This application claims priority to Provisional Indian Patent Application No.
2985/DEL/2014, filed on 20th October 2014, the contents of which are incorporated herein in
their entirety.
FIELD OF THE INVENTION
The present invention relates to an ophthalmic formulation which comprises carbonic
anhydrase inhibitor(s) (CAIs) alone, in an aqueous solution and a manufacturing process thereof.
The ophthalmic formulation(s) of the present invention can also be used in combination
with a second therapeutically active agent(s) to a mammal in need thereof, wherein said second
therapeutically active agent is selected from, but not limited to, beta-blockers, prostaglandin
analogs, prostamides, alpha 2-adrenergic agonists, miotics, neuroprotectants and combinations
thereof.
The ophthalmic formulation(s) of the present invention can also be used in combination
with a third therapeutically active agent(s) to a mammal in need thereof, wherein said third
therapeutically active agent is selected from, but not limited to, beta-blockers, prostaglandin
analogs, prostamides, alpha 2-adrenergic agonists, miotics, neuroprotectants and combinations
thereof.
The present invention relates to an ophthalmic formulation comprises carbonic anhydrase
inhibitor(s) alone, in an aqueous solution and/or in combination with second intraocular pressure
(IOP) reducing and/or glaucoma treatment agents or further in combination of third intraocular
pressure (IOP) reducing and/or glaucoma treatment agents and methods(s) of manufacturing
process thereof.
The present invention further relates to the composition(s) manufactured by the process
described herein and methods for treating persons suffering from glaucoma or ocular
hypertension.
BACKGROUND OF THE INVENTION
Brinzolamide is a carbonic anhydrase inhibitor used to lower intraocular pressure in patients with
ocular hypertension or open-angle glaucoma. Brinzolamide is chemically (R)-(+)-4-ethylamino-
2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e]-l,2-thiazine-6-sulfonamide-1,1-dioxide and
3
has the empirical formula C12H21N3O5S3. Brinzolamide has a molecular weight of 383.5 and a
melting point of about 131° C.
This compound is disclosed in U. S. Pat. No. 5,378,703 (Dean, et al.). The compound is
also disclosed in European patent EP 527801. US Pat. No. 6,071,904 discloses processes for
preparation of brinzolamide ophthalmic composition.
Brinzolamide in the form of ophthalmic suspension is developed and marketed by Alcon
Laboratories Inc. in United States under the brand name Azopt® (brinzolamide ophthalmic
suspension 1%). Brinzolamide suspension is indicated for lowering elevated intra-ocular
pressure (IOP) in patients with open- angle glaucoma or ocular hypertension (OHT).
Various methods or techniques have been disclosed in the prior for the preparation of
brinzolamide ophthalmic suspension.
International patent application WO 98/25620 teaches that conventional sterilization
methods cannot be employed in the manufacture of suspensions comprising brinzolamide since
the compound recrystallizes as large needle-shaped crystals, upon cooling, after autoclaving.
According to WO 98/25620, dry heat sterilization is also not suitable, since it causes melting of
the material, whereas sterilization by ethylene oxide and gamma irradiation introduces
unacceptable degradation products.
EP0941094 discloses a process for making brinzolamide suspension by autoclaving of
concentrated slurry of brinzolamide and tyloxapol; or brinzolamide and Triton X in milling
bottle, and ball milling of the hot slurry after autoclaving, and then adding the slurry to the rest of
the ingredients. It should be noted here that high temperatures and pressures of autoclave will
dissolve brinzolamide. Later, when autoclaving is complete, upon cooling brinzolamide
precipitates as large shaped crystals, having particle size of 1000 to 5000μm. However,
inclusion of tyloxapol and/or Triton X in the slurry allows the crystals to break up easily by ball
milling. Brinzolamide cannot be administered as these large needle shaped crystals, as they will
damage the eyes. Hence, precipitated brinzolamide crystals need to be milled to reduce their
particle size.
Thus, the reference discloses autoclaving of the slurry of brinzolamide and surfactant and
further ball milling the slurry. However, the drawback associated with this method is that it
requires a milling bottle in which the slurry of brinzolamide could initially be autoclaved and
4
then ball milled for further size reduction of needle shaped crystals of brinzolamide that are
formed during autoclaving.
Dry heat sterilization causes melting of the material. Sterilization by ethylene oxide
introduces unacceptable degradation products and residues, and sterilization by gamma
irradiation of micronized material produces degradation products unacceptable for regulatory
filing.
In most cases crystallization of active ingredients useful for ophthalmic use like carbonic
anhydrase inhibitor, or others actives, occurs during preparation. Sterilization by autoclaving at
temperature of 121° C and 115 lbs of pressure leads to increase in solubility of the actives in the
preparation and at that temperature brinzolamide goes into solution. However, upon cooling,
brinzolamide precipitates as needle shaped crystals. These needle-shaped crystals are difficult to
break and suspend. In different references either tyloxapol is used in solution so that the crystals
are easier to break or special equipment such as ball mill and/or jet mill is used to break the large
needle-shaped crystals.
The majority of the brinzolamide suspensions disclosed in the references faced the
problem of crystallization and agglomeration of active ingredients during preparation as well as
during storage. Crystallization or agglomeration of active leads to non-uniformity of dose,
difficulty of administration, irritation to eye due to large drug particles and/ or any ocular adverse
effect due to high drug concentration.
So, there remains an unmet medical need to formulate a dosage form in which drugs like
brinzolamide, but not limited to, having low solubility can be solubilized, to increase the
permeability and bioavailability of the drug. None of the reference disclosed above teaches
about increased solubility of brinzolamide or converting it in completely solution form.
Herein, the inventors of the present invention have surprisingly found that with the
addition of the polymers such as Soluplus® and surfactants such as polysorbate 80 into the
active ingredient brinzolamide to make the formulation completely dissolved in the solution
form, the inventors of the present invention have surprisingly managed to reduce the
concentration of brinzolamide solution, without effecting the safety and efficacy of the
formulation.
The process of manufacturing of the ophthalmic formulation described herein is efficient,
economic, and feasible for commercial scale preparation and in which the formulation does not
5
require the use of specific equipment such as ball mill and/or jet mill as compared to the
brinzolamide suspension known in the references.
Furthermore, the brinzolamide solution is easy to administer to the patients, the dosing
variability’s is also reduced as the general disadvantages of the suspension such as the settling of
the drug particles, caking, agglomeration is not found in the brinzolamide solution of the present
invention. Hence the formulation of the present invention is more patient compliant.
Thus, the objective of the present invention is to reduce the concentration of the active
ingredient brinzolamide, wherein the active ingredient brinzolamide is in the solution form.
Another objective of the present invention is to provide an ophthalmic solution
comprising brinzolamide alone or in combination with a second and/or a third IOP reducing
and/or glaucoma treatment agents along with pharmaceutically acceptable ingredients(s) wherein
the ophthalmic solution does not require the use of specific equipment such as ball mill and/or jet
mill.
Herein, the inventors of the present invention have formulated a sterile, ophthalmic
pharmaceutical formulation, wherein when the active ingredient with low aqueous solubility
(such as CAIs such as but not limited to brinzolamide,) in combination with polymers like
Soluplus® and a surfactant like polysorbate 80, is dissolved after heating above 50oC, the active
ingredient brinzolamide does not precipitate and stays in solution form with the help of
solubilizer Soluplus® and a surfactant like polysorbate 80.
The ophthalmic formulations of the present invention comprising a carbonic anhydrase
inhibitor(s) (CAIs) such as latanoprost, travoprost, unoprostone, tafluprost, bimatoprost and the
like, more specifically brinzolamide can also be used in combination with a second IOP reducing
and/or glaucoma treatment agents, such as, but not limited to, beta-blockers, prostaglandin
analogs, prostamides, alpha 2-adrenergic agonists, miotics, neuroprotectantsand combinations
thereof, wherein the ophthalmic formulations of the present invention is in the solution form.
The ophthalmic formulations of the present invention comprising a carbonic anhydrase
inhibitor(s) (CAIs) such as latanoprost, travoprost, unoprostone, tafluprost, bimatoprost and the
like, more specifically brinzolamide can also be used in combination with a third IOP reducing
and/or glaucoma treatment agents, such as, but not limited to, beta-blockers, prostaglandin
analogs, prostamides, alpha 2-adrenergic agonists, miotics, neuroprotectants and combinations
thereof, wherein the ophthalmic formulations of the present invention is in the solution form.
6
The present invention provides an ophthalmic formulation comprising a pharmaceutically
effective amount of brinzolamide in a solution form at about half of its current dose of 1.0% ,
preferably around 0.5% in combination with a second therapeutically active agent and its
pharmacologically active metabolites, salts and racemates thereof or further in combination with
third therapeutically active agent and its pharmacologically active metabolites, salts, solvates and
racemates thereof wherein the ophthalmic formulation is in the solution form and a method of
treating glaucoma and ocular hypertension and manufacturing process thereof.
