U.S. patent application number 13/170716 was filed with the patent office on 2011-12-29 for polymeric delivery system for a nonviscous prostaglandin-based solution without preservatives.
This patent application is currently assigned to Laboratoires THEA. Invention is credited to Fabrice Mercier.
Application Number | 20110319487 13/170716 |
Document ID | / |
Family ID | 43064334 |
Filed Date | 2011-12-29 |
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United States Patent
Application |
20110319487 |
Kind Code |
A1 |
Mercier; Fabrice |
December 29, 2011 |
POLYMERIC DELIVERY SYSTEM FOR A NONVISCOUS PROSTAGLANDIN-BASED
SOLUTION WITHOUT PRESERVATIVES
Abstract
This invention concerns an ophthalmic solution including: at
least one prostaglandin; a solubilizing agent; a gelling agent of
the carbomer type; a carbomer polymerization-inhibiting agent; a
co-gelling/co-solubilizing agent.
Inventors: |
Mercier; Fabrice;
(Clermont-Ferrand, FR) |
Assignee: |
Laboratoires THEA
Clermont-Ferrand
FR
|
Family ID: |
43064334 |
Appl. No.: |
13/170716 |
Filed: |
June 28, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61359699 |
Jun 29, 2010 |
|
|
|
Current U.S.
Class: |
514/530 ;
514/622 |
Current CPC
Class: |
A61K 47/14 20130101;
A61K 31/5575 20130101; A61P 27/02 20180101; A61K 9/0048 20130101;
A61K 45/06 20130101; A61K 31/557 20130101; A61P 27/06 20180101;
A61K 31/557 20130101; A61K 2300/00 20130101; A61K 31/5575 20130101;
A61K 2300/00 20130101 |
Class at
Publication: |
514/530 ;
514/622 |
International
Class: |
A61K 31/216 20060101
A61K031/216; A61P 27/02 20060101 A61P027/02; A61P 27/06 20060101
A61P027/06; A61K 31/165 20060101 A61K031/165 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 29, 2010 |
FR |
1055236 |
Claims
1- An ophthalmic solution including: at least one prostaglandin; a
solubilizing agent; a gelling agent of the carbomer type; a
carbomer polymerization-inhibiting agent; a
co-gelling/co-solubilizing agent.
2- Solution as claimed in claim 1, characterised in that it has a
Brookfield viscosity at 25.degree. C. that is between 8 and 20
mPas, advantageously between 10 and 14 mPas.
3- Solution as claimed in claim 1, characterised in that the
concentration of the carbomer gelling agent is between 0.05 and
0.15% (w/v).
4- Solution as claimed in claim 1, characterised in that it
contains no antimicrobial preservatives, advantageously of the
quaternary ammonium type, and even more advantageously benzalkonium
chloride (BAK).
5- Solution as claimed in claim 1, characterised in that the
prostaglandin is chosen from the group including 17-phenyl-13,14
dihydro trinor prostaglandin F.sub.2.alpha. isopropyl ester
(latanoprost), 20-ethyl prostaglandin F.sub.2.alpha.,
(+)-fluprostenol isopropyl ester (travoprost), 17-phenyl trinor
prostaglandin F.sub.2.alpha. amide, 17-phenyl-13,14 dihydro trinor
prostaglandin F.sub.2.alpha. ethyl amide (bimatoprost), tafluprost
prostaglandin F.sub.2.alpha. ethanolamide, bimatoprost (free
acid)-d.sub.4, bimatoprost-d.sub.4, latanoprost ethyl amide, 13,14
dihydro-15-keto-20-ethyl prostaglandin F.sub.2.alpha.
(unoprostone), 13,14 dihydro-15-keto-20-ethyl prostaglandin
F.sub.2.alpha. isopropyl ester (unoprostone isopropyl ester),
advantageously latanoprost.
6- Solution as claimed in claim 1, characterised in that the
concentration of prostaglandins in the solution is between 0.002
and 0.15% (w/v).
7- Solution as claimed in claim 1, characterised in that the agent
inhibiting the polymerization of the carbomer is a source of sodium
ions, advantageously sodium EDTA, sodium acetate or sodium
chloride.
8- Solution as claimed in claim 1, characterised in that the
solubilizing agent is macrogolglycerol hydroxystearate.
9- Solution as claimed in claim 1, characterised in that the
co-gelling/co-solubilizing agent is a polymer chosen from the group
including polyethylene glycol (PEG), polyvinyl alcohol (PVA) or
polyvinylpyrrolidone (PVP).
10- Solution as claimed in claim 1, characterised in that the
solution is stable for at least 18 months at ambient temperature
(25 or 30.degree. C.).
11- Solution as claimed in claim 1, characterised in that the
solution is compatible with single-use or multi-dose bottles made
of LDPE containing no additives.
12- Solution as claimed in claim 1, characterised in that it also
contains an antiglaucoma agent chosen from the group including beta
blockers, carbonic anhydrase inhibitors and alpha-adrenergic
agonists.
