Stable ophthalmic composition containing latanoprost

Abstract

The present invention relates to an aqueous ophthalmic composition comprising latanoprost in an amount of 0.003% to 0.007% by weight, macrogolglycerol hydroxystearate 40 in an amount of 0.3% to 0.7% by weight, and propylene glycol in an amount of 0.05% to 0.09% by weight, wherein the composition does not contain preservatives and stabilizers. Further, the present invention relates to use in the treatment of ocular hypertension and / or glaucoma.

Description

Technical Field

[0001] The present invention relates to a stable aqueous ophthalmic latanoprost composition that does not contain any stabilizers and preservatives. Further, the latanoprost composition is provided with at least one additional active ingredient selected, for example, from timolol and brinzolamide.

[0002] The present invention discloses an aqueous ophthalmic latanoprost composition. Latanoprost, isopropyl-(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptanoate, CAS number 130209-82-4 is a prostaglandin F2α analogue and is known for its use in ophthalmic compositions. In particular, latanoprost has been proposed as an active ingredient of ophthalmic compositions in the treatment of glaucoma and ocular hypertension. As additional active ingredients in these compositions, brinzolamide and timolol, for example in the form of timolol maleate, have been proposed.

[0003] Some of these formulations are already commercially available and are sold, for example, under the trademarks Xalatan®, Monoprost®, Xaloptic® and Fixaprost®.

[0004] Generally, ophthalmic compositions need to be stable and need to be solubilized so that the active ingredient is delivered to the site of action. For this purpose, in many cases, a large amount of surfactant is added to the solution, which can cause side effects such as eye inflammation.

[0005] In ophthalmic compositions, providing compositions that are stable and do not cause side effects such as eye inflammation in patients is a constant challenge. Attempts to stabilize latanoprost eye drops have been made by using benzalkonium chloride (Xaloptic®) or by adjusting the pH value of the eye drops to 5.0-6.25. Each product was marketed under the trademark "Xalatan® pH6". In both cases, side effects such as eye inflammation have been reported.

[0006] However, even if these side effects are acceptable for products such as Xalatan®, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines recommend not storing these compositions above 25°C. This recommendation is based on the results of stability tests for each composition. As temperatures are rising in many parts of the world, this recommendation necessitates storing the compositions in a refrigerator if one is available.

[0007] Therefore, the object of the present invention is to overcome the shortcomings of the prior art and provide an aqueous ophthalmic latanoprost composition that does not contain preservatives or stabilizers and exhibits remarkable stability even without stabilizers.

[0008] The object of the present invention is to provide an aqueous ophthalmic composition that does not contain preservatives or stabilizers, exhibits high stability even at high temperatures, and is well-acceptable.

[0009] The object of the present invention is to be solved by providing the aqueous ophthalmic composition described in claim 1 and the preferred embodiments described in the dependent claims.

[0010] Therefore, the object of the present invention is to provide an aqueous ophthalmic composition comprising 0.003% to 0.007% by weight of latanoprost, 0.3% to 0.7% by weight of macrogolglycerol hydroxystearate 40, and 0.05% to 0.09% by weight of propylene glycol, wherein the composition is free from preservatives and stabilizers.

[0011] Macrogolglycerol hydroxystearate 40 is also known as Kolliphor® RH 40 and Polyoxyl 40 hydrogenated castor oil.

[0012] In the aqueous ophthalmic composition according to the present invention, it is preferable that macrogol glycerol hydroxystearate 40 is the sole surfactant in the composition, and / or propylene glycol is the sole nonionic isotonic agent in the composition, either completely or substantially completely.

[0013] The aqueous ophthalmic composition according to the present invention is more preferably the composition to contain at least 0.004% by weight of latanoprost, and / or at least 0.4% by weight of macrogol glycerol hydroxystearate 40, and / or at least 0.06% by weight of propylene glycol.

[0014] The aqueous ophthalmic composition according to the present invention is more preferably the composition to contain at least 0.005% by weight of latanoprost, and / or at least 0.5% by weight of macrogol glycerol hydroxystearate 40, and / or at least 0.07% by weight of propylene glycol.

[0015] The aqueous ophthalmic composition according to the present invention is particularly preferably composed of at least one further active ingredient.

[0016] The aqueous ophthalmic composition according to the present invention is more preferably characterized in that at least one further active ingredient is selected from timolol, brinzolamide, and pharmaceutically acceptable salts thereof.