SUMMARY OF THE INVENTION
The present invention relates to a sterile, ophthalmic pharmaceutical formulation in a
solution form, comprising active ingredient(s) such as carbonic anhydrase inhibitors (CAIs) like
brinzolamide in combination with a polymer like Soluplus® and a surfactant like polysorbate 80
and/or other pharmaceutically acceptable excipients.
The ophthalmic formulations of the present invention comprising a carbonic anhydrase
inhibitor(s) (CAIs) such as latanoprost, travoprost, unoprostone, tafluprost, bimatoprost and the
like, more specifically brinzolamide can also be used in combination with a second IOP reducing
and/or glaucoma treatment agents, such as, but not limited to, beta-blockers, prostaglandin
analogs, prostamides, carbonic anhydrase inhibitors (CAIs), alpha 2-adrenergic agonists, miotics,
neuroprotectants and combinations thereof, wherein the ophthalmic formulations of the present
invention is in the solution form.
The ophthalmic formulations of the present invention comprising a carbonic anhydrase
inhibitor(s) (CAIs) such as latanoprost, travoprost, unoprostone, tafluprost, bimatoprost and the
like, more specifically brinzolamide can also be used in combination with a third IOP reducing
and/or glaucoma treatment agents, such as, but not limited to, beta-blockers, prostaglandin
analogs, prostamides, alpha 2-adrenergic agonists, miotics, neuroprotectants and combinations
thereof, wherein the ophthalmic formulations of the present invention is in the solution form.
The present invention relates to a sterile, ophthalmic pharmaceutical formulation
comprising a combination of carbonic anhydrase inhibitors (CAIs) and prostaglandins and a
polymer like Soluplus® along with other pharmaceutically acceptable excipients for the
treatment of persons suffering from glaucoma and associated elevations of intraocular pressure
(IOP) and/or ocular hypertension.
7
The present invention relates to a sterile, ophthalmic pharmaceutical formulation
comprising a combination of carbonic anhydrase inhibitors (CAIs) and beta-blockers and a
polymer like Soluplus® along with other pharmaceutically acceptable excipients for the
treatment of persons suffering from glaucoma and associated elevations of intraocular pressure
(IOP) and/or ocular hypertension.
The present invention provides an ophthalmic formulation comprising a pharmaceutically
effective amount of brinzolamide in a solution form at about half of its current dose of 1.0% ,
preferably around 0.5% in combination with a second therapeutically active agent and its
pharmacologically active metabolites, salts and racemates thereof or further in combination with
third therapeutically active agent and its pharmacologically active metabolites, salts, solvates and
racemates thereof wherein the ophthalmic formulation is in the solution form.
The present invention provides a method of treating glaucoma or ocular hypertension in a
subject in need of such treatment, the method comprising administering to a subject in need
thereof an ophthalmic formulation comprising a pharmaceutically effective amount of
brinzolamide and its pharmacologically active salts thereof in combination with a second
therapeutically active agent and its pharmacologically active metabolites, salts and racemates
thereof or further in combination with third therapeutically active agent and its
pharmacologically active metabolites, salts, solvates and racemates thereof wherein the
ophthalmic formulation is in the solution form.
The present invention provides a process of manufacturing an ophthalmic formulation
comprising a pharmaceutically effective amount of brinzolamide and its pharmacologically
active salts thereof in combination with a second therapeutically active agent and its
pharmacologically active metabolites, salts and racemates thereof or further in combination with
third therapeutically active agent and its pharmacologically active metabolites, salts, solvates and
racemates thereof wherein the ophthalmic formulation is in the solution form.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “second therapeutically active agent” is selected from, but not
limited to, beta-blockers, prostaglandin analogs, prostamides, alpha 2-adrenergic agonists,
miotics, neuroprotectants and combinations thereof.
8
As used herein, the term “third therapeutically active agent” is selected from, but not
limited to, beta-blockers, prostaglandin analogs, prostamides, alpha 2-adrenergic agonists,
miotics, neuroprotectants and combinations thereof.
As used herein, the terms “second therapeutically active agent” and “second intraocular
pressure (IOP) reducing and/or glaucoma treatment agents” is interchangeably used.
As used herein, the terms “third therapeutically active agent” and “third intraocular
pressure (IOP) reducing and/or glaucoma treatment agents” is interchangeably used.
As used herein, the term "treat" is to mean to relieve, reduce or alleviate at least one
symptom of a disease in a subject. For example, the term "treat" may mean to reduce or alleviate
elevated intraocular pressure and/or to reduce or prevent further damage or loss of retinal
ganglion cells. For example, treatment can be diminishment of one or several symptoms of a
disorder or complete eradication of a disorder.
As used herein, the term "topical application" as means application by way of a liquid,
solution, suspension, gel, cream or ointment to the external corneal surface of a subject.
As used herein, the term “Soluplus®” wherever appears is an amphiphilic polyvinyl
caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVCap-PVAc-PEG).
As used herein, the term “API” wherever appears is an abbreviation for “brinzolamide”.
As used herein, the term "poorly soluble" when referring to a chemical compound in
relation to its solubility in water or an oil, as defined in U.S. Pharmacopeia and National
Formulary (USP- NF). According to this definition, solubility is stated in terms of the parts of the
solvent needed to dissolve one part of the solute. A compound that is sparingly soluble in a
particular solvent, such as water, requires 30-100 parts of the solvent to dissolve one part of the
compound. A compound that is slightly soluble requires 100-1000 parts of the solvent. A
compound that is very slightly soluble requires 1000-10,000 parts of the solvent. A compound
that is insoluble requires more than 10,000 parts of the solvent to dissolve one part of the solute.
The present invention is to formulate a sterile, ophthalmic pharmaceutical formulation,
wherein the poorly soluble drug/active ingredient such as carbonic anhydrase inhibitors (CAIs),
solubilizes during either cooling after autoclaving or cooling after heating above 50oC in highly
solubilized form.
The present invention furthermore relates to the highly solubilized form of poorly
insoluble drugs/active ingredient(s) to improve its bio-availability and manufacturability.
9
The present invention further relates to provide a process, wherein brinzolamide solution
is formed by the use of ophthalmically acceptable ingredients such as polymers like Soluplus®
{polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVCap-PVAc-
PEG)} and surfactants like polysorbate 80 (Polyoxyethylene (20) sorbitan monooleate), in
combination with a second and/or a third IOP reducing and/or glaucoma treatment agents along
with pharmaceutically acceptable ingredients(s).
This present invention additionally provides a process for preparation of an ophthalmic
formulation, wherein the inventors of the present invention have surprisingly managed to reduce
the concentration of brinzolamide, without effecting the safety and efficacy of the formulation as
compared to the concentration of brinzolamide present in suspension and the process described
herein being efficient, economic, and feasible for commercial scale preparation and in which the
formulation does not require the use of specific equipment such as ball mill and/or jet mill.
Further the invention provides a process which ameliorates one or more drawbacks of the
reference cited processes.
In one embodiment, the second IOP reducing and/or glaucoma treatment agents is
selected from the group comprising such as, but not limited to, beta-blockers, prostaglandin
analogs, prostamides, alpha 2-adrenergic agonists, miotics, neuroprotectants, a
parasympathomimetic drug, and combinations thereof.
In one embodiment, the second agent is a prostaglandin analog selected from, but not
limited to, latanoprost, travoprost, unoprostone, tafluprost, bimatoprost and the like.
In one embodiment, the second agent is an alpha 2-receptor agonist selected from, but not
limited to, brimonidine, apraclonidine and the like.
In one embodiment, the second agent is an alpha 1-receptor antagonist selected from, but
not limited to, bunazosin and the like.
In one embodiment, the second agent is beta -receptor antagonist (beta-blockers) selected
from, but not limited to, timolol, befunolol, carteolol, nipradilol, betaxolol, levobunolol,
atenolol,metipranolol and the like.
In one embodiment, the second agent is neuroprotectants selected from, but not limited
to, lubezole, nimodipine and the like.
In one embodiment, the second agent is a carbonic anhydrase inhibitor (CAIs) analog
selected from, but not limited to, dorzolamide, brinzolamide, methazolamide, dichlorphenamide,
10
diamox,acetazolamide and the like. In one embodiment, the second agent is a
parasympathomimetic drug selected from, but not limited to, carbachol, echothiophate,
pilocarpine and the like.
In one embodiment, the third IOP reducing and/or glaucoma treatment agents is selected
from the group comprising such as, but not limited to, beta-blockers, prostaglandin analogs,
prostamides, alpha 2-adrenergic agonists, miotics, neuroprotectants, a parasympathomimetic
drug and combinations thereof.
In one embodiment, the third agent is a prostaglandin analog selected from, but not
limited to, latanoprost, travoprost, unoprostone, tafluprost, bimatoprost and the like.
