TECHNICAL FIELD OF THE INVENTION
The present invention is directed to the provision of multi-dose, aqueous
pharmaceutical compositions comprising two or more therapeutic agents selected from
brinzolamide, brimonidine or a combination thereof in conjunction with a preservative other
than benzalkonium chloride (BAC). Instead, the compositions contain either Benzododecinium
Bromide (BDDB) or Sodium Perborate or Polyquaternium-1 as a preservative for improved
1 0 preservation of the compositions.
15
More particularly, the present invention IS related to multi-dose, pharmaceutical
ophthalmic compositions that lacks borate-polyol complex formation and without use of BAC
even at low concentration and still possess sufficient antimicrobial activity to satisfy USP
preservative efficacy requirements, as well as similar other preservative standards.
BACKGROUND OF THE INVENTION
Glaucoma is a degenerative disease of the eye wherein the intraocular pressure is too
high to permit normal eye function. As a result, damage may occur to the optic nerve head and
result in irreversible loss of visual function. In particular, a glaucoma patient will develop
20 peripheral visual field loss followed by central field loss usually in the presence of elevated
intraocular pressure, which if left untreated it may eventually lead to blindness.
Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic
nerve head damage or characteristic glaucomatous visual field defects, is now believed by the
majority of ophthalmologists to represent merely the earliest phase in the onset of glaucoma.
25 Most patients with glaucoma are treated with topical medication that controls elevated ocular
pressure. Medications most commonly used are Alpha (a)-adrenergic receptor agonists,
epinephrine compounds, prostaglandins that reduce ocular pressure by increasing aqueous
outflow, ~-adrenergic receptor antagonists and carbonic anhydrase inhibitors that work by
decreasing aqueous production. Even though the typical treatment regimen for lowering
30 intraocular pressure is topical ~-blockers, in the recent years the use of prostaglandins as initial
therapy is increased.
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Carbonic anhydrase inhibitors are also used for the treatment of ocular hypertension
related to glaucoma. The drugs that belong to this family inhibit the enzyme carbonic anhydrase
and thus, they reduce the contribution of the aqueous humor formation made by the carbonic
anhydrase pathway. However, these drugs cannot be used via a systemic route because they
5 would inhibit the enzymatic activity of carbonic anhydrase throughout the entire body. In
general, the enzyme carbonic anhydrase plays a major role in regulating pH and fluid levels in
the human body by converting carbon dioxide to carbonic acid and bicarbonate ions.
Brinzolamide R-(+)-4ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H thieno[3,2,e]
1,2-thiazene-6 sulfonamide-1,1-dioxide) is a carbonic anhydrase inhibitor disclosed in U.S.
10 Pat. No. 5,378,703 and sold in a topical ophthalmic formulation (Azopt™) for lowering
elevated intra-ocular pressure (lOP) in patients with open-angle glaucoma or ocular
hypertension (OHT) (Alcon Laboratories, Inc., Fort Worth, Tex.).
Alpha-2-adrenergic agonist is another well characterized class of drugs used for the
treatment of high intraocular pressure related with glaucoma. The drugs of this class act via
15 decreasing synthesis of aqueous humor and increasing the amount that drains from the eye
through uveoscleral outflow.
The present invention relates to compositions containing alpha-2-adrenergic agonists.
Brimonidine tartrate ( ( 5-bromo-6-2-imidzolidisny lideneamino) quinozoline L-tartrate)
hereinafter "brimonidine" is a relatively selective alpha-2-adrenergic agonist sold in a topical
20 ophthalmic formulation (Alphagan™) for lowering elevated lOP in patients with open angleglaucoma
or ocular hypertension (Allergan, Inc., Irvine, Calif.).
The topical use of brimonidine to lower intraocular pressure in patients with glaucoma
or ocular hypertension is known. The first ophthalmic brimonidine product in the U.S. was
approved by the FDA in 1996. That product, sold under the trade name Alphagan, contained
25 brimonidine in the form of brimonidine tartrate at a concentration of 0.2%. The preservative
contained in Alphagan is benzalkonium chloride, the most widely used preservative for topical
ophthalmic compositions.
In 2001, a second ophthalmic brimonidine product was approved by the U.S. FDA. This
product, sold under the trade name Alphagan® P, contained brimonidine tartrate at two
30 brimonidine concentrations, 0.15% and 0.1 %, each of which is lower than the 0.2%
brimonidine concentration in Alphagan®. Alphagan® P has a pH range that is higher than that
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of Alphagan®. According to the product label, the lower concentration Alphagan® P
formulation is sold at a pH of 7.4 to 8.0; the higher concentration is sold at a pH of 6.6 to 7.4.
The preservative contained in Alphagan® P is chlorine dioxide. See U.S. Patent numbers
US5424078 and US6562873.
U.S. Pat. No. 6,316,441 discloses the use of brinzolamide in combination with
brimonidine to treat ocular diseases which have their etiology in compromised blood flow.
These diseases include, but are not limited to glaucoma, occlusion conditions, diabetic
retinopathy, and ocular neovascularization. These agents can be used either alone, in separate
compositions dosed within 5 to 10 min of each other, or together in a single formulation. In all
1 0 the formulations, it discloses the use of Benzalkonium Chloride as a preservative.
The U.S. Pat. Nos. 9,421,265 and 9,044,484 discloses pharmaceutical compositions that
contain borate-polyol complexes for improved preservation of the compositions. More
specifically the present invention relates to aqueous pharmaceutical compositions (e.g., multidose
ophthalmic compositions) containing two or more different polyols in conjunction with
15 borate and a preservative, particularly benzalkonium chloride (BAC).
Further, it is well established in the prior that a detergent preservative used in the above
references such as benzalkonium chloride was known to be somewhat irritating to the eye. It
is well known in the reference literature that small organic compounds, such as benzalkonium
chloride (BAC), chlorhexidine, thimerosal have excellent antimicrobial activity; however, it is
20 now known that these small organic antimicrobials are often toxic to the sensitive tissues of
the eye and can accumulate in cornea, contact lenses, particularly soft, hydrophilic contact
lenses. Medications with BAC may cause disruption of the corneal surface with lower
concentrations of BAC.
Gasset and Grant et al. showed that BAC accumulates in ocular tissue and remains there
25 for long periods, adversely affecting both the corneal surface and the conjunctiva. Therefore,
cessation of the medications may not immediately improve the condition and function of the
ocular surface. These findings also suggest that corneal cell necrosis may occur in some
patients who are taking multiple BAC-preserved ocular medications over long periods of time,
even when the amount of BAC in any one medication is below the threshold concentration at
30 which necrosis occurs.
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The U.S. Pat. Nos. 9,421,265 and 9,044,484 further disclose that it would be
particularly desirable to provide an ophthalmic composition, which includes borate-polyol
complex formed with lower concentrations of particular polyols and/or borate and includes low
concentrations of BAC while exhibiting improved anti-microbial activity and desirable
5 buffering activity. However, in the present invention, the inventors have surprisingly and
unexpectedly found that their formulations are stable and achieved the preservative efficacy
without having any borate-polyol complexes therefore there is no need of these excipients in
their formulation.
So, there is an unmet medical need to prepare a pharmaceutical composition comprising
1 0 brinzolamide or their salts thereof, brimonidine or their salts thereof or a combination thereof
that contain preservatives other than benzalkonium chloride (BAC), the other preservatives
being less toxic than BAC in nature. Instead, the compositions contain either Benzododecinium
Bromide (BDDB) or Sodium Perborate or Polyquaternium-1 as a preservative for improved
preservation of the composition, which is less irritating to the eye( s) of a patient in need thereof.
