Ropinirole stable pharmaceutical composition

Abstract

The present invention relates to a pharmaceutical aqueous composition, such as a solution, comprising ropinirole or a pharmaceutically acceptable salt thereof as an active ingredient, the composition having a reduced iron content. The composition exhibits improved chemical stability of the active ingredient. The composition can be used in the preparation of an eye drop composition for inducing vomiting in animals, especially pets (such as dogs and cats) when vomiting is desired.

Description

Technical Field

[0001] The present invention relates to an aqueous pharmaceutical composition, in particular a solution, containing ropinirole or a pharmaceutically acceptable salt thereof as an active ingredient. The composition exhibits improved chemical stability against degradation of the active ingredient. The composition can be used, for example, in the preparation of eye drops in the veterinary field for inducing vomiting in cases involving ingestion of potentially toxic substances or foreign bodies by companion animals such as dogs or cats. Background of the Invention

[0003] WO 2015 / 044504 ​​describes a method of inducing vomiting in animals by administering an effective amount of an eye drop composition comprising a selective D2 family dopamine agonist, such as ropinirole, as an active ingredient. Aqueous eye drops containing 10 or 40 mg / ml ropinirole hydrochloride rapidly and continuously produce vomiting in dogs without causing unnecessary prolonged vomiting.

[0004] The development of an aqueous solution of ropinirole described in WO 2015 / 044504 ​​revealed the chemical instability of ropinirole in aqueous solution. Chemical instability is considered a disadvantage due to its implications for the limited shelf life of the drug product. SUMMARY OF THE INVENTION

[0006] It has been found that trace amounts of iron present in the composition are associated with the chemical instability of ropinirole. The sources of such trace amounts of iron have been found to be impurities in the raw materials used to prepare the composition, especially impurities in the active ingredient itself, and the container material used to prepare the composition.

[0007] Thus, according to one embodiment of the present invention, there is provided a stable aqueous pharmaceutical composition comprising 1% to 15% by weight of the solution of ropinirole or a pharmaceutically acceptable salt thereof, wherein the iron content is less than 140 ppb by weight of the composition.

[0008] According to another embodiment, the present invention provides a stable aqueous pharmaceutical composition having reduced iron content comprising 1% to 15% by weight of the solution of ropinirole or a pharmaceutically acceptable salt thereof, wherein the amount of iron is less than 140 ppb by weight of the composition.

[0009] According to another embodiment of the present invention, the iron content in the above composition is below 120 ppb, preferably below 100 ppb, more preferably below 80 ppb, still more preferably below 60 ppb, or below 40 ppb by weight of the composition.

[0010] According to another embodiment, the present invention provides a method for preparing a stable aqueous pharmaceutical composition comprising 1% to 15% by weight of the solution of ropinirole or a pharmaceutically acceptable salt thereof, the preparation method comprising the following steps:

[0011] a) dissolving ropinirole or a pharmaceutically acceptable salt thereof and optionally one or more excipients in water; and

[0012] b) treating the mixture of step (a) with an iron scavenger.

[0013] According to another embodiment of the present invention, the iron content after step (b) in the above method is less than 140 ppb, preferably less than 120 ppb, more preferably less than 100 ppb, still more preferably less than 80 ppb, still more preferably less than 60 ppb, or less than 40 ppb by weight of the composition. DETAILED DESCRIPTION OF THE INVENTION

[0015] As used herein, the term "ppb" means parts per billion by weight. Thus, 1 ppb by weight is equivalent to 1 μg / kg.

[0016] As used herein, the term "iron scavenger" refers to 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.

[0017] As used herein, the term "functionalized silica" refers to silica that has chemical groups bonded to it that act as an iron scavenger. Examples of functionalized silica include triaminetetraacetic acid bonded to silica or triaminetetraacetic acid sodium salt bonded to silica.

[0018] The term "silica" as used herein refers to silicon dioxide.

[0019] As used herein, the term "functionalized resin" refers to a polymeric material having chemical groups bonded thereto that act as iron scavengers. Examples include trimercaptotriazine bonded to macroporous polystyrene.

[0020] As used herein, the term "iron" refers to the chemical element having the symbol Fe in dissolved form, such as ionized or complexed form.

[0021] The term "eye drop composition" used herein refers to a liquid or semisolid pharmaceutical composition suitable for ocular administration. A typical example of an eye drop composition is an ophthalmic solution to be dropped into the eye.

[0022] The term "stable aqueous pharmaceutical composition" as used herein refers to a composition which, when filled (0.7 ml) in a 1 ml blow-fill-seal LDPE ampoule under nitrogen purge and further placed in an airtight aluminum laminate bag under nitrogen purge, contains less than 2%, preferably less than 1%, by weight of the composition of the degradation impurity B (4-[2-(dipropylamino)ethyl]indole-2,3-dione hydrochloride) after storage at 25°C / 60%RH for 36 months.

