DESC:FIELD OF INVENTION:
The present invention relates to an ophthalmic composition comprising NSAIDs which is free of preservatives reported to have toxic effects such as Benzalkonium chloride
(BAK), Polyquad, stabilized oxychloro complex (SOC) and sodium perborate. The present invention also relates to process for preparing the same in aqueous carrier.
BACKGROUND:
NEVANAC® is a USFDA approved 0.1% sterile topical Nepafenac ophthalmic
Suspension which is used for the treatment of pain and inflammation associated with
cataract surgery. NEVANAC® contains 0.1% Nepafenac as active ingredients and
10 further comprises inactive ingredients such as mannitol, carbomer 974P, sodium
chloride, tyloxapol, edetate disodium, benzalkonium chloride 0.005% (preservative),
sodium hydroxide and/or hydrochloric acid to adjust pH and purified water.
The Food and Drug Administration requires that multi-dose containers of medications
include a preservative to kill bacteria and fungi that may contaminate the formulation
15 in the container; as a result, for several years mostly all ophthalmic formulation
contained preservative to keep the active agents sterile during patient use and prolong
the shelf life by preventing biodegradation and maintaining drug potency.
Preservatives interfere with microbial organisms by causing lysis of plasma
membranes, inhibiting cellular metabolism, oxidizing or coagulating cellular
20 constituents, or promoting hydrolysis [Tripathi BJ, Tripathi RC, Kolli SP. Cytotoxicity
of ophthalmic preservatives on human corneal epithelium. Lens Eye Toxicol Res.
1992;9:361-375]. Preservatives can be classified in two main categories as oxidants or
detergents [Spickett C. Studies of Cellular Responses to Purite and Other Preservatives.
Strathclyde, UK: University of Strathclyde; 2001]. Oxidative preservatives, such as
25 stabilized oxychloro complex (SOC) and sodium perborate, are usually small
molecules that penetrate cell membranes and disrupt cellular function by modifying
lipids, proteins, and DNA [Block SS. Disinfection, Sterilization, and Preservation.
3
Malvern, Pa: Lea & Febiger; 1991]. Their membrane-destabilizing activity is less
potent than that of detergent preservatives.
Detergent preservatives, such as Benzalkonium chloride (BAK) and Polyquad, are
usually monomeric or polymeric compounds that have surfactant effects and alter cell
5 membrane permeability by causing lipid dispersion and lysis of cytoplasmic contents
[Kreiner C. Biochemical aspects of ophthalmic preservatives. Contacto. 1979;Nov:10-
14]. Some may have a similar action on eukaryotic cells and cause cytotoxic effects.
Mammalian cells cannot neutralize detergent preservatives, which can be incorporated
into the cell by liposomes or other intracellular vacuoles and cause cellular damage
10 [Grant WM, Schuman JS. Toxicology of the Eye. Springfield, Ill: Charles C Thomas;
1990]. There has been a growing evidence of preservative toxicity associated with
benzalkonium chloride(BAK) that is correlated with duration of use and multiple
doses. The disruption to the corneal barrier may contribute to the ocular surface toxicity
of BAK. The cytotoxic effects of BAK on ocular tissue cells (particularly conjunctival
15 and corneal epithelium) has been well studied and documented. The threshold
concentration at which toxicity from BAK occurs has been estimated to be 0.005%
much lower than many of its commercially used concentrations. Animal studies have
shown dose-dependent corneal epithelial damage and conjunctival inflammation
changes, findings which have been validated in human subjects. BAK has been shown
20 in patients to result in decreased goblet cell density which normally produce mucins
and participate in tear film stability. Since preservatives are used in multi-dose
ophthalmic products to prevent the growth of bacteria, fungi and other microbes
prolonged use of BAK may cause toxicity and damages the cells of ocular damages.
Therefore, there still remains a need for an effective ophthalmic pharmaceutical
25 composition containing Nepafenac with increased stability, improved solubility and
fewer side effects. In particular, there is a need for an ophthalmic composition that is
free from the preservatives reported to have toxic effect such as BAK, Polyquad,
4
stabilized oxychloro complex (SOC) and sodium perborate to be provided in a multiple
use container.
SUMMARY OF THE INVENTION:
The present invention provides an ophthalmic pharmaceutical composition comprising
5 non-steroidal anti-inflammatory prodrug (NSAID) wherein said composition does not
comprise preservatives reported to have toxic effect such as Benzalkonium chloride
(BAK), Polyquad, stabilized oxychloro complex (SOC) and sodium perborate.