15
20
Therefore, the present invention is directed to pharmaceutical compositions comprising
a combination of brinzolamide and brimonidine or their salts thereof that contain preservatives
other than benzalkonium chloride (BAC). Preferably, the compositions contain
Benzododecinium Bromide (BDDB) as a preservative for improved preservation of the
compositions.
SUMMARY OF THE INVENTION
The present invention is directed to a multi-dose, ophthalmic compositions comprising
Brinzolamide or their pharmaceutically acceptable salts thereof and Brimonidine or their
pharmaceutically acceptable salts thereof, in combination with a preservative(s) other than
25 benzalkonium chloride (BAC). Instead, the ophthalmic compositions contain either
Benzododecinium Bromide (BDDB) or Sodium Perborate or Polyquaternium-1 as a
preservative for improved preservation of the composition(s).
30
Preferably, the ophthalmic compositions contain Benzododecinium Bromide (BDDB)
as a sole preservative to preserve the composition(s) of the present invention.
Preferably, the ophthalmic compositions contain Sodium Perborate as a sole
preservative to preserve the composition(s) of the present invention.
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Preferably, the ophthalmic compositions contain Polyquaternium-1 as a sole
preservative to preserve the composition(s) of the present invention.
Particularly, the present invention is directed to topical ophthalmic compositions for
the decrease of intraocular pressure (lOP) in patients with ocular hypertension or open angle
5 glaucoma comprising a combination of Brinzolamide and Brimonidine or their pharmaceutical
acceptable salts thereof optionally with pharmaceutically acceptable excipients and a process
for the preparation thereof.
More particularly, the present invention is directed to develop a stable ophthalmic
composition that lacks borate-polyol complex formation and is free of microbes during storage
1 0 and for the duration of use; such formulation would provide a significant improvement in
preservation over the prior art formulations.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGURE 1: Comparison of Zeta Potential (m V) of reference products and present invention
15 formulations 5a, 5b & 5c.
FIGURE 2: Comparison of Surface Tension (mN/m) of reference products and present
invention formulations 5a, 5b & 5c.
FIGURE 3: Drug release profile of reference products and present invention formulations 5a,
5b & 5c.
20 FIGURE 4: Comparison of 2 theta value of reference products and present invention
formulations 5a, 5b & 5c.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a multi-dose, aqueous pharmaceutical compositions
25 comprising two or more therapeutic agents selected from brinzolamide or their salts thereof,
brimonidine or their salts thereof or a combination thereof, along with a preservative other than
benzalkonium chloride (BAC).
Instead, the compositions contain either Benzododecinium Bromide (BDDB) or
Sodium Perborate or Polyquaternium-1 as a preservative for improved preservation of the
30 present composition(s).
5
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Preferably, the ophthalmic compositions contain Benzododecinium Bromide (BDDB)
as a sole preservative to preserve the composition of the present invention.
Preferably, the ophthalmic compositions contain Sodium Perborate as a sole
preservative to preserve the composition(s) of the present invention.
Preferably, the ophthalmic compositions contain Polyquaternium-1 as a sole
preservative to preserve the composition(s) of the present invention.
More particularly, the present invention is related to multi-dose, pharmaceutical
ophthalmic compositions that lacks borate-polyol complex formation and still possess
sufficient antimicrobial activity to satisfy USP preservative efficacy requirements, as well as
1 0 similar other preservative standards.
15
As used herein, the term "BAC/BKC" wherever appears in the specification is an
abbreviation for "benzalkonium chloride".
As used herein, the "BDDB" wherever appears in the specification is an abbreviation
for "Benzododecinium Bromide".
As used herein, the "NMT" wherever appears is an abbreviation for "not more than"
and the "RH" wherever appears is an abbreviation for "relative humidity".
As used herein, the "lOP" wherever appears is an abbreviation for "intraocular
pressure".
Unless indicated otherwise, all ingredient amounts are presented m units of %
20 weight/volume(% w/v).
Brimonidine tartrate is a known compound that can be made by known methods and is
commercially available. See, for example, German Patent No. 2,538,620.
In one embodiment, the present invention is directed to a multi-dose, ophthalmic
compositions comprising a combination of Carbonic anhydrase inhibitors or their
25 pharmaceutically acceptable salts thereof and alpha-2-adrenergic agonist or their
pharmaceutically acceptable salts thereof, optionally with other pharmaceutical acceptable
excipients.
In another embodiment, the present invention is directed to an aqueous ophthalmic
composition comprising a combination of Carbonic anhydrase inhibitors and alpha-2-
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adrenergic agonist m combination with a preservative other than benzalkonium chloride
(BAC).
Instead, the compositions contain either Benzododecinium Bromide (BDDB) or
Sodium Perborate or Polyquaternium-1 as a preservative for the improved preservation of the
5 compositions of the present invention.
In one embodiment, the ophthalmic compositions contain Sodium Perborate as a sole
preservative to preserve the composition of the present invention.
In another embodiment, the ophthalmic compositions contain Polyquaternium-1 as a
sole preservative to preserve the composition of the present invention.
1 0 According to the present invention, a carbonic anhydrase inhibitor is selected from
Brinzolamide or a pharmaceutically acceptable salt or solvate or hydrate thereof wherein the
concentration of brinzolamide in the composition is from about 0.01-0.5 % (w/v) of the
composition.
According to the present invention, an alpha-2 adrenergic receptor is selected from
15 Brimonidine or a pharmaceutically acceptable salt or solvate or hydrate thereof wherein the
concentration of brimonidine tartrate in the composition is from about 0.01-0.5 % (w/v) of the
composition.
20
In another embodiment, the present invention relates to compositions comprising a
combination of Brinzolamide and Brimonidine or their pharmaceutical acceptable salts thereof.
In another embodiment, the present invention relates to compositions comprising a
combination of Brinzolamide and Brimonidine or their pharmaceutical acceptable salts thereof
along with a buffer other than borate buffer.
In another embodiment, the ophthalmic compositions of the present invention are
substantially free of borate buffer and thus lacks borate-polyol complex formation and is free
25 of microbes during storage and for the duration of its use.
In another embodiment, the ophthalmic compositions of the present invention contain
Tromethamine as a sole buffer to stabilize or maintain the ophthalmic formulation at the desired
pH.
In yet another embodiment, the present invention is directed to topical ophthalmic
30 compositions for the decrease of intraocular pressure in patients with ocular hypertension or
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open angle glaucoma comprising a combination of Brinzolamide and Brimonidine or their
pharmaceutical acceptable salts thereof optionally with pharmaceutically acceptable
excipients.
In yet another embodiment, particularly the present invention is directed to develop a
5 stable ophthalmic composition that lacks borate-polyol complex formation and is free of
microbes during storage and for the duration of use.
In another embodiment, the present invention is directed to such compositions that
would provide a significant improved preservation over the prior art compositions.
In a preferred embodiment, however, the ophthalmic composition is a single or multi-
1 0 dose ophthalmic composition containing a combination of two or more therapeutic agents
optionally with pharmaceutically acceptable excipients.
