Technical Field;
The present invention relates to a Stabilization of Prostaglandins. More particularly, the
present invention relates to a pharmaceutical composition comprising prostaglandin
packaged in polyethylene container along with oxygen scavenger.
Background & Prior Art:
Containers commonly used for medicinal products comprising prostaglandins include glass containers, polypropylene containers, and polyethylene containers. However, since glass containers are rigid and not squeezable, they are not very suitable for medicinal preparations which are conveniently dispensed on a drop-by-drop basis. Moreover, there is glass delamination problem associated with use of glass. Typical user-friendly containers, dispensers, or bottles for medicinal preparations are formed from e.g. polyethylene, polypropylene, or polyethylene terephthalates (PET), which in most instances provide a suitable combination with a pharmaceutical preparation, resulting in a packaged medicinal product that is user-friendly for dispensing of the pharmaceutical preparation on a drop-by-drop basis.
Plastic containers have been favoured being light weight and more resistant to shock and other mechanical influences, cost effective and offer more design possibilities. Polypropylene and Polyethylene are the plastics required by different FDA authorities.
US Patent No. 6235781 discloses that aqueous prostaglandin compositions packaged in polypropylene containers are more stable than those packaged in polyethylene containers. The '781 further teaches that the stability of prostaglandin formulations is affected by polyethylene containers as compared to polypropylene containers at different stability conditions.
Polypropylene is known to be stronger, stiffer, and more high temperature resistant than low density polyethylene. However, polypropylene has a poor resistance to oxidizing agents such as oxygen and acids, which can lead to fissures and yellowing of the plastic.

Also polypropylene does not provide superior flexibility and processability as compared to polyethylene and hence it is not a first choice of material of containers for sterile compositions. Also polypropylene is not a cost effective option as compared to polyethylene.
Further PCT application No. WO2002022106 discloses that unless refrigerated (2-8°C), lipid soluble prostaglandin derivatives and analogues show unacceptable stability in standard low density polyethylene containers. The requirement that the ophthalmic preparation should be refrigerated greatly reduces the availability of the treatment to those in under developed countries. Furthermore, even where available, refrigeration of the preparation increases the cost of the treatment to the patient, and thus, further reduces its availability to those in need.
US20100216877 teaches that the stability of prostaglandin compositions can be increased when these compositions are packaged in low density polyethylene (LDPE) containers.
The present inventors have found against the teachings of prior art, especially '877, i.e. prostaglandins are not stable in alone LDPE containers, but it requires oxygen scavengers, an aluminium pouch along with LDPE container to protect the oxidation degradation.
Summary of the Invention:
The present invention provides a method of increasing the stability of a pharmaceutical composition comprising an active compound selected from a prostaglandin, a prostaglandin derivative or a prostaglandin analogue and pharmaceutically acceptable excipients wherein the method comprises of providing the composition in polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.

The present invention further provides a method of increasing the stability of a pharmaceutical composition comprising an active compound selected from a prostaglandin, a prostaglandin derivative or a prostaglandin analogue, preservative and pharmaceutically acceptable excipients wherein the method comprises of providing the composition in polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.
The present invention further provides a method of increasing the stability of a pharmaceutical composition comprising an active compound selected from a prostaglandin, a prostaglandin derivative or a prostaglandin analogue, optionally preservative and pharmaceutically acceptable excipients wherein the method comprises of providing the composition in single dose or multidose polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.
Detail Description:
The present invention relates to a pharmaceutical composition comprising prostaglandin packaged in polyethylene container along with oxygen scavenger.
The present invention relates to method of increasing the stability of pharmaceutical composition comprising prostaglandin and pharmaceutically acceptable excipients wherein the method comprises of providing composition in polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.
The prostaglandins, which may be utilized in the present invention, include all pharmaceutically acceptable prostaglandins, their derivatives and analogues, and their pharmaceutically acceptable esters and salts. Such prostaglandins include the natural compounds: PGE,, PGE2, PGE3, PGFa, PGF2a, PGF3a, PGD2 and PGI2 (prostacyclin), as well as analogues and derivatives of these compounds which have similar biological activities of either greater or lesser potencies. Analogues of the natural prostaglandins