[0017] In a further preferred embodiment of the aqueous ophthalmic composition according to the present invention, at least one further active ingredient is timolol or a pharmaceutically acceptable salt thereof in an amount of 0.4 to 0.6% by weight based on free base timolol.

[0018] The aqueous ophthalmic composition according to the present invention is more preferably characterized in that at least one further active ingredient is timolol or a pharmaceutically acceptable salt thereof in an amount of at least 0.5% by weight based on free base timolol.

[0019] In a particularly preferred embodiment of the present invention, the aqueous ophthalmic composition comprises at least one ionic isotonic agent selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.

[0020] The aqueous ophthalmic composition according to the present invention is more preferably composed of a buffering system.

[0021] In a preferred embodiment of the present invention, the aqueous ophthalmic composition includes a buffer system which is a phosphate buffer system.

[0022] Particularly preferred is the aqueous ophthalmic composition according to the present invention, wherein the pH value of the composition is 6.4 to 7.0, preferably 6.5 to 6.9, and especially preferably 6.6 to 6.8.

[0023] In a preferred embodiment of the present invention, the aqueous ophthalmic composition is provided as a single dose.

[0024] Particularly preferred is the use of the aqueous ophthalmic composition according to the present invention in the treatment of ocular hypertension and / or glaucoma.

[0025] Even more preferred is the use of the aqueous ophthalmic composition according to the invention for the treatment of ocular hypertension and / or glaucoma.

[0026] Preferably, the aqueous ophthalmic composition according to the invention is provided as eye drops.

Brief Description of the Drawings

[0027] [Figure 1] The results of the survival rate test of the composition according to the invention are shown as compared with Xalacom (registered trademark) and Xalatan (registered trademark). [Figure 2] The results of the survival rate test of the composition according to the invention are shown as compared with Monoprost (registered trademark) and Fixaprost (registered trademark).

Modes for Carrying Out the Invention

[0028] Surprisingly, it has been found that the composition according to the invention exhibits excellent stability even when stored at 40°C. The results of the stability test indicate that the composition according to the invention is stable at 40°C for at least 6 months.

[0029] And furthermore, the cell viability test indicates that the composition according to the invention further exhibits high tolerance. This means that, unlike the prior art approaches, improving stability is not accompanied by side effects or incompatibilities.

[0030] The aqueous ophthalmic composition according to the invention contains latanoprost, macrogol glycerol hydroxystearate 40 (Kolliphor (registered trademark) RH 40), propylene glycol, a buffer system and an ionic isotonic agent, such as sodium chloride, and is adjusted to pH 6.4 - 7.0 using sodium hydroxide or hydrochloric acid. To achieve the object of the present invention, no further additives are required. And most importantly, this composition does not contain preservatives and stabilizers.

[0031] Therefore, in addition to at least one active ingredient latanoprost, the composition according to the present invention comprises macrogol glycerol hydroxystearate 40 as a surfactant, and propylene glycol as a solvent and isotonic agent for adjusting the osmolality of the composition.

[0032] In a preferred embodiment of the aqueous ophthalmic composition according to the present invention, the buffer system is a phosphate buffer prepared from sodium dihydrogen phosphate monohydrate and anhydrous disodium phosphate.

[0033] A preferred embodiment of the aqueous ophthalmic composition according to the present invention includes at least one further active ingredient, such as timolol or brinzolamide, or a physiologically acceptable salt thereof.

[0034] Stability tests were conducted using preferred embodiments of the present invention, as described below.

[0035] Stability data Using blow-fill seal technology, a preferred embodiment (0.05 mg / mL latanoprost solution disclosed in Table 1) is filled into strips of LDPE single-dose containers. The single-dose containers are labeled. Two of the five filled ampoules are placed in an aluminum foil bag.

[0036] Stability tests were performed on three batches (19001, 19002, and 19003) of the preferred embodiment under accelerated conditions. The compositions of the tested compositions are shown in Table 1. The results of the stability tests under accelerated conditions are shown in Table 2, and the results of the stability tests under long-term conditions are shown in Table 3.

[0037] Each single-dose container of the drug contains 0.2 mL or more of latanoprost 0.05 mg / mL eye drops. The drug is a colorless, transparent solution, sterile, and virtually particle-free. The nominal pH of the solution is 6.7, and the osmolality of the solution is 250–320 mOsmol / kg. [Table 1] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5]

[0038] After demonstrating the excellent stability of the composition according to the present invention, the inventors investigated whether the presence of propylene glycol in the composition according to the present invention affects the stability of the composition.