In a preferred embodiment, the therapeutic agents are selected from the groups
including prostaglandin analogs (e.g., latanoprost, travoprost and unoprostone), hypotensive
lipids (e.g., bimatoprost), and glucocorticoids (e.g., prednisolone, dexamethasone and
15 lotoporednol), beta blockers such as acebutolol, atenolol, labetalol, metoprolol, propranolol,
timolol (e.g., timolol maleate) and derivatives thereof, olopatadine (e.g., olopatadine
hydrochloride), Carbonic anhydrase inhibitors such as brinzolamide, dorzolomide,
acetazolamide, alpha-2 adrenergic agonist comprises L-norepinephrine, clonidine, brimonidine
(e.g., brimonidine tartrate), emadastine, tandospirone, roscovitine, nepafenac, bradykinin,
20 PDE4 inhibitor or combinations thereof.
In another embodiment, the compositions are typically configured for topical
application to the eye (e.g., as drops directly to the eye) in a patient in need thereof.
As used herein, the term "polyol" if used, includes but not limited to, mannitol, glycerin,
xylitol, sorbitol, propylene glycol or combination thereof and is present in a concentration from
25 about 0.01% to 0.5% (w/v) of the composition.
In another embodiment, one or more pharmaceutical acceptable excipients if included
would be selected from a group, but not limited to buffering agents, preservatives, tonicity
agents, surfactants, viscosity-modifying agents or a suspending agent and so on.
Examples of viscosity-modifying agents or suspending agents include, without
30 limitation, carboxyvinyl polymer (Carbomer 974 P), xanthan gum, gellan gum, sodium
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carboxymethyl cellulose alginic acid, carageenans. Highly preferred examples of anionic
polymers include carboxyvinyl polymer, xanthan gum or a combination thereof and is present
from about 0.05% to about 5.0% by weight of the composition.
A surfactant may be used, and the preferred surfactants are tyloxapol, polysorbate 80
5 and Polyoxyethylene (POE) (40) Hydrogenated Castor oil (or PEG (40 Hydrogenated castor
oil) (HC0-40).
According to the present invention, a preservative is selected from benzododecinium
halide, chlorobutanol, sodium perborate, cetrimonium chloride, thiomersal, methyl
parahydroxybenzoate, propyl parahydroxybenzoate, sorbic acid and derivatives thereof,
10 polyquaternium ammonium chloride, polyaminopropyl biguanide, phenyl mercuric nitrate,
phenyl mercuric acetate, hydrogen peroxide. Instead, when the preservative is included in the
present invention, the preservative is preferably benzododecinium halide, preferably
benzododecinium bromide and present in the range of 0.001% to 0.1% (w/v), more preferable
in the range of 0.005% to 0.03% (w/v) benzododecinium bromide.
15 In one of the embodiment, the preservative if present is substantially free or entirely
free of any preservatives other than benzododecinium bromide (BDDB).
In one of the embodiment, the preservative if present is substantially free or entirely
free of any preservatives other than Sodium perborate.
In one of the embodiment, the preservative if present is substantially free or entirely
20 free of any preservatives other than Polyquaternium -1(PQ-1).
In another embodiments, the compositions of the present invention may include a
polyol as a tonicity agent selected from the group comprising but not limited to mannitol,
sorbitol or combination thereof or the like. Of these, it typically preferred that the only polyol
be substantially entirely mannitol. The polyol is typically present in the range of about 0.01
25 w/v% to about 5 w/v% of the ophthalmic composition.
The present invention is particularly directed to the provision of multi-dose ophthalmic
compositions that have sufficient antimicrobial activity to allow the compositions to satisfy the
USP preservative efficacy requirements, as well as other preservative efficacy standards for
aqueous pharmaceutical compositions.
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In yet another embodiment various alternative preservative system were used which
have better tolerability then benzalkonium chloride (BAC/BKC).
Polyquaternium -1 (PQ-1) is a hydrophilic cationic polymer used as a preservative in
both dry eye preparations and glaucoma medications It has been used in various USFDA
5 approved ophthalmic products since long.
Sodium perborate, is an oxidative-type preservative which alters protein synthesis
within bacterial cells through oxidative mechanisms and is effective against bacteria and the
fungus Aspergillus niger. When combined with water, sodium perborate is converted to
hydrogen peroxide and it has been used in several dry eye products.
1 0 In another embodiment, the compositions of the present invention m addition to
therapeutic agents preferably also contains a buffering agent to stabilize or maintain the
ophthalmic formulation at the desired pH. Any suitable buffering agent can be used which is
compatible with the other ingredients of the ophthalmic composition of present invention.
Examples of suitable ophthalmically acceptable buffering agents include but not limited to
15 acetate buffers, citrate buffers, phosphate buffers, tromethamine and mixtures thereof. Specific
buffering agents useful in the present invention include Tromethamine, sodium citrate, sodium
acetate, and mixtures thereof. In the present invention, the buffer is present in at least about
0.05 w/v% to 5.0 w/v% of the ophthalmic composition.
In another embodiments, the pH adjusting agents include but not limited to,
20 hydrochloric acid, sodium hydroxide, phosphoric acid, acetic acid and the like.
The compositions of the present invention will typically have a pH in the range of 4 to
8, preferably 5.5 to 8.0. Particularly desired pH ranges are 6.0 to 7.8 and more specifically 6.2
to 7.7. The pH of the present invention compositions are not more than 8.0.
In another embodiments, the compositions will have an osmolality of 200 to 400 or 450
25 milliosmoles per kilogram (mOsm/kg), more preferably 240 to 360 mOsm/kg.
In one embodiment, the present invention is directed to a multi-dose ophthalmic
compositions for the decrease of intraocular pressure (lOP) in patients with ocular hypertension
or open angle glaucoma comprising a combination of therapeutic agents and a method for their
preparation thereof.
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In another embodiment, the compositions of the present invention will generally be
formulated as a sterile aqueous solutions, emulsions or suspensions so as to be compatible with
the eye and/or other tissues to be treated with the compositions.
In an embodiment, the present invention provides the ophthalmic compositions in the
5 form of aqueous liquids, solutions, emulsion, dispersion, suspension, reverse emulsion and
microemulsion, nanoemulsion, nano reservoir system, in-situ gel drops, nanoparticulate
system, liposomal drops, bioadhesive gel drops, drops and the like.
In another embodiment, the present invention preferably provides the ophthalmic
composition for topical ophthalmic delivery comprising administering said composition in the
1 0 eyes, ear, and/or nose of the humans or animals.
In yet another embodiments, any pharmaceutically acceptable packaging material may
be use, preferably pharmaceutically acceptable packaging materials include but are not limited
to low density polyethylene ("LDPE"), high density polyethylene ("HDPE"), polypropylene,
polystyrene, polycarbonate, polyesters (such as polyethylene terephthalate and polyethylene
15 naphthalate), nylon, polyvinyl chloride), poly(vinylidine chloride), poly(tetrafluoroethylene)
and other materials known to those of ordinary skill in the art. Flexible bottles prepared from,
or comprising, LDPE, HDPE or polypropylene are particularly preferred.
In an embodiment, the present invention provides a method to lower intraocular
pressure in patients with glaucoma or ocular hypertension wherein the method comprises a
20 topical application to the eye of the patient in need of an ophthalmic composition comprising
a combination of Brinzolamide and Brimonidine or their salts thereof optionally with a
pharmaceutically acceptable excipients.
The present invention further provides a method of using the ophthalmic compositions
of present invention for lowering intraocular pressure in patients with glaucoma or ocular
25 hypertension.
