the invention provides for a kit comprising any
one of the compositions as described above, and a container for
holding said composition. Said container preferably comprises a
dispensing means adapted for topical administration of the
composition to an eye sac, lower eyelid to an eye or ophthalmic
tissue, such as an eye dropper.
[0048] In a further preferred embodiment, the dispensing means
comprises a dropper of dimensions such as to dispense droplets
having a volume of 8 to 15 .mu.L, preferably of about 8-12 .mu.l,
more preferably of about 10 .mu.l. With a small droplet volume,
precise dosing to the eye can be achieved and an excess amount of
discharge of a substantial fraction of the composition from the eye
subsequent to administration can be avoided.
[0049] The compositions of the invention moreover can be
administered to the eye or eye tissue up to four times per day;
preferably with one drop (ca. between 8 to 15 .mu.L in volume)
administered per eye, and per dose. Treatment may last up to at
least six weeks. In one embodiment of the invention, the
compositions is administered at a dose of 1 drop of about between 8
to 15 .mu.L volume, preferably of about 10 .mu.l volume to each eye
three to four times per day.
EXAMPLES
Preparation of
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
(2-Perfluorohexyl-octane, C.sub.14F.sub.13H.sub.17)
[0050] The compound
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
may be prepared as follows: radical addition of perfluorohexyl
iodide with 1-octene in the presence of a radical initiator (herein
perfluorohexyl iodide is mixed with 1-octene and a radical
initiator as AIBN and the obtained solution is maintained at
80.degree. C. for 30 min and cooled down), followed by reduction of
the resulting iodo adduct with hydride (i.e. LiALH4) or via
hydrogenation (i.e. catalytic hydrogenation in presence of a
catalyst such as Pd/C) to form 2-perfluorohexyl-octane, followed by
purification by fractional distillation.
[0051]
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.-
3: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 2.17-2.33 (m, 1H, CH),
1.67-1.77 (m, 2H, CH.sub.2), 1.25-1.40 (m, 8H, CH.sub.2), 1.15 (d,
3H, CH.sub.3), 0.9 (t, 3H, CH.sub.3)
[0052] In Vitro Cytotoxicity Assay
[0053] The cytotoxicity of a composition comprising 1.3 wt %
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
and 95.8 wt % CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 was
assessed by a cell growth inhibition test which predicts cytotoxic
or necrotic effects with good correlation to animal experiments and
high sensitivity.
[0054] The composition was extracted by cell culture medium (DMEM
supplemented with 10% FBS) under agitation for .about.24 hours. The
resulting extract was then incubated with mouse cell line L929
cells for 68-72 hours, before the protein content was analyzed
using a BCA (bicinchoninic acid) test as a measure for
cytotoxicity. No inhibition of cell growth or cell lysis was
observed.
[0055] An analogous in vitro cytotoxicity assay is conducted for a
composition comprising about 23.7 wt %
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
and about 75.6 wt % F6H8.
[0056] Tear Film Analysis Studies
[0057] A composition comprising 98.3 wt % of
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and 1.2 wt % of
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
was tested in an observational study in patients with mild to
moderate evaporative dry eye disease. The clear colorless liquid
composition was provided in a 5 ml bottle equipped with a dropper
dimensioned to dispense of droplets of .about.10 .mu.l per drop
into the eye sac. Patients wearing contact lenses were excluded
from the study. After informed consent had been obtained, patients
were advised to apply 3-4 drops, daily in both eyes, translating to
a daily dose of 30-40 .mu.l. Patients returned after 5-7 weeks for
follow-up. Clinical data for 29 patients were collected at baseline
and at the 5-7 week follow-up visit.
[0058] a) Tear Film Analysis
[0059] Tear film fluid and tear film stability improved over the
study period, as can be seen in the increase in Schirmer I and the
TFBUT. The retrospective statistical analysis is strengthening this
observation, as the difference in TFBUT at baseline and follow-up
is highly significant (paired two-sided t-test: p=0.0026 (right
eyes) and p=0.0006 (left eyes)). No changes were detected in tear
osmolarity.
[0060] The subjective dry eye questionnaire (Ocular Surface Disease
Index, OSDI) revealed that patient's subjective symptom severity
decreased after the use of the composition comprising 98.3 wt % of
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and 1.2 wt % of
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
over a 5-7 week period, as can be seen in the lower scores at
follow-up and the retrospective statistical analysis (paired two
sided t-test: p<0.0001).