In one embodiment, the third agent is an alpha 2-receptor agonist selected from, but not
limited to, brimonidine, apraclonidine and the like.
In one embodiment, the third agent is an alpha 1-receptor antagonist selected from, but
not limited to, bunazosin and the like.
In one embodiment, the third agent is beta -receptor antagonist (beta-blockers) selected
from, but not limited to, timolol, befunolol, carteolol, nipradilol, betaxolol, levobunolol, atenolol,
metipranolol and the like.
In one embodiment, the third agent is neuroprotectants selected from, but not limited to,
lubezole, nimodipine and the like.
In one embodiment, the third agent is a carbonic anhydrase inhibitor (CAIs) analog
selected from, but not limited to, dorzolamide, brinzolamide, methazolamide, dichlorphenamide,
diamox acetazolamide and the like.
In one embodiment, the third agent is a parasympathomimetic drug selected from, but not
limited to, carbachol, echothiophate, pilocarpine and the like.
The concentration of the alpha 2-receptor agonist in an eye drop is not particularly
limited, but, in the case of brimonidine, an eye drop containing brimonidine at a concentration of
from 0.01 to 5 w/v %, preferably from 0.1 to 0.5 w/v %, more preferably 0.1 w/v %, 0.15 w/v %,
0.2 w/v % or 0.5 w/v % can be instilled once or several times per day. Further, in the case of
apraclonidine, an eye drop containing apraclonidine at a concentration of from 0.01 to 5 w/v %,
preferably from 0.5 to 1 w/v %, more preferably 0.5 w/v % or 1 w/v % can be instilled once or
several times per day.
11
The concentration of the alpha 1-receptor antagonist in an eye drop is not particularly
limited, but, in the case of bunazosin, an eye drop containing bunazosin at a concentration of
from 0.001 to 0.3 w/v %, preferably from 0.003 to 0.03 w/v %, more preferably 0.01 w/v % can
be instilled once or several times per day.
The concentration of the beta-receptor antagonist (beta-blockers) in an eye drop is not
particularly limited, but, in the case of timolol, an eye drop containing timolol at a concentration
of from 0.01 to 5 w/v %, preferably from 0.1 to 0.5 w/v %, more preferably 0.1 w/v %, 0.25 w/v
% or 0.5 w/v % can be instilled once or several times per day. Further, in the case of befunolol,
an eye drop containing befunolol at a concentration of from 0.01 to 5 w/v %, preferably from
0.25 to 1 w/v %, more preferably 0.25 w/v %, 0.5 w/v % or 1 w/v % can be instilled once or
several times per day. In the case of carteolol, an eye drop containing carteolol at a concentration
of from 0.01 to 5 w/v %, preferably from 1 to 2 w/v %, more preferably 1 w/v % or 2 w/v % can
be instilled once or several times per day. In the case of nipradilol, an eye drop containing
nipradilol at a concentration of from 0.01 to 5 w/v %, preferably 0.25 w/v % can be instilled
once or several times per day. In the case of betaxolol, an eye drop containing betaxolol at a
concentration of from 0.01 to 5 w/v %, preferably from 0.25 to 0.5 w/v %, more preferably 0.25
w/v % or 0.5 w/v % can be instilled once or several times per day. In the case of levobunolol, an
eye drop containing levobunolol at a concentration of from 0.01 to 5 w/v %, preferably from
0.25 to 0.5 w/v %, more preferably 0.25 w/v % or 0.5 w/v % can be instilled once or several
times per day. In the case of metipranolol, an eye drop containing metipranolol at a concentration
of from 0.01 to 5 w/v %, preferably 0.3 w/v % can be instilled once or several times per day.
The concentration of the parasympathomimetic drug in an eye drop is not particularly
limited, but, in the case of pilocarpine, an eye drop containing pilocarpine at a concentration of
from 0.01 to 20 w/v %, preferably from 0.1 to 5 w/v %, more preferably 0.5 w/v %, 1 w/v %, 2
w/v %, 3 w/v % or 4 w/v % can be instilled once or several times per day.
The concentration of the carbonic anhydrase inhibitor (CAIs) in an eye drop is not
particularly limited, but, in the case of dorzolamide, an eye drop containing dorzolamide at a
concentration of from 0.01 to 5 w/v %, preferably from 0.5 to 2 w/v %, more preferably 0.5 w/v
%, 1 w/v % or 2 w/v % can be instilled once or several times per day. Further, in the case of
brinzolamide, an eye drop containing brinzolamide at a concentration of from 0.01 to 5 w/v %,
preferably from 0.1 to 2 w/v %, more preferably 1 w/v % can be instilled once or several times
12
per day. Further, in the case of acetazolamide, an eye drop containing acetazolamide at a
concentration of from 0.01 to 5 w/v %, preferably from 1 to 5 w/v % can be used. Incidentally, in
the case where acetazolamide is orally administered, a daily dose of from 250 to 1000 mg can be
used.
The concentration of the prostaglandin in an eye drop is not particularly limited, but, in
the case of latanoprost, an eye drop containing latanoprost at a concentration of from 0.0001 to 5
w/v %, preferably from 0.0005 to 1 w/v %, more preferably 0.001 to 0.1 w/v %, further more
preferably 0.005 w/v % can be instilled once or several times per day. In the case of isopropyl
unoprostone, an eye drop containing isopropyl unoprostone at a concentration of from 0.001 to 5
w/v %, preferably from 0.01 to 1 w/v %, more preferably 0.12 to 0.15 w/v %, further more
preferably 0.12 w/v % or 0.15 w/v % can be instilled once or several times per day. In the case of
bimatoprost, an eye drop containing bimatoprost at a concentration of from 0.0001 to 5 w/v %,
preferably from 0.001 to 1 w/v %, more preferably 0.01 to 0.03 w/v %, further more preferably
0.01 w/v % or 0.03 w/v % can be instilled once or several times per day. In the case of
travoprost, an eye drop containing travoprost at a concentration of from 0.0001 to 5 w/v %,
preferably 0.001 to 1 w/v % more preferably 0.004 w/v % can be instilled once or several times
per day.
The concentration of the Rho-kinase inhibitor in an eye drop is not particularly limited,
but an eye drop containing the Rho-kinase inhibitor at a concentration of from 0.0001 to 5 w/v
%, preferably from 0.001 to 1 w/v % can be instilled once or several times per day.
In any embodiment of the present invention, the preferred ophthalmic agents are carbonic
anhydrase inhibitor (CAI) such as latanoprost, travoprost, unoprostone, tafluprost, bimatoprost
and the like, more specifically brinzolamide or a combinations thereof, wherein the ophthalmic
formulations of the present invention is in the solution form.
More preferably the ophthalmic agent is selected from the group comprising of
brinzolamide and dorzolamide, or pharmaceutically acceptable salts thereof, in combination with
beta-blockers or a pharmaceutically acceptable salt thereof (preferably timolol maleate), or in
combination with prostaglandin analogs or a pharmaceutically acceptable salt thereof (preferably
brimonidine tartrate) or in combination with alpha 2-adrenergic agonists.
Particularly preferred combination formulations of the present invention are carbonic
anhydrase inhibitor (CAI) and prostaglandins or carbonic anhydrase inhibitor (CAI) and alpha 2-
13
adrenergic agonists or carbonic anhydrase inhibitor (CAI) and prostamides or carbonic
anhydrase inhibitor (CAI) and beta-blockers or carbonic anhydrase inhibitor (CAI) and
parasympathomimetic.
More particularly preferred combination formulations of the present invention are
carbonic anhydrase inhibitor (CAI) and prostaglandins and beta-blockers or carbonic anhydrase
inhibitor (CAI) and alpha 2-adrenergic agonists and beta-blockers or carbonic anhydrase
inhibitor (CAI) and prostamides and beta-blockers or carbonic anhydrase inhibitor (CAI) and
parasympathomimetic and beta-blockers.
In a related embodiment, the methods as defined above further comprise the prior,
simultaneous or sequential, application of a second and/or third ophthalmic agent.
In an embodiment, the present invention provides an ophthalmic formulation comprising
a pharmaceutically effective amount of brinzolamide in a solution form at about half of its
current dose of 1.0% , preferably around 0.5% in combination with a second therapeutically
active agent and its pharmacologically active metabolites, salts and racemates thereof or further
in combination with third therapeutically active agent and its pharmacologically active
metabolites, salts, solvates and racemates thereof wherein the ophthalmic formulation is in the
solution form.
In one of the embodiment, the present invention provides a method of treating glaucoma
or ocular hypertension in a subject in need of such treatment, the method comprising
administering to a subject in need thereof an ophthalmic formulation comprising a
pharmaceutically effective amount of brinzolamide and its pharmacologically active salts thereof
in combination with a second therapeutically active agent and its pharmacologically active
metabolites, salts and racemates thereof or further in combination with third therapeutically
active agent and its pharmacologically active metabolites, salts, solvates and racemates thereof
wherein the ophthalmic formulation is in the solution form.