The main embodiment of the present invention is to provide an aqueous ophthalmic
composition, comprising:
a therapeutically effective amount of brimonidine or their salts thereof;
a therapeutically effective amount of brinzolamide or their salts thereof;
11
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buffers at a concentration that is at least about 0.05% w/v to 5.0% w/v of the
ophthalmic composition;
a preservative and;
pharmaceutically acceptable excipients, wherein the pH of said composition is
less than 8.0.
In another embodiment of the present invention, wherein the composition comprises
0.01-0.5% (w/v) ofbrimonidine tartrate.
In another embodiment of the present invention, wherein the composition comprises
0.01-0.5% (w/v) ofbrinzolamide.
1 0 In another embodiment of the present invention, wherein the buffer includes, but not
limited to, acetate buffers, citrate buffers, phosphate buffers, tromethamine and mixtures
thereof.
In another embodiment of the present invention, wherein the composition IS
substantially free of borate buffers.
15 In another ernbodirnent of the present invention, wherein the pH of the composition is
not more than 8.0.
In another embodiment of the present invention, wherein the composition has a pH at
least 4 but less than 8.0.
In another embodiment of the present invention, wherein the preservative is selected
20 from benzododecinium bromide (BDDB), chlorobutanol, sodium perborate, cetrimonium
chloride, thiomersal, methyl parahydroxybenzoate, propyl parahydroxybenzoate, sorbic acid
and derivatives thereof, polyquaternium ammo mum chloride, polyquaternium-1,
polyaminopropyl biguanide, phenyl mercunc nitrate, phenyl mercuric acetate, hydrogen
peroxide and their mixture thereof.
25 In another embodiment of the present invention, wherein the composition IS
substantially free of benzalkonium chloride.
In another ernbodirnent of the present invention, wherein the composition satisfies Ph.
USP, Ph. Eur. B or both.
12
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In another embodiment of the present invention, wherein one or more pharmaceutical
acceptable excipients if included, would be selected from a group, but not limited to buffering
agents, preservatives, tonicity agents, surfactants, viscosity-modifying agents or a suspending
agent and mixtures thereof.
In another embodiment of the present invention, wherein the composition further
comprising a suspending agent.
In another embodiment of the present invention, wherein the suspending agent is
selected from carboxyvinyl polymer (Carbomer 974 P), xanthan gum, gellan gum, sodium
carboxymethyl cellulose alginic acid, carageenans.
10 In another ernbodiment of the present invention, wherein the composition further
comprising one or more polyols.
In another embodiment of the present invention, wherein the polyol if used, includes
but not limited to, mannitol, glycerin, xylitol, sorbitol, propylene glycol or combination thereof.
In another embodiment of the present invention, wherein the composition is a sterile
15 aqueous suspensiOn.
In another embodiment of the present invention, wherein the composition is for topical
ophthalmic delivery comprising administering said composition in the eyes in need thereof.
In another embodiment of the present invention, wherein the sterile aqueous suspension
is suitable for ophthalmic use.
20 In another embodiment of the present invention, wherein the composition IS
administered either once a day or twice a day to each eye in need thereof.
Another embodiment of the present invention provides a method of reducing intraocular
pressure in a patient in need thereof, comprising administering to the patient the composition
of claims 1 to 19, the administered composition comprising a therapeutically effective amount
25 of brimonidine tartrate and brinzolamide each at a concentration that is at least about 0.05%
w/v to 5.0% w/v of the ophthalmic composition.
Another embodiment of the present invention provides use of a composition for
reducing intraocular pressure in a patient in need thereof comprising safe and a therapeutically
effective amount of brimonidine tartrate and brinzolamide.
13
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Yet another embodiment of the present invention provides an aqueous ophthalmic
composition, comprising:
a therapeutically effective amount of brimonidine or their salts thereof;
a therapeutically effective amount of brinzolamide or their salts thereof;
buffers at a concentration that is at least about 0.05% w/v to 5.0% w/v of the
ophthalmic composition;
a preservative;
one or more polyols;
a suspending agent and;
optionally pharmaceutically acceptable excipients, wherein the pH of said
composition is less than 8.0.
The scope of the present invention is illustrated by the following examples which is 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
15 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.
EXAMPLES
The scope of the present invention is illustrated by the following examples which is not
20 meant to restrict the scope of the invention in any manner whatsoever.
Example 1:
Ingredients Quantity(% w/v)
Brinzolamide 1.0
Brimonidine Tartrate 0.2
Benzododecinium 0.01
Tromethamine (Tris 0.5
Buffer)
Tyloxapol 0.025
Mannitol 0.3
Propylene Glycol
0.75
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Carbo mer 97 4 P 0.40
Sodium Chloride 0.25
Sodium Hydroxide
q.s. to adjust pH to 6.5
Hydrochloric Acid
Milli -Q Water q.s. to 100 mL
Method of Preparation:
In one of the embodiments, there is provided a process for preparing a composition
suitable for preparing Ophthalmic formulations as described herein comprising
5 Brinzolamide and Brimonidine Tartrate Ophthalmic Suspension. The procedure is divided
into four main steps:
1. Preparation of Polymer phase
2. Preparation of Brimonidine Tartrate and Buffer phase
3. Preparation of Brinzolamide and Tyloxapol slurry
10 4. Bulk preparation
15
20
1.0 Preparation of Polymer Phase:
1) Take 45 % (of actual batch size) of milli Q water in a clean glass beaker.
2) Add slowly the dispensed quantity of Mannitol into the above mili-Q water under
continuous stirring (rpm 800±100) to get a clear solution.
3) Slowly add dispensed quantity of Carbomer 974P into the above solution at increased
rpm (2000±100) via sprinkling. Decrease the stirring rate to 1200±100 after complete
addition and stirred for 60 mins. to get homogeneous dispersion.
4) Add slowly the dispensed quantity of sodium chloride to above dispersion under
continuous stirring (rpm 1200±100) to get it dissolved completely.
5) Add slowly the dispensed quantity of Tromethamine (Previously dissolved in milli-Q
water to prepare 10% stock solution) to above dispersion under continuous stirring (rpm
2000±100) and volume of the dispersion made up to 60% of the standard batch size and
stir for 1.0 hrs to mix it completely.
25 6) Filter the solution through 20 11m PP filter for clarification of Polymer phase.
7) Autoclave the Carbomer phase at 121 oc for 30 min in a Schott glass bottle. Then cool
it at room temperature.
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2.0 Preparation of Brimonidine Tartrate and Buffer Phase:
1) Take 10 % (of actual batch size) of milli Q water in a clean glass beaker.
5 2) Add slowly dispensed quantity of Propylene Glycol and Benzododecinium Bromide
one by one under continuous stirring (rpm 800±100) to get a clear solution.
10
15
3) Add dispensed quantity of Brimonidine Tartrate to above solution under continuous
stirring (rpm 800 ± 100) and stir for 30 mins or till it get clear solution.
4) Volume of the solution made up to 15% (of the actual batch size) and stir for 15 mins.
3.0 Preparation of Brinzolamide + Tyloxapol Slurry:
1) Take 2.0% (of actual batch size) hot milli Q water. Dissolve weighed quantity of
Tyloxapol with hot milli-Q water and stir for 15 mins. Volume of the solution made
upto 2.57% of the standard batch size and stir for 15 mins. Filter the solution with 0.2
11m PES filter in a separate beaker.
2) Add slowly dispensed quantity of API (Brinzolamide) to it under continuous stirring,
Volume of the slurry made upto 5% (of actual batch size) and stir for 2 hrs.
