JP2010275259A - Uniform and stable latanoprost ophthalmic liquid composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an excellent latanoprost-containing ophthalmic liquid inhibiting the chemical decomposition of the latanoprost which is an active ingredient of the latanoprost ophthalmic liquid agent, also stabilizing the latanoprost easily adsorbed to a resin container to a degree as capable of preserving it at room temperature, and further stabilized for a long period of time without requiring refrigeration and shading. <P>SOLUTION: The uniform and stable latanoprost ophthalmic liquid composition obtained by blending the latanoprost, polysorbate 80 and disodium edetate includes 0.01 to 0.5% (w/v) content of the polysorbate 80, and 0.001 to 0.5% (w/v) content of the disodium edetate. The ophthalmic liquid agent containing such the ophthalmic liquid composition can be preserved at room temperature and not requires shaded preservation. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to an ophthalmic solution containing latanoprost as an active ingredient, and more specifically, by blending polysorbate 80 and sodium edetate, even when stored at room temperature, latanoprost is contained as an active ingredient. The present invention relates to a latanoprost ophthalmic solution composition that exists in a uniform and stable state.

  Latanoprost has the chemical name (+)-isopropyl (Z) -7-[(1R, 2R, 3R, 5S) -3,5-dihydroxy-2-[(3R) -3-hydroxy-5-phenylpentyl]. Cyclopentyl] -5-heptenoate is a prostaglandin compound, which is being developed as a therapeutic agent for glaucoma and ocular hypertension.

The pharmaceutical preparation is an ophthalmic solution containing 0.005% latanoprost [trade name: Xalatan (registered trademark) ophthalmic solution: Pfizer Inc.], and includes benzalkonium chloride, sodium hydrogen phosphate, phosphoric acid as additives. Sodium dihydrogen and an isotonic agent are blended. However, these preparations have low chemical stability and low light stability, and are required to be shielded from light and refrigerated at 2-8 ° C. (package insert).
Therefore, various developments of latanoprost-containing eye drop preparations with improved stability during storage have been reported.

For example, Patent Document 1 discloses that an ophthalmic composition containing latanoprost as an active ingredient and substantially free of benzalkonium chloride is administered to a subject patient in need of treatment for ocular hypertension and glaucoma. Methods for treating ocular hypertension and glaucoma are disclosed.
Patent Document 1 discloses a method for preparing a latanoprost-containing ophthalmic solution comprising benzalkonium chloride, polysorbate 80, sodium edetate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, and sodium chloride.

  Specifically, the uniformity of latanoprost in ophthalmic solution when benzalkonium chloride is not included is improved by adding polysorbate 80 (88.3% to 100.0%), 0.01% The uniformity of latanoprost in ophthalmic solution when containing benzalkonium chloride is improved from blending polysorbate 80 or blending polysorbate 80 and sodium edetate (97.3% to 99.9%) It has been disclosed.

  However, this patent document only discloses that the uniformity of ophthalmic solution after stirring for 7 hours and after standing for 30 minutes is improved by blending polysorbate 80 or polysorbate 80 and sodium edetate. No mention is made of the chemical stability of the subsequent ophthalmic solution and latanoprost itself, or the stability to light.

Patent Document 2 discloses a pharmaceutical composition containing a polyethoxylated sorbitol alkanoic acid ester in order to enhance the chemical stability of prostaglandins.
However, although latanoprost, polysorbate 80, sodium edetate as an antioxidant and the like are described, latanoprost ophthalmic solution has not been studied and there is no specific disclosure. In addition, it has been described that an antioxidant reduces the oxidation rate and helps to extend the shelf life of the product, but there is no specific disclosure about ophthalmic solutions containing latanoprost.

Non-Patent Document 1 reports a study on the stability of latanoprost contained in the xalatan ophthalmic solution.
It is disclosed that it is stable at room temperature within one month, which is a guideline for the expiration date, and can be stored in a light-shielding bag. Further, it is disclosed that the latanoprost content does not change even when stored in a polyethylene container at 25 ° C., 50% RH, white light 2500 lux (20 days). Furthermore, if stored in the dark, no change was observed for 3 months even at room temperature, 30 ° C, 75% RH, 1 drop each day after opening, and when stored in the dark, after 6 weeks, Although the content was slightly reduced, there was no difference compared to the unopened one until 4 weeks, and it was disclosed that after 6 weeks, fine particles were observed in 1 of 13 bottles.
However, the use of sodium edetate added in the present invention is not described.

Patent Document 3 discloses an aqueous pharmaceutical composition containing a preservative such as latanoprost and benzalkonium chloride, and edetic acid or a salt thereof.
In this aqueous pharmaceutical composition, the addition of sodium edetate suppresses the appearance of insoluble foreign matter by 60% or more by storage after 1 week at 40 ° C., and this effect is independent of the concentration of sodium edetate. It is disclosed that it can be obtained. However, the combination of sodium edetate and a surfactant such as polysorbate 80 used in the present invention is not described.