13- Solution as claimed in claim 1, characterised in that it also
contains an additive chosen from the group including isotonic
agents, antioxidants and buffer systems.
14- Solution as claimed in claim 1 for its use in treating glaucoma
and/or reducing intraocular pressure.
15- Solution as claimed in claim 14 consisting in topically
administering one drop of said solution a day to each eye in humans
or animals.
16- Single-use or multi-dose bottle made of LDPE containing no
additives containing the ophthalmic solution covered by claim 1.
Description
RELATED APPLICATIONS
[0001] The present application claims priority under 35 U.S.C.
.sctn.119(a) to French application no. 1055236, filed Jun. 29,
2010, and claims priority under 35 U.S.C. .sctn.119(e) to U.S.
provisional application, U.S. Ser. No. 61/359,699, filed Jun. 29,
2010, each of which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The invention concerns eye drops or an ophthalmic solution
whose active ingredient includes at least one prostaglandin, said
solution containing no antimicrobial agents, notably of the
quaternary ammonium type (such as benzalkonium chloride [BAK]).
[0003] More precisely, and in the context of the invention, a
polymeric delivery system has been developed to allow the
prostaglandin solution to be as effective as a solution containing
BAK, but without the disadvantages from a toxicological and
allergenic point of view.
BACKGROUND OF THE INVENTION
[0004] Prostaglandins are well-known active ingredients
administered topically to humans or animals in the form of eye
drops for the treatment of glaucoma. The usual dosage of these
formulas is 1 drop a day in each eye, it being understood that
prostaglandins can also be used in combination with a second
antiglaucoma agent such as, for example, beta blockers, carbonic
anhydrase inhibitors or alpha-adrenergic agonists.
[0005] The first disadvantage of prostaglandins is that they are
not water-soluble, meaning that they require a solubilization step
before including them in the eye drop solution.
[0006] Furthermore, another constraint for the formulator is to
propose an ophthalmic solution that is chemically stable over time
at ambient temperature, in practice over a period of 18 to 24
months. Another characteristic required of the ophthalmic solution
is that it should remain stable in relation to the packaging in
which it is stored, notably plastic packaging such as low-density
polyethylene (LDPE).
[0007] One last constraint that can arise is avoiding contamination
of the ophthalmic solution by antimicrobial agents, notably in
multi-dose packaging. This problem can be solved, however, using
single-dose unit packaging or a specialized system for this
(ABAK.RTM. or COMOD.RTM. systems, for example).
[0008] Thus, to date, most prostaglandin-based ophthalmic solutions
on the market include a preservative which, beyond its
antimicrobial properties, also ensures solubilization of the active
ingredient and, partially, its stabilization. An example of this is
the product sold by Pfizer under the Xalatan.RTM. brand, which
combines latanoprost and BAK at 0.02% by weight. It should be
pointed out that, despite the presence of BAK, these eye drops are
not stable at ambient temperature and must be stored cold, at a
temperature of approximately 5.degree. C. Furthermore, the Allergan
company sells eye drops under the Lumigan.RTM. brand, combining
bimatoprost and BAK at 0.005% by weight.
[0009] However, many publications discourage the use of
antimicrobial preservatives, and particularly BAK, for long-term
treatments in ophthalmology, as is notably the case of glaucoma,
due to tolerance problems (on this subject, see "The New Class of
Ophthalmic Agents: Here's how to choose the right prostaglandin for
the each patient" by J. James Thimons, O.D., F.A.A.O.--Optometric
Management, May 2002).
[0010] It thus has now been established that antimicrobial
preservatives are toxic in long-term use, to such an extent that
today there is a tendency to limit their use by reducing their
concentration as much as possible in eye drops or, even better, to
eliminate them completely from the formulas.
[0011] This problem was taken into account in document WO 97/29752,
for example, which discloses the use of a non-ionic agent of the
Cremophor.RTM. type instead of BAK. In the proposed formula, the
BAK concentration is limited to 0.01% by weight, the concentration
of Cremophor.RTM. EL being 0.05% by weight. A product sold by
Alcon, called Travatan.RTM., can be found on the market, combining
Travoprost, BAK and Cremophor.RTM..
[0012] Polysorbate 80 has also been proposed in ophthalmic
solutions to partially reduce the concentration of BAK, as is the
case, for example, of the product sold by Novartis under the
Rescula.RTM. brand, combining unoprostone with a mixture of BAK and
polysorbate 80 at 0.015% by weight of the solution.
[0013] On the other hand, document US2004/0082660 describes an
ophthalmic solution with no BAK and containing a mixture of
latanoprost and polysorbate 80.
[0014] The problem that the invention proposes to solve is
therefore that of developing a prostaglandin-based formula that
meets at least the following conditions: [0015] it contains no
antimicrobial preservatives; [0016] it is stable over time in a
solution at ambient temperature (18 to 24 months, as a minimum);
[0017] it is compatible with the plastic packaging in which it is
usually stored, notably LDPE packaging; [0018] it is practically as
effective in terms of reducing intraocular pressure (TOP) as
products available with a BAK base.
