Stable pharmaceutical composition of ropinirole

Abstract

The present invention relates to a pharmaceutical aqueous composition, e.g., a solution, containing ropinirole or a pharmaceutically acceptable salt thereof as an active ingredient and having a reduced iron content. The composition exhibits improved chemical stability of the active ingredient. The composition can be used, for example, in the preparation of an eye drop composition for inducing emesis in animals, e.g., companion animals such as dogs or cats, in situations where emesis is desired.

Description

Technical Field

[0001] The present invention relates to an aqueous pharmaceutical composition containing ropinirole or a pharmaceutically acceptable salt thereof as an active ingredient, particularly a solution. This composition exhibits improved chemical stability against the decomposition of the active ingredient. The composition can be used, for example, in the preparation of ophthalmic drugs in the field of veterinary medicine to induce vomiting in situations involving the ingestion of potentially toxic substances or foreign bodies by companion animals such as dogs or cats.

Background Art

[0002] A method of inducing vomiting in animals by administering an effective amount of an ophthalmic composition containing a selective D2 family dopamine agonist such as ropinirole as an active ingredient is described in Patent Document 1. An aqueous ophthalmic solution containing 10 or 40 mg / ml of ropinirole hydrochloride causes rapid and consistent vomiting in dogs without inducing vomiting for a longer duration than required.

[0003] The development of the aqueous ropinirole solution described in Patent Document 1 revealed that ropinirole is chemically unstable in aqueous solution. Chemical instability is regarded as a drawback because it is associated with a limited shelf life of the pharmaceutical product.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

[0005] It has been found that trace amounts of iron present in the composition are associated with the chemical instability of ropinirole. The source of such trace amounts of iron has been found to be impurities in the raw materials used in the preparation of the composition, particularly impurities in the active ingredient itself, as well as the material of the container used in the preparation of the composition.

[0006] Thus, according to one embodiment of the present invention, the present invention provides a stable aqueous pharmaceutical composition comprising ropinirole or a pharmaceutically acceptable salt thereof in an amount of 1 to 15% by weight of the solution and having an iron content of less than 140 ppb based on the weight of the composition.

[0007] According to another embodiment, the present invention provides a stable aqueous pharmaceutical composition having a reduced iron content, comprising ropinirole or a pharmaceutically acceptable salt thereof in an amount of 1 to 15% by weight of the solution and having an iron content of less than 140 ppb based on the weight of the composition.

[0008] According to another embodiment of the present invention, the iron content in the above composition is less than 120 ppb, preferably less than 100 ppb, more preferably less than 80 ppb, even more preferably less than 60 ppb, or even less preferably less than 40 ppb, based on the weight of the composition.

[0009] According to another embodiment, the present invention is a method for preparing a stable aqueous pharmaceutical composition comprising ropinirole or a pharmaceutically acceptable salt thereof in an amount of 1 to 15% by weight of the composition, comprising: a) dissolving ropinirole or a pharmaceutically acceptable salt thereof and optionally one or more excipients in water; and b) treating the mixture of step (a) with an iron scavenger and provides a method.

[0010] According to another embodiment of the present invention, the amount of iron after step (b) in the above method is less than 140 ppb, preferably less than 120 ppb, more preferably less than 100 ppb, even more preferably less than 80 ppb, still more preferably less than 60 ppb, or even less preferably less than 40 ppb, based on the weight of the composition.

Mode for Carrying Out the Invention

[0011] As used herein, the term "ppb" means one part per billion by weight. Thus, 1 ppb / weight corresponds to 1 μg / kg.

[0012] As used herein, the term "iron scavenger" means any material that reacts with, captures, or otherwise removes iron from a solution. Examples of metal scavengers include, but are not limited to, functionalized silica, functionalized resins, and activated carbon.

[0013] As used herein, the term "functionalized silica" means silica to which a chemical group that acts as an iron scavenger is attached. Examples of functionalized silica include triamine tetraacetic acid attached to silica or the sodium salt of triamine tetraacetic acid attached to silica.

[0014] As used herein, the term "silica" means silicon dioxide.

[0015] As used herein, the term "functionalized resin" means a polymeric material to which a chemical group that acts as an iron scavenger is attached. Examples include trimercaptotriazine attached to macroporous polystyrene.

[0016] As used herein, the term "iron" means the chemical element of the symbol Fe in a solubilized form, such as ionized or complexed form.

[0017] As used herein, the term "ophthalmic composition" means a liquid or semi-solid pharmaceutical composition adapted for administration to the eye. A typical example of an ophthalmic composition is an ophthalmic solution that is instilled into the eye.

