FIELD OF THE INVENTION
The present invention relates to a storage stable composition of prostaglandin derivative.
BACKGROUND OF THE INVENTION
Glaucoma is an ophthalmic disease that often manifests as a progressive increase in
intraocular pressure. Untreated glaucoma leads to severe defects in the structure of the eye,
and particularly damages the head of the optic nerve, resulting in reduction of the visual field
and optical atrophy.' In certain instances, the pathology is related to insufficient drainage of
aqueous humor from the eye. Other factors, including the production of aqueous humor and
pressure on the episcleral veins, may also contribute to development of the condition.
Prostaglandin derivatives are one of the known poorly soluble drugs and are administered via
ophthalmic route for treating elevated intraocular pressure. One of the prostaglandin
derivatives, latanoprost has been approved in the United States of America for the reduction
of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
I t is recommended for this product that the unopened bottles be stored under refrigeration at a
temperature of approximately 2' to 8OC and during shipment to the patient, the bottle may be
maintained at temperatures up to 40°C for a period not exceeding days. Once the bottle is
opened for use, it may be stored at room temperature up to 25°C for 6 weeks.
Heat sensitive drugs demand temperature conditions both in transport and storage. Very
sensitive items, tend to lose their potency quickly when exposed to higher temperatures
especially to temperatures above 25OC or 40°C for extended periods of time. In tropical
countries like India there is always the chance of exposure to high temperatures. Hence this
particular composition demands an effective cold chain shipment.
All heat sensitive items are usually dispatched with precautions like, but not limited to, the
ones listed below:
1. They are transported by air, the field is informed about the date and time of arrival.
2. They are transported in insulated packaging boxes coated with ice packs. These boxes
maintain the correct temperature for at least 72 hours after leaving the supplier.
_ ___._p__l_l_O___~_ i---e---e-----.c--*-----F-. -----... - -- . - ---. -
g!..~f.r..g; $,.@.&, c a,s.... ..:u 2 - ~,..it. a:. -. 8 P e: a e .. 8.. .p$: ' .by .q-
- . - - - B a - e = - - - - - a a - - . d , - & - - - - d . P
Id
3. In order not to interrupt the cold chain, it is recommended to transport the cold boxes to
the place of destination and to put the drugs in the refrigerator upon arrival.
4. They must be accompanied by a cold chain monitor card, data loggers, etc.
It is obvious for those in the field that in order to maintain the conditions as exampled above
increases the transit costs of each shipment and eventually has bearing on the price and shelf
life of the product.
Hence, there is a need for a storage stable composition of latanoprost, which is stable at room
temperature and'capable of being supplied without the need of a cold chain.
OBJECT OF THE INVENTION
An object of the invention is to provide a storage stable composition of latanoprost that may
be stored and transported at 25OC.
SUMMARY OF THE INVENTION
Provided herein are storage stable ophthalmic composition for the treatment of ophthalmic
conditions, including conditions related to intraocular pressure (IOP).
.
DETAILED DESCRIPTION OF THE INVENTION
The stable ophthalmic composition of the present invention is used for the treatment of
glaucoma, ocular hypertension, or combinations thereof. Further, the stable ophthalmic
composition described herein is used for treating high IOP.
The ophthalmic composition of the present invention exhibits chemical stability, physical
stability and physiological stability on storage at 25°C.
The present invention discloses a stable ophthalmic composition comprising a prostaglandin
derivative; a preservative; an isotonic agent; a buffer agent; a stabilizer or stabilizing agent
along with pharmaceutically acceptable excipients.
The stable ophthalmic composition of the present invention, is for a prostaglandin derivative,
preferably the prostaglandin derivative is latanoprost.
'4'
The composition of the present invention is stable on storage at temperatures 25°C and above
upto 40°C for extended periods of time, and is well-tolerated when administered to the eye,
even during long-term therapy. The composition of the present invention after 6 months of
storage at 25" C comprises at least 98% of the initial amount of latanoprost. Thus, in some
embodiments, composition, containing the active agents (e.g., as formulated) described
herein are thermally stable. In certain embodiments, composition containing the active agents
(e.g., as formulated) described herein are thermally stable at reduced temperature, at room
temperature, at ambient temperatures, at about 25" C., at elevated temperatures, at about 40"
C., or the like.
The composition of the present invention as disclosed herein comprises a unique'stabilizing
system.