[0019] Another objective is to propose a formulation that is
sufficiently fluid to be packaged using an aseptic packaging
technique such as "Blow-Fill-Seal" (single-dose unit).
DESCRIPTION OF THE INVENTION
[0020] The Applicant has developed a new delivery system enabling
prostaglandin to act with the same effectiveness as that reported
with BAK.
[0021] Beyond its preservative role, BAK, and more generally
quaternary ammonium molecules, have a so-called "soap" effect
providing greater penetration by the active ingredient molecules
into the eye tissue, but on the other hand they have a toxic effect
(irritation, ocular dryness, inflammation, etc.). The delivery
system developed in the invention therefore provides equivalent
penetration and activity using a different mechanism of action. In
any case, it does not have the disadvantages of the conventional
preservatives of the BAK type.
[0022] More precisely, this invention concerns an ophthalmic
solution including: [0023] at least one prostaglandin; [0024] a
solubilizing agent; [0025] a gelling agent of the carbomer type;
[0026] a carbomer polymerization-inhibiting agent; [0027] a
co-gelling/co-solubilizing agent.
[0028] As mentioned above, such a solution advantageously contains
no antimicrobial preservatives, advantageously of the quaternary
ammonium type, and even more advantageously benzalkonium chloride
(BAK).
[0029] In the rest of the description, "antimicrobial preservative"
designates a preservative with antimicrobial properties, i.e. a
compound capable of protecting the ophthalmic solution from
possible microbial contamination. Such a preservative as meant in
the invention is to be distinguished from preservatives acting on
the solution's chemical preservation, for example antioxidants such
as EDTA.
[0030] The solution claimed contains at least one prostaglandin as
its active ingredient. In practice, there is at least one
prostaglandin in the solution and these are chosen from the group
including 17-phenyl-13,14 dihydro trinor prostaglandin
F.sub.2.alpha. isopropyl ester (latanoprost), 20-ethyl
prostaglandin F.sub.2.alpha., (+)-fluprostenol isopropyl ester
(travoprost), 17-phenyl trinor prostaglandin F.sub.2.alpha. amide,
17-phenyl-13,14 dihydro trinor prostaglandin F.sub.2.alpha. ethyl
amide (bimatoprost), tafluprost prostaglandin F.sub.2.alpha.
ethanolamide, bimatoprost (free acid)-d.sub.4, bimatoprost-d.sub.4,
latanoprost ethyl amide, 13,14 dihydro-15-keto-20-ethyl
prostaglandin F.sub.2.alpha. (unoprostone), 13,14
dihydro-15-keto-20-ethyl prostaglandin F.sub.2.alpha. isopropyl
ester (unoprostone isopropyl ester). Advantageously, latanoprost is
used.
[0031] According to another characteristic, the concentration of
prostaglandin in the solution is between 0.002 and 0.15% (w/v).
[0032] Conventionally, the prostaglandin(s) can be combined with a
second active ingredient, notably with other classes of
antiglaucoma agents so they can thus work synergistically. For
example, these may include beta blockers chosen from the group
including timolol maleate and carteolol chloride, carbonic
anhydrase inhibitors such as those, for example, chosen from the
group including dorzolamide chloride, or alpha-adrenergic agonist
such as, for example, brimonidine tartrate. Examples of
combinations of prostaglandins and beta blockers include, for
example:
Xalacom.RTM.--Pfizer: Latanoprost 0.005%+Timolol 0.5%,
Ganfort.RTM.--Allergan: Bimatoprost 0.03%+Timolol 0.5%
DuoTrav.RTM.--Alcon: Travoprost 0.004%+Timolol 0.5%.
[0033] In practice, the antiglaucoma agent accounts for between 0.1
and 0.5% (w/v) of the solution.
[0034] As indicated above, such a solution requires the presence of
a so-called solubilizing agent capable of solubilizing the
prostaglandin(s). This solubilizing agent, preferably non-ionic,
advantageously has surface-active properties. Ideally, this would
be macrogolglycerol hydroxystearate (hydrogenated ethoxylated
castor oil or PEG-40 Hydrogenated Castor Oil; CAS number
61788-85-0). Another potential candidate is polyoxyl 15
hydroxystearate or macrogol 15 hydroxystearate (CAS number
70142-34-6), or polysorbate 20 (CAS number 9005-64-5), or
polysorbate 60 (CAS number 9005-67-8) or polysorbate 80 (CAS number
9005-65-6). The concentration of the solubilizing agent in the
solution is typically between 0.1 and 20% (w/v), advantageously
between 0.5 and 5% (w/v).
[0035] Another important characteristic of the ophthalmic solution
is its viscosity. This is advantageously between 8 and 20 mPas
(cP), even more advantageously between 10 and 14 mPas (cP), when
measured with a Brookfield RVDV III rotational viscometer at
25.degree. C. This solution can indeed be distinguished from an
aqueous gel, typically characterized by a viscosity between 400 and
800 mPas (cP) and which constitutes a long-acting form to obtain
sustained release of the active ingredient.