[0039] For this purpose, the stability of the two compositions was compared. Composition RD20-131 is the composition according to the present invention and therefore contains propylene glycol. Its composition is shown in Table 4.

[0040] Composition RD20-132, shown in Table 5, differs from RD20-131 only in that RD20-132 does not contain propylene glycol. [Table 4]

[0041] RD20-132 has the same composition but does not contain propylene glycol. [Table 5]

[0042] Both compositions (RD20-131 and RD20-132) were stored for 5 days at 2°C–8°C (as a control) and 60°C.

[0043] To determine the stability of the composition, the appearance of the solution, pH value, osmolality, assay, and impurities were determined.

[0044] As shown in the results summarized in Table 6, the presence of propylene glycol does not affect the stability of the solution. Both compositions, namely RD20-131 and RD20-132, exhibit the same stability. [Table 6]

[0045] This means that propylene glycol does not have a stabilizing effect on the composition according to the present invention and therefore cannot be considered a stabilizer.

[0046] Rather, propylene glycol appears to enhance the solubilization of the active ingredient and is useful in adjusting the osmolality.

[0047] As already mentioned, the high stability of ophthalmic compositions often comes with adverse side effects for users. The reason for these side effects is, in most cases, the preservatives and stabilizers used, or further stabilization parameters of the solution, such as pH levels.

[0048] Safety and tolerance To investigate the safety and tolerability of the composition according to the present invention, cell viability tests were performed according to a cell proliferation assay. To achieve this objective, the effects of the latanoprost composition on cell proliferation and cell viability were studied using HCE-T cells. The results of the study were compared with the results of parallel tests conducted with commercially available latanoprost compositions. Figures 1 and 2 show the results of the test model graphically. The tests and results are described in detail below.

[0049] The tests show high acceptance of the composition according to the present invention, particularly very high acceptance compared to Xalacom®, Xalatan®, Monoprost®, and Fixaprost®.

[0050] Test model cell proliferation assay (cell viability test) Test model: HCE-T cells, where HCE-T stands for "immortalized human corneal epithelial cell line".

[0051] Test Procedure: The general procedure followed the approach described by Huhtala et al. in J. Ocul. Pharmacol. Ther. 2003, 19(1), 11-21.

[0052] Immortalized HCE-T cells were cultured according to internal procedures. Cells were exposed to the formulation once daily for 15 minutes over four days. Cell viability was then measured by the MTS assay (see Malich et al. in Toxicology 1997, 124(3), 179-192). Cells were similarly treated with Krebs-Ringer assay and lysis buffer for both negative and positive controls of the test model.

[0053] Survival rate studies were conducted in comparison with commercially available latanoprost compositions. These commercially available compositions are listed below based on publicly available information.

[0054] Xalatan (registered trademark) pH6 Xalatan® 50 micrograms / mL latanoprost eye drops contain 0.05 mg of latanoprost, 0.20 mg of benzalkonium chloride, sodium chloride, 7.70 mg of sodium dihydrogen phosphate monohydrate, 1.55 mg of anhydrous disodium phosphate, and water for injection per 1 mL.

[0055] There is no further data available.

[0056] Xalacom (registered trademark) Xalacom eye drops, packaged in a multi-dose container, contain 0.05 mg of latanoprost, 6.80 mg of timolol malate (equivalent to 5.00 mg of free timolol base), sodium dihydrogen phosphate monohydrate, anhydrous disodium phosphate, sodium chloride, benzalkonium chloride, and water for injection per 1 mL.

[0057] Monoprost (registered trademark) Monoprost® 50 micrograms / mL latanoprost eye drops contain 0.05 mg of latanoprost, 50 mg of macrogol glycerol hydroxystearate 40, sorbitol, carbomer 974P, macrogol 4000, disodium edetate, sodium hydroxide, and water for injection per 1 mL.

[0058] This means the composition contains a relatively large amount of surfactant, which may result in a relatively reduced tolerance of the composition.

[0059] Fixaprost (registered trademark) Fixaprost® is an eye drop solution containing 0.05 mg of latanoprost, 5 mg of timolol (in the form of timolol malate), 50 mg of macrogol glycerol hydroxystearate, sorbitol, macrogol 4000, carbomer 974P, sodium edetate, sodium hydroxide, and water for injection per 1 mL.