Further, Patent Document 4 discloses an ophthalmic solution with improved stability over time, characterized by containing polysorbate 80 in an ophthalmic solution containing latanoprost as an active ingredient. That is, it is disclosed that the addition of polysorbate 80 suppresses a decrease in the residual rate of latanoprost in the ophthalmic solution and improves the stability over time.
Specifically, the residual rate of latanoprost in the ophthalmic solution was 97.3% with no polysorbate 80 added under conditions of storage at 40 ° C. for 2 weeks in a polyethylene container. By adding 0.05% (w / v), it was improved to 99.6%, and under storage conditions at 40 ° C. for 4 weeks, polysorbate 80 was 86.1% without addition of polysorbate 80. By adding 80, it was improved to 99.3%. Under the conditions of storage at 60 ° C. for 2 weeks, the residual rate without addition of polysorbate 80 was 76.2%, but by adding polysorbate 80, It is disclosed that it has been improved to 92.5%.
However, the combined use with sodium edetate used in the present invention has not been studied, and there is no description as to whether the residual rate is improved.

Patent Document 5 discloses a uniform and stable ophthalmic solution that can be stored at room temperature by blending polyethylene glycol monostearate with an ophthalmic solution containing latanoprost as an active ingredient.
Specifically, by blending polyethylene glycol monostearate, it is possible to suppress the adsorption of the active ingredient to the resin container, and an ophthalmic solution with excellent stability that can be stored at room temperature is obtained. In contrast to eye drops, it is disclosed that the residual ratio of latanoprost is 96 to 101.0% in a polyethylene container in the presence of one or two types of polyethylene glycol monostearate at 60 ° C. for 4 weeks. Yes.
However, the use of sodium edetate contained in the present invention is not disclosed at all.

JP-T-2006-503913 JP 2008-528490 A JP 2008-247828 A JP 2008-040727 A JP 2009-040749 A Pharmaceutical Journal, Vol.42 (6), p.1725 (2006)

  In view of the above situation, the present invention suppresses chemical degradation of latanoprost, which is an active ingredient of a latanoprost-containing ophthalmic solution, and stabilizes latanoprost that is easily adsorbed on a resin container to such an extent that it can be stored at room temperature. Furthermore, another object of the present invention is to provide an excellent ophthalmic solution containing latanoprost that is stable for a long period of time and does not need to be stored under refrigeration and shading.

The present inventor conducted intensive research on the above-described prior art, considering that although the long-term stability of latanoprost in latanoprost-containing eye drop preparations has been improved to some extent, further improvement is necessary.
As a result, in the ophthalmic solution preparation containing latanoprost, by combining polysorbate 80 and sodium edetate as additives, a novel fact that latanoprost is stable over a long period of time was found. It came to complete the latanoprost ophthalmic solution composition of this invention.

That is, the present invention basically has the following configuration.
(1) A uniform and stable latanoprost ophthalmic solution composition containing latanoprost, polysorbate 80 and sodium edetate.
(2) The above (1), wherein the content of polysorbate 80 is 0.01 to 0.5% (w / v), and the content of sodium edetate is 0.001 to 0.5% (w / v). The ophthalmic solution composition described in 1.
(3) An ophthalmic solution characterized by being capable of being stored at room temperature, comprising the latanoprost ophthalmic solution composition described in (1) or (2) above.
(4) An ophthalmic solution characterized by not requiring light-shielding preservation comprising the latanoprost ophthalmic solution composition described in (1) or (2) above.

The latanoprost ophthalmic solution composition provided by the present invention has the advantage that latanoprost, which is an active ingredient, is present in a uniform and stable state for a long period of time.
Therefore, the latanoprost ophthalmic solution comprising such an ophthalmic solution composition does not require refrigerated storage at 2 to 8 ° C. under the light-shielding conditions found in conventional formulations, and places a great burden on the subject to be treated. Absent.

  In addition, the latanoprost ophthalmic solution composition provided by the present invention does not adsorb to, for example, a plastic container and suppresses the generation of decomposition products. As a result, the residual rate is also good, and the ophthalmic solution composition The latanoprost ophthalmic solution formulation comprising a product has an advantage that it can be provided as a safer ophthalmic formulation.

  As described above, the present invention is a uniform and stable latanoprost ophthalmic solution containing latanoprost, polysorbate 80 and sodium edetate, and an ophthalmic solution comprising such an ophthalmic solution composition, which is stored at room temperature. It is an ophthalmic solution that can be stored and that does not need to be protected from light.