[0018] As used herein, the term "stable aqueous pharmaceutical composition" means a composition that, when filled into a 1 ml blow-fill-seal LDPE ampoule (0.7 ml) and further placed in an airtight aluminum laminate pouch under nitrogen purge, contains less than 2%, preferably less than 1%, of degradation impurity B (4-[2-(dipropylamino)ethyl]indoline-2,3-dione hydrochloride) relative to the weight of the composition after storage at 25 °C / 60% RH for 36 months.

[0019] The present invention relates to a stable aqueous pharmaceutical composition comprising ropinirole or a pharmaceutically acceptable salt thereof in an amount of 1 to 15%, preferably 2 to 10%, more preferably 3 to 8% by weight of the solution, and having an iron content of less than 140 ppb relative to the weight of the composition.

[0020] According to another embodiment of the present invention, the amount of iron in the above composition is less than 120 ppb, preferably less than 100 ppb, more preferably less than 80 ppb, even more preferably less than 60 ppb, or less than 40 ppb relative to the weight of the composition.

[0021] The above composition comprises a) dissolving ropinirole or a pharmaceutically acceptable salt thereof and optionally one or more excipients in water; and b) treating the mixture of step (a) with an iron scavenger and can be produced by a method comprising.

[0022] According to one embodiment of the present invention, the amount of iron after step (b) in the above method is less than 140 ppb, preferably less than 120 ppb, more preferably less than 100 ppb, even more preferably less than 80 ppb, still more preferably less than 60 ppb, or less than 40 ppb relative to the weight of the composition.

[0023] According to one embodiment of the present invention, the amount of iron after step (a) in the above method is more than 60 ppb, or more than 80 ppb, or more than 100 ppb, or more than 120 ppb, or more than 140 ppb, or more than 160 ppb, or more than 200 ppb, or more than 300 ppb, or more than 500 ppb.

[0024] According to one embodiment of the present invention, the amount of iron after step (a) in the above method is 60 - 800 ppb, or 80 - 800 ppb, or 100 - 800 ppb, or 120 - 800 ppb, or 140 - 800 ppb, or 160 - 800 ppb, or 200 - 800 ppb, or 300 - 800 ppb, based on the weight of the composition.

[0025] The use of an iron scavenging process in the preparation of an aqueous ropinirole composition such as a solution has been found to significantly improve the chemical stability of the active ingredient in the solution, as iron appears to be associated with the decomposition of ropinirole.

[0026] The iron scavenger used in this method is preferably a solid-phase iron scavenger. Suitable solid-phase iron scavengers include functionalized silica, functionalized resins, and activated carbon. Functionalized silica is a preferred solid-phase iron scavenger. In particular, triamine tetraacetic acid bonded to silica and the sodium salt of triamine tetraacetic acid bonded to silica are available from SiliCycle Inc. as "SiliaMetS® TAAcOH" and "SiliaMetS® TAAcONa".

[0027] The composition of the present invention can be prepared by dissolving an appropriate amount of ropinirole or a pharmaceutically acceptable salt thereof, such as ropinirole hydrochloride, and optionally one or more excipients in sterile water. If necessary, the iron content in the mixture can be measured at this stage to quantify the amount of iron scavenger required.

[0028] The solution containing ropinirole is then mixed with a suitable solid-phase iron scavenger, and the mixture is stirred for a time sufficient to reduce the iron content, for example, 1 to 4 hours. The required amount of iron scavenger can usually be calculated from the technical manual of a commercially available iron scavenger brand. For example, about 4 to 8 molar equivalents of a SilicaMetS® functionalized silica product can be used relative to the ionic concentration of the mixture. The progress of scavenging can be monitored by conventional analytical techniques. The iron content in the solution can be analyzed by known analytical methods such as inductively coupled plasma mass spectrometry (ICP-MS).

[0029] Once the iron content in the mixture has been sufficiently reduced, the solid-phase iron scavenger is removed by known methods, such as filtration. Pharmaceutical excipients required for the final pharmaceutical product can be added to the mixture if they were not added prior to the iron capture step.

[0030] Also, for example, since the iron scavenger is used in a continuous flow mode, it is also possible to carry out process (b) by packing the solid-phase iron scavenger in a cartridge or the like. Such cartridges are commercially available, for example, from Silicycle.

[0031] According to one embodiment, the stable aqueous pharmaceutical composition of the present invention contains ropinirole or a pharmaceutically acceptable salt thereof as the sole active ingredient.