[0036] This invention is based on the development of a suitable
gelling system, based on the combination of two gelling agents to
obtain a nonviscous polymeric delivery system: [0037] a first
gelling agent, a carbomer in this case, normally suitable for
polymerizing and forming a gel but whose polymerization, expansion
or maintenance in gel form is inhibited by a so-called breaking
agent. Said agent inhibits the polymerization of the carbomer and
can be a source of sodium ions, advantageously sodium EDTA, sodium
acetate or sodium chloride. Alternatively, it can be a polyol with
a low molecular weight such as glycerol (see FR 2 604 906).
Furthermore, the carbomer is present in the solution at controlled
concentrations, advantageously between 0.05 and 0.2% (w/v).
Obviously, the relative concentration of the inhibiting agent is
also important: between 0.01 and 1% (w/v) in the case of sodium
ions, for example 0.02 to 0.1% for sodium EDTA or 0.5 to 3% (w/v)
in the case of polyols, for example glycerol; [0038] a second
agent, called a co-gelling/co-solubilizing agent, is used to ensure
the desired level of viscosity and to potentiate the solubilization
of the active ingredient, prostaglandin. This is typically a
polymer such as polyethylene glycol (PEG) or vinyl derivatives such
as polyvinyl alcohol (PVA) or polyvinylpyrrolidone (PVP).
Advantageously, its concentration is between 0.5 and 2.5%
(w/v).
[0039] In the frame of the present invention, a carbomer is defined
according to the European Parmacopoeia, i.e. "a cross-linked
polymer of acrylic acid of very high relative molecular mass,
comprising a large proportion of carboxylic groups" and by its CAS
number 9003-01-4. There are several grades of carbomers which can
be used in the invention: 910/934/934P/940/941/971 and 974P,
advantageously 974P.
[0040] In the frame of the present invention, PEG or macrogol is
defined according to the European Parmacopoeia, i.e. "a mixture of
polymers with the general formula H--(OCH.sub.2--CH.sub.2)n-OH
where n represents the average number of oxyethylene groups". The
type of macrogol is defined by a number that indicates the average
relative molecular mass. More advantageously, PEG 4000 having CAS
number 25322-68-3 is used.
[0041] Of course, the composition of the invention may contain the
usual additives excluding antimicrobial preservatives. These may
include, for example, non-ionic ionizing agents such as polyols
(sorbitol, for example). They may also be antioxidants or buffer
systems (for example, sodium hydroxide as a neutralizing
agent).
[0042] According to a preferred embodiment, the claimed composition
is made of the ingredients listed in the table below,
advantageously in the mentioned amounts:
TABLE-US-00001 CENTESIMAL FORMULA PRODUCTS FUNCTION (g/100 ml)
Carbomer 974 P gelling agent 0.10 Sorbitol isotonic agent 3.50 PEG
4000 co-gelling/co-solubilizing agent 1 EDTA Na+ ion source 0.05
sodium hydroxide Neutralizing agent qs pH = 7.0 Prostaglandine
F2.alpha. Active ingredient 0.005 Macrogol glycerol solubilizing
agent 5.0 hydroxystearate 40 water vehicle qsp 100 ml
[0043] The formulation of the invention can be presented in
single-use (single-dose unit) bottles or in multi-dose bottles, for
example Abak.RTM. or Comod.RTM. or the equivalent, such bottles
allowing the eye drops to be applied over several days without
preservatives.
[0044] The subject of the invention is thus a single-use
(single-dose unit) or multi-dose bottle containing the ophthalmic
solution described above, made of EP-quality LDPE containing no
additives.
[0045] Indeed, the solution's fluidity, combined with the product's
stability when packaged in a LDPE container, makes its production
compatible with BFS technology.
[0046] Furthermore, the solution according to the invention is
stable for at least 18 months, or even at least 24 months, at
ambient temperature (25.degree. C.-30.degree. C.).
[0047] Of course, the invention also concerns the use of the
ophthalmic solution as described above in the production of a
medicine to treat glaucoma in humans or animals, notably its
capacity to reduce intraocular pressure and/or provide
neuroprotection to the retinal tissue.
[0048] Thus, in this context, it has been demonstrated that this
delivery system is less aggressive to eye tissue than the
solubilization systems in the prior art, insofar as the reduction
in intraocular pressure is more regular and linear after
administration of the solution.
[0049] In practice, the eye drops are administered at a dose of one
drop a day in each eye.
[0050] The invention also concerns a therapeutic treatment method
for glaucoma in humans or animals consisting in instilling the
previously described ophthalmic solution at a dose of one drop a
day in each eye.
[0051] The present application reveals that contrary to the
technical solutions disclosed in the prior art, administering a
composition according to the present invention leads to a regular
and progressive decrease of the intra-ocular pressure (TOP),
without an intermediary initial IOP increase. Thanks the present
composition, the IOP decrease starts earlier, with an end-effect at
least equal possibly better. Without being bound to a theory, this
effect on TOP could be due to the presence of the delivery system
able to counteract or at least to attenuate the agressivity of the
solubilizing agent. Moreover, a composition according to the
invention is safe and well-tolerated.