The composition of the present invention comprises a prostaglandin derivative, a
preservative, an isotonic agent, a buffer and a stabilizer and optionally other pharmaceutically
acceptable excipients.
The composition disclosed herein comprises a prostaglandin derivative. Preferably the
prostaglandin derivative is latanoprost. The amount of latanoprost present in the invention
may be in the range of 0.001-0.5 wt%, preferably 0.003-0.01 wt%, most preferably 0.005
wt%.
The composition of the present invention comprises a preservative. The preservative is
selected from group comprising benzalkonium chloride and other quaternary ammonium
preservative agents, phenylmercuric salts, sorbic acid, chlorobutanol, disodium edetate,
thimerosal, methyl and propyl paraben, benzyl alcohol, and phenyl ethanol, preferably
benzalkonium chloride and is present in the range of 0.001 to 0.03 wt%, more preferably in
the range of 0.01 to 0.02 wt%.
The composition of the present invention comprises an isotonic agent. The isotonic agent is
selected from group comprising dextrose, glycerol, sodium chloride, potassium chloride,
mannitol, sorbitol and xylitol, preferably the isotonic agent is sodium chloride and is present
in the range of 0.1 to 0.5wt%, more preferably in the range of 0.2 to 0.3wt%.
The composition of the presentinvention is such that the pH of the composition is maintained
in the range of pH 6.0-7.5. The composition of the present - invention maintains pH in the
- , _ _ _ ____;_____=___,--A - --=-.--.------- -.--------= - - - --
,-
G. 6.-61 kt.& b,&,. w-?&. 4' L - n.,.;,. p:. -- ,A bit.. 6. k,. 5 - .d:P- :'.;.>P-:<. . -~ -
--- ~ l ' g ~ " o ~ T ~ 0 ~ 7 3 "pedrloEd oZfT~=hEeif f'Iile. ThepH ;f the composition is >
b',
maintained by using a buffer selected from the group comprising phosphate buffers, MES,
Bis-Tris, ADA, aces, PIPES, MOPSO, Bis-Tris Propane, BES, MOPS,TES, HEPES,
Disodium hydrogen phthalatel Sodium dihydrogen orthophosphate, Dipotassium hydrogen
phthalatel Potassium dihydrogen orthophosphate, Potassium dihydrogen orthophosphatel
sodium hydroxide, Barbitone sodium1 Hydrochloric acid buffers. Preferably, the buffer is a
phosphate buffer and is present in the range of 0.4 to 0.8wt%, preferably in the range of 0.6 to
0.7wt%.
The pH of the composition of the present invention is in the range of 6.5 to 6.7.
The composition of the present invention also comprises a stabilizer or a stabilizing agent,
The stabilizing agent enhances the chemical stability, physiological, andlor physical stability
of the composition or compositions. The stabilizer is selected from of the group comprising
polysorbate 80, poloxarners, including poloxamer 188, polyethoxylated castor oil and
polyethoxylated hydrogenated castor oil, and polyoxyl40 stearate. polyoxyl40 hydrogenated
castor oil, polyoxyl 35 hydrogenated castor oil, polyoxyethylenesorbitan fatty acid esters,
poloxamers, vitamin E-TPGS 1000, polyoxyethylene alkyl ethers, Solutol HS-15, Tagat TO,
Peglicol 6-oleate, polyoxyethylenesterates, and saturated polyglycolyzed glycerides; and
wherein the substituted cellulosic polymer is selected from the group consisting of
hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC),
hydroxyethylcellulose, methylcellulose, maltodextrin, and povidones.
In some embodiments, a composition or compositions described herein comprises about 2
wt% to about 10 wt% of a stabilizer.
The composition of the present invention may be effectively stored in natural polyethylene
containers without any drug loss, the inventors surprisingly found that when, the
prostaglandin derivatives were formulated as disclosed' in the present invention, they were
found to be stable in PEG containers.
The composition of the present invention is stable after 6 months of storage at 40°C and 75%
relative humidity, the composition comprises about 98% or more of the initial amount of the
active ingredient such as latanoprost.