[0023] The present invention relates to a stable aqueous pharmaceutical composition, such as an eye drop composition, comprising ropinirole or a pharmaceutically acceptable salt thereof in an amount of 1%-15%, preferably 2%-10%, more preferably 3%-8% by weight of the solution, wherein the iron content is less than 140 ppb by weight of the solution.

[0024] 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, still more preferably less than 60 ppb, or less than 40 ppb by weight of the composition.

[0025] The above composition can be prepared by a method comprising the following steps:

[0026] a) dissolving ropinirole or a pharmaceutically acceptable salt thereof and optionally one or more excipients in water; and.

[0027] b) treating the mixture of step (a) with an iron scavenger.

[0028] According to one embodiment of the present invention, the iron content after step (b) in the above method is less than 140 ppb, preferably less than 120 ppb, more preferably less than 100 ppb, still more preferably less than 80 ppb, still more preferably less than 60 ppb, or less than 40 ppb by weight of the composition.

[0029] According to one embodiment of the present invention, the iron content after step (a) in the above method is higher than 60 ppb, or higher than 80 ppb, or higher than 100 ppb, or higher than 120 ppb, or higher than 140 ppb, or higher than 160 ppb, or higher than 200 ppb, or higher than 300 ppb, or higher than 500 ppb.

[0030] According to one embodiment of the present invention, the iron content after step (a) in the above method is 60-800ppb, or 80-800ppb, or 100-800ppb, or 120-800ppb, or 140-800ppb, or 160-800ppb, or 200-800ppb, or 300-800ppb by weight of the composition.

[0031] It has been found that the use of an iron removal process in the preparation of an aqueous ropinirole composition (eg, solution) can significantly improve the chemical stability of the active ingredient in the solution, as iron appears to be involved in the degradation of ropinirole.

[0032] The iron scavenger used in the 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, especially triaminetetraacetic acid bound to silica or triaminetetraacetic acid sodium salt bound to silica, which is available from SiliCycle Inc. as “ TAAcOH" and TAAcONa”.

[0033] The composition according to the present invention can be prepared by dissolving an appropriate amount of ropinirole or a pharmaceutically acceptable salt thereof (e.g. ropinirole hydrochloride) and optionally one or more excipients in sterile water. If necessary, the iron content of the mixture can be determined at this stage to determine the amount of iron scavenger required.

[0034] The solution containing ropinirole is then mixed with a suitable solid phase iron scavenger and the mixture is stirred for a sufficient time, e.g., 1-4 hours, to reduce the iron content. The amount of iron scavenger required can generally be calculated from the technical manual of the commercial brand of iron scavenger. For example, in terms of the iron concentration in the mixture, about 4-8 molar equivalents of Functionalized silica product. The removal process can be followed using 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).

[0035] When the iron content of the mixture is sufficiently reduced, the solid phase iron scavenger is removed by known methods, such as by filtration. Pharmaceutical excipients required for the final drug product may be added to the mixture if not already added prior to the iron scavenging step.

[0036] The treatment step (b) can also be performed by packing the solid phase iron scavenger in a column, for example using the iron scavenger in a continuous flow mode. Such columns are commercially available from SiliCycle Inc., for example.

[0037] According to one embodiment, the stable aqueous pharmaceutical composition according to the present invention comprises ropinirole or a pharmaceutically acceptable salt thereof as the sole active ingredient.

[0038] The selection of suitable excipients depends on the intended use and route of administration of the drug. When preparing an eye drop composition, ropinirole or a pharmaceutically acceptable salt thereof can be formulated into a dosage form suitable for administration to the eye by combining the bulk drug with conventional pharmaceutical diluents and carriers commonly used in eye drop compositions. The eye drop composition used in the method of the present invention can be, for example, in liquid or semisolid form, such as a solution, emulsion or suspension. Solutions are particularly preferred.

[0039] Preferably, the eye drop composition is in the form of an aqueous solution suitable for administration to the eye of an animal. In the composition, for example in an eye drop composition, the concentration of ropinirole or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) is suitably about 1% to about 15% (w / w), more typically about 2% to about 10% (w / w), more typically 3% to 8% (w / w), by weight of the composition.

[0040] According to one embodiment, the aqueous composition (e.g., eye drop composition) comprises about 1% to about 15% (by weight of the composition) of ropinirole or a pharmaceutically acceptable salt thereof, and about 85% to about 99% (by weight of the composition) of sterile water. According to another embodiment, the composition comprises about 2% to about 10% (by weight of the composition) of ropinirole or a pharmaceutically acceptable salt thereof, and about 90% to about 98% (by weight of the composition) of sterile water. According to another embodiment, the composition comprises about 3% to about 8% (by weight of the composition) of ropinirole or a pharmaceutically acceptable salt thereof, and about 92% to about 97% (by weight of the composition) of sterile water.