[0052] The invention and the resulting advantages will become more
apparent with the following embodiments supported by the appended
figure.
[0053] FIG. 1 illustrates the effects of 2 eye drop formulations
containing 0.005% latanoprost (EXAMPLE 1 composition indicated by
full triangles and Xalatan.RTM. indicated by full circles) on
intraocular pressure (TOP) in rats.
[0054] FIG. 2 reports clinical data concerning the tolerability of
EXAMPLE 1 composition versus Xalatan.RTM.: A/ ocular subjective
symptoms score upon instillation; B/ ocular subjective symptoms not
upon instillation; C/ overall conjunctival hyperaemia.
I/ COMPOSITIONS ACCORDING THE PRESENT INVENTION
1a/ Example 1 Composition
TABLE-US-00002 [0055] CENTESIMAL FORMULA PRODUCTS (g/100 ml)
Carbomer/gelling agent 0.10 g Sorbitol/isotonic agent 3.50 g
PEG/co-gelling/co-solubilizing agent 1.00 g EDTA/Na+ ion source
0.05 g 1N sodium hydroxide/Neutralizing agent qs pH = 7.0
Latanoprost/Active ingredient 0.005 g Macrogol glycerol
hydroxystearate 40/solubilizing agent 5.00 g WFI-grade
water/Vehicle qs 100 ml
1b/ Example 2 Composition
TABLE-US-00003 [0056] CENTESIMAL FORMULA PRODUCTS (g/100 ml)
Carbomer/gelling agent 0.10 g Sorbitol/isotonic agent 3.50 g
PVP/co-gelling/co-solubilizing agent 2.00 g Sodium acetate/Na+ ion
source 0.8 g 1N sodium hydroxide/Neutralizing agent qs pH = 7.0
Latanoprost/Active ingredient 0.005 g Macrogol glycerol
hydroxystearate 40/solubilizing agent 5.00 g WFI-grade
water/Vehicle qs 100 ml
1c/ Example 3 Composition
TABLE-US-00004 [0057] CENTESIMAL FORMULA PRODUCTS (g/100 ml)
Carbomer/gelling agent 0.15 g Sorbitol/isotonic agent 2.25 g
PVA/co-gelling/co-solubilizing agent 0.50 g Sodium chloride/Na+ ion
source 0.25 g 1N sodium hydroxide/Neutralizing agent qs pH = 7.0
Travoprost/Active ingredient 0.004 g Macrogol 15
hydroxystearate/solubilizing agent 0.50 g WFI-grade water/Vehicle
qs 100 ml
2/CHARACTERIZATION OF THE EXAMPLE 1 FORMULATION
[0058] The solution obtained is opalescent, free of visible
particles, with pH between 6.6 and 7.2 (pH-neutral formulation) and
osmolality between 270 and 340 mosmol/kg (isotonic
formulation).
[0059] The solution's viscosity, measured with a Brookfield
rotational viscometer (Mobile no. 00/UL measurement chamber), is
between 8.0 and 14.0 mPas at 25.degree. C.
[0060] Furthermore, the solution has been demonstrated to be stable
for at least 24 months at ambient temperature (25 or 30.degree.
C.).
3/EFFECTIVENESS OF THE EXAMPLE 1 COMPOSITION
Evaluation of Effectiveness in Reducing Intraocular Pressure after
Administration to the Eyes of Normotensive Albino Rats
[0061] The effects of the eye drops in the EXAMPLE 1 formulation on
intraocular pressure were evaluated in normotensive rats, compared
with clinically available eye drops, i.e. Xalatan.RTM., each
product containing latanoprost at a concentration of 0.005%.
Importantly, Xalatan.RTM. contains the antimicrobial agent
benzalkonium chloride (BAK), whereas the EXAMPLE 1 formulation does
not.
[0062] Sixteen male albino rats (Wistar) were involved in this
study. They were distributed into 2 groups of 8 animals each,
dedicated to the EXAMPLE 1 formulation and to the reference
product, Xalatan.RTM., respectively. All the animals were treated
in the right eye with 4 instillations of 10 .mu.l each, once every
2 min, for a total of 2 .mu.g of latanoprost. Intraocular pressure
(TOP) was measured using the "Tonolab rebound tonometer" system on
both eyes 1 hour, 2 hours, 4 hours, 6 hours and 8 hours after
administration.
[0063] The results of this study are shown in FIG. 1. In the Wistar
rat, the dose of Xalatan.RTM. administered produced a biphasic
change in IOP, i.e. an increase in the initial pressure (+11.4%),
with a peak at 1 hour, followed by a prolonged hypotensive response
from 2 to 8 hours after treatment, with an IOP reduction peak at
t=4 hours (-18.4%). The same dose (2 .mu.g) of latanoprost in the
EXAMPLE 1 formulation reduced the IOP constantly and progressively,
achieving a 16% reduction at t=4 hours after topical
administration. This effect lasted for 4 to 8 hours, with a maximum
IOP reduction peak (-20%) at t=6 hours.