The composition of the present invention may be used for lowering the intra-ocular pressure
. ' in a mammal. -
___._______"___F___s___ _B_---__- -_------I --.-- - - - -
, , U B j ~ l b PP ;. a, ...D C. ,4. - 8,.@!8 ,. -- 2'R't.L.. 8, k..~ B. $5 - .s.s.-x.;-
-'--Ab-LDr--.mdh--------ra--
id^
ADVANTAGES
The composition of the present invention is storage stable and does not require a cold chain
for transport. The composition is suitable for tropical countries, where there .is huge
fluctuation in temperature. Further the composition of the present invention is suitable for
administration to mammals without any adverse effects during its shelf life.
The present invention is illustrated by way of examples here below. The examples are meant
to illustrate the invention and not limit the scope of the present application in any manner.
Example 1: Composition ofthe present invention
Various compositions of the present invention as set out in the detailed description were
prepared by varying the components as set out in Table 1. A composition as currently
available in the market was also prepared for comparison purposes.
Table 1: Compositions of the present invention
I 'Name of
Ingredients
m Chloride
chloride
dihydrogen
phosphate
I monohvdrate
Anhydrous
disodium
Polyoxyl35
Poloxamer
1188
----
Quantity (% wlv)
Latanopros
t ED with
HCO 40
ARDOOlA
0.005
0.02
0.3
0.7
0.6
0.5
X
X
X
- -4s. 30 rD;,- B I
Latanopro
st ED with
HCO 35
ARD002A
0.005
0.02
0.3
0.7
0.6
X
0.5
X
X
-*E-*.------& i -QS $t&-,
Latanoprost
ED with
Poloxamer
407
ARD004A
0.005
0.02
0.3
0.7
0.6
X
X
0.2
X
zr;+Yq7 Sz-t0---
=lrsC------..,-
Latanoprost
ED with
HCO 40 +
3 5
ARD003A
0.005
0.02
0.3
0.7
0.6
0.25
0.25
X
X
--,~;% .-IQ~- -
Latanoprost
ED with
Poloxamer
188
ARDOOSA
0.005
0.02
0.3
0.7
0.6
X
X
X
0.1
= q~S~t0-
Latanoprost
ED with
Poloxamer
407 + 1 88
ARD006A
0.005
0.02
0.3
0.7
0.6
X
X
0.1
0.05
-~TsP~o---
Fomulation
currently
available in
market
0.005
0.04
+
+
+
X
X
X
X
-q7s~t-to---
All the components were formulated into a composition and tested for its physicochemical
parameters. Based on the various comparison of the physicochemical parameters ARDOOlA
was proceeded for further tests.
Example 2: Scale up of the composition of the present invention.
Table 2: A composition of the present invention
Based on the various physicochemical parameters the composition of the present invention
Name of Ingredients
Latanoprost
Benzalkonium Chloride
Solution
Sodium chloride
Sodium dihydrogen
phosphate monohydrate
Anhydrous disodium
phosphate
Polyoxyl40 castor oil
(Cremophor RH-40)
Water for injections
was scaled up. Various quantities of the components of the composition were measured as
set out in Table 2. Sodium chloride was dissolved in 750ml Water for Injection (80"- 85OC)
by stirring and until a clear solution is obtained. To this solution, sodium dihydrogen
Quantity (%w/v)
0.005
0.02
0.3
0.7
0.6
0.5
q.s. to 100 ml
phosphate monohydrate was dissolved by stirring. Further Disodium hydrogen phosphate
anhydrous and benzalkonium chloride Solution was solubilized sequentially. In a separate
Qty Used for 1 liter
0.05
0.2
3
7
6
5
q.s. to 1 liter
container, Polyoxyl-40 hydrogenated castor oil is dissolved in 50 ml of WFI, by stirring, the
solution is cooled to 25OC and calculated quantity of Latanoprost is dissolved in the same
until a clear solution is obtained. Both the solutions are mixed, the pH is adjusted to a range .
of pH 6.5-6.8, and the final volume is made to 1L to provide the composition of the present
invention. --------v-~-~----- ~ --..---------... -..--..--= ~ -=-- - .- -~ -- - - u. a . a , . - - -- a . . 0.. a. :-5.e- o - - a I..u. U. K,. L. .XS,. -7s n . ~
. . Mr._Y...-. -...s..P I.-.. - > * ... . -;-.;*l-dC._..-A , _ - _ b r -,RY .... _ . " .. . .-- ... .. Am... *." ,-.. , . .. .. . . , I.,. r i . I. I . . . ; &..L.
1/
Example 3: Stability studies of a composition of the present invention
The composition of the present invention as described herein at Example 2 was subjected to
stability testing and results are provided herein at Table 3.