include but are not limited to: alkyl substitutions (e.g., 15-methyl or 16,16-dimethyl), which confer enhanced or sustained potency by reducing biological metabolism or alter selectivity of action; saturation (e.g., 13,14-dihydro) or unsaturation (e.g., 2,3-didehydro, 13,14-didehydro), which confer sustained potency by reducing biological metabolism or alter selectivity of action; deletions or replacements (e.g., 11-deoxy, 9-deoxo-9-methylene), chloro (or halogen) for oxygen (e.g., 9.beta.-chloro), oxygen for carbon (e.g., 3-oxa), lower alkyl for oxygen (e.g., 9-methyl), hydrogen for oxygen (e.g., l-CH.sub.20H,l-CH.sub.20Acyl) which enhance chemical stability and/or selectivity of action; and .omega.-chain modifications (e.g., 18,19,20-trinor-17-phenyl, 17,18,19,20-tetranor-16-phenoxy), which enhance selectivity of action and reduce biological metabolism. Derivatives of these prostaglandins include all pharmaceutically acceptable salts and esters, which may be attached to the 1 -carboxyl group or any of the hydroxyl groups of the prostaglandin by use of the corresponding alcohol or organic acid reagent, as appropriate. It should be understood that the terms "analogues" and "derivatives" include compounds that exhibit functional and physical responses similar to those of prostaglandins per se. The prostaglandins suitable for use in the compositions of the present invention can be selected from group consisting of travoprost, latanoprost, bimatoprost, tafluprost and the like.
In one embodiment, the present invention provides a method of increasing the stability of a pharmaceutical composition comprising an active compound selected from a prostaglandin, a prostaglandin derivative or a prostaglandin analogue wherein the method comprises of providing the composition in polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.
In one embodiment, the present invention provides a method of increasing the stability of a pharmaceutical composition comprising an active compound selected from a prostaglandin, a prostaglandin derivative or a prostaglandin analogue and pharmaceutically acceptable excipients wherein the method comprises of providing the

composition in polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.
In one embodiment, the present invention provides a method of increasing the stability of a pharmaceutical composition comprising an active compound selected from a prostaglandin, a prostaglandin derivative or a prostaglandin analogue, preservative and pharmaceutically acceptable excipients wherein the method comprises of providing the composition in polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.
In one embodiment, the present invention provides a method of increasing the stability of a pharmaceutical composition comprising Travoprost wherein the method comprises of providing the composition in polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.
In one embodiment, the present invention provides a method of increasing the stability of a pharmaceutical composition comprising Travoprost and pharmaceutically acceptable excipients wherein the method comprises of providing the composition in polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.
In one embodiment, the present invention provides a method of increasing the stability of a pharmaceutical composition comprising Travoprost, preservative and pharmaceutically acceptable excipients wherein the method comprises of providing the composition in polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.
In one embodiment, the present invention provides a method of increasing the stability of a pharmaceutical composition comprising Travoprost, Benzalkonium chloride and

pharmaceutically acceptable excipients wherein the method comprises of providing the composition in polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.
In one embodiment, the present invention provides a method of increasing the stability of a pharmaceutical composition comprising Latanoprost wherein the method comprises of providing the composition in polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.
In one embodiment, the present invention provides a method of increasing the stability of a pharmaceutical composition comprising Latanoprost and pharmaceutically acceptable excipients wherein the method comprises of providing the composition in polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.
In one embodiment, the present invention provides a method of increasing the stability of a pharmaceutical composition comprising Latanoprost, preservative and pharmaceutically acceptable excipients wherein the method comprises of providing the composition in polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.
In one embodiment, the present invention provides a method of increasing the stability of a pharmaceutical composition comprising Bimatoprost wherein the method comprises of providing the composition in polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.
In one embodiment, the present invention provides a method of increasing the stability of a pharmaceutical composition comprising Bimatoprost and pharmaceutically acceptable excipients wherein the method comprises of providing the composition in

polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.
In one embodiment, the present invention provides a method of increasing the stability of a pharmaceutical composition comprising Bimatoprost, preservative and pharmaceutically acceptable excipients wherein the method comprises of providing the composition in polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.
In one embodiment, the present invention provides a method of increasing the stability of a pharmaceutical composition comprising an active compound selected form a prostaglandin, a prostaglandin derivative or a prostaglandin analogue, preservative and pharmaceutically acceptable excipients wherein the method comprises of providing the composition in multi dose polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.
In one embodiment, the present invention provides a method of increasing the stability of a pharmaceutical composition comprising an active compound selected from a prostaglandin, a prostaglandin derivative or a prostaglandin analogue or combination thereof, preservative and pharmaceutically acceptable excipients wherein the method comprises of providing the composition in multi dose polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.
In one embodiment, the present invention provides a method of increasing the stability of a pharmaceutical composition comprising an active compound selected from a prostaglandin, a prostaglandin derivative or a prostaglandin analogue or combination thereof and pharmaceutically acceptable excipients wherein the method comprises of providing the composition in multi dose polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.