In another embodiment, the present invention provides a process of manufacturing an
ophthalmic formulation comprising a pharmaceutically effective amount of brinzolamide and its
pharmacologically active salts thereof in combination with a second therapeutically active agent
and its pharmacologically active metabolites, salts and racemates thereof or further in
combination with third therapeutically active agent and its pharmacologically active metabolites,
salts, solvates and racemates thereof wherein the ophthalmic formulation is in the solution form.
14
In one of the embodiment, there is provided a process for preparing a composition
suitable for preparing ophthalmic formulations as described herein comprising brinzolamide
solution. The procedure is divided into four main steps:
1. Preparation of Remaining Product Vehicle (RPV)
2. Preparation of sterile Milli Q water
3. Preparation of solution containing API
4. Bulk preparation
1.0 Preparation of Remaining Product Vehicle (RPV)
1) Take 60% (of actual batch size) of milli Q water in a clean glass beaker.
2) Add slowly dispensed quantity of disodium edetate followed by mannitol under
continuous stirring (rpm 800±100).
3) Slowly add dispensed quantity of carbomer into the above solution at increased rpm
(2000±100) via sprinkling. Decrease the stirring rate to 1200±100 after complete
addition.
4) After the carbomer has dissolved completely add dispensed quantity of sodium chloride
under continuous stirring and stir till the solution is clear.
5) Check the initial pH of the solution, and adjust the pH to 7.5 with 5 N sodium hydroxide
solution.
6) Make up the volume with milli Q water upto 80% (of actual batch size).
7) Filter the bulk solution through 47 mm, 20 micron PP filters.
8) Autoclave the RPV at 121°C for 30 min in a Schott glass bottle.
Note: About 10% RPV excess is prepared to compensate the loss of RPV during filtration
and autoclaving. Please note the formulation is stating the exact quantities. However,
dispensed quantities will be in 10% excess.
2.0 Preparation of Sterile milli Q water
1) In a Schott glass bottle autoclave enough water that will comprise 20% of total weight of the
product. This can be autoclaved in a separate bottle, while autoclaving RPV. Autoclaving to
be done at 121°C for 30 min.
15
3.0 Preparation of solution containing API
1) Take 10% (of actual batch size) of 0.25% tyloxapol solution (if required in formulation,
otherwise simply use water) added in a clean glass beaker.
2) Add slowly dispensed quantity of Polysorbate 80 followed by soluplus to it under
stirring.
3) Add slowly dispensed quantity of Benzalkonium chloride to the above solution under
continuous stirring and stir till the solution is clear.
4) Add slowly dispensed quantity of API (brinzolamide, followed by Latanoprost) to it
under continuous stirring.
5) Decrease the pH of the slurry to approximately 3.5 with 5 N hydrochloric acid till the
API dissolves completely.
6) Make up the volume of the solution to 20% of the bulk solution and adjust the pH of the
solution to 6.0 with 5 N sodium hydroxide
7) Filter through 47 mm, 0.45 micron PVDF filter followed by 47 mm, 0.22 micron PVDF
filter into a large sterile container under laminar flow hood.
4.0 Bulk preparation
1) To the above prepared sterile API solution which is 20% of the bulk solution, add
previously autoclaved RPV to make up the weight to 90%. That is addition of about 70%
of the RPV by weight.
2) Make up the volume with previously sterilized milli Q water upto 100.0% (of actual
batch size)
3) Stir the solution for 2 hours in aseptic conditions.
4) Fill the final solution in previously sterilized bottles, suitable for ophthalmic use.
As used herein, a "combination of agents" and similar terms refer to a combination of two
types of agents: (1) carbonic anhydrase inhibitors and/or pharmacologically active metabolites,
salts, solvates and racemates of CAIs agents and (2) prostaglandin analogs and/or
pharmacologically active metabolites, salts, solvates and racemates of prostaglandin analogs.
As used herein, a "combination of agents" and similar terms refer to a combination of
three types of agents: (1) carbonic anhydrase inhibitors and/or pharmacologically active
16
metabolites, salts, solvates and racemates of CAIs agents and (2) prostaglandin analogs and/or
pharmacologically active metabolites, salts, solvates and racemates of prostaglandin analogs and
(3) beta-blockers and/or pharmacologically active metabolites, salts, solvates and racemates of
prostaglandin analogs.
Pharmacologically active metabolites include those that are inactive but are converted
into pharmacologically active forms in the body after administration.
Administration of the combination includes administration of the combination in a single
formulation or unit dosage form, administration of the individual agents of the combination
concurrently but separately, or administration of the individual agents of the combination
sequentially by any suitable route.
The dosage of the individual agents of the combination may require more frequent
administration of one of the agents as compared to the other agent in the combination. Therefore,
to permit appropriate dosing, packaged pharmaceutical products may contain one or more dosage
forms that contain the combination of agents, and one or more dosage forms that contain one of
the combinations of agents, but not the other agent(s) of the combination.
The optimal dose of the combination of agents use in the methods described herein can
be determined empirically for each individual using known methods and will depend upon a
variety of factors, including, though not limited to, the degree of advancement of the disease; the
age, body weight, general health, gender and diet of the individual; the time of administration;
and other medications the individual is taking. Optimal dosages may be established using routine
testing and procedures that are well known in the art.
Frequency of dosage may vary depending on the formulation used and the particular
condition to be treated or prevented and the patient's/subject's medical history. In general, the use
of the minimum dosage that is sufficient to provide effective therapy is preferred. Patients may
generally be monitored for therapeutic effectiveness using assays or tests suitable for monitoring
IOP or retinal damage for the condition being treated or prevented, which will be familiar to
those of ordinary skill in the art.
In one embodiment, the prostaglandin include prostaglandins disclosed in JP-A-59-1418
(particularly, a natural prostaglandin such as prostaglandin F2 alpha), prostaglandins such as
latanoprost disclosed in JP-T-3-501025, prostaglandins such as isopropyl unoprostone disclosed
in JP-A-2-108, prostaglandins such as bimatoprost disclosed in JP-T-8-501310, prostaglandins
17
such as travoprost disclosed in JP-A-10-182465, prostaglandins such as AL-6598 disclosed in
Surv Opthalmol 47 (Suppl 1): S13-S33, 2002, and prostaglandins such as PF-04475270 disclosed
in Exp Eye Res. 89: 608-17, 2009. Among these, the prostaglandin is preferably PGF2alpha or a
PGF2 alpha derivative, more preferably isopropyl unoprostone, latanoprost, travoprost or
bimatoprost.
In one embodiment, the alpha 2-receptor agonist includes brimonidine and apraclonidine.
In one embodiment, the alpha 1-receptor antagonist includes bunazosin.
In one embodiment, the beta -receptor antagonist include timolol, befunolol, carteolol,
nipradilol, betaxolol, levobunolol and metipranolol.
In one embodiment, the carbonic anhydrase inhibitor includes dorzolamide, brinzolamide
and acetazolamide.
According to one embodiment of the present invention, there is provided a sterile
ophthalmic formulation prepared by the process as described herein comprising brinzolamide in
an amount from 0.01% to 5.0% by weight.
In preferred embodiments, the present invention provides sterile ophthalmic formulations
in the form of aqueous liquids, solutions, emulsion, solid dispersion, suspension, reverse
emulsion and microemulsion, nanoemulsion, liposomes, nano reservoir system, in-situ gel drops,
nanoparticulate system, liposomal drops, bioadhesive gel drops, drops and the like.
In another preferred embodiment, the present invention provides ophthalmic formulations
for topical ophthalmic delivery comprising administering said composition in the eyes. Other
preferred embodiments include otic and/or nasal formulations for administration to the ear and/or
nose of a human or animal.
In a more preferred embodiment of the present invention, the pharmaceutically
acceptable excipients are selected from but not limited to at least one polymer, at least one
surfactant, at least one isotonicity agent, at least one viscosity enhancing agent, at least one
solvent, at least one buffer, at least one pH adjusting agents, at least one antioxidants, at least one
chelating agents and at least one preservative.
In one of the embodiments, the polymers that may be used is selected from the group
consisted of, but are not limited to Carbomer® such as Carbomer 974 P, Soluplus® (polyvinyl
caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer), povidone,
18
hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose and mixtures
thereof, wherein the said polymers may be used in amount from 0.01% to 5.0%.
In one of the embodiments, the preservatives that may be used is selected from the group
consisted of, but are not limited to benzethonium chloride, phenyl ethanol, phenyl propanol,
phenyl mercuric acetate, phenyl mercuric nitrate, phenyl mercuric borate, chlorhexidine acetate
or gluconate, cetrimide, chlorocresol, benzoic acid, benzyl alcohol, butylparaben, propylparaben,
methylparaben, chlorobutanol, phenoxyethanol, sodium methyl paraben, sodium propyl paraben,
thimerosal, benzalkonium chloride, hydrogen peroxide, sodium chlorite and mixtures thereof,
wherein the said preservatives may be used in an amount from 0.005% to 0.5%.