3) Milled the API slurry with 2000 RPM agitator speed and 300 RPM pump flow rate for
20 mins for particle size reduction using Netzsch bead mill. After milling rinse the mill
20 with milli Q water and volume of the slurry made upto 20 % of the batch size.
4.0 Bulk preparation
1) Filter the solution of Brimonidine Tartrate and Buffer phase of step 2 through 0.2 11
PES filter and transferred to previously cooled autoclave phase of Carbomer 974 P of
25 step 1 under stirring and stir for 30 mins to mix it completely.
2) Then add and mix the milled Brinzolamide and Tyloxapol slurry of step 3 to above
phase under stirring and stir for 30 mins. The pH of the suspension was checked, if
required adjusted to 6.5±0.3 using 1N Sodium Hydroxide/lN Hydrochloric acid
solution.
30 3) Make up the volume with previously sterilized milli Q water upto 100.0% (of actual
batch size)
4) Stir the suspension for 2 hours in aseptic conditions.
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5) Fill the final suspension in previously sterilized LDPE three piece bottles, suitable for
ophthalmic use.
Conclusion of the Preservative efficacy test (PET): The present composition is formulated
with 75% oflabel claim ofBenzododecinium Bromide (BDDB) and Tromethamine Buffer and
5 done the PET study with 75% of label claim of Benzododecinium Bromide which is complying
Preservative Efficacy requirement of USPIEP and achieved sufficient anti-bacterial activity.
Results are mentioned in the below tables 1 & 3.
10
Table 1: Log Reduction Value (As per USP Preservative Standards)
S. No. Organism Log Reduction
Initial Log Value 5.27
1 E. Coli
7 Days 5.27
14 Days 5.27
28 Days NI
Initial Log Value 5.77
2 S. Aureus
7 Days 5.77
14 Days 5.77
28 Days NI
Initial Log Value 5.08
7 Days 5.08
3 P. Aeruginosa
14 Days 5.08
28 Days NI
Initial Log Value 5.65
7 Days 3.54
4 C. Albicans
14 Days 3.81
28 Days NI
Initial Log Value 5.28
7 Days 3.20
5 A. Brasiliensis
14 Days 5.28
28 Days NI
Table 2: The preservative efficacy standards/ acceptance criteria for multi-dose ophthalmic
compositions in the U.S. is set forth in the following table:
Log Reduction
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7Days 14 Days 28 days
Bacteria
NLT 1 log from initial NLT 3 log from initial NI from 14 days
value value count at 28 days
Fungi NI from initial count NI from initial count NI from initial count
NI: - No Increase, NA: - Not Applicable
Table 3: Log Reduction Value (As per EP Preservative Standards):
S.No. Organism Log Reduction
Initial Log Value 5.77
24 Hrs. 3.77
1 S. Aureus 7 Days 5.77
14 Days 5.77
28 Days NI
Initial Log Value 5.08
24 Hrs. 2.76
2 P. Aeruginosa 7 Days 5.08
14 Days 5.08
28 Days NI
Initial Log Value 5.65
24 Hrs. NA
3 C. Albicans 7 Days 3.54
14 Days 3.81
28 Days NI
Initial Log Value 5.28
24 Hrs. NA
4 A. Brasiliensis 7 Days 3.20
14 Days 5.28
28 Days NI
5 Table 4: The preservative efficacy standards/ acceptance criteria for multi-dose ophthalmic
compositions as per the B-Criteria of EP is set forth in the following table:
Log Reduction#
18
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24 Hrs. 7Days 14 Days 28 days
Bacteria 1 3 NA NI
Fungi NA NA 1 NI
#Note: Cntena given m terms of Log reductiOn m the number of viable micro-orgamsms agamst the value
obtained for inoculum.
NI: No increase, NA: Not Applicable.
Further, the present invention formulation(s) is/are stable without using borate-polyol
complex and complies the preservative efficacy test as per USP specification.
Example 2:
Ingredients Quantity(% w/v)
Brinzolamide 1.0
Brimonidine Tartrate 0.2
Benzododecinium Bromide 0.01
Tromethamine (Tris Buffer) 0.5
Tyloxapol 0.025
Mannitol 2.3
Carbo mer 97 4 P 0.40
Sodium Chloride 0.25
Sodium Hydroxide q.s. to adjust pH to 6.5
Hydrochloric Acid q.s. to adjust pH to 6.5
Milli -Q Water q.s. to 100 mL
10 Table 1:
Test Parameters Example 1 Example 2
(US PROD-088-23) (US PROD-88-25)
pH 6.50 6.48
Osmolality(mOsmol) 239 240
Viscosity(cps) CPA 52Z 22.87 40.70
@ 60RPM
Particle Size Distribution
d(O.l)!lm
0.41 0.45
d(O.S)11m 1.05 1.25
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d(0.9)!lm 2.49 2.71
Zeta Potential
-33.7 -34.1
It is observed from the results in Table 1 that all physiochemical properties like pH, zeta
potential, viscosity, particle size of the batch manufactured with Example 1 is similar to batches
manufactured in Example 2 wherein Example 1 contains a combination of two polyols and
Example 2 contains single polyol. It suggests that there is no need to add two polyols in single
5 formulation, even use of single polyol achieves the same results related to physiochemical
properties. It also suggests that both these approaches can be useful for further development.
Examples 3 & 4:
Ingredients
Example 3 Example 4
Quantity(% w/v) Quantity(% w/v)
Brinzolamide 1.0 1.0
Brimonidine Tartrate 0.2 0.2
Sodium Perborate 0.005 ---
Polyquaternium-1
--- 0.01
(Polyquad)
Tromethamine 0.5 0.5
Tyloxapol 0.025 0.025
Mannitol 0.3 0.3
Propylene Glycol
0.75 0.75
Carbo mer 97 4 P 0.40 0.40
Sodium Chloride 0.25 0.25
Sodium Hydroxide q.s. to adjust pH to 6.5 q.s. to adjust pH to 6.5
Hydrochloric Acid q.s. to adjust pH to 6.5 q.s. to adjust pH to 6.5
Milli -Q Water q.s. to 100 mL q.s. to 100 mL
10
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Table 2:
Test Parameters Example 3 Example 4
(US PROD-088-49) (US PROD-088-50)
pH 6.54 6.45
Osmolality(mOsmol) 226 271
Viscosity(cps) CPA 52Z 62.01 35.58
@ 60RPM
Particle Size Distribution
d(O.l)!lm
0.415 0.32
d(0.5)!lm 1.05 0.72
d(0.9)!lm 2.47 1.97
Zeta Potential
-27.8 -27.0
Results from Table 2 suggested that all physiochemical properties like pH, zeta
5 potential, viscosity, particle size of these examples 3 & 4 are closely matching. The present
invention formulations are also compared with reference product (Simbrinza) for particle size,
zeta potential, rheology, drug release and found comparable in all these parameters.
10
15
Example 5:
In this example, quantity of tromethamine buffer is reduced to 0.09% from 0.5 % of
Example 1 and pH adjustment was done with sodium hydroxide. The reduction was done to
evaluate the viscosity parameters and Sodium hydroxide may useful to increase the viscosity
of this formulation. These batches further subjected to stability and characterized for various
in vitro parameters.