[0064] In conclusion, it should be pointed out that: [0065] there
is an early hypertension phase that is present with Xalatan.RTM.
but does not exist with the EXAMPLE 1 formulation in normotensive
rats; [0066] the EXAMPLE 1 formulation brought about a reduction in
IOP that is relatively similar to that observed with the clinically
available reference product, i.e. Xalatan.RTM.; [0067] the absence
of BAK in the EXAMPLE 1 solution does not compromise its effect on
the reduction of IOP.
4/ OCULAR TOLERANCE TO THE EXAMPLE 1 COMPOSITION
[0068] Ocular tolerance to the EXAMPLE 1 product compared with
Xalatan.RTM. was tested at 28 days with two instillations a day (50
.mu.l) in pigmented rabbits.
[0069] The study gave the following results: [0070] In terms of
general tolerance, all the animals presented normal development in
terms of body weight, good health and no particular symptoms. Water
and food consumption were also normal. [0071] In terms of ocular
tolerance, administration of the EXAMPLE 1 product did not cause
any ocular effects except a slight, transitory redness in 1 animal
out of 10. Xalatan.RTM. did not cause any ocular effects except for
a slight, transitory redness in 2 animals out of 10. Whatever the
treatment, cornea coloring was observed in some animals: [0072] 1.
EXAMPLE 1: slight to moderate for 6 animals out of 10; [0073] 2.
Xalatan.RTM.: slight for 4 animals out of 10; [0074] 3. Control
group: slight to moderate for 7 animals out of 10. [0075] This
ocular effect is commonly observed during tolerance tests involving
repeated daily topical administration to the eyes for 28
consecutive days. [0076] No other ocular effects were observed
during this study. [0077] The administration of EXAMPLE 1 or
Xalatan.RTM. did not have any macroscopic effects on the organs.
[0078] The histological analysis of both eyes (treated and
untreated) did not reveal any signs of pathology, whatever the
treatment. [0079] As was the case for Xalatan.RTM., the
administration of EXAMPLE 1 did not have any microscopic ocular
effects.
[0080] In conclusion, after two daily instillations of 50 .mu.l of
EXAMPLE 1 (latanoprost 0.005%) for 28 days in the right eye of
pigmented rabbits, very slight ocular effects were observed,
similar to the control group treated with Xalatan.RTM. 0.005% eye
drops. The ocular effects observed are considered to be
non-specific and essentially due to repeated daily instillations
over 28 consecutive days. Consequently, under these experimental
conditions, the administration of EXAMPLE 1 was tolerated very well
on the macroscopic and microscopic levels, as was the case for
Xalatan.RTM..
5/ CLINICAL TESTS ON THE EXAMPLE 1 COMPOSITION
5-1/ Efficacy
Introduction
[0081] A 3-month exploratory, randomized, double blind,
multicenter, cross-over, phase II pilot clinical study including 30
patients was designed to compare the pharmacokinetics, efficacy and
safety of the EXAMPLE 1 ophthalmological preparation (latanoprost
0.005%) compared with another ophthalmological preparation also
containing latanoprost at 0.005% (Xalatan.RTM.) in patients
recently diagnosed with open-angle glaucoma or ocular
hypertension.
[0082] The objective of this study was to compare the latanoprost
single dose unit ophthalmic preparation (without preservative) and
Xalatan.RTM. eye drops (benzalkonium chloride-preserved) after a 6
weeks treatment with one medication and 6 weeks with the other
medication in newly diagnosed glaucomatous patients and in newly
diagnosed patients with ocular hypertension.
[0083] This study was conducted according to accepted standards of
Good Clinical Practice (GCP), the specific guidelines if any, and
in agreement with the Declaration of Helsinki (2004) and local
regulations.
Protocol
[0084] At the first visit (Visit 1), the patients were chosen at
random to receive one of the 2 following treatments: [0085]
Latanoprost 0.005% formulation with a preservative (Multi-dose
[MD], Xalatan.RTM.) once a day at 8 PM for 6 weeks in both eyes;
[0086] Latanoprost 0.005% formulation without preservatives
(Single-dose unit [SDU], EXAMPLE 1) once a day at 8 PM for 6 weeks
in both eyes.
[0087] After these 6 weeks, the subjects were exchanged and took
the other study medicine (with no washout period), in other words,
those who received the first formulation with the preservative
received the formation without preservatives during the second
period and vice-versa. The second period also lasted 6 weeks.
[0088] All patients were attended 3 visits at the investigation
centre during the study: the inclusion visit (Day 0), the follow-up
visit (Day 42) and the final visit (Day 84). IOP was evaluated in
each eye at Day 0, Day 42 and Day 84, at 8 AM (.+-.30 min), 12 PM
(.+-.30 min), 4 PM (.+-.30 min) and 8 PM (.+-.30 min). Global
efficacy was also assessed by the investigator. Safety and
tolerance were also evaluated both by the patients and the
investigators.