[0032] The selection of suitable excipients depends on the intended use and the route of administration of the pharmaceutical product. In the preparation of an ophthalmic composition, ropinirole or a pharmaceutically acceptable salt thereof can be formulated into a dosage form suitable for administration to the eye by mixing the drug with conventional pharmaceutical diluents and carriers commonly used in ophthalmic compositions. The ophthalmic compositions useful in the method of the present invention can be in liquid or semi-solid form, such as, for example, in the form of a solution, emulsion or suspension. A solution is particularly preferred.

[0033] Preferably, the eye drop composition is in the form of an aqueous solution suitable for administration to the eyes of an animal. The concentration of ropinirole or a pharmaceutically acceptable salt thereof, such as hydrochloride, in the composition, for example, the eye drop composition, is suitably in the range of about 1 to about 15% (w / w), more typically about 2 to about 10% (w / w), even more typically 3 to 8% (w / w) based on the weight of the composition.

[0034] According to one embodiment, an aqueous composition, such as an eye drop composition, contains about 1 to about 15% of ropinirole or a pharmaceutically acceptable salt thereof and about 85 to about 99% of sterile water based on the weight of the composition. According to another embodiment, the composition contains about 2 to about 10% of ropinirole or a pharmaceutically acceptable salt thereof and about 90 to about 98% of sterile water based on the weight of the composition. According to yet another embodiment, the composition contains about 3 to about 8% of ropinirole or a pharmaceutically acceptable salt thereof and about 92 to about 97% of sterile water based on the weight of the composition.

[0035] The aqueous composition of ropinirole, such as an eye drop composition, additionally contains an isotonic agent such as sodium chloride, a pH adjuster or buffer such as sodium hydroxide, hydrochloric acid, citric acid / sodium citrate, tartaric acid, fumaric acid, an antioxidant such as butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT), a chelating agent such as disodium edetate, a thickening agent such as sodium carboxymethyl cellulose and other components commonly used in the preparation of eye drop compositions.

[0036] The pH of an aqueous composition containing ropinirole or a pharmaceutically acceptable salt thereof, such as hydrochloride, for example, an eye drop composition, is suitably in the range of about 2.5 to about 8, preferably 3 to about 6, for example about 3.5 to about 5.

[0037] The eye drop composition can be provided in the form of a veterinary kit including the eye drop composition, a package containing the composition, and instructions for administering the composition to the eyes of an animal, particularly a companion animal such as a dog, to induce vomiting. Preferably, the package is an applicator capable of dosing a fixed volume of the composition of the present invention, such as a squeezable prefilled single-use bottle, an ampoule or a pipette. The squeezable bottle, ampoule or pipette is preferably manufactured from a polymeric material such as LDPE. Suitably, the volume of a suitable bottle, ampoule or pipette ranges from about 0.5 to 5 ml. For example, an eye drop composition of about 0.5 to about 2 ml can be filled into a single-use molded and filled simultaneously (BFS) LDPE ampoule with a volume of 0.5 ml, 1 ml or 2 ml.

[0038] The present invention will be further illustrated by the following examples, which are not intended to limit the scope of the present invention.

Examples

[0039] Formulation Example 1 (Eye Drops) Ropinirole hydrochloride 11.4 mg (equivalent to 10 mg of ropinirole base) Adjusted to pH 4 with hydrochloric acid Sodium chloride Adjust osmotic pressure (300 - 400 mosm / kg) Water for injection Up to 1 ml

[0040] Formulation Example 2 (Eye Drops) Ropinirole hydrochloride 45.6 mg (equivalent to 40 mg of ropinirole base) Sodium chloride Adjust osmotic pressure (300 - 400 mosm / kg) Water for injection Up to 1 ml pH 4

[0041] Formulation Example 3 (Eye Drops) Ropinirole hydrochloride 34.2 mg (equivalent to 30 mg of ropinirole base) Citric acid monohydrate 2.5 mg Sodium citrate 2.1 mg Sodium chloride For osmotic pressure adjustment (300 - 400 mosm / kg) Hydrochloric acid / Sodium hydroxide If necessary for adjusting to pH 4 Water for injection Up to 1 ml

[0042] Formulation Example 4 (Eye drops) Ropinirole hydrochloride 57 mg (equivalent to 50 mg of ropinirole base) Citric acid monohydrate 2.5 mg Sodium citrate 2.1 mg Sodium chloride For osmotic pressure adjustment (300 - 400 mosm / kg) Hydrochloric acid / Sodium hydroxide If necessary for adjusting to pH 4 Water for injection Up to 1 ml

[0043] Experiment 1. Reduction of iron level using sodium salt of triamine tetraacetic acid bound to silica (SiliaMetS® TAAcONa, obtained from Silicycle) 102 mg of silica - bound metal scavenger (SiliaMetS® sodium triamine tetraacetate) was placed in a vial. Then, 10 ml of ropinirole HCl aqueous solution (34.2 mg / ml) containing 86 ppb of iron (Fe) was added to the vial. The mixture was stirred for 1.5 hours. The silica was removed by filtration. The iron content was measured from the filtrate. The filtrate contained 55 ppb of iron (Fe).