The present invention provides an ophthalmic formulation comprising synergistic
combination of antimicrobial preservative system to preserve the composition against
10 microbial growth without causing Cytotoxicity to ocular tissue.
In another aspect the ophthalmic formulation is an aqueous solution further comprises
solubilizer mixture which improve the solubility, stability and bioavailability of
Nepafenac in aqueous carrier which doesn’t causes irritation associated with
ophthalmic suspension.
15 DETAILED DESCRIPTION OF THE INVENTION
While the making and using of various embodiments of the present invention are
discussed in detail below, it should be appreciated that the present invention provides
many applicable inventive concepts that can be embodied in a wide variety of specific
contexts. The specific embodiments discussed herein are merely illustrative of specific
20 ways to make and use the invention and do not delimit the scope of the invention. To
facilitate the understanding of this invention, several terms are defined below. Terms
defined herein have meanings as commonly understood by a person of ordinary skill
in the areas relevant to the present invention. Terms such as "a", "an" and "the" are not
intended to refer to only a singular entity but include the general class of which a
25 specific example may be used for illustration.
5
"Nepafenac and salts thereof" is not particularly limited as long as it is a
pharmaceutically acceptable salt, and may for example be: a metal salt with lithium,
sodium, potassium, calcium, magnesium, zinc, or the like; a salt with an inorganic acid.
By “pharmaceutically acceptable” is meant a material that is not biologically or
5 otherwise undesirable, i.e., the material can be administered to an individual along with
the relevant active compound without causing clinically unacceptable biological
effects or interacting in a deleterious manner with any of the other components of the
pharmaceutical composition or formulation in which it is contained.
By “effective amount” as used herein means an amount of one or more of the disclosed
10 compounds, effective at dosages and for periods of time necessary to achieve the
desired or therapeutic result. An effective amount may vary according to factors known
in the art, such as the disease state, age, sex, and weight of the human or animal being
treated. Although particular dosage regimes may be described in examples herein, a
person skilled in the art would appreciate that the dosage regime may be altered to
15 provide optimum therapeutic response.
“Excipient” is used herein to include any other compound that may be contained in or
combined with one or more of the disclosed inhibitors that is not a therapeutically or
biologically active compound. As such, an excipient should be pharmaceutically or
biologically acceptable or relevant (for example, an excipient should generally be non20 toxic to the subject). “Excipient” includes a single such compound and is also intended
to include a plurality of excipients. For the purposes of the present disclosure the term
“excipient” and “carrier” are used interchangeably throughout the description of the
present disclosure and said terms are defined herein as, “ingredients which are used in
the practice of formulating a safe and effective pharmaceutical composition.”
25 As used herein, the term “ophthalmic composition” refers to formulation suitable for
administration to the eye or ocular surface in the form of solution, suspension, gel,
patch or ointment.
6
The present invention provides a topical stable ophthalmic composition comprising a
pharmaceutically acceptable non-steroidal anti- inflammatory drug (NSAID) in an
aqueous carrier, wherein the composition is substantially free of BAK, SOC and
sodium perborate.
5 Accordingly, the present invention provides a stable, ophthalmic composition
comprising a non-steroidal anti-inflammatory drug (NSAID) and/or pharmaceutically
acceptable excipients for the treatment of ocular inflammation and pain after cataract
surgery.
Further the present invention provides an ophthalmic composition comprising non10 steroidal anti- inflammatory drug (NSAID) in aqueous carrier wherein NSAID is
Nepafenac or its pharmaceutically acceptable salts thereof. Nepafenac is classified as
a class IV compound as per BCS meaning it has low water solubility and low tissue
permeability. Therefore, due to this reason Nepafenac is mostly marketed as
ophthalmic suspension. But the inventors of the present invention have able to develop
15 an aqueous solution comprising Nepafenac or its pharmaceutically acceptable salts
thereof by using a synergistic combination of complexing agents and surfactants which
act as solubilizers and increases the aqueous solubility of Nepafenac and increases the
aqueous stability and bioavailability of Nepafenac and decreases drug irritation which
was associated with the use suspension.