Table 3: Stability testing of the composition of the present invention
From the table above, it may be noted that the composition of the present invention was
found to be stable up to 6 months at accelerated storage condition.
Sample Analysis Report Storage Condition: 40°C/75%RH
Example 4: Synergist effect of the compound of the present invention.
To examine synergistic effect of the composition of the present invention, various
combinations of the components of the present invention were carried out and the same are
listed herebelow at Table 4.
Product
Name
Batch No.
Latanoprost Ophthalmic 0.005% wlv
Solution
Pack.
Spec.
Label claim
2.5 ml LDPE vials
Specification
Clear
colorless
solution
Between 6.0
and 7.5
90-110%
of LC
SI.
No
.
1
2
3
Results
ARDOO 1 A
Parameters
Description
PH
Assay of
Latanoprost
6 .
Months
Clear
colorless
solution
6.57
98.3 1
Mfg.
Date
Initial
Clear
colorless
solution
6.70
98.26
Jun. 20 1 1
1
Month
Clear
colorless
solution
6.67
97.86
4
Months
Zlear
colorless
solution
6.65
97.13
2
Months
Clear
colorless
solution
6.72
97.94
3
Months
Clear
colorless
solution
6.63
97.18
LC1
Table 4: Composition of the present invention without certain components
From Table 4, it may be noted that several compositions of the present invention being (7AName
of .
Ingredients
Latanoprost
Benzalkonium
Chloride
Sodium
chloride
Sodium
dihydrogen
phosphate
monohydrate
Anhydrous
disodium
phosphate
Polyoxyl40
castor oil
(Cremophor
RH-40)
Water for
injections
10A) were prepared in which one of the various components has not been added.
Composition 11A is a composition of the present invention comprising all components. All
Quantity (% wlv)
compositions were prepared as per Example 2 and packaged in LDPE containers and then
tested for the specified parameters of Ophthalmic Solutions analysis such as Description, pH,
Osmolarity and Assay of Latanoprost. The results are'provided in Table 5.
ARDOllA
0.005
0.02
0.3
0.7
0.6
0.5
q.s. to
100%
ARD007A
0.005
0.02
X
0.7
0.6
0.5
q.s. to
100%
Table 5: Physicochemical tests of composition listed at Table 4.
ARDOOSA
0.005
0.02
0.3
X
0.6
0.5
q.s. to
100%
Description
Parameters
ARD009A
0.005
0.02
0.3
0.7
X
0.5
q.s. to 100%
Compositions
ARDOlOA ARDOllA
ARDOlOA
0.005
0.02
0.3
0.7
0.6
X
q.s. to
100%
ARD007A
Clear
colorless
solution
colorless I colorless I
ARDOOSA
Clear
colorless
solution
Clear
solution I solution
I I
ARD009A
Clear
colorless
solution
Clear
From Table 5, it may be noted that the composition 10A & 11A possess suitable parameters
and were thus tested for their storage stability at 40°C/75%RH for 6 months for further
stability: These samples were analyzed for Description, pH and Latanoprost assay at regular
intervals. Table 6 shows results of stability.testing.
Osmolarity
Assay of '
Latanoprost
Table 6: Stability tests of composition ARDOlOA and ARDOllA
From table 6, it can be noted that the composition the composition comprising all
components, being'11A is stable upto 6 months.
286
98.79%
185
98.97%
Parameters
Description
PH
Osmolarity
Assay of
Latanoprost
283
98.09%
Stability Results
285
98.22%
ARDOlOA
284
98.15%
lmonth
Clear
colorless
solution
6.66
287
98.01%
ARDOllA
lmonth
Clear
colorless
solution
6.61
283
98.46%
3 month
Clear
colorless
solution
6.60
289
73.53%
6 month
Clear
colorless
solution
6.56
284
41.14%
3 month
Clear
colorless
solution
6.58
28 1
98.21%
6 month
Clear
colorless
solution
6.54
286
98.03%
f.4'
From example 4, it can be concluded that all components of the composition of the present
invention act in a synergistic manner and in toto the composition of the present invention is
synergistic.
Example 5: Stability studies of the marketed Product with the product of the present
invention
The product of the present invention was tested for its stability in comparison with the
already marketed product as listed at example 1. The results of the stability testing are listed
here below at Table 7.