[0044] Experiment 2. Reduction of iron level using triamine tetraacetic acid bound to silica (SiliaMetS® TAAcOH, obtained from Silicycle) 101 mg of silica - bound metal scavenger (SiliaMetS® triamine tetraacetic acid) was placed in a vial. Then, 10 ml of ropinirole HCl aqueous solution (34.2 mg / ml) containing 86 ppb of iron (Fe) was added to the vial. The mixture was stirred for 1.5 hours. The silica was removed by filtration. The iron content was measured from the filtrate. The filtrate contained 40 ppb of iron (Fe).

[0045] Experiment 3. Reduction of iron level using activated carbon (Norit SX Ultra (registered trademark), obtained from Sigma-Aldrich) 105 mg of activated carbon (Norit SX Ultra (registered trademark)) was placed in a vial. Then, 10 ml of a ropinirole HCl aqueous solution (34.2 mg / ml) containing 86 ppb of iron (Fe) was added to the vial. The mixture was stirred for 1.5 hours. The activated carbon was removed by filtration. The iron content was measured from the filtrate. The filtrate contained 52 ppb of iron (Fe).

[0046] Experiment 4. Reduction of iron level using sodium salt of triamine tetraacetic acid bound to silica (SiliaMetS (registered trademark) TAAcONa, obtained from Silicycle) 101 mg of silica-bound metal scavenger (SiliaMetS (registered trademark) sodium triamine tetraacetate) was placed in a vial. Then, 10 ml of a ropinirole HCl aqueous solution (34.2 mg / ml) containing 330 ppb of iron (Fe) was added to the vial. The mixture was stirred for 2 hours. The silica was removed by filtration. The iron content was measured from the filtrate. The filtrate contained 139 ppb of iron (Fe).

[0047] Experiment 5. Reduction of iron level using triamine tetraacetic acid bound to silica (SiliaMetS (registered trademark) TAAcOH, obtained from Silicycle) 99 mg of silica-bound metal scavenger (SiliaMetS (registered trademark) triamine tetraacetic acid) was placed in a vial. Then, 10 ml of a ropinirole HCl aqueous solution (34.2 mg / ml) containing 330 ppb of iron (Fe) was added to the vial. The mixture was stirred for 2 hours. The silica was removed by filtration. The iron content was measured from the filtrate. The filtrate contained 81 ppb of iron (Fe).

[0048] Experiment 6. Reduction of iron level using activated carbon (Norit SX Ultra (registered trademark), obtained from Sigma-Aldrich) 103 mg of activated carbon (Norit SX Ultra (registered trademark)) was placed in a vial. Then, 10 ml of a ropinirole HCl aqueous solution (34.2 mg / ml) containing 330 ppb of iron (Fe) was added to the vial. The mixture was stirred for 2 hours. The activated carbon was removed by filtration. The iron content was measured from the filtrate. The filtrate contained 122 ppb of iron (Fe).

[0049] Experiment 7. Reduction of iron level using triamine tetraacetic acid bound to silica (SiliaMetS (registered trademark) TAAcOH, obtained from Silicycle) 100 mg of silica-bound metal scavenger (SiliaMetS (registered trademark) triamine tetraacetic acid) was placed in the vial. Then, 10 ml of a ropinirole HCl aqueous solution (34.2 mg / ml) containing 580 ppb of iron (Fe) was added to the vial. The mixture was stirred for 2 hours. The silica was removed by filtration. The iron content was measured from the filtrate. The filtrate contained 95 ppb of iron (Fe).