TABLE-US-00001 Parameter Baseline Follow up Schirmer I (mm/5 min)/
10.7 .+-. 3.7 16.3 .+-. 8.9 Right eye TFBUT (sec) Right eye: 5.7
.+-. 2.6 Right eye: 7.9 .+-. 5.1 Left eye: 5.7 .+-. 2.6 Left eye :
8.6 .+-. 6.0 Osmolarity 315.7 .+-. 12.8 311.4 .+-. 14.7 OSDI 53.9
.+-. 22.5 35.8 .+-. 22.9
[0061] b) Corneal Staining (Oxford Grading Scheme)
[0062] Corneal fluorescein staining is an indicator of corneal
damage (loss of cell-to-cell junctions). The data indicate a
reduction of corneal damage after 5-7 weeks of treatment, as can be
seen in the shift of numbers of patients diagnosed with Grade 1 or
2 at baseline towards Grade 0 at follow-up. This difference to the
intial level of damage was statistically significant, as shown by
Wilcoxon signed rank test: p=0.0013 (right eyes) and p=0.0041 (left
eyes).
TABLE-US-00002 Baseline (n = 29) Follow up (n = 28) Grade 0 Grade 1
Grade 2 Grade 0 Grade 1 Grade 2 Right eye (n) 8 (1) 16 4 25 2 1
Left eye (n) 8 (1) 16 4 19 9 0
[0063] c) Symptom Assessment by Physician
[0064] Patients were asked by the physician whether they currently
suffer from typical dry eye symptoms both at the baseline and at
the follow-up visit. As can be seen in the table below, a lower
number of DED -associated symptoms were reported after 5-7 weeks of
treatment.
TABLE-US-00003 Baseline Follow up Red eyes 25 9 Itching 21 10
Clotted eyes 9 2 Stringy mucous 4 1 Headache 2 1
[0065] d) Meibum Secretion Analysis
[0066] In a healthy eye, meibum is secreted from the meibomian
glands as a clear liquid. More opaque and thicker meibum is an
indicator of dysfunctioning meibomian glands. Patients' meibum was
descriptively examined at both the baseline and the follow-up
visit. According to the data obtained, meibum quality improved in a
number of cases. In seven cases, the treatment induced a reduction
of expressible meibum (changing from clear meibum to none).
TABLE-US-00004 Baseline Follow up Clear 20 17 Whitish 6 3 Thick 1 0
None 2 9
[0067] e) Safety Parameters
[0068] No changes were seen in either visual acuity or intraocular
pressure, indicating that the use of composition comprising 98.3 wt
% of CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and 1.2 wt-%
of
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
over 5-7 weeks is safe and does not interfere with these
ophthalmological parameters.
TABLE-US-00005 Baseline Follow up Visual acuity 0.8 (0.7-1.0) 0.9
(0.8-1.0) Intraocular pressure (mm HG) 14.9 .+-. 2.6 14.6 .+-.
3.2
[0069] Differential Scanning Calorimetry
[0070] Differential Scanning calorimetry (DSC 1, Mettler Toledo,
Greifensee, Switzerland) is used to characterize structure and
phase behavior of mixtures of
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
and CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3. DSC was
employed to obtain data on transitions by temperature rising scans
with heating rate of 1.degree. C./min. Sealed standard aluminum
crucibles (40 .mu.l, Mettler Toledo) were used.
TABLE-US-00006 wt % Melting transition
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
.DELTA.H (J/g) Onset (.degree. C.) Peak (.degree. C.) Endset
(.degree. C.) 0 -36.57 -6.33 -4.53 -2.14 5.91 -33.36 -10.32 -7.99
-7.24 12.03 -29.42 -13.74 -10.44 -9.58 23.74 -24.09 -21.56 -15.38
-14.17
TABLE-US-00007 wt % Low temperature transition
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
.DELTA.H (J/g) Onset (.degree. C.) Peak (.degree. C.) Endset
(.degree. C.) 0 -0.69 -45.47 -40.37 -38.32 5.91 -0.56 -50.61 -45.77
-42.93 12.03 -0.44 -55.18 -48.58 -45.53 23.74 -0.19 -60.75 -54.39
-52
[0071] The presence of
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
in a mixture of
CF.sub.3(CF.sub.2).sub.5--(CH.sub.2).sub.7--CH.sub.3 (F6H8)
resulted in a significant reduction in the melting temperature. The
melting enthalpy is also decreased, which suggests that this
semifluorinated alkane does not crystallize. Such differences will
have a beneficial effect in respect of the application of this
compound to the eye as a tear film substitute or lubricant; for
example, in terms of its ability to mix with, and to modulate the
tear film lipid layer. Such effects can moreover be advantageously
tuned by varying the amounts of this compound in the ophthalmic
compositions of the invention.