[0041] Aqueous compositions of ropinirole, such as eye drop compositions, may additionally contain tonicity agents, such as sodium chloride, pH adjusters or buffers, such as sodium hydroxide, hydrochloric acid, citric acid / sodium citrate, tartaric acid, fumaric acid, antioxidants, such as butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT), chelating agents (such as disodium edetate), thickeners (such as sodium carboxymethylcellulose), and other ingredients commonly used in the preparation of eye drop compositions.

[0042] The pH value of an aqueous composition (eg, an eye drop composition) containing ropinirole or a pharmaceutically acceptable salt thereof (eg, hydrochloride) is suitably about 2.5 to about 8, preferably 3 to about 6, for example about 3.5 to about 5.

[0043] The eye drop composition can be provided in the form of a veterinary kit, which includes an eye drop composition, a package for accommodating the composition, and instructions for applying the composition to the eyes of an animal (especially a companion animal, such as a dog) to induce vomiting. Preferably, the package is an applicator, such as a squeezable pre-filled disposable bottle, an ampoule, or a pipette capable of quantitatively administering the composition of the present invention. The squeezable bottle, ampoule, or pipette is preferably prepared with a polymer material (such as LDPE). Suitably, the volume range of a suitable bottle, ampoule, or pipette is about 0.5-5ml. For example, about 0.5-about 2ml eye drop composition can be filled into a disposable blow-fill-seal (BFS) LDPE ampoule with a volume of 0.5ml, 1ml, or 2ml.

[0044] The present invention is further illustrated by the following examples, which are not intended to limit the scope of the present invention.

[0045] Preparation Example 1 (eye drops)

[0046]

[0047] Preparation Example 2 (eye drops)

[0048] Ropinirole hydrochloride 45.6 mg (equivalent to 40 mg ropinirole base)

[0049] Sodium chloride to adjust osmotic pressure (300-400mosm / kg)

[0050] Water for injection up to 1 ml

[0051] pH4

[0052] Preparation Example 3 (eye drops)

[0053]

[0054] Preparation Example 4 (eye drops)

[0055]

[0056] Experiment 1. Using sodium triaminetetraacetic acid salt ( TAAcONa (obtained from SiliCycle Inc.) reduces iron levels

[0057] 102 mg of silica-bound metal scavenger ( 10 ml of ropinirole hydrochloride aqueous solution (34.2 mg / ml) containing 86 ppb of iron (Fe) was then added to the vial. The mixture was stirred for 1.5 hours. The silica was removed by filtration. The iron content in the filtrate was determined. The filtrate contained 55 ppb of iron (Fe).

[0058] Experiment 2. Using triaminetetraacetic acid (TAA) combined with silica TAAcOH (obtained from SiliCycle Inc.) reduces iron levels

[0059] 101 mg of silica-bound metal scavenger ( 10 ml of ropinirole hydrochloride aqueous solution (34.2 mg / ml) containing 86 ppb of iron (Fe) was then added to the vial. The mixture was stirred for 1.5 hours. The silica was removed by filtration. The iron content in the filtrate was determined. The filtrate contained 40 ppb of iron (Fe).

[0060] Experiment 3. Use activated carbon (Norit SX obtained from Sigma-Aldrich Inc.) to reduce iron levels

[0061] 105 mg of activated carbon (Norit SX ) was placed in a vial. Then, 10 ml of an aqueous solution of ropinirole hydrochloride (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 in the filtrate was determined. The filtrate contained 52 ppb of iron (Fe).

[0062] Experiment 4 .Use sodium triaminetetraacetic acid salt combined with silica ( TAAcONa (obtained from SiliCycle Inc.) reduces iron levels

[0063] 101 mg of silica combined with metal scavenger ( 10 ml of ropinirole hydrochloride aqueous solution (34.2 mg / ml) containing 330 ppb of iron (Fe) was then added to the vial. The mixture was stirred for 2 hours. Silica was removed by filtration. The iron content in the filtrate was determined. The filtrate contained 139 ppb of iron (Fe).

[0064] Experiment 5. Using triaminetetraacetic acid (TAA) combined with silica TAAcOH (obtained from SiliCycle Inc.) reduces iron levels

[0065] 99 mg of silica-bound metal scavenger ( 10 ml of ropinirole hydrochloride aqueous solution (34.2 mg / ml) containing 330 ppb of iron (Fe) was then added to the vial. The mixture was stirred for 2 hours. Silica was removed by filtration. The iron content in the filtrate was determined. The filtrate contained 81 ppb of iron (Fe).