20 Thus in an embodiment the present invention provides an aqueous composition of
Nepafenac comprising a synergistic combination of complexing agent and a surfactant,
wherein the complexing agent is cyclodextrins selected from natural cyclodextrins (a,
ß- and ?-CDs) and (b) their hydroxyl-propyl derivates (HPa-, HPß- and HP?-CDs),
more preferably Hydroxy propyl beta cyclodextrin and wherein the surfactant is
25 Examples of surfactant include but 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, Octoxynol, polysorbates, tyloxapol, polyoxyl
7
35 castor oil, sorbitan mono laureates, poloxamer and mixtures thereof most preferably
Octoxynol.
In a preferred embodiment the present invention provides an ophthalmic solution
comprising effective amount of Nepafenac or pharmaceutically acceptable salts thereof
5 and one or more pharmaceutical excipients.
In an another embodiment the present invention provides an ophthalmic solution
further comprising one or more additional active agents.
In one embodiment one or more additional active agent is anti-microbial agents
selected from gentamycin, kanamycin, amikacin, sisomicin and tobramycin;
10 quinolones such as norfloxacin, Moxifloxacin, ofloxacin, cinoxacin, ciprofloxacin,
delafloxacin, gemifloxacin, levofloxacin, norfloxacin and a pharmaceutically
acceptable salt thereof.
In an another embodiment the present invention provides ophthalmic solution
comprising Nepafenac and Moxifloxacin including its pharmaceutically acceptable
15 salts.
In one embodiment the present invention provides ophthalmic solution comprising
Nepafenac present in an amount from about 0.05 to 1% w/v and Moxifloxacin
hydrochloride present in an amount from about 0.05 to 1% w/v.
In a preferred embodiment the present invention provides an aqueous ophthalmic
20 solution comprising Nepafenac, a synergistic solubilizer mixture comprising a
complexing agent and a surfactant, and a synergistic non-oxidative/non-detergent
preservative mixture comprising EDTA, Mannitol, propylene glycol, borate and zinc
or salt thereof.
In an another embodiment the ophthalmic solution according to the invention may also
25 comprise conventional excipients used in ophthalmic compositions, such as chelating
agent soothing agents, pH adjusters, tonicity agents and the like.
8
In an embodiment the examples of soothing agents include but not limited to cellulose
derivatives; dextran 70; gelatin; glycerol, Propylene Glycol, polyvinyl alcohol and
povidone most preferably Propylene Glycol.
The pH of the ophthalmic aqueous solution according to the invention pH of such
5 solutions should preferably be maintained between 4.5 and 8.0 with pH adjusters,
common pH adjusting agents such as sodium hydroxide and/or hydrochloric acid may
be used.
In an embodiment the present invention provides an aqueous ophthalmic solution
which comprises Nepafenac, a complexing agent, a surfactant, a non-detergent/non10 oxidative preservative system, a surfactant and pH adjustor, wherein the complexing
agent is hydroxypropyl cyclodextrin, wherein the non-detergent/non-oxidative
preservative system consist of EDTA in combination zinc chloride, propylene glycol
Mannitol, borate, wherein the surfactant is octoxynol and pH adjustor is Sodium
hydroxide.
15 In an embodiment according to the invention is an aqueous ophthalmic solution which
comprises 0.1% w/v to 0.3% w/v nepafenac, a synergistic solubilizer mixture of
Hydroxy propyl cyclodextrin and Octoxynol and synergistic combinations of EDTA
with zinc chloride, mannitol, borate as antimicrobial preservative system, and sodium
hydroxide as pH adjustor.
20 In an embodiment an ophthalmic solution of present invention comprises Nepafenac in
an amount of about 0.1% w/v to 0.5% w/v more preferably 0.1%w/v.
In an another embodiment an ophthalmic solution of present invention comprises a
complexing agent i.e. hydroxypropyl cyclodextrin present in the range of 2.0 % to 30%
more preferably 9.0% w/v to 27% w/v.
25 In an embodiment an ophthalmic solution further comprises EDTA present in the range
of 0.05% to 0.5% more preferably 0.1%.
9
In an another embodiment the present invention further comprises Zinc chloride
present in the range of, 0.001 to 0.05% more preferably 0.0025%.
In an another embodiment the present invention further comprises Mannitol present in
the range of 0.01% to 1.0% more preferably 0.5%.
5 In an another embodiment the present invention further comprises boric acid present
in the range of boric acid present in the range of 0.05% to 0.1% more preferably 0.5%.