Results
[0089] The results are presented in the following table:
Average IOP Obtained after Treatment with Xalatan.RTM. or Example
1
TABLE-US-00005 After 6 weeks of treatment Xalatan .RTM.- Mean IOP
at Baseline Xalatan .RTM. EXAMPLE 1 EXAMPLE 1 8 AM 22.63 16.20
16.91 -0.71 12 PM 23.56 16.43 16.85 -0.42 4 PM 22.55 16.47 16.28
0.19 8 PM 21.62 16.71 16.43 0.27 Diurnal 22.59 16.45 16.65 -0.20
average
[0090] The differences between mean IOP between the two products
were not statistically significant whatever the timepoint. The mean
diurnal IOP was reduced of 6.14 mmHg (27.2%) after 6 weeks of
Xalatan therapy and of 5.94 mmHg (26.3%) after 6 weeks of EXAMPLE 1
therapy.
[0091] Efficacy in reducing IOP was therefore comparable with both
treatments, with a "normal" IOP being obtained after both
treatments.
[0092] Considering the measurements at the physiologic peak of IOP
at 8 AM, Xalatan.RTM. had a reducing effect on IOP that was
slightly better by approximately 0.7 mmHg. However, this difference
is not statistically significant (p=0.118).
[0093] Furthermore, this tendency decreases throughout the day and
is reversed during the afternoon and evening. Thus, it illustrates
the effect throughout the day of the EXAMPLE 1 formulation, already
observed in the evaluation study on the IOP reduction in
normotensive rats.
[0094] Consequently, the EXAMPLE 1 formulation is effective on IOP
starting at 8 AM and remains just as effective throughout the day,
even though it does not contain any preservatives.
[0095] In conclusion, diurnal IOPs after 6 weeks of the 2
treatments were not statistically different, with an efficacy,
characterized by a so-called "normal" IOP, maintained throughout
the day with the EXAMPLE 1 formulation containing no
preservatives.
5-2/Safety
Introduction
[0096] The aim of this study (clinical test/phase III) was to
assess the safety of EXAMPLE 1 (Latanoprost 0.005% single dose
non-preserved eye drops) versus Xalatan (Latanoprost 0.005%
preserved eye drops) following once daily treatment for 3 months in
ocular hypertensive or glaucomatous patients.
Protocol
[0097] International, multicentre, randomised, investigator-masked,
2 parallel groups study versus reference product in 360 evaluable
patients treated for 3 months. Once screening visit (D-42), one
inclusion visit (D0) and 3 post-baseline visits (D15, D42, D84)
were planned.
[0098] A total of 463 patients were selected, 404 patients were
included and randomised and 402 took the study treatment: 213 in
the EXAMPLE 1 group and 189 in the Xalatan group. In all 392
patients completed the study: 206 in the EXAMPLE 1 group and 186 in
the Xalatan group.
[0099] The Safety Set was composed of 213 patients in the EXAMPLE 1
group and 189 patients in the Xalatan group. The modified
Intent-to-treat (mITT) Set was composed of 353 patients: 189 in the
EXAMPLE 1 group and 164 in the Xalatan group. The Per protocol (PP)
Set was composed of 177 patients in the EXAMPLE 1 group and 153 in
the Xalatan group.
[0100] In the Safety Set, there was no relevant difference between
treatment groups for demographics and other baseline
characteristics, except slightly higher rate of female patients in
the EXAMPLE 1 group (53.5%) than in the Xalatan group (45.5%). Age
ranged between 24 and 93 years with a mean.+-.SD of 64.7.+-.11.5
years.
[0101] In the Safety Set, corneal thickness at D-42 ranged between
500 and 610 .mu.m with a mean.+-.SD value of 542.+-.22 .mu.m in the
EXAMPLE 1 group and of 543.+-.22 .mu.m in the Xalatan group.
[0102] The mean treatment duration (on average 83 days) was similar
in both treatment groups. Treatment compliance based upon
instillation was >98% in each treatment group.
Results
Ocular Adverse Events
[0103] Ocular adverse events (AEs) were reported in 18 (8.5%)
patients in the EXAMPLE 1 group versus 22 (11.6%) in the Xalatan
group. The most frequent ocular AE regardless of treatment groups
was drug intolerance which was reported in 1 (0.5%) patient in the
EXAMPLE 1 group versus 4 (2.1%) patients in the Xalatan group.
There was one severe ocular discomfort reported in the EXAMPLE 1
group and most other ocular AEs were of mild or moderate
intensity.
[0104] Ocular AEs with a relationship with the study drug were
reported in 8 (3.8%) patients in the EXAMPLE 1 group (including 1
patient with 1 moderate photophobia, and 1 patient with 1 mild
optic disc haemorrhage, for which the relationship could not be
assessed) versus 10 (5.3%) patients in the Xalatan group.
[0105] The study drug was withdrawn due to an ocular AE in 2
patients from the EXAMPLE 1 group (1 moderate drug intolerance on
D7 and 1 moderate eye pruritus on D28) and in 1 patient in the
Xalatan group (1 moderate allergic conjunctivitis on D9). All
ocular AEs causing drug withdrawal were related to the study drug
according to the investigator. All patients recovered when drug was
withdrawn. No serious ocular AE was reported in this study.