In one embodiment, the present invention provides a pharmaceutical composition comprising a prostaglandin compound that can be stored stable in a polyethylene container.
In one embodiment, the present invention provides a pharmaceutical composition comprising a prostaglandin compound in polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.
In one embodiment, the present invention provides a pharmaceutical composition suitable for ophthalmic use comprising prostaglandin derivatives that is stable on storage at room temperature.
The prostaglandin composition of the present invention is stored in polyethylene container, preferably low density polyethylene container (LDPE).
The prostaglandin composition of the present invention in polyethylene containers, which is packaged in aluminium pouch along with oxygen scavenger, is suitable for topical administration to the ears, nose or eyes, preferably eyes.
In addition to one or more prostaglandins, the composition of the present invention also contains surfactants, antimicrobial preservatives, tonicity agents, and buffers.
Examples of suitable surfactants includes polyethoxylated castor oil, polysorbates, polaxamers, alcohol ethoxylates, ethylene glycol-propylene glycol, block copolymer, alkylphenol ethoxylates, and phospholipid

Examples of suitable buffering agents include acetic acid, citric acid, carbonic acid, phosphoric acid, boric acid, pharmaceutically acceptable salt of the foregoing and tromethamine.
Examples of antimicrobial preservatives include benzalkonium chloride, thiomersal, chlorbutanol, methylparaben, propyl paraben, pollyol complexes, boric acid, phenylethyl alcohol, edentate sodium and polyquad.
Examples of suitable tonicity agents include sodium chloride, potassium chloride, dextrose, mannitol, propylene glycol and glycerin.
The present invention will be further illustrated by the following examples, which are intended to be illustrative but not limiting.
Example 1

Sr. No. Ingredients mg/ml
A B C
1 Travoprost 40 microgram 40 microgram 40 microgram
2 Polyoxyethylene hydrogenated castor oil 5.0 3.5 6.5
3 Boric acid 10.0 14.0 8.0
4 Propylene glycol 7.5 9.5 5.5
5 Sorbitol 2.5 1.5 5.5
6 Zinc chloride 0.025 0.005 0.045
7 Sodium hydroxide q.s q.s. q.s.
8 Hydrochloric acid q.s q.s. q.s.
9 Water for injection q.s q.s. q.s.
Manufacturing Process:

A. Buffer Solution
1. Boric acid, zinc chloride, propylene glycol and sorbitol were dissolved in water for injection one after another under stirring.
2. pH of the solution was adjusted to 5.5 ± 0.5 with sodium hydroxide or hydrochloric acid solution and was heated to temperature 60°C ± 5°C.
B. Travoprost Stock Solution
3. Polyoxyl 40 hydrogenated castor oil was heated to temperature 60°C ± 5°C. Part quantity of buffer solution of step was added to molten Polyoxyl 40 hydrogenated castor oil under stirring. Solution was further cooled to ambient temperature.
4. Travoprost was added to solution of step 3 and stirred until a clear solution is obtained.
C. Mixing of A&B
5. Solution of step 2 and step 4 was mixed under stirring.
6. pH was adjusted with 0.1N sodium hydroxide / 0.1N hydrochloric acid, if required.
7. Volume was made with water of injection, solution was filtered using a suitable filter & further filled and packed in suitable sterile container.
Example 2

Sr.
No. Ingredients mg/ml
D E F
1 Travoprost 40 microgram 40 microgram 40 microgram
2 Polyoxyethylene hydrogenated castor oil 5.0 7.0 3.0
3 Boric acid 3.0 1.0 7.0
4 Tromethamine 1.2 2.4 3.0
5 Mannitol 46 26 66
6 Edetate sodium dihydrate 0.1 0.05 0.2

7 Benzalkonium chloride 0.15 0.25 0.05
8 Hydrochloric acid q.s q.s. q.s.
9 Sodium hydroxide q.s q.s. q.s.
Manufacturing Process:
A. Buffer Solution:
1. Disodium edetate dehydrate, boric acid, and mannitol were dissolved in water of injection one after another under stirring.
2. Polyoxyl 40 hydrogenated castor oil was heated to temperature 60°C ± 5°C and was mixed with water for injection at temperature 60°C ± 5°C under stirring, solution of step 2 was added to step 1.
3. Tromethamine was added further under stirring.
4. pH of the solution was adjusted to 5.5 ± 0.5 with sodium hydroxide or hydrochloric acid solution.
5. Benzalkonium chloride was added to part quantity of above solution and was stirred to obtain a clear solution.
B. Travoprost Stock Solution:
6. Travoprost was added to solution of step 5 and stirred to achieve a clear solution. This travoprost solution was then added to step 4.
7. pH of the solution was adjusted with 0.1N sodium hydroxide / 0.1N hydrochloric acid, if required.
8. Volume was made with water for injection, solution was filtered using a suitable filter and further filled and packed in a suitable sterile container.