In another embodiment, the surfactants that may be used is selected from the group
consisted of, but are not limited to sodium lauryl sulfate, docusate sodium, polyoxyalkyl ethers,
polyoxylalkyl phenyl ethers, polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), polyoxyl
40 stearates, polyoxy hydrogenated castor oil, polyoxy sorbitan esters, sorbitan esters,
polysorbates, polyoxyl 35 castor oil, sorbitan monolaureates, poloxamer and mixtures thereof,
wherein the said surfactants may be used in amount from 0.001% to 15 %, preferably 0.01% to
0.5%.
In another embodiment, the nonionic surfactant that may be used is selected from the
group consisted of, but are not limited to tyloxapol; polyoxyethylene sorbitan esters, such as
polysorbate 20, polysorbate 60, and polysorbate 80; polyethoxylated castor oils, such as
Cremaphor EL; polyethoxylated hydrogenated castor oils, such as HCO-40; and poloxamers.
wherein the said surfactants may be used in amount from about 0.01 - 0.2 %.
In one of the embodiments, the tonicity agents that may be used is selected from the
group consisted of, but are not limited to mannitol, dextrose, glycerin, potassium chloride,
sodium chloride and mixtures thereof, wherein the tonicity agents may be used in amount from
about 0.1% to 5.0% or is added in such an amount that makes the osmotic pressure of the
composition identical to that of tears.
In other embodiments, the solvent, preferably a polar organic solvent, is selected from the
group consisting of, but not limited to N-methyl pyrrolidinone, aliphatic and aromatic alcohols,
ethanol, dimethyl sulfoxide (DMSO), dimethyl acetamide, ethoxydiglycol, isopropyl myristate,
triacetin, polyethylene glycols, and propylene glycol.
19
In another embodiment, the viscosities enhancing agents that may be used is selected
from the group comprising of, but are not limited to, carboxymethylcellulose sodium,
hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl
methylcellulose, methylcellulose carbomer, poloxamer, polyvinyl alcohol, povidone,
polyethylene oxide, carboxymethylcellulose calcium.
In another embodiment of the present invention, the buffers include acetates such as
sodium acetate; phosphates such as sodium dihydrogenphosphate, disodium hydrogenphosphate,
potassium dihydrogenphosphate and dipotassium hydrogenphosphate; ε-aminocaproic acid;
amino acid salts such as sodium glutamate; and boric acid and a salt thereof, wherein the buffer
is generally contained in a proportion of 0.01 to 2.0 w/v % relative to the entire composition.
In another embodiment of the present invention, the buffer should have buffering
capacity in the range of pH 4.5 - 8.5.
In one of another embodiment of the present invention, the pH adjusting agent include
but are not limited to, hydrochloric acid, citric acid, phosphoric acid, acetic acid, tartaric acid,
sodium hydroxide, potassium hydroxide, sodium carbonate and sodium hydrogencarbonate.
In one of another embodiment of the present invention, the chelating agents include but
are not limited to edetate disodium, edetate trisodium, edetate tetrasodium, diethyleneamine
pentaacetate and mixtures thereof, wherein the chelating agent is generally present in an amount
from 0.005 - 0.2 w/v % relative to the entire composition.
In one of another embodiment of the present invention, the antioxidants include but are
not limited to sodium bisulfite, potassium bisulfite, magnesium bisulfite, calcium bisulfite,
sodium metabisulfite, potassium metabisulfite, calcium metabisulfite, sodium thiosulfate and
sodium hydrogensulfite, ascorbic acid, sodium ascorbate, tocopherol and sulfite salts like sodium
sulfite, potassium sulfite, magnesium sulfite, calcium sulfite, wherein the sulfite salt is generally
being present in an amount from 0.01 – 1.0 % w/v.
In one of another embodiment of the present invention, the sterile, ophthalmic
pharmaceutical formulation may be aseptically sterilized using membrane filters such as PES
(Polyethersulphone), PVDF (Polyvinylidene Fluoride) having pore size of about 0.45 microns to
0.22 microns to filter the formulation vehicle. In another embodiment of the present invention,
the ophthalmic formulation of brinzolamide prepared according to the process as described
20
herein may be filled in LDPE or HDPE or PET or polycarbonate vials of suitable capacity in
volumes of 0.5 to 20 mL.
Another embodiment of the present invention consists of the active ingredient which is
useful in the treatment or prevention of diseases associated with the eye(s) like elevated
intraocular pressure in patients with ocular hypertension or open-angle glaucoma, ocular surface
pain, uveitis, scleritis, episcleritis, keratitis, surgically-induced inflammation, endophthalmitis,
iritis, atrophic macular degeneration, retinitis pigmentosa, iatrogenic retinopathy, retinal tears,
retinal vein and artery occlusion, optic neuropathy, neovascular glaucoma, corneal
neovascularization, cyclitis, sickle cell retinopathy, pterygium, seasonal allergic conjunctivitis,
palpebral and bulbar conjunctiva, acne rosacea, superficial punctuate keratitis, herpes zoster
keratitis, iritis, cyclitis, selected infective conjunctivitides, and post-operative inflammation
following ocular surgery.
Accordingly, the main embodiment of the present invention provides an aqueous sterile,
ophthalmic pharmaceutical formulation for lowering intraocular pressure in a patient suffering
from elevated intraocular pressure comprising a carbonic anhydrase inhibitor or its
pharmaceutically acceptable salt as an active agent and a polymer and a second or, third
therapeutically active agent optionally along with pharmaceutically acceptable excipients and/or
mixtures thereof, wherein the formulation is in solution form.
In another embodiment of the present invention, the carbonic anhydrase inhibitor is
selected from a group, but not limited to, brinzolamide, dorzolamide, acetazolamide and/or,
mixtures thereof.
In another embodiment of the present invention, the carbonic anhydrase inhibitor is
brinzolamide.
In another embodiment of the present invention, the brinzolamide is present in amount
from 0.01 to 5 w/v % of the formulation.
In another embodiment of the present invention, the brinzolamide is present in amount
from 0.1 to 2 w/v % of the formulation.
21
In another embodiment of the present invention, the brinzolamide is present in amount
from 0.3 to 1.0 % of the formulation.
In another embodiment of the present invention, the second therapeutically active agent is
selected from a group comprising (i) beta-blockers (ii) prostaglandin analogs, (iii) prostamides,
(iv) alpha 2-adrenergic agonists, (v) miotics, (vi) neuroprotectants, (vii) parasympathomimetic
drug, or, their pharmacologically active metabolites, salts and racemates and/or mixtures thereof.
In another embodiment of the present invention, the second therapeutically active agent is
selected from a group comprising latanoprost, travoprost, unoprostone, tafluprost, bimatoprost,
brimonidine, apraclonidine, bunazosin, timolol, befunolol, carteolol, nipradilol, betaxolol,
levobunolol, atenolol, metipranolol, lubezole, nimodipine, carbachol, echothiophate, pilocarpine
and/or, mixtures thereof.
In another embodiment of the present invention, the second therapeutically active agent is
timolol.
In another embodiment of the present invention, the third therapeutically active agent, is
selected from a group comprising (i) beta-blockers, (ii) prostaglandin analogs, (iii) prostamides,
(iv) alpha 2-adrenergic agonists, (v) miotics, (vi) neuroprotectants, (vi) parasympathomimetic
drug or, their pharmacologically active metabolites, salts, racemates and/or mixtures thereof.
In another embodiment of the present invention, the third therapeutically active agent is
selected from a group comprising latanoprost, travoprost, unoprostone, tafluprost, bimatoprost,
brimonidine, apraclonidine, bunazosin, timolol, befunolol, carteolol, nipradilol, betaxolol,
levobunolol, atenolol, metipranolol, lubezole, nimodipine, dorzolamide, brinzolamide,
methazolamide, dichlorphenamide, diamox acetazolamide, carbachol, echothiophate, pilocarpine
and/or mixtures thereof,
In another embodiment of the present invention, the third therapeutically active agent is
latanoprost.
In another embodiment of the present invention, the polymer is selected from a group
comprising Carbomer 974 P (Carbomer®), polyvinyl caprolactam-polyvinyl acetate22
polyethylene glycol graft copolymer (Soluplus®), povidone, hydroxypropylmethylcellulose,
hydroxypropylcellulose, hydroxyethylcellulose and/or mixtures thereof.
In another embodiment of the present invention, the polymer is polyvinyl caprolactampolyvinyl
acetate-polyethylene glycol graft copolymer.
In another embodiment of the present invention, the polymer is present in amount from
0.01% to 5.0% by weight of the formulation.
In another embodiment of the present invention, the polymer is present in amount from
0.1 to 3.0% by weight of the formulation.