[0050] Experiment 8. Stability of ropinirole HCl aqueous solution (34.2 mg / ml) The stability of ropinirole HCl ophthalmic aqueous solution (34.2 mg / ml) with various iron contents was investigated. The test solution (0.7 ml) was filled into 1 ml molded co-filled LDPF ampoules under nitrogen purge. The sealed ampoules were placed in an airtight aluminum laminate pouch under nitrogen purge, and the pouch was maintained at 25 °C / 60% RH for 36 months. The degradation rate of ropinirole HCl was determined by measuring the degradation impurities of ropinirole (impurity B, (4-[2-(dipropylamino)ethyl]indoline-2,3-dione hydrochloride)) at release, after 1 month, 2 months, 3 months, 24 months, and 36 months. The results are shown in Table 1. It can be seen that the iron content in the solution is consistent with the degradation rate of ropinirole.

[0051]

Table 1

[0052] Experiment 9. Stability of Ropinirole HCl Aqueous Solution (34.2 mg / ml) The stability of ropinirole HCl ophthalmic aqueous solution (34.2 mg / ml) having an iron content of 127 ppb or 37 ppb was examined. The test solution was filled into 1-ml formed and simultaneously filled LDPF ampoules under nitrogen purge. The sealed ampoules were placed in an airtight aluminum laminate pouch under nitrogen purge, and the pouch was maintained at 25°C / 60% RH for 12 months. The decomposition rate of ropinirole HCl was determined by measuring the decomposition impurities of ropinirole (Impurity B, (4-[2-(dipropylamino)ethyl]indoline-2,3-dione hydrochloride)) at the time of release and at various time points. The results are shown in Table 2. It can be seen that the iron content in the solution coincides with the decomposition rate of ropinirole.

[0053] [Table 2]

Claims

1. A stable aqueous pharmaceutical composition comprising ropinirole or a pharmaceutically acceptable salt thereof in an amount of 1 to 15% by weight of the composition and having an iron content of less than 140 ppb by weight of the composition.

2. The composition according to claim 1, wherein the iron content is less than 120 ppb by weight of the composition.

3. The composition according to claim 2, wherein the iron content is less than 100 ppb by weight of the composition.

4. The composition according to claim 3, wherein the iron content is less than 80 ppb by weight of the composition.

5. The composition according to claim 4, wherein the iron content is less than 60 ppb by weight of the composition.

6. The composition according to any one of claims 1 to 5, comprising ropinirole or a pharmaceutically acceptable salt thereof in an amount of 2 to 10% by weight of the composition.

7. The composition according to claim 6, comprising ropinirole or a pharmaceutically acceptable salt thereof in an amount of 3 to 8% by weight of the composition.

8. The composition according to any one of claims 1 to 7, comprising ropinirole or a pharmaceutically acceptable salt thereof in an amount of 1 to 15% by weight of the composition and sterile water in an amount of 85 to 99% by weight of the composition.

9. The composition according to claim 8, comprising ropinirole or a pharmaceutically acceptable salt thereof in an amount of 2 to 10% by weight of the composition and sterile water in an amount of 90 to 98% by weight of the composition.

10. The composition according to claim 9, comprising ropinirole or a pharmaceutically acceptable salt thereof in an amount of 3 to 8% by weight of the composition and sterile water in an amount of 92 to 97% by weight of the composition.

11. The composition according to any one of claims 1 to 10, which is in the form of a solution.

12. The composition according to any one of claims 1 to 11, which is an ophthalmic composition adapted for administration to the eyes of an animal, particularly a companion animal such as a dog or a cat, for inducing vomiting.

13. A method for preparing a stable aqueous pharmaceutical composition comprising ropinirole or a pharmaceutically acceptable salt thereof in an amount of 1 to 15% by weight of the composition, comprising: a) dissolving ropinirole or a pharmaceutically acceptable salt thereof and optionally one or more excipients in water; and b) treating the mixture of step (a) with an iron scavenger The method comprising.

14. The method according to claim 13, wherein the iron scavenger is a solid-phase iron scavenger.

15. The method according to claim 14, wherein step (b) comprises flowing the mixture of step (a) through a cartridge of a solid iron scavenger.

16. The method according to claim 14, wherein step (b) comprises mixing the mixture of step (a) with an iron scavenger in a solid state and then removing the iron scavenger in a solid state from the mixture.

17. The method according to any one of claims 13 to 16, wherein the amount of iron after step (b) is less than 140 ppb based on the weight of the composition.

18. The method according to claim 17, wherein the amount of iron after step (b) is less than 120 ppb based on the weight of the composition.

19. The method according to claim 18, wherein the amount of iron after step (b) is less than 100 ppb based on the weight of the composition.

20. The method according to claim 19, wherein the amount of iron after step (b) is less than 80 ppb based on the weight of the composition.

21. The method according to claim 20, wherein the amount of iron after step (b) is less than 60 ppb based on the weight of the composition.

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