[0072] DSC measurements of a series of mixtures of 23.74 wt % of
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
and CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 with
tetradecane (C14) was also performed. Data on transitions were
obtained with temperature rising scans (heating rates 0.2, 0.5 and
1.degree. C./min). Extrapolation to a heating rate of 0.degree.
C./min was used to determine endset temperatures while average from
the three measurements were used to determine onset temperatures. A
decrease in the melting enthalpy was observed, compared to mixtures
of tetradecane with pure
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3, suggesting that
some of the tetradecane is dissolved in the liquid fraction of
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
and that this compound has a stronger solubilizing capacity
compared to CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3.
[0073] Refractive Index and Evaporation Time
[0074] The evaporation time of mixtures of the semifluorinated
alkane CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
was evaluated. A droplet of 10 .mu.L volume of each mixture was
placed on a glass surface at room temperature. Time until
evaporation was recorded by video-monitoring.
TABLE-US-00008 CF.sub.3(CF.sub.2).sub.5 Relative
(CH.sub.2).sub.7CH.sub.3/ Evaporation Evaporation Sample %
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.-
3/% time/s Time 1 99.84 0.16 13260 1 2 96.53 3.05 12960 0.97 3 26.3
64.1 9960 0.75
[0075] It was observed that an increasing percentage of the
semifluorinated alkane
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
decreases the evaporation time of the mixtures (FIG. 1) By varying
the amount of this semifluorinated alkane in the mixture, it may
feasible to adapt and fine-tune the composition to the requirements
of the intended ophthalmic use, such as in terms of prolonging or
reducing the residence time of the composition on the eye
surface.
[0076] The refractive index of the mixtures was also determined.
For topically applied ophthalmic compositions, the refractive index
of the composition should preferably similar, or adapted to that of
the eye and lens, for instance as close to that of physiological
tear fluid as possible. If the refractive index of a composition is
not similar, when applied to the surface of the eye, a patient may
experience blurring or impaired vision. It is observed, that the
amount of the semifluorinated alkane
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
has an effect on refractive index (see FIG. 2, which depicts an
increasing refractive index value with increased content of the
2-perfluorohexyloctane). By varying the amount of this
semifluorinated alkane in the mixture, it may also be feasible to
adapt the composition to the requirements of the intended
ophthalmic use, for instance adapting to a patient with an altered
tear fluid composition and refractive index, due to an eye
condition and/or age.
[0077] Ex Vivo Eye Irritation Test (EVEIT)
[0078] A comparison in respect of corneal healing process was
conducted for two compositions comprising
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3, namely
compositions consisting of a mixture of the semifluorinated alkane
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
(Composition A with 0.17 wt % of
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
and Composition B, with 64 wt % of
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3)
with hyaluronic acid (HYLO-COMOD.RTM.) as a reference and 0.01% BAC
(benzalkonium chloride) as a positive control using an Ex Vivo Eye
Irritation Test (EVEIT), similar to as described in M. Frentz et
al, Altern. to Lab. Anim., 2008 (36) p 25-32; and N. Schrage et al,
Graefes Arch Clin Exp Ophthalmol 2012 (250), 1330-1340).
[0079] Method. Rabbit corneas were obtained and placed in an
artificial anterior ocular chamber which was gently filled with
serum-free minimal essential medium (Eagle's MEM) containing
Earle's salts and HEPES buffer for nutrition. The medium was
contstantly replenished by a micropump to imitate the physiological
condition of the eye. The culture chambers were held at 32.degree.
C. under normal air without supplementary CO.sub.2 and >95%
relative humidity. Five corneas per test substance (n=5) were used
except for the postive control with which two corneas (n=2) were
tested.