In another embodiment of the present invention, the polymer is present in amount from
0.3 to 1.0% by weight of the formulation.
In another embodiment of the present invention, the formulation further comprising a
surfactant selected from a group comprising sodium lauryl sulfate, docusate sodium,
polyoxyalkyl ethers, polyoxylalkyl phenyl ethers, polyoxyl 40 hydrogenated castor oil
(Cremophor RH 40), polyoxyl 40 stearates, polyoxy hydrogenated castor oil, polyoxy sorbitan
esters, sorbitan esters, polysorbates, polyoxyl 35 castor oil, sorbitan monolaureates, poloxamer
and/or mixtures thereof.
In another embodiment of the present invention, the surfactant is polysorbate, preferably
polysorbate 80.
In another embodiment of the present invention, the surfactant is present in amount from
0.001% to 15 % by weight of the formulation.
In another embodiment of the present invention, the surfactant is present in amount from
0.01 to 5.0% by weight of the formulation.
In another embodiment of the present invention, the surfactant is present in amount from
0.05 to 3.0 % by weight of the formulation.
23
In another embodiment of the present invention, the pharmaceutically acceptable
excipients are selected from group comprising a tonicity agent, a viscosity enhancing agent, a
non-aqueous solvent, a buffer, a pH adjusting agent, an antioxidant, a chelating agent, a
preservative, and/or a combination of two or more thereof.
In another embodiment of the present invention, the formulation is in the form of aqueous
liquids, solutions, emulsion, solid dispersion, suspension, reverse emulsion and microemulsion,
nanoemulsion, liposomes, nano reservoir system, in-situ gel drops, nanoparticulate system,
liposomal drops, bioadhesive gel drops, drops.
In another embodiment of the present invention, the formulation comprises brinzolamide,
polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polysorbate 80
and either a second or third therapeutically active agent and pharmaceutically acceptable
excipients and/or mixtures thereof.
In another embodiment of the present invention, the formulation comprises brinzolamide,
polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polysorbate 80
and latanoprost as second therapeutically active agent and pharmaceutically acceptable
excipients and/or mixtures thereof.
In another embodiment of the present invention, the formulation comprises brinzolamide,
polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polysorbate 80
and timolol as third therapeutically active agent and pharmaceutically acceptable excipients
and/or mixtures thereof.
In another embodiment of the present invention, the formulation has application in the
treatment of elevated intraocular pressure in patients with glaucoma or ocular hypertension.
Yet another embodiment of the present invention provides a method of treating elevated
intraocular pressure in patients with glaucoma or ocular hypertension in a subject in need of such
treatment, the method comprising administering to a subject in need thereof an ophthalmic
formulation containing a pharmaceutically effective amount of brinzolamide or, its salts thereof
and optionally in combination with a second or third therapeutically active agent and its
24
pharmacologically active metabolites, salts or, racemates thereof and/or pharmaceutically
acceptable excipients.
In another embodiment of the present invention, the formulation is administered once a
day to each eye in need thereof.
In another embodiment of the present invention, the formulation is administered twice or
three times a day to each eye in need thereof.
In another embodiment of the present invention, the condition treatable includes elevated
intraocular pressure.
In another embodiment of the present invention, the formulation pH ranges from 5.5 to 8.
EXAMPLES
The scope of the present invention is illustrated by the following examples which are not
meant to restrict the scope of the invention in any manner whatsoever.
The term 'q.s.' wherever appears in the examples is an abbreviation for 'quantity
sufficient' which is the amount of the excipient in such quantities that is just sufficient for its use
in the composition of the present invention.
Various exemplary embodiments can be formulated as shown in the table follows:
Ingredients Quantity (% w/v)
Active pharmaceutical ingredient (API) 0.001 – 5
Graft co-polymer 0.01- 3
Surfactant 0.05 – 5
Wetting agent 0 – 2
Chelating agent. 0.001 – 2
Osmotic agent 0.5 – 20
Viscosity modifier 0.01 – 5
Osmotic agent 0 – 10
Preservatives 0 – 0.1
pH adjusting agent. q.s. to adjust pH to 4.5 – 7.5
pH adjusting agent. q.s. to adjust pH to 4.5 – 7.5
Purified water q.s. to 100 mL
25
The scope of the present invention is illustrated by the following examples which are not
meant to restrict the scope of the invention in any manner whatsoever.
Formula 1:
Ingredient Quantity (% w/w)
Brinzolamide 0.3-0.5
Soluplus 0.4-0.8
Polysorbate – 80 1.0
Tylaxapol 0.0-0.05
Edetate disodium 0.01
Mannitol 3.3
Carbomer 0.4-0.45
NaCl 0.19
Benzalkonium Chloride 0.0-0.01
NaOH q.s. to adjust pH to 6.0
HCl q.s. to adjust pH to 6.0
Milli Q q.s. to 100 mL
Method of Preparation:
The manufacturing process is as follows: The procedure is divided into four main steps
1. Preparation of Remaining Product Vehicle (RPV)
2. Preparation of sterile Milli Q water
3. Preparation of solution containing API
4. Bulk preparation
1.0 Preparation of Remaining Product Vehicle (RPV)
1) Take 60% (of actual batch size) of milli Q water in a clean glass beaker.
2) Add slowly dispensed quantity of disodium edetate followed by mannitol under
continuous stirring (rpm 800±100).
3) Slowly add dispensed quantity of carbomer into the above solution at increased rpm
(2000±100) via sprinkling. Decrease the stirring rate to 1200±100 after complete
addition.
26
4) After the carbomer has dissolved completely add dispensed quantity of sodium chloride
under continuous stirring and stir till the solution is clear.
5) Add slowly dispensed quantity of Benzalkonium chloride to the above solution under
continuous stirring and stir till the solution is clear.
6) Check the initial pH of the solution, and adjust the pH to 7.5 with 5 N sodium hydroxide
solution.
7) Make up the volume with milli Q water upto 80% (of actual batch size).
8) Filter the bulk solution through 47 mm, 20 micron PP filters.
9) Autoclave the RPV at 121°C for 30 min in a Schott glass bottle.
Note: About 10% RPV excess is prepared to compensate the loss of RPV during filtration
and autoclaving. Please note the formulation is stating the exact quantities. However,
dispensed quantities will be in 10% excess.
2.0 Preparation of Sterile milli Q water
1) In a Schott glass bottle autoclave enough water that will comprise 20% of total weight of
the product. This can be autoclaved in a separate bottle, while autoclaving RPV.
Autoclaving to be done at 121°C for 30 min.
3.0 Preparation of solution containing API
1) Take 10% (of actual batch size) of 0.25% tyloxapol solution (if required in formulation,
otherwise simply use water) added in a clean glass beaker.
2) Add slowly dispensed quantity of Polysorbate 80 followed by soluplus to it under
stirring.
3) Add slowly dispensed quantity of API to it under continuous stirring.
4) Decrease the pH of the slurry to approximately 3.5 with 5 N hydrochloric acid till the
API dissolves completely.
5) Make up the volume of the solution to 20% of the bulk solution and adjust the pH of the
solution to 6.0 with 5 N sodium hydroxide.
6) Filter through 47 mm, 0.45 micron PVDF filter followed by 47 mm, 0.22 micron PVDF
filter into a large sterile container under laminar flow hood.
27
1.1 Bulk preparation
1) To the above prepared sterile API solution which is 20% of the bulk solution, add
previously autoclaved RPV to make up the weight to 90%. That is addition of about 70%
of the RPV by weight.
2) Make up the volume with previously sterilized milli Q water upto 100.0% (of actual
batch size)
3) Stir the solution for 2 hours in aseptic conditions.
4) Fill the final solution in previously sterilized bottles, suitable for ophthalmic use.
Formula 2:
Ingredient Quantity (% w/w)
Brinzolamide 0.3-0.5
Latanoprost 0.005
Soluplus 0.4-0.8
Polysorbate – 80 1.0
Tylaxapol 0.0-0.05
Edetate disodium 0.01
Mannitol 3.3
Carbomer 0.4-0.45
NaCl 0.19
Benzalkonium Chloride 0.0-0.01
NaOH q.s. to adjust pH to 6.0
HCl q.s. to adjust pH to 6.0
Milli Q q.s. to 100 mL
Method of Preparation:
The manufacturing process is as follows: The procedure is divided into four main steps
1. Preparation of Remaining Product Vehicle (RPV)
2. Preparation of sterile Milli Q water
3. Preparation of solution containing API
4. Bulk preparation
28
1.0 Preparation of Remaining Product Vehicle (RPV)
1) Take 60% (of actual batch size) of milli Q water in a clean glass beaker.
2) Add slowly dispensed quantity of disodium edetate followed by mannitol under
continuous stirring (rpm 800±100).
