AND USES THEREOF

Background of the Disclosure

[0001] This application relates to a stable liquid pharmaceutical composition of

apomorphine HCl.

[0002] This application also relates to novel apomorphine HCl compositions in an aqueous solution, comprising apomorphine HCl that is free or substantially free of additives. This application also relates to a method of making and using the apomorphine composition. The present compositions and methods are designed to improve patient tolerance and compliance, while at the same time maintain the stability of the pharmaceutical formulation.

[0003] Apomorphine hydrochloride is a non-ergoline dopamine agonist.

Apomorphine hydrochloride is chemically designated as 6a -Aporphine- 10, 1 1-diol hydrochloride hemihydrate with a molecular formula of C17H17 O2 . HCl .1/2H2O. Its structural formula is:

[0004] Apomorphine HCl is marketed generically in the United States and worldwide under the trade names of Apokyn® and others (IXENSE, SPONTANE, UPRIMA). It is approved for several indications including erectile dysfunction and acute intermittent treatment of episodes of hypomobility associated with advanced Parkinson's disease. It is also used as an adjunct to other anti- Parkinson's disease agents.

[0005] A well-known problem of aqueous solutions of apomorphine HCl is stability, since the compound is highly susceptible to oxidation. To improve the stability of apomorphine HCl in an aqueous solution, the use of suitable antioxidants (for example, sodium metabisulfite) was thought to be essential. Aqueous solutions of apomorphine HCl currently sold generally also contain the antioxidant sodium metabisulfite, which is thought to stabilize the pharmaceutical product.

[0006] While improving the stability of apomorphine HCl formulations, antioxidant agents such as sodium metabisulfite can cause undesirable effects when administered to humans. Some of these undesirable effects include severe, life-threatening allergic reactions in some people, especially in people with asthma.

[0007] It would therefore be desirable to have a stable apomorphine HCl solution that does not have the potential for producing adverse effects upon administration.

[0008] The current application relates to novel apomorphine HCl compositions that maintain the stability of the pharmaceutical formulation in an aqueous solution and are substantially free or free of additives.

[0009] It has been surprisingly found that an aqueous composition containing

apomorphine HCl, benzyl alcohol, sterilized water, and a pH-adjusting agent, with minimal or no antioxidant, is stable with minimal or without the addition of sodium metabisulfite. The formulation pH was in the acidic range and the solution was prepared under inert gas.

Brief Summary of the Disclosure

[0010] This application relates to a stable aqueous pharmaceutical composition, free, or substantially free of antioxidants, said composition comprising an apomorphine salt and water, wherein the pH of the composition is from about 2.0 to about 6.0, and wherein said composition is sealed in an airtight container having a headspace volume occupied by an inert gas. The stable aqueous pharmaceutical composition may also contain from about 5 to about 15 mg/mL of the apomorphine salt and also about 10 mg of the apomorphine salt, wherein the salt is the HC1 salt. The antioxidant may be sodium metabisulfite.

[0011] The pH of the stable aqueous composition is from about 2.0 to less than about

6.0 and may also be about 2.5. The pH of the composition may be adjusted by the addition of a pH-adjusting agent, such as hydrochloric acid and sodium hydroxide. The composition may be stable for at least 3 months at 40° C/75% RH and may be suitable form for subcutaneous injection.

[0012] This application also relates to an aqueous composition containing an

apomorphine salt, for instance the HC1 salt, with water for injection, a pH- adjusting agent, an antioxidant, for instance, sodium metabisulfite, and also a preservative for instance, benzyl alcohol.

[0013] In one embodiment of the present application, the aqueous pharmaceutical composition is substantially free of antioxidant agents. In a further embodiment of the present application, the aqueous pharmaceutical composition is substantially free of sodium metabisulfite.

[0014] In further embodiments of the application, the aqueous pharmaceutical

composition contains less than about 1 mg/mL, by weight, less than about 0.2 mg/mL, by weight, or is substantially free of antioxidant agents. In still other embodiments of the application, the aqueous pharmaceutical composition contains no antioxidants, such as sodium metabisulfite.

[0015] Other advantages of the application will be evident from the description, or may be learned by practice of the application as applicable. It is to be understood that the general and detailed description of this application are explanatory only and are not restrictive of the application.

Detailed Description of the Disclosure

[0016] The term "stable" refers to the minimal change in physical and chemical properties of the apomorphine salt composition (such as the hydrochloride salt) over time relative to when it is manufactured. Stability over time may be evaluated based on pre-defined criteria including assay of active and related compounds, appearance, particulate matter, and pH, etc.

[0017] The term "substantially free" refers to compositions that have significantly reduced levels of antioxidants. In one embodiment, antioxidants are not added to the composition, but may be otherwise present as an impurity.