Stability Data: Table 1.
Name of product: Travoprost ophthalmic solution
Strength : 0.004%
Storage Condition: 40° C ± 2° C / 25% ± 5% RH Fill volume: 2.5 ml

Stability period 1 Month 2 Months 3 Months 6 Months
Stability condition Initial 40°C/25%RH 40°C/25%RH 40°C/25%RH 40°C/25 %RH
Parameter s Limits as per USP monogr aph Oxyge
n
scave
nger With Oxyg
en scave
nger No Oxyge
n
scave
nger With Oxyg
en
scave
nger No Oxyge
n
scave
nger With Oxyg
en
scave
nger No Oxyge
n
scave
nger Yes
Assay (%) 90.0-110.0% 100 95.2 95.7 95.0 NP 95.3 NP 97.7
Degradation products (%)
5,6-trans isomer NMT 5.0 % 2.2 2.2 2.0 1.9 2.0 1.9 1.5 1.8
15-keto Derivative NMT 1.0% ND 0.26 0.3 0.16 0.75 0.11 1.4 0.11
Single
unknown
maximum NMT 1.0% 0.23 0.29 0.3 0.12 0.36 0.26 0.79 0.27
Total impurities NMT 5.50% 2.4 2.9 2.9 2.2 4.8 2.4 7.1 2.4
NA: Not Analyzed
Remark: From the stability data it can be concluded that oxygen scavenger along with aluminum pouch is required for stabilization of prostaglandin solution.

Table 2.
Name of product: Travoprost ophthalmic solution
Strength : 0.004%
Storage Condition: 40° C ± 2° C / 25% ± 5% RH Fill volume: 5.0 ml

Stability period 1 Month 2 Months 3 Months 6 Months
Stability condition Initial 40°C/25%RH 40°C/25%RH 40°C/25%RH 40°C/25 %RH
Parameter s Limits as per USP monogr aph Oxyge
n
scave
nger Yes No Oxyge
n
scave
nger Yes No Oxyge
n
scave
nger Yes No Oxyge
n
scave
nger Yes
Assay (%) 90.0-110.0% 100 95.6 94.8 96.9 NA 95.9 NA 96.7
Degradation products ( %)
5,6-trans isomer NMT
5.0 % 2.2 2.2 2.0 1.9 2.0 1.9 0.8 1.8
15-keto Derivative NMT 0.3% ND 0.25 0.24 0.31 0.75 0.1 2.1 0.09
Single
unknown
maximum NMT 1.0% 0.23 0.35 0.4 0.21 0.36 0.24 6.1 0.22
Total impurities NMT 5.50% 2.4 2.9 2.7 2.8 4.8 2.3 21.6 2.2
NA: Not Analyzed.
Remark: From the stability data it can be concluded that oxygen scavenger along with
aluminum pouch is required for stabilization of prostaglandin solution.

We Claim:
1. A method for increasing the stability of pharmaceutical composition comprising prostaglandin, optionally preservative and pharmaceutically acceptable excipients wherein the method comprises of providing the composition in polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.
2. The method of claim 1, wherein the prostaglandin is selected from the group consisting of travoprost, latanoprost and bimatoprost.
3. The method of claim 1 wherein the polyethylene container is single dose or multi dose container.
4. The method of claim 1, wherein the pharmaceutically acceptable excipients are one or more of surfactants, tonicity agents and buffers.
5. The method of claim 1, wherein the pharmaceutical composition is stable for at least six months at 40°C ± 2°C and 25% ± 5% relative humidity.
6. The method of claim 1, wherein the pharmaceutical composition is stable at room temperature.

7. The method of claim 1, wherein the preservative is selected from the group comprising of benzalkonium chloride, thiomersal, chlorbutanol, methylparaben, propyl paraben, pollyol complexes, boric acid, phenylethyl alcohol, edetate sodium, polyquad and mixtures thereof.
8. The method of claim 1, wherein the pharmaceutical composition is without preservative.

9. The method of claiml, wherein the pharmaceutical composition is a topical liquid
dosage form for ophthalmic use.
10. The method of claim 1, wherein the prostaglandin includes its pharmaceutically
acceptable derivatives, analogues, pharmaceutically acceptable esters and salts.

Abstract
The present invention relates to a Stabilization of Prostaglandins. The present invention relates to method of increasing the stability of pharmaceutical composition comprising prostaglandin and pharmaceutically acceptable excipients wherein the method comprises of providing composition in polyethylene container, which is packaged in aluminium pouch along with oxygen scavenger.