3) Slowly add dispensed quantity of carbomer into the above solution at increased rpm
(2000±100) via sprinkling. Decrease the stirring rate to 1200±100 after complete
addition.
4) After the carbomer has dissolved completely add dispensed quantity of sodium chloride
under continuous stirring and stir till the solution is clear.
5) Check the initial pH of the solution, and adjust the pH to 7.5 with 5 N sodium hydroxide
solution.
6) Make up the volume with milli Q water upto 80% (of actual batch size).
7) Filter the bulk solution through 47 mm, 20 micron PP filters.
8) Autoclave the RPV at 121°C for 30 min in a Schott glass bottle.
Note: About 10% RPV excess is prepared to compensate the loss of RPV during filtration
and autoclaving. Please note the formulation is stating the exact quantities. However,
dispensed quantities will be in 10% excess.
2.0 Preparation of Sterile milli Q water
1) In a Schott glass bottle autoclave enough water that will comprise 20% of total weight of
the product. This can be autoclaved in a separate bottle, while autoclaving RPV.
Autoclaving to be done at 121°C for 30 min.
3.0 Preparation of solution containing API
1) Take 10% (of actual batch size) of 0.25% tyloxapol solution (if required in formulation,
otherwise simply use water) added in a clean glass beaker.
2) Add slowly dispensed quantity of Polysorbate 80 followed by soluplus to it under
stirring.
29
3) Add slowly dispensed quantity of Benzalkonium chloride to the above solution under
continuous stirring and stir till the solution is clear.
4) Add slowly dispensed quantity of API (brinzolamide, followed by Latanoprost) to it
under continuous stirring.
5) Decrease the pH of the slurry to approximately 3.5 with 5 N hydrochloric acid till the
API dissolves completely.
6) Make up the volume of the solution to 20% of the bulk solution and adjust the pH of the
solution to 6.0 with 5 N sodium hydroxide
7) Filter through 47 mm, 0.45 micron PVDF filter followed by 47 mm, 0.22 micron PVDF
filter into a large sterile container under laminar flow hood.
4.0 Bulk preparation
1) To the above prepared sterile API solution which is 20% of the bulk solution, add
previously autoclaved RPV to make up the weight to 90%. That is addition of about 70%
of the RPV by weight.
2) Make up the volume with previously sterilized milli Q water upto 100.0% (of actual
batch size)
3) Stir the solution for 2 hours in aseptic conditions.
4) Fill the final solution in previously sterilized bottles, suitable for ophthalmic use.
Formula 3:
Ingredients Quantity (% w/w)
Brinzolamide 0.5
Timolol maleate (equivalent to
0.5% timolol)
0.683
Soluplus 0.8
Polysorbate - 80 1
Edetate disodium 0.01
Mannitol 3
Carbomer 0.42
30
NaCl 0.1
Benzalkonium Chloride (50%) 0.02
NaOH q.s. to adjust pH to 6.0
HCl q.s. to adjust pH to 6.0
Milli Q q.s. to 100mL
Method of Preparation:
The manufacturing process is as follows: The procedure is divided into four main steps
1.0 Preparation of Remaining Product Vehicle (RPV)
1) Take 60% (of actual batch size) of milli Q water in a clean glass beaker.
2) Add slowly dispensed quantity of disodium edetate followed by mannitol under
continuous stirring (rpm 800±100).
3) Slowly add dispensed quantity of carbomer into the above solution at increased rpm
(2000±100) via sprinkling. Decrease the stirring rate to 1200±100 after complete
addition.
4) After the carbomer has dissolved completely add dispensed quantity of sodium chloride
under continuous stirring and stir till the solution is clear.
5) Add slowly dispensed quantity of Benzalkonium chloride to the above solution under
continuous stirring and stir till the solution is clear.
6) Check the initial pH of the solution, and adjust the pH to 6.0 with 5 N sodium hydroxide
solution.
7) Make up the volume with milli Q water upto 80% (of actual batch size).
8) Filter the bulk solution through 47 mm, 20 micron PP filters.
9) Autoclave the RPV at 121°C for 30 min in a Schott glass bottle.
Note: About 10% RPV excess is prepared to compensate the loss of RPV during filtration
and autoclaving. Please note the formulation is stating the exact quantities. However,
dispensed quantities will be in 10% excess.
31
2.0 Preparation of Sterile Milli Q water
1) In a Schott glass bottle autoclave enough water that will comprise 20% of total weight of
the product. This can be autoclaved in a separate bottle, while autoclaving RPV.
Autoclaving to be done at 121°C for 30 min.
3.0 Preparation of solution containing API
1) Take 10% (of actual batch size) of Sterile Milli Q water in a clean glass beaker.
2) Add slowly dispensed quantity of Polysorbate 80 followed by soluplus to it under
stirring.
3) Add slowly dispensed quantity of API (timolol followed by brinzolamide) to it under
continuous stirring.
4) Decrease the pH of the slurry to approximately 3.5 with 5 N hydrochloric acid till the
API dissolves completely.
5) Make up the volume of the solution to 20% of the bulk solution and adjust the pH of the
solution to 6.0 with 5 N sodium hydroxide
6) Filter through 47 mm, 0.45 micron PVDF filter followed by 47 mm, 0.22 micron PVDF
filter into a large sterile container under laminar flow hood.
4.0 Bulk preparation
1) To the above prepared sterile API solution which is 20% of the bulk solution, add
previously autoclaved RPV to make up the weight to 90%. That is addition of about 70%
of the RPV by weight.
2) Make up the volume with previously sterilized milli Q water upto 100.0% (of actual
batch size)
3) Stir the solution for 2 hours in aseptic conditions.
4) Fill the final solution in previously sterilized bottles, suitable for ophthalmic use.
Formula 4:
Ingredients Quantity (% w/w)
Brinzolamide 0.50
Timolol maleate (equivalent to 0.5% 0.683
32
timolol)
Soluplus 0.80
Polysorbate - 80 1.00
Mannitol 2.50
Carbomer 0.42
Boric Acid 0.188
Sodium Borate 0.012
Zinc Chloride 0.10
Benzalkonium Chloride (50%) 0.01
Sodium metabisulphite 0.20
NaOH q.s. to adjust pH to 6.0
HCl q.s. to adjust pH to 6.0
Milli Q q.s. to 100 mL
STABILITY STUDIES:
A sterile, ophthalmic pharmaceutical formulation of the present invention is prepared by
the process described herein in the specification and is tested for stability at stress conditions for
4 weeks at 50° C and at accelerated conditions for one month at 40° C, at not more than 25%
relative humidity (RH). The results of the same are provided in Table 1.
An accelerated study comprises placing the formulation is filled in 10 mL 3 piece opaque
LDPE bottles, opaque LDPE nozzle and orange colored cap. (Sterilized by ETO gas
Sterilization) and maintaining at 40° C, at not more than 25% relative humidity (RH) in the dark.
As understood by those of skill in the art, when the drug comprises brinzolamide, the
impurities preferably measured include Impurity A (S)-4-(ethylamino)-3,4-dihydro-2-(3-
methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6- sulfonamide 1,1-dioxide; Impurity B, (R)-4-
(amino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-
dioxide, Impurity C (S)-4-(hydroxy)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-
thiazine-6-sulfonamide 1,1-dioxide and Impurity D 6-(amino-hydroxy-oxo-6-sulfanyl)-2-(3-
methoxypropyl)-1,1-dioxo-3H-thieno[3,2-e]thiazin-4-one and total impurities, as well as
identification of the amount of the any independent unspecified impurity.
33
As understood by those of skill in the art, when the drug comprises timolol, the impurities
preferably measured include Impurity-1 3- Chloro-4(N-Morpholino-1,2,5-thiadazole), and total
impurities, as well as identification of the amount of the any independent unspecified impurity.
Table 1: Stability data of brinzolamide and timolol formulation (Formula 3) as prepared
by process disclosed herein the specification at stress (4 Week/ 50°C) and accelerated (1 Month/
(40°C/NMT 25% RH)) stability condition.
Parameters Specification Initial 2 Week/ 50°C 4 Week/ 50°C 1 Month/
(40°C/NMT
25% RH)
Description Not specified White opalescent viscous solution
Assay of
Brinzolamide
90% -110% 99.60% 99.50% 100.10% 100.00%
Impurity of Brinzolamide
Impurity A NMT 2.0% ND 0.57% 0.92% 0.26%
Impurity B NMT 0.5% 0.11% 0.07% 0.07% 0.08%
Impurity C Not specified ND ND ND ND
Impurity D Not specified ND ND ND ND
Any single
unspecified
Impurity
NMT 0.5% 0.06% 0.06% 0.07% 0.06%
Total Impurity NMT 2% 0.17% 0.19% 0.20% 0.19%
Assay of
Timolol
90% -110% 102.10% 101.90% 102.80% 102.70%
Impurity of Timolol
Timolol
Impurity – 1
NMT 0.15% ND ND ND ND
Any single
unspecified
Impurity
NMT 0.5% 0.03% 0.02% 0.02% 0.03%
Total Impurity Not more
than 1.5%
0.03% 0.02% 0.02% 0.03%
pH TBE 6.08 6.07 6.07 6.07
Osmolality 260 to 330
mOsm/kg
315 314 315 311
ND: Not Detected; NMT: Not More Than; RH: Relative Humidity; TBE: To Be Established
34
RESULTS:
The results of stress stability at 50°C for 4 weeks for formulation 3:
The brinzolamide content is measured to be 100.1% (Limit: 90.0 -110.0%) which is in
the acceptable limit range, all the known impurities (Impurity A; B; C & D) are well within the
acceptable limit range as shown in table 1 and total impurity is measured to be 0.2% (Limit:
NMT 2.0%) which is in the acceptable limit range.