In an another embodiment the present invention further comprises propylene glycol in
the range of 0.5% to 5.0% more preferably 0.9%
In an embodiment the ophthalmic solution further comprises surfactant i.e. octoxynol
10 present in the range of 0.05% to 1.0% more preferably 0.1%.
In an another embodiment the present invention provides an ophthalmic solution
comprises:
i. Nepafenac or pharmaceutically acceptable salts thereof present in an amount of
0.1% w/v to 0.3% w/v and;
15 ii. Hydroxy propyl beta cyclodextrin present in an amount of 9 to 27% and;
iii. Octoxynol present in an amount of 0.1% and;
iv. Mannitol present in an amount of 0.5% and;
v. Propylene glycol present in an amount of 0.9% and;
vi. Disodium Edetate present in an amount of 0.1% and;
20 vii. Zinc Chloride present in an amount of 0.0025% and;
viii. Boric acid present in an amount of 0.5%.
The ophthalmic solution of present invention is prepared by using water for injections
as an aqueous carrier and pH was adjusted to 6.5 to 8 with sodium hydroxide.
10
In an another embodiment the present invention provides an ophthalmic solution
comprises:
i. Nepafenac or pharmaceutically acceptable salts thereof present in an amount of
0.1% w/v to 0.3% w/v and;
5 ii. Moxifloxacin Hydrochloride present in an amount of 0.5% w/v to 1% w/v and;
iii. Hydroxy propyl beta cyclodextrin present in an amount of 9 to 27% and;
iv. Octoxynol present in an amount of 0.1% and;
v. Mannitol present in an amount of 0.5% and;
vi. Propylene glycol present in an amount of 0.9% and;
10 vii. Disodium Edetate present in an amount of 0.1% and;
viii. Zinc Chloride present in an amount of 0.0025% and;
ix. Boric acid present in an amount of 0.5%.
In a yet further preferred embodiment, the present invention provides a process of
preparing a stable, ophthalmic composition wherein the composition comprises less
15 preservatives reported to have toxic effect, ophthalmic composition comprising
Nepafenac and/or pharmaceutically acceptable excipients.
In an another embodiment the present invention provides process of preparation of
Nepafenac ophthalmic solution comprising following steps:
1. Add and dissolve Disodium Edetate in water for injection with continuous
20 stirring and;
2. Add and dissolve boric acid in the solution obtained in step 1 with continuous
stirring and;
3. Add and dissolve propylene glycol in to solution obtained in step 2 with
continuous stirring and;
11
4. Add and dissolve mannitol in to solution obtained in step 3 and stir the solution
and;
5. Add and dissolve zinc chloride into solution obtained in step 4 and stir the
solution and;
5 6. Add and dissolve hydroxyl propyl betacyclodextrin in step 5 and stir the
solution, adjust the ph by using sodium hydroxide solution
7. In a separate container add and dissolve octoxynol in water for injection and
stir the solution.
8. Add Nepafenac in solution obtain in step 7 and stir the solution.
10 9. Transfer the solution obtained from step 8 into step 6. Adjusting the Ph if
necessary by adding sodium hydroxide solution.
The following examples provide a detailed illustration of compositions of the present
invention. However, they are illustrative only and not intended to limit the scope of the
invention.
15 EXAMPLE-1
Table-1: Composition details of 0.1% Nepafenac Ophthalmic Solution
S.NO COMPOSITION LABEL CLAIM
1 Nepafenac 0.1% w/v
2 Hydroxy propyl beta cyclodextrin 9.0%
3 Octoxynol 40 0.1%
4 Mannitol 0.5%
5 Propylene glycol 0.9%
6 Disodium Edetate 0.1%
12
7 Zinc Chloride 0.0025%
8 Boric acid 0.5%
9 Water for Injections q.s.
10 Sodium hydroxide For pH adjustment
Process: Dissolve Disodium Edetate in water for injections and stir the solution. To
this solution add and dissolve Boric acid into the solution and stir the solution. To this
solution add propylene glycol followed by mannitol with continuous stirring. To this
5 obtained solution add Zinc chloride and hydroxyl propyl betacyclodextrin. The pH was
adjusted using required quantities of sodium hydroxide solution.
Separately add and dissolve Octoxynol-40 in water for injections. To this solution add
and mix Nepafenac with continuous stirring. Transfer this solution to the above
solution and stir the solution till clear solution is obtained. Make up the solution and
10 fill in vial.