Example Sa Example Sb with Example Sc with
(Benzododecinium (Polyqauternium - 1 (Sodium Perborate as
Bromide as a as a preservative) a preservative)
preservative) US-PROD-088-37 US-PROD-088-36
(US-PROD-088-38)
Ingredients Quantity(% w/v) Quantity(% w/v) Quantity(% w/v)
Brinzolamide 1.0 1.0 1.0
Brimonidine Tartrate 0.2 0.2 0.2
Benzododecinium 0.01 X X
Bromide
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Polyquaternium-1 X 0.01 X
Sodium Perborate X X 0.005
Tromethamine (Tris 0.09 0.09 0.09
Buffer)
Tyloxapol 0.025 0.025 0.025
Mannitol 0.3 0.3 0.3
Propylene Glycol 0.75 0.75 0.75
Carbo mer 97 4 P 0.40 0.40 0.40
Sodium Chloride 0.24 0.24 0.24
Sodium Hydroxide
q.s. to adjust pH to 6.5
Hydrochloric Acid
Milli -Q Water q.s. to 100 mL
Table 3: Physiochemical data of reference product (Simbrinza) batches:
Reference product Lot NO Reference product lot No
105DD 103JJ
Initial Initial
Description off white suspension off white suspension
pH 6.44 6.51
Osmolality 265 267
Assay of
Brinzolamide 100.4 99.5
Assay of
Brimonidine 100.4 100.6
Particle Size d(O.l)!lm 0.320
Distribution (!lm) d(O.l)!lm 0.317
d(O.S)11m 0.686
d(O.S)11m 0.731
d(0.9)1lm 1.66
d(0.9)1lm 1.62
Redispersibility I No agglomerates were observed in No agglomerates were observed
Resuspendablity sample and on the walls of in sample and on the walls of
container after 15 sec vigorous container after 15 sec vigorous
shaking shaking
5 Table 4: Stability Study results of Formulations 5a, 5b and 5c:
Brinzolamide and Brimonidine Tartrate Ophthalmic Suspension 1% & 0.2%
(B.No.: US-PROD-088-38)
Test Parameters Initial 1 Week/60°C
2 1M (40°C/
Week/60°C NMT25%RH)
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Description
off white off white off white off white
suspensiOn suspensiOn suspensiOn suspensiOn
pH 6.52 6.51 6.51 6.56
Osmolality(mOsmol) 226 228 232 224
Viscosity( cps) 54.42 46.28 51.09 45.73
Assay of 99.0
Brinzolamide 98.8 99.1
(%,By HPLC) 98.3
Assay of Brimonidine 99.4
Tartrate(%, By 100.5 100.1
100.4
HPLC)
Related Substances of Brinzolamide (%, By HPLC)
Highest Unknown 0.03 0.03 0.03 0.14
impurity
Total Impurity 0.12 0.13 0.14 0.23
Related Substances of Brimonidine
Total Impurities 0.04 0.32 0.61 0.09
d(O.l)!lm 0.311
d(O.l)!lm d(O.l)!lm d(O.l)!lm 0.329
0.507 0.453
d(0.5)!lm 0.817
Particle Size d(O.S)11m 0.731
d(O.S)11m 1.65 d(O.S)11m
Distribution (in nm) d(0.9)!lm 1.83 1.41
d(0.9)!lm; 2.10
d(0.9)!lm 4.09
d(0.9)!lm;
3.54
No agglomerates
were observed
No in sample and on
agglomerates the walls of
were observed container after
Redispersibility I in sample and 15 sec vigorous
Resuspendability on the walls of shaking
container after
15 sec vigorous
shaking
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Brinzolamide and Brimonidine Tartrate Ophthalmic Suspension 1% & 0.2%,
(B No.: US-PROD-088-37)
2 1M (40°C/
Test Parameters Initial 1 Week/60°C Week/60° NMT25%RH)
c
off white off white
off white off white
Description
suspensiOn suspensiOn
suspensw suspensiOn
n
pH 6.51 6.52 6.52 6.56
Osmolality(mOsmol) 226 227 229 224
Viscosity( cps) 57.52 53.10 51.09 55.58
Assay of
98.1 98.7 100.7 99.0
Brinzolamide (%,
Assay of Brimonidine 100.1 101.7
99.2
Tartrate(%, By 99.6
Related Substances of Brinzolamide (%, By HPLC)
Highest Unknown 0.03 0.03 0.03 0.15
impurity
Total Impurity 0.16 0.13 0.14 0.25
Related Substances of Brimonidine Tartrate
Total Impurities 0.04 0.33 0.58 0.10
d(O.l)!lm 0.311 d(O.l)!lm d(O.l)!lm d(O.l)!lm 0.329
0.447 0.453
d(O.S)11m 0.606
d(O.S)11m 0.817
Particle Size d(O.S)11m 1.43 d(O.S)!lm
Distribution( 11m) d(0.9)!lm 1.40 1.41 d(0.9)!lm 2.10
d(0.9)!lm 3.53
d(0.9)!lm
3.54
No
agglomerates
No agglomerates were observed
were observed in in sample and
Redispersibility I sample and on the
NA NA on the walls of
Resuspendablity walls of container container after
after 15 sec 15 sec vigorous
vigorous shaking shaking
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Brinzolamide and Brimonidine Tartrate Ophthalmic Suspension 1% & 0.2%,
(B. No.: US-PROD-088-36)
1
2 1M 40°C/
Test Parameters Initial Week/60° NMT25%RH
Week/60°C c
Description
off white off white off white off white
suspensiOn suspensiOn suspensiOn suspensiOn
pH 6.61 6.62 6.60 6.70
Osmolality(mOsmol) 227 227 230 224
Viscosity( cps) 60.15 63.33 57.91 59.46
Assay of Brinzolamide 98.5 98.4 98.8
98.0
(%,By HPLC)
Assay of Brimonidine 99.6 98.0
Tartrate(%, By HPLC) 99.7 99.9
Related Substances of Brinzolamide (%, By HPLC)
Highest Unknown impurity 0.03 0.03 0.03 0.19
Total Impurity 0.14 0.13 0.14 0.33
Related Substances of Brimonidine Tartrate
Total Impurities 0.05 0.38 0.64 0.14
d(O.l)!lm d(O.l)!lm d(0.1)!lm 0.369
0.507 0.518
Particle Size Distribution d(0.5)!lm -0.96
*NA d(O.S)11m- d(O.S)11md(
0.9)!lm 2.23
(!lm) 1.65 1.68
d(0.9)!lm d(0.9)!lm
4.09 3.96
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No No
agglomerates agglomerates
were were observed
observed in in sample and
Redispersibility I sample and on the walls of
Resuspendablity NA NA container after
on the walls
15 sec vigorous
of container shaking
after 15 sec
vigorous
shaking
*Not reported due to variability
The stress study results depicted that the present formulations are stable and there is no
drop in assay during stress study condition. There is also no increase in related substance
Brinzolamide during the stress stability. The slight increase in impurity in Brimonidine tartrate
5 was observed, however it is within the ICH impurity level. Further there is no impact on other
physiochemical properties like pH, viscosity and osmolality during the stress testing. There is
observed a slight increase in particle size during 1 week stress condition; however there is no
increase or change in particles size from 1 week stress to 2 week stress condition, stable
thereafter.
10 These formulations are also subjected to ICH stability study condition. Similarly,
stability data at 1M 40°C/ NMT25%RH indicate that all formulations are stable for pH,
osmolality, viscosity, assay and impurities. There is no change in particles size during the
stability in all three proposed formulation after lmonth at 40°C/ NMT25%RH.