The timolol content is measured to be 102.8% (Limit: 90.0 -110.0%) which is in the
acceptable limit range, the known impurity (Impurity 1) is below detection level and total
impurity is measured to be 0.02% (Limit: NMT 1.5%) which is in the acceptable limit range.
The results of accelerated stability at 40°C and NMT 25% RH for one month for
formulation 3:
The brinzolamide content is measured to be 100% (Limit: 90.0 -110.0%) which is in the
acceptable limit range, all the known impurities (Impurity A; B; C & D) are well within the
acceptable limit range as shown in table 1 and total impurity is measured to be 0.19% (Limit:
NMT 2.0%) which is in the acceptable limit range.
The timolol content is measured to be 102.7% (Limit: 90.0 -110.0%) which is in the
acceptable limit range, the known impurity (Impurity 1) is below detection level and total
impurity is measured to be 0.03% (Limit: NMT 1.5%) which is in the acceptable limit range.
Rest all other parameters such as pH; Osmolality and the physical parameters are well
within the specifications i.e. as per the label claim.
Hence it is concluded from the above stability data that all the formulations are stable and
well within the specifications.
UTILITY OF THE INVENTION
The present inventors provides an aqueous sterile, ophthalmic pharmaceutical formulation
comprising a carbonic anhydrase inhibitor or its pharmaceutically acceptable salt as an active
agent and a polymer and a second or, third therapeutically active agent optionally along with
pharmaceutically acceptable excipients and/or mixtures thereof. The present formulation is to be
utilized for lowering intraocular pressure in a patient suffering from elevated intraocular pressure
or, glaucoma.

WE CLAIM:
1. An aqueous sterile, ophthalmic pharmaceutical formulation for lowering intraocular
pressure in a patient suffering from elevated intraocular pressure comprising a carbonic
anhydrase inhibitor or its pharmaceutically acceptable salt as an active agent and a
polymer and a second or, third therapeutically active agent optionally along with
pharmaceutically acceptable excipients and/or mixtures thereof, wherein the formulation
is in solution form.
2. The formulation as claimed in claim 1, wherein the carbonic anhydrase inhibitor is
selected from a group, but not limited to, brinzolamide, dorzolamide, acetazolamide
and/or, mixtures thereof.
3. The formulation as claimed in claim 1, wherein the carbonic anhydrase inhibitor is
brinzolamide.
4. The formulation as claimed in claim 1, wherein the brinzolamide is present in amount
from 0.01 to 5 w/v % of the formulation.
5. The formulation as claimed in claim 1, wherein the brinzolamide is present in amount
from 0.1 to 2 w/v % of the formulation.
6. The formulation as claimed in claim 1, wherein the brinzolamide is present in amount
from 0.3 to 1.0 % of the formulation.
7. The formulation as claimed in claim 1, wherein the second therapeutically active agent is
selected from a group comprising (i) beta-blockers (ii) prostaglandin analogs, (iii)
prostamides, (iv) alpha 2-adrenergic agonists, (v) miotics, (vi) neuroprotectants, (vii)
parasympathomimetic drug, or, their pharmacologically active metabolites, salts and
racemates and/or mixtures thereof.
36
8. The formulation as claimed in claims 1 or 7, wherein the second therapeutically active
agent is selected from a group comprising latanoprost, travoprost, unoprostone,
tafluprost, bimatoprost, brimonidine, apraclonidine, bunazosin, timolol, befunolol,
carteolol, nipradilol, betaxolol, levobunolol, atenolol, metipranolol, lubezole, nimodipine,
carbachol, echothiophate, pilocarpine and/or, mixtures thereof.
9. The formulation as claimed in claim 1 or 7, wherein the second therapeutically active
agent is timolol.
10. The formulation as claimed in claim 1, wherein the third therapeutically active agent, is
selected from a group comprising (i) beta-blockers, (ii) prostaglandin analogs, (iii)
prostamides, (iv) alpha 2-adrenergic agonists, (v) miotics, (vi) neuroprotectants, (vi)
parasympathomimetic drug or, their pharmacologically active metabolites, salts,
racemates and/or mixtures thereof.
11. The formulation as claimed in claim 1 or 10, wherein the third therapeutically active
agent is selected from a group comprising latanoprost, travoprost, unoprostone,
tafluprost, bimatoprost, brimonidine, apraclonidine, bunazosin, timolol, befunolol,
carteolol, nipradilol, betaxolol, levobunolol, atenolol, metipranolol, lubezole, nimodipine,
dorzolamide, brinzolamide, methazolamide, dichlorphenamide, diamox acetazolamide,
carbachol, echothiophate, pilocarpine and/or mixtures thereof,
12. The formulation as claimed in claim 1 or 10, wherein the third therapeutically active
agent is latanoprost.
13. The formulation as claimed in claim 1, wherein the polymer is selected from a group
comprising Carbomer 974 P (Carbomer®), polyvinyl caprolactam-polyvinyl acetatepolyethylene
glycol graft copolymer (Soluplus®), povidone,
hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose and/or
mixtures thereof.
37
14. The formulation as claimed in claims 1 or 13, wherein the polymer is polyvinyl
caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.
15. The formulation as claimed in claims 1 or 13, wherein the polymer is present in amount
from 0.01% to 5.0% by weight of the formulation.
16. The formulation as claimed in claims 1 or 13, wherein the polymer is present in amount
from 0.1 to 3.0% by weight of the formulation.
17. The formulation as claimed in claims 1 or 13, wherein the polymer is present in amount
from 0.3 to 1.0% by weight of the formulation.
18. The formulation as claimed in claim 1, wherein the formulation further comprising a
surfactant selected from a group comprising sodium lauryl sulfate, docusate sodium,
polyoxyalkyl ethers, polyoxylalkyl phenyl ethers, polyoxyl 40 hydrogenated castor oil
(Cremophor RH 40), polyoxyl 40 stearates, polyoxy hydrogenated castor oil, polyoxy
sorbitan esters, sorbitan esters, polysorbates, polyoxyl 35 castor oil, sorbitan
monolaureates, poloxamer and/or mixtures thereof.
19. The formulation as claimed in claims 1 or 18, wherein the surfactant is polysorbate,
preferably polysorbate 80.
20. The formulation as claimed in claims 1 or 18, wherein the surfactant is present in amount
from 0.001% to 15 % by weight of the formulation.
21. The formulation as claimed in claims 1 or 18, wherein the surfactant is present in amount
from 0.01 to 5.0% by weight of the formulation.
22. The formulation as claimed in claims 1 or 18, wherein the surfactant is present in amount
from 0.05 to 3.0 % by weight of the formulation.
38
23. The formulation as claimed in claim 1, wherein the pharmaceutically acceptable
excipients are selected from group comprising a tonicity agent, a viscosity enhancing
agent, a non-aqueous solvent, a buffer, a pH adjusting agent, an antioxidant, a chelating
agent, a preservative, and/or a combination of two or more thereof.
24. The formulation as claimed in claim 1, wherein the formulation is in the form of aqueous
liquids, solutions, emulsion, solid dispersion, suspension, reverse emulsion and
microemulsion, nanoemulsion, liposomes, nano reservoir system, in-situ gel drops,
nanoparticulate system, liposomal drops, bioadhesive gel drops, drops.
25. The formulation as claimed in claim 1, wherein the formulation comprises brinzolamide,
polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer,
polysorbate 80 and either a second or third therapeutically active agent and
pharmaceutically acceptable excipients and/or mixtures thereof.
26. The formulation as claimed in claims 1 or 25, wherein the formulation comprises
brinzolamide, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft
copolymer, polysorbate 80 and latanoprost as second therapeutically active agent and
pharmaceutically acceptable excipients and/or mixtures thereof.
27. The formulation as claimed in claims 1 or 25, wherein the formulation comprises
brinzolamide, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft
copolymer, polysorbate 80 and timolol as third therapeutically active agent and
pharmaceutically acceptable excipients and/or mixtures thereof.
28. The formulation as claimed in claims 1 and 25, wherein the formulation pH ranges from
5.5 to 8.