The blending amount of latanoprost in the latanoprost ophthalmic solution composition provided by the present invention is preferably 0.005% (w / v) from the viewpoint of medical treatment.
However, it is not limited to this blending amount, and the blending amount can be appropriately increased or decreased for treatment, and the polysorbate 80 and sodium edetate blending amount to be contained may be selected according to the blending amount.

In the present invention, the blended polysorbate 80 is used as a solubilizing agent for latanoprost or as a nonionic surfactant that imparts a buffering action.
The blending amount of polysorbate 80 is not particularly limited as long as it is a pharmacologically acceptable amount, but is 0.01 to 0.5% (w / v), preferably 0.1 to the total amount of ophthalmic solution. It is ˜0.3% (w / v), particularly preferably 0.15% (w / v).

  On the other hand, sodium edetate blended with polysorbate 80 is not particularly limited as long as it is a pharmacologically acceptable amount, but is preferably 0.001 to 0.5% (w / v), preferably based on the total amount of eye drops. Is 0.01 to 0.2% (w / v), particularly preferably 0.05% (w / v).

In the ophthalmic solution composition provided by the present invention, polysorbate 80 and sodium edetate are added in combination.
In this case, the blending amount of polysorbate 80 in the combined addition is preferably 0.01 to 0.5% (w / v) with respect to the total amount of the ophthalmic solution, and sodium edetate is preferably 0.001 to 0.00. The blending amount is 5% (w / v). Particularly preferably, polysorbate 80 is 0.1 to 0.3% (w / v) and sodium edetate is preferably 0.01 to 0.2% (w / v) based on the total amount of the eye drop. Amount.

Particularly, the blending ratio of both is preferably in the range of 1: 1 to 20: 1 in the blending ratio (w / v) ratio of polysorbate 80 and sodium edetate.
The present invention is particularly characterized in that the chemical stability of latanoprost and the stability to light are improved by blending polysorbate 80 and sodium edetate in combination, and among them, When the blending ratio of both is within the above range, the stability is particularly excellent.

  In addition to the above, the eyedrops of the present invention may contain additives that can be used in normal eyedrops. For example, buffering agents, preservatives, isotonic agents, pH adjusting agents and the like can be mentioned.

  Examples of the buffer include phosphoric acid, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, sodium citrate, sodium carbonate, boric acid, borax and the like. Preferred are sodium dihydrogen phosphate and disodium hydrogen phosphate.

  Examples of tonicity agents include sodium chloride, potassium chloride, calcium chloride, glycerin, propylene glycol, mannitol and the like. Of these, sodium chloride is preferred.

  Examples of the preservative include benzalkonium chloride, benzethonium chloride, sorbic acid, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, and chlorhexidine gluconate. Among these, benzalkonium chloride is preferable, and the blending amount is preferably about 0.02% or less.

  Moreover, hydrochloric acid, sodium hydroxide, potassium hydroxide, acetic acid etc. can be mentioned as a pH adjuster. Of these, hydrochloric acid and / or sodium hydroxide are preferable, but not limited thereto.

Hereinafter, the present invention will be described in detail with reference examples and examples. However, the following examples do not limit the scope of rights of the present invention.
In the following reference examples and examples, polysorbate 80 was manufactured by Kao Corporation, and sodium edetate was manufactured by Nacalai Tesque Corporation.
Further, “%” in the blending amount is “% (w / v)”.

Reference Example 1: Stability test by blending polysorbate 80 In polyethylene container, benzalkonium chloride 0.01%, sodium hydrogen phosphate hydrate 1.2%, sodium dihydrogen phosphate hydrate as additives Ophthalmic solutions containing 0.005% latanoprost containing 0.75% and sodium chloride 0.3% as basic parts, and further blended with polysorbate 80 (0.04%, 0.07% and 0.15%) Prepared.
The above ophthalmic solution and commercially available xalatan ophthalmic solution were compared for stability when stored at 60 ° C. for 1 week and 2 weeks.

The residual amount was measured and the result is shown in Table 1 below.
It was found that when polysorbate 80 was added to the remaining rate of xalatan ophthalmic solution 81.5% when stored at 60 ° C. for 2 weeks, the stability deteriorated depending on the concentration.
That is, the stability is 84.4% when polysorbate 80 is mixed at 0.04%, and 80.0% when 0.07% is blended, and 0.15%. When blended, the residual rate was 64.9%, and it was found that the stability decreased in a concentration-dependent manner when polysorbate 80 was blended alone.

Reference Example 2: Stability test by blending with sodium edetate Polysorbate 80 0.15%, benzalkonium chloride 0.01%, sodium hydrogenphosphate hydrate 1.2% in polyethylene containers as additives , 0.75% sodium dihydrogen phosphate hydrate and an appropriate amount of sodium chloride (an amount adjusted to an osmotic pressure ratio of 0.9 to 1.0) as basic parts, and sodium edetate (0.01% and 0.1%). 05%), and various other latanoprost 0.005% ophthalmic solutions were prepared by adding 0.7% of aminoethylsulfonic acid and 1% of epsilon aminocaproic acid as other stabilizers.
The above ophthalmic solution and commercially available xalatan ophthalmic solution were compared for stability when stored at 60 ° C. for 1 week and 2 weeks.