EXAMPLE-2
Table 2: Composition details of 0.3% w/v Nepafenac Ophthalmic Solution
S.NO COMPOSITION LABEL CLAIM
1 Nepafenac 0.3% w/v
2 Hydroxy propyl beta cyclodextrin 27.0%
3 Octoxynol 40 0.1%
4 Mannitol 0.5%
5 Propylene glycol 0.9%
6 Disodium Edetate 0.1%
13
7 Zinc Chloride 0.0025%
8 Boric acid 0.5%
9 Water for Injections q.s.
10 Sodium hydroxide For pH adjustment
EXAMPLE-3 Stability studies
The Nepafenac 0.1% w/v solution prepared from example 1 was subjected to stability
under different temperature.
5 Example 3(a)-Temp. 40° ± 2°C & RH 25 ± 5%
Table 3(a) results obtained when stored at Temp. 40° ± 2°C & RH 25 ± 5%
Test Acceptance
criteria
Initial
testing
After 01
month
After 02
months
After 03
months
After 06
months
Description Greenish
yellow to
yellowish
orange
colored
solution
filled in
three piece
LDPE vial
Greenish
yellow
colored
solution
filled in
three piece
LDPE vial
Greenish
yellow
colored
solution
filled in
three piece
LDPE vial
Greenish
yellow
colored
solution
filled in
three piece
LDPE vial
Greenish
yellow
colored
solution
filled in
three piece
LDPE vial
Greenish
yellow
colored
solution
filled in three
piece LDPE
vial
pH Between
6.0 to 8.0
7.41 7.37 7.22 7.52 7.41
Related substance (by HPLC)
Nepafenac As below
Nepafenac
impurity E
Not more
than 1.0%
0.008% BDL 0.053% 0.178% 0.262%
14
Nepafenac
impurity D
Not more
than 1.0%
0.146 0.143 0.151 0.282 0.499
Nepafenac
impurity B
Not more
than 1.0%
BDL BDL BDL BDL BDL
Nepafenac
Impurity C
Not more
than 1.0%
BDL 0.016% BDL BDL BDL
Nepafenac
Impurity A
Not more
than 1.0%
BDL 0.032 BDL BDL BDL
Single
maximum
impurity
Not more
than 1.0%
0.041 0.200 0.240 0.303 0.605
Total
impurity
(unknown +
known)
Not more
than 3.0%
0.245% 0.324 0.416 0.575 1.127
Assay
Nepafenac
0.1% w/v
Not less
than
0.090%
w/v & not
more than
0.110%
w/v (not
less than
90% & not
more than
110% of
label claim)
0.0981%
w/v
98.1%
0.09774%
w/v
97.74%
0.0995%
w/v
99.50%
0.0988%
w/v
98.82%
0.0971% w/v
97.05 %
The Nepafenac solution 0.1% w/v prepared by example 1 was found to be stable after
06 months of accelerated stability study (Temp. 40° ± 2°C & RH 25 ± 5%).
Example 3(b): 30° ± 2°C & RH 35 ± 5%
15
Table 3(b) results obtained when stored at Temp. 30° ± 2°C & RH 35 ± 5%
Test Acceptance
criteria
Initial
testing
After 03
month
After 06
months
After 09
months
After 12
months
After 18
months
Description Greenish
yellow to
yellowish
orange
colored
solution
filled in
three piece
LDPE vial
Greenish
yellow
colored
solution
filled in
three
piece
LDPE
vial
Greenish
yellow
colored
solution
filled in
three
piece
LDPE
vial
Greenish
yellow
colored
solution
filled in
three
piece
LDPE
vial
Greenish
yellow
colored
solution
filled in
three
piece
LDPE
vial
Greenish
yellow
colored
solution
filled in
three
piece
LDPE vial
Yellowish
orange
colored
solution
filled in
three
piece
LDPE
vial
pH Between
6.0 to 8.0
7.41 7.62 7.51 7.56 7.41 7.24
Related substance (by HPLC)
Nepafenac As below
Nepafenac
impurity E
Not more
than 1.0%
0.008% 0.060 % 0.090 % 0.057 % 0.172 % 0.019%
Nepafenac
impurity D
Not more
than 1.0%
0.146% 0.168 0.142 0.082 0.275 0.335
Nepafenac
impurity B
Not more
than 1.0%
BDL BDL BDL BDL BDL BDL
Nepafenac
Impurity C
Not more
than 1.0%
BDL BDL BDL BDL BDL BDL
Nepafenac
Impurity A
Not more
than 1.0%
BDL BDL BDL BDL BDL BDL
Single
maximum
impurity
Not more
than 1.0%
0.041 0.069 0.128 0.307 0.371 0.567
Total
impurity
Not more
than 3.0%
0.245% 0.103 0.197 0.415 1.032 1.271
16
(unknown +
known)
Assay
Nepafenac
0.1% w/v
Not less
than
0.090%
w/v & not
more than
0.110%
w/v (not
less than
90% & not
more than
110% of
label
claim)
0.0981%
w/v
98.1%
0.098%
w/v
98.08%
0.0967%
w/v
96.67%
0.0973%
w/v
97.34%
0.0996%
w/v
99.63 %
0.098%
w/v
98.24%
The Nepafenac solution 0.1% w/v prepared by example 1 was found to be stable after
18 months of intermediate stability study (Temp. 30° ± 2°C & RH 35 ± 5%).