[0080] After 12 h of stabilization in the culture chamber, the
corneas were evaluated by microscopy and corneas with intact
epithelium and without opacities were selected. Four small
abrasions (2.3-4.3 mm.sup.2) were applied to the surface of the
selected corneas with a cornea drill. All defects were monitored by
fluorescein sodium staining (0.17% aq. solution) and
microscopy.
[0081] The test substances were administered one hour after
induction of the corneal erosion and were applied six times daily
onto the apex of the corneas (30-50 .mu.L every four hours). A
soft-tipped cannula, with continuous suction was placed on the
lowest part of the corneoscleral region within the culturing
chamber to remove any excess fluid. Experiments were terminated
after 3 days of application. Biomicroscopic images of the corneas
were taken daily to document the corneal healing process using a
phase-contrast microscope integrated camera (KY-F1030U, JVC, (Bad
Vilbel, DE) mounted on a Z16 APO Microscope (Wetzlar, DE)). All
defects were monitored by fluorescein sodium stains (0.17% aq.
solution) with yellow green fluorescence indicating the areas of
epithelial defects. Erosion sizes were determined using a software
tool of the microscope (DISKUS). At the end of the 3 days, the
experiment was terminated and all corneas were fixed in 3.7%
formaldehyde and stained with a hematoxylin-eosin dye for
microscopic evaluation. To monitor the metabolic activity of the
cornea, glucose and lactate concentrations were photometrically
quantified in the outflow medium from the artificial anterior
chambers.
[0082] Results. Both mixtures of the semifluorinated alkanes
(Composition A and B as referenced above) were observed to have a
similar positive effect in respect of the corneal healing process
after the induction of corneal erosion as compared with the
standard reference hyaluronic acid composition
(HYLO-COMOD.RTM.).
[0083] Corneal Erosion Size Measurements/Mean mm.sup.2 (SD)
TABLE-US-00009 Composition Day 0 Day 1 Day 2 Day 3 A (n = 5) 12.8
(0.98) 3.018 (0.89) 0 (0) 0 (0) B (n = 5) 12.23 (1.46) 3.59 (0.53)
0 (0) 0 (0) HYLO COMOD .RTM. 12.13 (1.29) 3.11 (0.76) 0.01 (0.02) 0
(0) 0.01% BAC 11.57 (0.86) 5.91 (0.28) 8.74 (7.6) 17.46 (6.43)
[0084] Day 3 Histological Observations
TABLE-US-00010 Composition A (n = 5) Multilayered epithelium and
dense stroma in all corneas. Keratocytes are well formed and
arranged except if lost from initial erosion area. Descemet
membrane appears intact, endothelial cells are present. B (n = 5)
Healed epithelial layer with closed multilayer of epithelial cells.
Dense stroma and regular formed keratocytes although typically
reduced in number under the initial erosion area. Descemet membrane
and endothelial layer present without structural defects Hylo Comod
.RTM. Multilayered epithelium and dense stroma with regular
arranged (reference) and formed keratocytes except under the
initial erosion areas where keratocytes are totally lost in the
upper stroma. Descemet membrane and endothelial layer are present
without any defects in structure. 0.01% BAC Severe alterations of
the superficial cornea with disintegration of (positive whole
corneal structures; observation of distinct edema control) Reduced
staining of background substance indicating chemical alteration of
collagen Severe reduction in number of keratocyte cells which also
appear rounded and pycnotic. Descemet membrane is present with
intact endothelium
[0085] No significant differences in terms of a positive corneal
healing was noted between composition B comprising 64 wt %, based
on total weight of the composition of semifluorinated alkane
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
and composition A. With both compositions, as with the reference
composition, the mechanically induced epithelial erosions were
found to be significantly reduced and essentially absent after day
2 of treatment. FIG. 3 depicts the corneal erosion size
measurements of the tested compositions, reference and positive
controls for days 0-3 of the EVEIT experiment.
[0086] As noted in the table above, microscopic histological
examination of the cross-sections of the corneas after termination
of the experiment on day 3 revealed no significant remaining
defects or differences in the corneas treated wtih compositions A,
B and the reference HYLO-COMOD.RTM..
[0087] Furthermore, no corneal toxicity, based on the metabolic
activity as indicated by the glucose/lactate measurements was
observed for these compositions.
[0088] In significant contrast, the positive control comprising
0.01% of the preservative BAC, a progressive increase of the
induced epithelial lesions was observed over the course of the
three days of the experiment.
* * * * *