The proposed formulations using alternative preservatives to BAC have shown good
15 stability along with compliance to preservative efficacy standard. The all proposed
preservatives BDDB, PQ-1 and sodium borate are surprisingly compatible. The results indicate
that the proposed formulations are surprisingly stable without using borate- polyol complex.
Also, Tromethamine (Tris) (pKa 8.1) as an alternative to boric acid buffer can be used
as a substitute near neutral pH conditions. The enhanced chemical and physical stability of
20 Tromethamine make it amenable to steam sterilization. Due to its weak basicity, it is also less
corrosive to manufacturing equipments and safer to handle when compared to the inorganic
bases. Tromethamine is mild base and can provide stable formulation particularly at
physiological pH. The use of tromethamine buffer has imparted stability and there is no change
in pH of formulations during the stress stability in all three examples 5a, 5b & 5c.
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Also, surprisingly the tromethamine can alone be used for the neurotisation of carbomer
as an alternative to Sodium hydroxide. It is well known that Tromethamine is an ideal
neutralizer in carbomer gels that use low molecular weight alcohols as co-solvents for drug
molecules. Carbomer salts of tromethamine exhibit greater compatibility with alcohols
5 compared to the inorganic bases. Thus, along with buffering capacity it can be work as
neutralization alternative to sodium hydroxide.
Re-suspendability is also a critical quality attribute and any suspension should be resuspended
similar to reference product. There is no impact on the re-suspendability of
suspension of present formulations, the proposed suspension/formulations is redispersed within
10 15 seconds of vigorous shaking with no agglomerate and results are comparable to reference
product.
15
20
25
Further few other parameters are also evaluated for the present invention formulations and
their results, observations are described below.
(a) Zeta potential: One critical attribute to demonstrate the equivalence of present
inevntion formulations to the reference product is zeta potential. The zeta potential is a
measure of electrical charge of particles that are suspended in liquid and is a function
of surface charge of the particles, any adsorbed layer at interface and nature and
composition of surrounding medium. The zeta potential has proven to be extremely
relevant to practical study and control of colloidal stability and flocculation processes.
The present invention stable formulations quoted in above examples were characterized
for zeta potential and the results are comparable with reference products. However,
slightly lower zeta of two batches could be due to testing variability.
Reference Reference US- USUP-
PRODTest
Lot No Lot No PROD- PROD-
088-38
103JJ 105DD 088-36 088-37
Zeta
Potential -34.5 -30.8 -16.7 -16.3 -34.7
(mV)
A Comparison of Zeta Potential (m V) of reference products and present invention
formulations 5a, 5b & 5c are shown in Figure 1.
27
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10
15
20
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(b) Surface tension: The surface tension of ophthalmic formulations affects the rate of its
evaporation, the interaction with the lacrimal film of tears or the airway mucosal lining,
as well as how easily it would spread along a biological surface. To minimize irritation
one would expect that liquid formulations in general would mimic the natural surface
tension of the particular area of administration and thus maximize interactions.
For a suspension product, the surface tension is critically important as the interfacial
free energy between particles can affect the physical attributes of suspensions such as
settling, aggregation, dispersability and physical stability. These attributes have the
potential to affect the performance of a product, in its intended use. Furthermore,
surface tension of an ophthalmic product directly influences the eye-drop volume [ref],
other than the engineering design parameters of the eye-dropper drop-tip.
Surface tension of two reference product (Lot# 103JJ, 105DD) and present invention
formulations 5a, 5b & 5c (US-PROD-088-36, UP-PROD-088-37, UP-PROD-088-38)
were measured, using a certified surface tensiometer (Wilhelmy plate method, Model
DY -700 DyneMaster Surface Tensiometer, and were analyzed at Exponential Business
and Technology Company (Ebatco), an ISO 17025 certified laboratory). Results
suggested that surface tension of reference product and present invention formulations
5a, 5b & 5c are comparable.
Reference Reference
US-PRODUPUP-
PRODTest
Lot No Lot No
088-36
PROD-
088-38
103JJ 105DD 088-37
Surface
Tension 39.5 40.1 44.5 43.0 38.6
(mN/m)
A comparison of Surface Tension (mN/m) of reference products and present invention
formulations 5a, 5b & 5c are shown in Figure 2.
(c) Drug release profile: The dissolution profile of a suspension-based ophthalmic eyedrop
product is a critical quality attribute and a performance characteristic for a
suspension. The rate of drug dissolution affects the bioavailable drug, since it is the
dissolved drug fraction that is absorbed by tissues. Given that approximately 95% of
28
5
10
15
20
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each eye-drop is washed away rapidly by naso-lacrimal drainage, parameters that can
affect the dissolution of a suspension are particle size, solid-state microstructure and
viscosity. In terms of particle size, theory dictates that the rate of dissolution is higher
for smaller particles, provided the crystals have equivalent degrees of crystallinity and
solid-state microstructure. Dissolution was performed using Flow through cell (USP
Type IV) Sotax Cp7 smart System (Closed System) in Simulated Tear Fluid pH 7.4.
Results are presented in below table.
%drug Reference Lot Reference Lot US-PRODUPUP-
PRODPRODrelease
No 103JJ No 105DD 088-36
088-37
088-38
5 46 45 40 53 55
10 74 72 64 78 85
15 85 85 74 85 94
20 91 92 81 90 97
25 94 96 87 93 98
30 96 98 90 95 98
45 98 99 95 97 98
60 98 100 96 98 98
The drug release profile of reference product and present invention formulations are
comparable. A drug release profile of reference products and present invention
formulations 5a, 5b & 5c are shown in Figure 3.
(d) Rheology: Viscosity of a fluid is defined as resistance to fluid flow. For an ophthalmic
drug product, the residence time of the eye-drop on the ocular surface is often a function
of the viscosity of the formulation. Thus, viscosity is normally considered a critical
quality attribute when establishing sameness between the branded product and the
ANDA product. Since viscosity is driven by the polymer in the formulation (Carbomer
974P), data from the reference product and present invention formulations as a function
of increasing shear rate must be obtained to perform a complete comparative analysis.
Anionic polymers such as Carbomer 974P are shear-thinning. Eye-drops applied onto
the ocular surface are subjected to shear forces imparted by blinking, thinning the
applied formulation. Comparative analysis should include the rates of shear thinning of
the test batches, compared to reference product. The study was done using Brookfield
29
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RPM
10
20
30
40
50
60
70
80
90
100
Ametek LV DV2T Cone and Plate viscometer with Spindle CPA-52Z at 60 RPM at 25
± O.l°C
Reference Reference Lot US-PROD- US-PROD- US-PRODLot
No 103JJ No 105DD 088-36 088-37 088-38
167.40 153.50 130.20 125.60 98.60
118.60 113.90 93.02 89.76 74.88
97.36 94.88 76.59 73.17 65.42
84.41 82.79 66.51 63.72 59.53
75.16 74.42 59.35 56.74 55.07
68.21 68.06 50.23 51.94 51.47
62.72 62.99 47.09 48.10 48.50
58.49 58.60 44.55 45.11 46.28
54.88 55.09 44.55 42.58 44.03
51.90 52.09 42.32 40.56 42.14
The results indicate that the rheology of reference product and present invention
5 formulations are comparable.