Example 3(c)
5 Table 3(c) results obtained when stored at 25° ± 2°C & RH 40 ± 5%
Test Acceptance
criteria
Initial
testing
After 03
month
After 06
months
After 09
months
After 12
months
After 18
months
Description Greenish
yellow to
yellowish
orange
colored
solution
filled in
Greenish
yellow
colored
solution
filled in
three
piece
Greenish
yellow
colored
solution
filled in
three
piece
Greenish
yellow
colored
solution
filled in
three
piece
Greenish
yellow
colored
solution
filled in
three
piece
Greenish
yellow
colored
solution
filled in
three
Yellowish
orange
colored
solution
filled in
three
piece
17
three piece
LDPE vial
LDPE
vial
LDPE
vial
LDPE
vial
LDPE
vial
piece
LDPE vial
LDPE
vial
pH Between
6.0 to 8.0
7.41 7.60 7.55 7.56 7.15 7.18
Related substance (by HPLC)
Nepafenac As below
Nepafenac
impurity E
Not more
than 1.0%
0.008% 0.074 % BDL 0.097 % 0.172 % 0.019%
Nepafenac
impurity D
Not more
than 1.0%
0.146% 0.176 0.132 0.170 0.281 0.265
Nepafenac
impurity B
Not more
than 1.0%
BDL BDL BDL BDL BDL BDL
Nepafenac
Impurity C
Not more
than 1.0%
BDL BDL BDL BDL BDL BDL
Nepafenac
Impurity A
Not more
than 1.0%
BDL BDL BDL BDL BDL BDL
Single
maximum
impurity
Not more
than 1.0%
0.041 0.077 0.119 0.201 0.716 0.948
18
Total
impurity
(unknown +
known)
Not more
than 3.0%
0.245% 0.119 0.162 0.201 0.716 0.948
Assay
Nepafenac
0.1% w/v
Not less
than
0.090%
w/v & not
more than
0.110%
w/v (not
less than
90% & not
more than
110% of
label
claim)
0.0981%
w/v
98.1%
0.0971%
w/v
97.14%
0.0972%
w/v
97.15%
0.0922%
w/v
99.18%
0.0944%
w/v
94.39 %
0.0972%
w/v
97.24%
The Nepafenac solution 0.1% w/v prepared by example 1 was found to be stable after
18 months of long term stability study (Temp. 25° ± 2°C & RH 40 ± 5%).
5 Example-4 Stability study
The Nepafenac 0.3% w/v solution prepared from example 2 was subjected to stability
under different temperature.
19
Example 4(a)
Table 4(a) results obtained when stored at Temp. 40° ± 2°C & RH 25 ± 5%
Test Acceptance
criteria
Initial testing After 03 month After 06 months
Description Greenish yellow to
yellowish orange
colored solution
filled in three piece
LDPE vial
Greenish yellow
colored solution
filled in three
piece LDPE vial
Greenish yellow
colored solution
filled in three
piece LDPE vial
Greenish yellow
colored solution
filled in three piece
LDPE vial
pH Between 6.0 to 8.0 6.88 7.35 7.16
Related substances
Impurity A Not more than
1.0%
Not detected Not detected Not detected
Impurity B Not more than
1.0%
Not detected Not detected Not detected
Impurity C Not more than
1.0%
Not detected Not detected Not detected
Impurity D Not more than
2.0%
0.191% 0.465 1.376
Impurity E Not more than
1.0%
Not detected Not detected 0.544%
Single
maximum
impurity
Not more than
1.0%
0.018 0.026 0.305
Total
impurities
Not more than
3.0%
0.209% 0.514 2.440
Assay
20
Nepafenac
0.3 % w/v
(by HPLC)
Not less than
0.27% w/v & not
more than 0.33%
w/v
(not less than 90%
& not more than
110% of label
claim)
0.300% w/v
100.3%
0.3044% w/v
101.47%
0.3085% w/v
102.85%
The Nepafenac solution 0.1% w/v prepared by example 2 was found to be stable after
06 months of accelerated stability study (Temp. 40° ± 2°C & RH 25 ± 5%).