The residual amount was measured, and the results are shown in Table 2 below.
Residual rate of xaratan ophthalmic solution remaining at 81.5% when stored at 60 ° C for 1 week and 2 weeks, especially when sodium edetate 0.01% is more stable at 94.8% There was found. More preferably, 0.05% sodium edetate having a residual rate of 96.9% was blended.
In addition, it was more stable when sodium edetate was added than other stabilizers.

Example 1:
Purified water with sodium dihydrogen phosphate hydrate 1.4%, sodium hydrogen phosphate hydrate 0.63%, sodium chloride 0.3%, benzalkonium chloride 0.01%, polysorbate 80 0.04 %, Sodium edetate 0.1% and latanoprost 0.005% were added and stirred until the additive was completely dissolved, and then purified water was added to make up a total volume of 100 mL. This solution was filled in a polyethylene container to prepare an eye drop solution.

Examples 2-5:
In the same manner as in Example 1, various additives (blending amount:%) shown in Table 3 together with latanoprost were dissolved in purified water to prepare 0.005% latanoprost ophthalmic solution composition.
In the table, the formulation of Example 1 is also shown.

Stability test 1:
Residual rate (%) of latanoprost when the ophthalmic solution of Examples 1 to 5 and xalatan ophthalmic solution used in the medical field as a comparative example were stored at 40 ° C. for 1 month and at 60 ° C. for 2 weeks. The latanoprost concentration in the ophthalmic solution was measured by HPLC and calculated using a calibration curve.
The results are shown in Table 4 below.
In addition, in the table | surface, the compounding quantity of the polysorbate 80 and sodium edetate was shown together about Examples 1-5.

As can be seen from the results shown in Table 4, the latanoprost ophthalmic solution of the present invention has a lower concentration of polysorbate 80 when stored for 1 month at 40 ° C. compared to the xalatan ophthalmic solution as a comparison target. The residual rate of was low.
As can be seen from the results of Examples 1 to 3, in the combined use of polysorbate 80 and sodium edetate, in 3 cases where the same amount of sodium edetate was added, the residual rate was improved depending on the concentration of polysorbate 80. Admitted.
On the other hand, as can be seen from the results of Examples 3 to 5, in 3 cases in which the same amount of polysorbate 80 was added, an improvement in the residual rate depending on the concentration of sodium edetate was recognized.
From these results, in the combined use of polysorbate 80 and sodium edetate, the blending ratio of both is in the range of 1: 1 to 20: 1 in the blending percentage (w / v) ratio of polysorbate 80 and sodium edetate. It is understood that this is preferable.

Stability test 2:
Regarding the latanoprost ophthalmic solution of Example 4 and the xalatan ophthalmic solution as a comparison target, the residual rate under long-term storage conditions of 6 months at 40 ° C. was examined in the same manner as in the stability test 1.
As a result, the residual ratio was as follows.
Ophthalmic solution formulation of Example 4: 102.2%
Xalatan ophthalmic solution: 87.8%

Stability test 3:
Regarding the latanoprost ophthalmic solution of Example 4 and the xalatan ophthalmic solution as a comparison target, the residual ratio under irradiation conditions of 1.2 million Lux · hr was examined in the same manner as in the stability test 1.
As a result, the residual ratio was as follows.
Ophthalmic solution formulation of Example 4: 100.7%
Xalatan ophthalmic solution: 82.6%

  As can be seen from the results of the above stability tests 1 to 3, in the preparation of an ophthalmic solution containing latanoprost as an active ingredient, by blending polysorbate 80 and sodium edetate at the same time, the uniformity of the formulation, long-term over time It was observed that stability and light stability were improved.

  As described above, the latanoprost ophthalmic solution comprising the latanoprost ophthalmic solution composition provided by the present invention is excellent in uniformity, long-term stability over time and light stability even after storage or after opening the container. Yes, its usefulness in the medical industry is tremendous.

Claims (4)

  A uniform and stable latanoprost ophthalmic solution composition containing latanoprost, polysorbate 80 and sodium edetate.   The instillation according to claim 1, wherein the content of polysorbate 80 is 0.01 to 0.5% (w / v), and the content of sodium edetate is 0.001 to 0.5% (w / v). Liquid composition.   An ophthalmic solution comprising the latanoprost ophthalmic solution composition according to claim 1 and capable of being stored at room temperature.   An ophthalmic solution comprising the latanoprost ophthalmic solution composition according to claim 1, wherein the ophthalmic solution is not required to be protected from light.