[0060] As can be seen from the survival rate test results, the compositions according to the present invention exhibit a higher degree of tolerability compared to products tested in parallel. Both compositions Xalatan® and Xalacom® contain benzalkonium chloride, which is known to exhibit toxic effects on HCE-T cells. This effect can be seen in the survival rate data in Figure 1.

[0061] Furthermore, the data provided in Figure 2 shows that Monoprost® and Fixaprost® are less tolerable than the compositions according to the present invention. Both compositions contain a much larger amount of surfactant, namely 50 mg / mL, compared to 5 mg / mL in the compositions according to the present invention.

[0062] Therefore, the composition according to the present invention was shown to be more tolerable and less harmful to the eyes than the comparative composition.

[0063] Combined use with timolol In a more preferred embodiment, the composition according to the present invention comprises timolol, preferably in the form of timolol malate. Timolol is a non-selective β-blocker and is used in combination with latanoprost in the treatment of ocular hypertension.

[0064] Timolol is added to the above-mentioned preferred embodiment of the latanoprost composition in an amount of 0.4 to 0.6% by weight, most preferably 0.5% by weight, based on the free base of timolol.

[0065] The most preferred composition according to the present invention, comprising timolol and latanoprost, contains the following components in 1 mL, as shown in Table 7. [Table 7]

[0066] A composition according to the present invention, wherein at least one further active ingredient is timolol, exhibits the same positive properties with respect to storage stability and resistance as a composition according to the present invention that does not contain a second active ingredient.

[0067] The reason for this is that, according to the present invention, the composition does not contain preservatives or stabilizers, and furthermore, the composition according to the present invention has a relatively low surfactant content.

[0068] The aqueous ophthalmic compositions according to the present invention may be provided in any ophthalmologically acceptable form, such as solutions, emulsions, suspensions, gels, and ointments.

Claims

1. An aqueous ophthalmic composition comprising 0.003% to 0.007% by weight of latanoprost, 0.3% to 0.7% by weight of macrogolglycerol hydroxystearate 40, and 0.05% to 0.09% by weight of propylene glycol, wherein the composition is free of preservatives and stabilizers.

2. The aqueous ophthalmic composition according to claim 1, characterized in that macrogol glycerol hydroxystearate 40 is the sole surfactant in the composition, and / or propylene glycol is the sole nonionic isotonic agent in the composition, either completely or substantially completely.

3. The aqueous ophthalmic composition according to claim 1 or 2, characterized in that the composition comprises at least 0.004% by weight of latanoprost and / or at least 0.4% by weight of macrogol glycerol hydroxystearate 40 and / or at least 0.06% by weight of propylene glycol.

4. The aqueous ophthalmic composition according to any one of claims 1 to 3, characterized in that the composition comprises at least 0.005% by weight of latanoprost and / or at least 0.5% by weight of macrogol glycerol hydroxystearate 40 and / or at least 0.07% by weight of propylene glycol.

5. The aqueous ophthalmic composition according to any one of claims 1 to 4, characterized in that the composition comprises at least one further active ingredient.

6. The aqueous ophthalmic composition according to claim 5, characterized in that the at least one further active ingredient is selected from timolol, brinzolamide, and pharmaceutically acceptable salts thereof.

7. The aqueous ophthalmic composition according to claim 6, characterized in that the at least one further active ingredient is timolol or a pharmaceutically acceptable salt thereof in an amount of 0.4 to 0.6% by weight based on free base timolol.

8. The aqueous ophthalmic composition according to claim 7, characterized in that the at least one further active ingredient is timolol or a pharmaceutically acceptable salt thereof in an amount of at least 0.5% by weight based on the free base timolol.

9. The aqueous ophthalmic composition according to any one of claims 1 to 8, characterized in that the composition comprises at least one ionic isotonic agent selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.

10. The aqueous ophthalmic composition according to any one of claims 1 to 9, characterized in that the composition includes a buffering system.

11. The aqueous ophthalmic composition according to claim 10, characterized in that the buffer system is a phosphate buffer system.

12. The aqueous ophthalmic composition according to any one of claims 1 to 11, characterized in that the pH value of the composition is 6.4 to 7.

0.

13. The aqueous ophthalmic composition according to any one of claims 1 to 12, characterized in that the composition is provided as a single dose.

14. Use of the aqueous ophthalmic composition according to any one of claims 1 to 13 in the preparation of a pharmaceutical for the treatment of ocular hypertension.

15. Use of the aqueous ophthalmic composition according to any one of claims 1 to 13 in the preparation of a pharmaceutical for the treatment of glaucoma.

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