5 Example 4(b)
Table 4(b) results obtained when stored at Temp. 30° ± 2°C & RH 35 ± 5%
Test Acceptance
criteria
Initial
testing
After 03
month
After 06
months
After 09
months
After 12
months
After 18
months
Description Greenish
yellow to
yellowish
orange
colored
solution
filled in
three piece
LDPE vial
Greenish
yellow
colored
solution
filled in
three
piece
LDPE
vial
Greenish
yellow
colored
solution
filled in
three
piece
LDPE
vial
Yellowish
orange
colored
solution
filled in
three
piece
LDPE
vial
Yellowish
orange
colored
solution
filled in
three
piece
LDPE
vial
Yellowish
orange
colored
solution
filled in
three
piece
LDPE
vial
Yellowish
orange
colored
solution
filled in
three
piece
LDPE
vial
pH Between
6.0 to 8.0
6.88 7.30 7.18 7.27 7.46 7.19
Related substances
21
Impurity A Not more
than 1.0%
Not
detected
Not
detected
Not
detected
Not
detected
Not
detected
Not
detected
Impurity B Not more
than 1.0%
Not
detected
Not
detected
Not
detected
Not
detected
Not
detected
Not
detected
Impurity C Not more
than 1.0%
Not
detected
Not
detected
Not
detected
Not
detected
Not
detected
Not
detected
Impurity D Not more
than 2.0%
0.191% 0.443 1.088 1.318 1.375 1.482
Impurity E Not more
than 1.0%
Not
detected
Not
detected
0.207% Not
detected
0.267 0.341
Single
maximum
impurity
Not more
than 1.0%
0.018 0.022 0.089 0.101 0.150 0.231
Total
impurities
Not more
than 3.0%
0.209% 0.487 1.384 1.318 1.822 2.205
Assay
Nepafenac
0.3 % w/v
(by HPLC)
Not less
than 0.27%
w/v & not
more than
0.33% w/v
(not less
than 90%
0.300%
w/v
100.23%
0.3119%
w/v
103.95%
0.3075%
w/v
102.50%
0.3016%
w/v
100.54%
0.2987%
w/v
99.57%
0.2949%
w/v
98.31%
22
& not more
than 110%
of label
claim)
Example 4(c)
Table 4(c) results obtained when stored at Temp. 25° ± 2°C & RH 25 ± 5%
Tests Acceptance
criteria
Initial
testing
After 03
month
After 06
months
After 09
months
After 12
months
After 18
months
Description Greenish
yellow to
yellowish
orange
colored
solution
filled in
three piece
LDPE vial
Greenish
yellow
colored
solution
filled in
three
piece
LDPE
vial
yellowish
colored
solution
filled in
three
piece
LDPE
vial
Yellowish
orange
colored
solution
filled in
three
piece
LDPE
vial
Yellowish
orange
colored
solution
filled in
three
piece
LDPE
vial
Yellowish
orange
colored
solution
filled in
three
piece
LDPE
vial
Yellowish
orange
colored
solution
filled in
three
piece
LDPE
vial
pH Between
6.0 to 8.0
6.88 7.35 7.21 7.40 7.48 7.16
Related substances
Impurity A Not more
than 1.0%
Not
detected
Not
detected
Not
detected
Not
detected
Not
detected
Not
detected
23
Impurity B Not more
than 1.0%
Not
detected
Not
detected
Not
detected
Not
detected
Not
detected
Not
detected
Impurity C Not more
than 1.0%
Not
detected
Not
detected
Not
detected
Not
detected
Not
detected
Not
detected
Impurity D Not more
than 2.0%
0.191% 0.420 0.842 1.069 1.086 1.303
Impurity E Not more
than 1.0%
Not
detected
Not
detected
Not
detected
Not
detected
0.163 0.254
Single
maximum
impurity
Not more
than 1.0%
0.018 0.023 Not
detected
0.051 0.075 0.124
Total
impurities
Not more
than 3.0%
0.209% 0.462 0.842 1.120 1.324 1.681
Assay
Nepafenac
0.3 % w/v
(by HPLC)
Not less
than 0.27%
w/v & not
more than
0.33% w/v
(not less
than 90%
& not more
than 110%
0.300%
w/v
100.23%
0.3062%
w/v
102.06%
0.3068%
w/v
102.27%
0.2990%
w/v
99.65%
0.2970%
w/v
99.00%
0.3044%
w/v
101.46%
,CLAIMS:An ophthalmic composition comprising a therapeutic amount of Nepafenac or its pharmaceutically acceptable salts thereof wherein the composition is free from benzalkonium chloride (BAK), Polyquad, stabilized oxychloro complex (SOC) and sodium perborate.