(e) XRD Study: The crystallinity is a critical parameter for suspension characterization,
and it impact on drug dissolution and drug release into the eyes. Any difference in
crystallinity/polymorph will impact on to the bioavailability of the drug in eye. XRD
study was done to characterize the polymorph/crystalline nature in drug product. Bruker
1 0 AXX/DS focus using Lynx eye detector was used for XRD determination.
An overlay of the XRPD patterns of the crystals harvested from the batches of reference
product and present invention formulations appears in Figure 4. The five XRPD
patterns display a number of discrete and well-resolved diffraction peaks, indicating
15 that the samples are crystalline. The patterns also display peaks at very similar 0 28
positions, as shown in the stacked plot in Figure 4, suggesting that they contain the
same solid form or mixture of solid forms, i.e., the same polymorph.
2 theta value
S.No
Reference Reference
US-PROD- US-PROD- US-PRODLot
No Lot No
088-36 088-37 088-38
103JJ 105DD
1 12.551 12.50 12.47 12.49 12.50
2 16.510 16,489 16,482 16.500 16.491
3 18.432 18.42 18.35 18.458 18.421
4 20.24 20.20 20.21 20.23 20.224
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5 21.037 21.03 21.02 21.068 21.028
6 22.094 22.09 22.041 22.098 22.093
7 22.556 22.52 22.539 22.566 22.547
8 23.121 23.10 23.059 23.11 23.093
9 24.135 24.127 24.077 24.134 24.115
10 25.088 25.05 24.949 25.071 25.089
A comparison of 2 theta value of reference products and present invention formulations 5a, 5b
& 5c are shown in Figure 4.
UTILITY OF THE PRESENT INVENTION
5 The present inventors have provided an aqueous ophthalmic composition. The composition
contains either Benzododecinium Bromide (BDDB) or Sodium Perborate or Polyquaternium··
1 as a preservative for improved preservation of the cornpositions. The composition has shovvn
potential effects in lowering intraocular pressure in patients with glaucoma or ocular
hypertension.

THE CLAIMS:
1. An aqueous ophthalmic composition, comprising:
a therapeutically effective amount of brimonidine or their salts thereof;
a therapeutically effective amount of brinzolamide or their salts thereof;
buffers at a concentration that is at least about 0.05% w/v to 5.0% w/v of the
ophthalmic composition;
a preservative and;
pharmaceutically acceptable excipients, wherein the pH of said composition is
less than 8.0.
2. The composition as claimed in claim 1, wherein the composition comprises 0.01-0.5%
(w/v) of brimonidine tartrate.
3. The composition as claimed in claim 1, wherein the composition comprises 0.01-0.5%
15 (w/v) of brinzolamide.
4. The composition as claimed in claim 1, wherein the buffer includes, but not limited to,
acetate buffers, citrate buffers, phosphate buffers, tromethamine and mixtures thereof.
20 5. The composition as claimed in claim 1, wherein the composition is substantially free
25
of borate buffers.
6. The composition as claimed in claim 1, wherein the pH of the composition is not more
than 8.0.
7. The composition as claimed in claim 1 to 8, wherein the composition has a pH at least
4 but less than 8.0.
8. The composition as claimed in claim 1, wherein the preservative is selected from
30 benzododecinium bromide (BDDB), chlorobutanol, sodium perborate, cetrimonium
chloride, thiomersal, methyl parahydroxybenzoate, propyl parahydroxybenzoate,
32
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sorbic acid and derivatives thereof, polyquaternium ammomum chloride,
polyquaternium-1, polyaminopropyl biguanide, phenyl mercuric nitrate, phenyl
mercuric acetate, hydrogen peroxide and their mixture thereof.
5 9. The composition as claimed in claim 1, wherein the composition is substantially free
10
15
of benzalkonium chloride.
10. The composition as claimed in claim 1, wherein the composition satisfies Ph. USP, Ph.
Eur. B or both.
11. The composition as claimed in claim 1, wherein one or more pharmaceutical acceptable
excipients if included, would be selected from a group, but not limited to buffering
agents, preservatives, tonicity agents, surfactants, viscosity-modifying agents or a
suspending agent and mixtures thereof.
12. The composition as claimed in claim 1, wherein the composition further comprising a
suspending agent.
13. The composition as claimed in claim 12 wherein the suspending agent is selected from
20 carboxyvinyl polymer (Carbomer 974 P), xanthan gum, gellan gum, sodium
carboxymethyl cellulose alginic acid, carageenans.
25
14. The composition as claimed in claim 1, wherein the composition further comprising
one or more polyols.
15. The composition as claimed in claim 14 wherein the polyol if used, includes but not
limited to, mannitol, glycerin, xylitol, sorbitol, propylene glycol or combination
thereof.
30 16. The composition as claimed in claim 1, wherein the composition is a sterile aqueous
suspensiOn.
33
wo 2021/220194 PCT/IB2021/053533
17. The composition as claimed in claim 1, wherein the composition IS for topical
ophthalmic delivery comprising administering said composition in the eyes in need
thereof.
5 18. The composition as claimed in claim 1, wherein the sterile aqueous suspensiOn IS
10
15
20
25
30
suitable for ophthalmic use.
19. The composition as claimed in claim 1, wherein the composition is administered either
once a day or twice a day to each eye in need thereof.
20. A method of reducing intraocular pressure in a patient in need thereof, comprising
administering to the patient the composition of claims 1 to 19, the administered
composition comprising a therapeutically effective amount of brimonidine tartrate and
brinzolamide each at a concentration that is at least about 0.05% w/v to 5.0% w/v of
the ophthalmic composition.
21. Use of a composition as claimed in claims 1 to 19 for reducing intraocular pressure in
a patient in need thereof comprising safe and a therapeutically effective amount of
brimonidine tartrate and brinzolamide.
22. An aqueous ophthalmic composition, comprising:
a therapeutically effective amount of brimonidine or their salts thereof;
a therapeutically effective amount of brinzolamide or their salts thereof;
buffers at a concentration that is at least about 0.05% w/v to 5.0% w/v of the
ophthalmic composition;
a preservative;
one or more polyols;
a suspending agent and;
optionally pharmaceutically acceptable excipients, wherein the pH of said
composition is less than 8.0.
34
wo 2021/220194 PCT/IB2021/053533
-40
Comparison of Zeta Potential (mV)
of reference products and present invention formulations 5a, 5b & 5c.
-35
- ~~
~~
-~~
~~
-30 -25 -20 -15 -10 -5 0
Zeta Potential in mV
FIGURE 1: Comparison of Zeta Potential (m V) of reference products and present invention
formulations 5a, 5b & 5c.
Comparison of Surface Tension (mN/m) of reference products and
present invention formulations 5a, 5b & 5c
UP-PR00-088-38 .
UP-PR00-088-37 .
USPR00-088-36
RLO(Batch NO 1 0500)
RLO (Batch NO 1 03JJ)
·i ------------------------------------------------ ----------------·
0 5 1 0 15 20 25 30 35 40 45 50
Surface Tension (mN/ m)
FIGURE 2: Comparison of Surface Tension (mN/m) of reference products and present
invention formulations 5a, 5b & 5c.
1/2
wo 2021/220194
100
90
80
70
ll! 60 "Q')
Q...j 50 Cl
.::.J. c 40 -,R. 0
30
20
10
0
0 10 20 30 40
Time in Min
PCT/IB2021/053533
---~---- RLO (Batch NO 1 03JJ)
---®--- RLO(Batch NO 1 0500)
c"':!i::"" U&PR00-088-36