[0018] In this context, the term "substantially free" means that the selected

composition contains less than a functional amount of the antioxidant, and may contain less than about 1.5 mg/mL by weight, and also less than about 1 mg/mL by weight, and also less than 0.5 mg/mL by weight and also less than 0. 2 mg/mL by weight of antioxidant.

[0019] The pure aqueous apomorhine salt solution of the present application has a total purity of greater than about 99%, by weight.

[0020] Surprisingly, the liquid compositions of apomorphine HCl solution can be produced with pharmaceutically acceptable stability of at least three (3) months at stressed accelerated conditions (40° C/75 %RH.) without the need of antioxidants.

[0021] In one embodiment, the compositions of the application contain no

antioxidants or are substantially free of antioxidants, such as sodium metabisulfite. In another embodiment the compositions of the application contain less than about 1.5 mg/mL of antioxidants. For example, the composition of the present application may contain less than 1 mg/mL, 0.9 mg/mL, 0.8 mg/mL, 0.7 mg/mL, 0.6 mg/mL, 0.5 mg/mL,0. 4 mg/mL, 0.3 mg/mL, 0.2 mg/mL, 0.1 mg/mL, 0.05 mg/mL, and O.Olmg/mL of antioxidants, such as sodium metabisulfite.

[0022] Another embodiment of the application is a pharmaceutical composition

comprising an aqueous solution of apomorphine HCl, wherein the pH of the composition is from about 1 to about 7. In yet another embodiment of the application, the pharmaceutical composition comprises an aqueous solution of apomorphine HCl, wherein the pH of the composition is from about 2 to about 6. A further embodiment of the application is a pharmaceutical composition comprising an aqueous solution of apomorphine HC1, wherein the pH is about 2.5.

[0023] In another embodiments, the pH of the composition may be from about 2.0 to about 6.0.

[0024] In other embodiments, the pH may be from about 2.75-6.0, wherein the

composition may also contain an alchol, such as tert-butanol. The concentration range of the alcohol may be from about 0.1% to about 1.5 %. The alcohol may also be in an amount of about 1 %.

[0025] Formulations of the present application may further comprise pH-adjusting agents. Such agents include may typically include pharmaceutically acceptable acids and bases, , such as hydrochloric acid, citric acid, sodium hydroxide solution, potassium hydroxide solution, calcium hydroxide, magnesium hydroxide, and/or mixtures thereof. In one embodiment of the application, sodium hydroxide is added to the composition to adjust the pH of the composition.

[0026] The amount of pH-adjusting agent may vary depending on the desired pH of the composition and the amount of apomorphine HC1 in the solution and these amounts may be determined by one of ordinary skill in the art. For example, the amount of a pH-adjusting agent, such as sodium hydroxide, in formulations of the present application will vary depending on the concentration of the apomorphine HC1. The exact amount of pH-adjusting agent used will depend on the particular agent and upon the buffering capacity of the aqueous medium and other components in the formulation.

[0027] The present application also provides for an aqueous pharmaceutical

composition comprising from about 5-15 mg/mL apomorphine HC1 and a titrated amount of sodium hydroxide or other base, dissolved in oxygen free water, to achieve a desired pH of the composition, for example from about 2 to about 6. [0028] In certain embodiments, suitable formulation materials may include, but are not limited to, antioxidants (such as sodium metabislfuite); and/or pharmaceutical excipients.

[0029] This application also relates to a method of making a pharmaceutical

composition comprising combining an aqueous solution of apomorphine HCl and a pH-adjusting agent, wherein the composition is substantially free of antioxidants and/or contains less than 0.1 mg/mL. The method may comprise the following: adding apomorphine HCl to nitrogen purged water for injection; adding a pH-adjusting agent until a pH of about 2.5 is reached and the apomorphine HCl is fully dissolved. Alternatively, apomorphine HCl can be added to an aqueous solution containing the pH adjusting solution. The resulting solution is a clear and colorless and may be readily passed through a sterilizing filter. The product is then poured into vials and an inert gas is placed over the solution prior to sealing. The inert gas is most typically nitrogen or argon.

[0030] All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present application.

[0031] All numbers expressing percentages components used in the claims are to be understood as being modified in all instances by the term "w/v." Accordingly, unless indicated to the contrary, the percentages set forth in the specification and attached claims are expressed in weight per unit volume.

[0032] The specific embodiments described herein are offered by way of example only and are not meant to be limiting in any way. It is intended that the specification and examples be considered as exemplary only.

[0033] The application is illustrated by the following non-limiting examples: Examples

Example 1 [0034] Preparation of an apomorphine HCl formulation without antioxidant (0%

sodium metabisulfite)

[0035] Ten grams of apomorphine HCl are added to approximately 0.75 liters of water containing five (5.0) grams of benzyl alcohol (preservative). A solution of hydrochloric acid and sodium hydroxide is used to adjust the pH to approximately 2.5 and the resulting solution was mixed for at least 30 min or until completely dissolved. Sufficient quantity of water for injection is added to make a total volume of 1.0 liter. Exposure to air is minimized by compounding under an oxygen-free environment. The product is filled into cartridges and exposure to oxygen is minimized by displacing the headspace with nitrogen or argon.