2. The ophthalmic composition as claimed in claim 1 is an aqueous solution comprising nepafenac and one or more pharmaceutical excipients.
3. The aqueous ophthalmic solution as claimed in claim 2 comprising Nepafenac, a synergistic solubilizer mixture comprising a complexing agent and a surfactant, and a synergistic non-oxidative/non-detergent preservative mixture
comprising EDTA, mannitol, propylene glycol, borate and zinc or salt thereof.
4. The aqueous ophthalmic solution as claimed in claim 2, wherein the amount of Nepafenac in the composition is from 0.1 to 0.5% w/v.
5. The aqueous ophthalmic solution as claimed in claim 3, wherein complexing agent is hydroxy propyl beta cyclodextrin and surfactant is octoxynol.
6. The aqueous ophthalmic solution as claimed in previous claim wherein the solution comprises:
i. Nepafenac or pharmaceutically acceptable salts thereof present in an amount of 0.1% w/v to 0.3% w/v and;
ii. Hydroxy propyl beta cyclodextrin present in an amount of 9 to 27 %
and;
iii. Octoxynol present in an amount of 0.1% and;
iv. Mannitol present in an amount of 0.5% and;
v. Propylene glycol present in an amount of 0.9% and;
25 vi. Disodium Edetate present in an amount of 0.1% and;
26
vii. Zinc Chloride present in an amount of 0.0025% and;
viii. Boric acid present in an amount of 0.5%.
7. A process of preparing preservative free ophthalmic solution comprising
Nepafenac comprising:
5 i. Add and dissolve Disodium Edetate in water for injection with continuous
stirring and;
ii. Add and dissolve boric acid in the solution obtained in step 1 with
continuous stirring and;
iii. Add and dissolve propylene glycol in to solution obtained in step 2 with
10 continuous stirring and;
iv. Add and dissolve mannitol in to solution obtained in step 3 and stir the
solution and;
v. Add and dissolve zinc chloride into solution obtained in step 4 and stir the
solution and;
15 vi. Add and dissolve hydroxyl propyl betacyclodextrin in step 5 and stir the
solution, adjust the pH by using sodium hydroxide solution
vii. In a separate container add and dissolve octoxynol in water for injection
and stir the solution.
viii. Add Nepafenac in solution obtain in step 7 and stir the solution.
20 ix. Transfer the solution obtained from step 8 into step 6. Adjusting the pH if
necessary by adding sodium hydroxide solution.
8. The ophthalmic solution as claimed in claim 2 have pH between 6.0 to 8.0
9. The ophthalmic solution as claimed in claim 2 further comprises additional
active agents selected from norfloxacin, moxifloxacin, ofloxacin, cinoxacin,
25 ciprofloxacin, delafloxacin, gemifloxacin, levofloxacin, norfloxacin.
10. The ophthalmic solution as claimed in claim 9 comprises:
a) Nepafenac present in an amount of 0.1% w/v to 0.3% w/v and;
27
b) Moxifloxacin Hydrochloride present in an amount of 0.5% w/v to 1% w/v
and;
c) Hydroxy propyl beta cyclodextrin present in an amount of 9 to 27% and;
d) Octoxynol present in an amount of 0.1% and;
5 e) Mannitol present in an amount of 0.5% and;
f) Propylene glycol present in an amount of 0.9% and;
g) Disodium edetate present in an amount of 0.1% and;
h) Zinc chloride present in an amount of 0.0025% and;
i) Boric acid present in an amount of 0.5%.