Table 7:.Marketed Product Analysis Report
From table 7, it can be clearly seen that the composition of the present invention is stable in
comparison with the marketed product. From the disclosure, it can be clearly understood that
Storage Condition: 40°C/75%RH
the product of the present invention is storage stable and does not require cold chain as I
Product
Name
Batch No.
Marketed product Label claim
S1.
No.
1
2
3
0.005% w/v
Inference: The product assay was found to be lower than the specified limits at accelerated
storage condition..
Results
203 583
Parameters
Description
PH
Assay of
Latanoprost
Pack. Spec.
Specification
Clear
colorless
solution
Between 6.0
and 7.5
90 - 110 %
of LC
Initial
Clear
:olorless
solution
6.72
98.58
3 ml LDPE vials
Mfg'
Date
3
Months
Clear
colorless
solution
6.63
71.91
Mar. 2012
1
Month
Clear
colorless
solution
6.69
90.24
2
Months
Clear
colorless
solution
6.76
80.48
4
Months
Clear
colorless
solution
6.55
63.16
6
Months
Clear
colorless
solution
6.69
40.22
C'
Example 6: Safety and toxicity studies
The composition of the present invention was tested for irritation or corrosion of the eye both
in rabbits and in rats of both sexes male and female in each species. From the studies, it was
noted that the composition of the present invention did not cause any change in the opacity of cornea, opacity of iris, conjunctival redness or chemosis regardless of the species and the sex
. of the animal. Hence, the composition of the present invention is safe and does not cause any
adverse effects.

We Claim:
1) A stable ophthalmic composition comprising a prostaglandin derivative; a
preservative; an. isotonic agent; a buffer agent; a stabilizer or stabilizing agent along
with pharmaceutically acceptable excipients.
2) The. composition as claimed in claim 1. wherein the prostaglandin derivative is . , .
Latanoprost and is present in the range of 0.001 to 0.5 wt%, more preferably in the
range of 0.003 to 0.01 wt%.
3) The composition as claimed in claim 1 wherein, the preservative is selected from
group comprising benzalkonium chloride and other quaternary ammonium
preservative agents, phenylmercuric salts, sorbic acid, chlorobutanol, disodium
edetate, thimerosal, methyl and propyl paraben, benzyl alcohol, and phenyl ethanol,
preferably benzalkonium chloride and is present in the range of 0.001 to 0.03 wt%,
more preferably in the range of 0.01 to 0.02 wt%.
4) The composition as claimed in claim 1 wherein, the isotonic agent is selected from
group comprising dextrose, glycerol, sodium chloride, potassium chloride, mannitol,
sorbitol and xylitol, preferably the isotonic agent is sodium chloride and is present in
the range of 0.1 to 0.5 wt%, more preferably in the range of 0.2 to 0.3 wt%.
5) The composition as claimed in claim 1 wherein, the buffering agent is selected from
the group comprising phosphate buffers, MES, Bis-Tris, ADA, aces, PIPES, MOPSO,
Bis-Tris Propane, BES, MOPS,TES, HEPES, Disodium hydrogen phthalatel Sodium
dihydrogen orthophosphate, Dipotassium hydrogen phthalatel Potassium dihydrogen
orthophosphate, Potassium dihydrogen orthophosphatel sodium hydroxide, Barbitone
sodium1 Hydrochloric acid buffers, preferably, the buffer is a phosphate buffer and is
present ih the range of 0.4 to 0.8 wt%, preferabl; in the range of 0.6 to 0.7 wt%.
6) The composition as claimed in claim 1 wherein, the stabilizer or stabilizing agent is
selected from the group comprising polysorbate 80, poloxamers, including poloxamer
188, polyethoxylated castor oil and polyethoxylated hydrogenated castor oil, and
polyoxyl 40 stearate, polyoxyl 40 hydrogenated castor oil, polyoxyl 35 hydrogenated -.-.-.-.-.=-, -..--*-..- =--- -=- -. - . - - . ---
a..t,e,c,. -1. &.. 8 , .A. , n.2:. rr. - .F . 1 - ~ - ~ * * ~ & ~ - - a ~ - ~ * ~ d -.I. - ~C& . --h IaC,.h.~ i~.J.:Iki..-~'.. 3.. X %i ,-.:K~ - - z ~ . -
castor oil, polyoxyethylene sorbitan fatty acidX