Example 2 [0036] Preparation of an apomorphine HCl formulation without antioxidant (0%

sodium metabisulfite) but with the addition of 1% tert-butyl alcohol

[0037] Ten grams of apomorphine HCl are added to approximately 0.75 liter of water containing 1% tert-butyl alcohol and five (5.0) grams of benzyl alcohol (preservative). A solution of hydrochloric acid and sodium hydroxide are used to adjust the pH to approximately 2.75 and the resulting solution is mixed for at least 30 minutes or until completely dissolved. Sufficient quantities of water for injection are added to make a total volume of 1.0 liter. Exposure to air is minimized by compounding under oxygen free environment. The product is filled into cartridges and exposure to oxygen is minimized by displacing the headspace with nitrogen or argon.

Example 3 [0038] Preparation of an apomorphine HCl formulation with (0.5 mg/mL sodium metabisulfite) [0039] Ten grams of apomorphine HC1 are added to approximately 0.75 liter of water containing five (5.0) grams of benzyl alcohol and a half (0.5) gram of sodium metabisulfite. A solution of hydrochloric acid and sodium hydroxide is used to adjust the pH to approximately 2.5 and the resulting solution is mixed for at least 30 min or until completely dissolved. A sufficient quantity of water for injection is added to make a total volume of 1.0 liter. Exposure to air is minimized by compounding under oxygen free environment. The product is filled into cartridges and exposure to oxygen is minimized by displacing the headspace with nitrogen or argon.

Example 4 [0040] Preparation of an apomorphine HC1 formulation with 1 mg/mL sodium

metabisulfite as antioxidant.

[0041] Ten grams of apomorphine HC1 are added to approximately 0.75 liter of water containing five (5.0) grams of benzyl alcohol and one (1.0) gram of sodium metabisulfite. A solution of hydrochloric acid and sodium hydroxide are used to adjust the pH to approximately 2.75 and the resulting solution is mixed for at least 30 min or until completely dissolved. A sufficient quantity of water for injection is added to make a total volume of 1.0 liter. Exposure to air is minimized by compounding under an oxygen free environment. The product is filled into cartridges and exposure to oxygen is minimized by displacing the headspace with nitrogen or argon

Example 5 [0042] Stability of apomorphine HC1 solutions is tested by producing solutions

containing different concentrations of sodium metabisulfite. The stability of a solution containing 0 mg/mL, 0.5 mg/mL, and 1 mg/mL sodium metabisulfite is examined. The three solutions are manufactured as described in Example 1 , 2, 3, and 4.

[0043] High performance liquid chromatography (HPLC) is used to assess the

apomorphine content of the three solutions. Also, measurements are taken of impurities and degradation products (related compounds). The visual appearance and pH values of each of the three solutions is also examined.

[0044] The apomorphine HCl assay values by HPLC analysis are presented in

Table 1.

[0045] Appearance and pH values remain constant over time between the three

formulations. As shown in Table I, there is no significant differences between each of the three solutions in apomorphine HCl content or purity.

Example 6

[0046] Stability of apomorphine HCl solutions is tested by producing solutions with 1 mg/mL t sodium metabisulfite and without the antioxidant sodium metabisulfite. The formulation solutions are prepared at three different pH values; 2.5, 3, and 5.5.

[0047] The results demonstrate surprisingly that the antioxidant sodium metabisulfite is not required to maintain a stable apomorphine HCl product if the formulation is made at a pH of about 2.5.

Tables

Table 1: Assay of apomorphine HCl (mg/mL) stored in cartridge containers at stressed stability conditions (40 °C/75% RH). Formulations were made with 1, 0.5, and 0% antioxidant and one formulation was made with 1 % tert butyl alcohol (TBA)

Table 2: Assay of apomorphine HCl (mg/mL) stored in cartridge containers at stressed stability conditions (40 °C/75% RH). Formulations were made with and without antioxidant at three different pH values (pH 2.5, pH 3.0, and pH 5.5)

Formulation pH 0 month 3 month

Apomorphine HCl formulation with 2.5 9.91 ± 0.17 9.71 ± 0.24

antioxidant (1 mg/ml sodium 3.0 9.99 ± 0.01 9.75 ± 0.16

metabisulfite) 5.5 9.80 ± 0.16 9.74 ± 0.11

Apomorphine HCl formulation 2.5 9.94 ± 0.09 9.75 ± 0.22

without antioxidant 3.0 9.80 ± 0.15 9.66 ± 0.18

5.5 9.84 ± 0.17 9.46 ± 0.04