[0066] Experiment 6. Use activated carbon (Norit SX obtained from Sigma-Aldrich Inc.) to reduce iron levels

[0067] 103 mg of activated carbon (Norit SX ) into a vial. Then, 10 ml of an aqueous solution of ropinirole hydrochloride (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 in the filtrate was determined. The filtrate contained 122 ppb of iron (Fe).

[0068] Experiment 7. Using triaminetetraacetic acid (TAA) combined with silica TAAcOH (obtained from SiliCycle Inc.) reduces iron levels

[0069] 100 mg of silica combined with metal scavenger ( 10 ml of ropinirole hydrochloride aqueous solution (34.2 mg / ml) containing 580 ppb of iron (Fe) was then added to the vial. The mixture was stirred for 2 hours. Silica was removed by filtration. The iron content in the filtrate was determined. The filtrate contained 95 ppb of iron (Fe).

[0070] Experiment 8. Stability of ropinirole hydrochloride aqueous solution (34.2 mg / ml)

[0071] The stability of ropinirole hydrochloride eye drops (34.2 mg / ml) with different iron contents was studied. The test solution (0.7 ml) was filled into 1 ml blow-fill-seal LDPE ampoules under nitrogen purge. The sealed ampoules were placed in airtight aluminum laminated bags under nitrogen purge, and the bags were stored at 25°C / 60% RH for 36 months. The degradation rate of ropinirole hydrochloride was determined by measuring the degradation impurities of ropinirole (impurity B, (4-[2-(dipropylamino)ethyl]indole-2,3-dione hydrochloride) at the time of placement, 1 month, 2 months, 3 months, 24 months and 36 months later. The results are shown in Table 1. It can be seen that the iron content in the solution corresponds to the degradation rate of ropinirole.

[0072] Table 1. Chemical stability of ropinirole hydrochloride

[0073]

[0074] na = not analyzed

[0075] Experiment 9 .Stability of ropinirole hydrochloride aqueous solution (34.2 mg / ml)

[0076] The stability of aqueous ropinirole hydrochloride eye drops (34.2 mg / ml) with an iron content of 127 ppb or 37 ppb was studied. The test solution was filled into 1 ml blow-fill-seal LDPE ampoules under nitrogen purge. The sealed ampoules were placed in an airtight aluminum laminate bag under nitrogen purge, and the bags were stored at 25°C / 60% RH for 12 months. The degradation rate of ropinirole hydrochloride was determined by measuring the degradation impurities of ropinirole (impurity B, (4-[2-(dipropylamino)ethyl]indole-2,3-dione hydrochloride) during storage and after different time points. The results are shown in Table 2. It can be seen that the iron content in the solution corresponds to the degradation rate of ropinirole.

[0077] Table 2. Chemical stability of ropinirole hydrochloride

[0078] Batch No. F Batch No. G Iron content: 127 ppb Iron content 37ppb Time (month) Impurity B(%) Impurity B(%) 0 0.118 0.065 1 0.162 na 2 0.215 na 3 0.239 0.142 4 0.273 na 5 0.302 na 6 0.354 0.213 9 na 0.300 12 0.506 0.375

[0079] na = not analyzed.

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, wherein the iron content is less than 140 ppb by weight of the composition.

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

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

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

5. A 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 5, comprising 1% to 15% by weight of the composition of ropinirole or a pharmaceutically acceptable salt thereof and 85% to 99% by weight of the composition of sterile water.

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

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

11. A composition according to any one of claims 1 to 5 in the form of a solution.

12. The composition according to any one of claims 1 to 5, which is an eye drop composition suitable for administration to the eyes of animals to induce emesis.

13. The composition according to claim 12, wherein the animal is a companion animal.

14. The composition according to claim 13, wherein the companion animal is a dog or a cat.

15. A composition according to any one of claims 1 to 5 having a reduced iron content.

16. 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 the steps of: 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, wherein after step (b), the iron content by weight of the composition is less than 140 ppb.

17. The method according to claim 16, wherein the iron scavenger is a solid phase iron scavenger.

18. The method of claim 17, wherein step (b) comprises passing the mixture of step (a) through a column of a solid phase iron scavenger.

19. The method of claim 17, wherein step (b) comprises mixing the mixture of step (a) with a solid iron scavenger and then removing the solid iron scavenger from the mixture.

20. The method of claim 16, wherein after step (b), the iron content is less than 120 ppb by weight of the composition.

21. A method according to claim 20 wherein after step (b) the iron content is less than 100 ppb by weight of the composition.

22. A method according to claim 21 wherein after step (b) the iron content is less than 80 ppb by weight of the composition.

23. A method according to claim 22 wherein after step (b) the iron content is less than 60 ppb by weight of the composition.

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