Systemic Adverse Events
[0106] Systemic AEs were reported in 28 (13.1%) patients in the
EXAMPLE 1 group versus 32 (16.9%) in the Xalatan group. None of the
systemic AEs were related to the study drug in the EXAMPLE 1 group
while 6 AEs reported in 4 (2.1%) patients in the Xalatan group were
considered by the investigator as related to treatment (2 headaches
in the same patient, 1 dizziness, 1 migraine, and 1 palpitation and
1 muscular weakness). All were of mild intensity. One major
depression in the EXAMPLE 1 group and one mild migraine in the
Xalatan group led to study drug withdrawal. Six patients had a
systemic serious AEs (SAEs): 5 patients in the EXAMPLE 1 group (1
tibia fracture, 1 major depression, 1 syncope, 1 chest pain, and 1
fibula fracture and 1 patient in the Xalatan group (1 renal colic).
None had a relationship with treatment according to the
investigator.
Subjective Symptoms Upon Instillation
[0107] Overall, the ocular subjective symptoms score upon
instillation (pruritus, burning/stinging, sticky eye, eye dryness
sensation, foreign body sensation) were significantly less frequent
in the EXAMPLE 1 group than in the Xalatan group on D42 (p=0.001)
and D84 (p=0.001) (see table below). This was primarily due to
burning/stinging: 5.2% vs. 14.0% on D15 (p=0.004), 6.8% vs. 15.1%
on D42 (p=0.006), and 7.3% vs. 19.9% on D84 (p<0.001) and to
pruritus (1.5% vs. 5.4% on D42 and 2.4% vs. 6.0% on D84).
TABLE-US-00006 Total subjective ocular symptom scores upon
instillation at each visit (Safety Set) Visit EXAMPLE 1 Xalatan P
value* D15 n 209 186 0.085 Mean .+-. SD 0.25 .+-. 0.81 0.40 .+-.
0.89 95% CI [0.14; 0.36] [0.27; 0.53] D42 n 208 186 0.001 Mean .+-.
SD 0.15 .+-. 0.51 0.41 .+-. 1.03 95% CI [0.08; 0.22] [0.26; 0.56]
D84 n 206 186 0.001 Mean .+-. SD 0.18 .+-. 0.66 0.46 .+-. 1.05 95%
CI [0.09; 0.27] [0.31; 0.61] *ANOVA adjusted for country
[0108] The corresponding results are shown on FIG. 2A.
Subjective Symptoms not Upon Instillation
[0109] Overall, there was a trend for less ocular subjective
symptoms not upon instillation in the worse eye in the EXAMPLE 1
group compared to the Xalatan group on D42 (0.47.+-.1.19 vs.
0.65.+-.1.54, p=0.057), and on D84 (0.47.+-.1.37 vs. 0.69.+-.1.73,
p=0.053). Similar results were shown for the contralateral
eyes.
[0110] Both in the worse and contralateral eyes,
irritation/burning/stinging not upon instillation were less
frequent in the EXAMPLE 1 group than in the Xalatan group on D42
(7.2% vs. 13.4%) and on D84 (6.8% vs. 12.9%) in the worse eye. The
corresponding results are shown on FIG. 2B.
[0111] Although the differences were not consistently statistically
significant, there is a trend in favour of EXAMPLE 1 which confirms
what is already observed for symptoms upon instillation.
Slit Lamp Examination
[0112] Overall conjunctival hyperaemia was less frequent in the
EXAMPLE 1 group than in the Xalatan group in the worse eye with a
significantly lower incidence in the EXAMPLE 1 group than in the
Xalatan group on D42 (20.2% vs. 30.6%, p=0.003) and on D84 (21.4%
vs. 29.1%, p=0.019). The corresponding results are shown on FIG.
2C. For other examination no difference between treatment was
shown.
Global Assessment by the Investigator and by the Patient
[0113] According to the investigator, the tolerance was very
satisfactory or satisfactory for more than 97% of patients in both
treatment groups. However, the rate of very satisfactory tolerance
was higher in the EXAMPLE 1 group than in the Xalatan group on D15
(65.1% vs. 59.7%), on D42 (74.0% vs. 65.1%) and on D84 (71.4% vs.
62.9%). Considering all assessments significant differences were
found between the two treatment groups for D42 (p=0.013) and D84
(p=0.047). The D15 results failed to reach statistical
significance.
[0114] At D42 and D84, more than 99% of patients in the EXAMPLE 1
group and more than 96% of patients in the Xalatan group felt the
treatment to be convenient.
[0115] Altogether, the safety results suggest a better local
tolerability of EXAMPLE 1 over Xalatan with less subjective
symptoms upon instillation (in particular pruritus, and
burning/stinging), and less hyperaemia. The tolerance was rated
more frequently "very satisfactory" in patients treated with
EXAMPLE 1.
[0116] In conclusion, this study demonstrates that the local
tolerability for EXAMPLE 1 appeared to be better than for Xalatan,
with at least the same efficacy on Intra ocular Pressure.
* * * * *