LONG-ACTING APOMORPHINE FORMULATIONS AND INJECTORS FOR THERAPEUTIC DELIVERY OF THE SAME

1 . A stable pharmaceutically acceptable formulation comprising:

a microsphere comprising:

a first biodegradable polymer; and

an active drug load of apomorphine or a pharmaceutically acceptable salt thereof.

2 . The stable pharmaceutically acceptable formulation of claim 1 , wherein the pharmaceutically acceptable salt is an acid addition salt of apomorphine.

3 . The stable pharmaceutically acceptable formulation of claim 1 or claim 2 , wherein the pharmaceutically acceptable salt is apomorphine hydrochloride.

4 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 3 , wherein the microsphere further comprises one or more additional biodegradable polymers.

5 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 4 , further comprising one or more antioxidants.

6 . The stable pharmaceutically acceptable formulation of claim 5 , wherein the one or more antioxidants comprises sodium metabisulfite.

7 . The stable pharmaceutically acceptable formulation of claim 5 or claim 6 , wherein the one or more antioxidants comprises sodium ascorbate.

8 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 7 , wherein the first biodegradable polymer is a copolymer.

9 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 8 , wherein the first biodegradable polymer is a multi-block copolymer.

10 . The stable pharmaceutically acceptable formulation of claim 9 , wherein the multi-block copolymer comprises at least one hydrolysable pre-polymer (A) segment and at least one hydrolysable pre-polymer (B) segment, wherein the segments are linked by a multifunctional chain extender, and wherein the segments are randomly and non-alternatingly distributed over the polymer chain.

11 . The stable pharmaceutically acceptable formulation of claim 10 , wherein the multi-block copolymer has a T g of about 37° C. or less and a T m of about 110° C. to about 250° C. under physiological conditions, and wherein the pre-polymer (A) segment comprises polyethylene glycol.

12 . The stable pharmaceutically acceptable formulation of claim 11 , wherein the polyethylene glycol has a M n of about 150 to about 5000 g/mol.

13 . The stable pharmaceutically acceptable formulation of claim 10 , wherein the multi-block copolymer is amorphous and has a glass transition temperature of 37° C. or less at physiological conditions.

14 . The stable pharmaceutically acceptable formulation of any one of claims 10 - 13 , wherein the pre-polymer (A) segment and/or the pre-polymer (B) segment comprises one or more linkages selected from the group consisting of: ester linkages, carbonate linkages, anhydride linkages, ether linkages, and combinations thereof.

15 . The stable pharmaceutically acceptable formulation of any one of claims 10 - 14 , wherein the pre-polymer (A) segment comprises one or more polyether groups.

16 . The stable pharmaceutically acceptable formulation of claim 15 , wherein the one or more polyether groups are selected from the group consisting of: polyethylene glycol, polyethylene glycol-polypropylene glycol, polytetramethylene ether glycol, and combinations thereof.

17 . The stable pharmaceutically acceptable formulation of claim 16 , wherein said polyether group is polyethylene glycol.

18 . The stable pharmaceutically acceptable formulation of any one of claims 10 - 17 , wherein a polyether is present as an additional pre-polymer in the multi-block copolymer.

19 . The stable pharmaceutically acceptable formulation of any one of claims 10 - 18 , wherein the pre-polymer (A) segment comprises products of a reaction of at least one cyclic monomer with at least one non-cyclic initiator selected from the group consisting of diols, dicarboxylic acids and hydroxycarboxylic acids.

20 . The stable pharmaceutically acceptable formulation of claim 19 , wherein the at least one cyclic monomer is selected from the group consisting of glycolide, lactide ( D and/or L ), ε-caprolactone, δ-valerolactone, trimethylene carbonate, 1,4-dioxane-2-one (para-dioxanone), 1,5-dioxanone-2-one, and a cyclic anhydride.

21 . The stable pharmaceutically acceptable formulation of claim 19 or claim 20 , wherein the at least one non-cyclic initiator is selected from the group consisting of succinic acid, glutaric acid, adipic acid, sebacic acid, lactic acid, glycolic acid, ethylene glycol, diethylene glycol, 1,4-butanediol, and 1,6-hexanediol.

22 . The stable pharmaceutically acceptable formulation of any one of claims 10 - 21 , wherein the pre-polymer (A) segment comprises reactions products of ester forming monomers selected from diols, dicarboxylic acids, and hydroxycarboxylic acids, preferably the pre-polymer (A) segment comprises reaction products of glycolide, lactide ( D and/or L ), ε-caprolactone, and/or δ-valerolactone.

23 . The stable pharmaceutically acceptable formulation of any one of claims 10 - 22 , wherein the content of pre-polymer (A) in the multi-block copolymer is from about 1% to about 90% based on total weight of the multi-block copolymer.

24 . The stable pharmaceutically acceptable formulation of any one of claims 10 - 23 , wherein the pre-polymer (A) segment has a M n of about 500 g/mol or more.

25 . The stable pharmaceutically acceptable formulation of any one of claims 10 - 24 , wherein the pre-polymer (B) segment comprises a polymer derived from hydroxyalkanoate, glycolide lactide ( D and/or L ), ε-caprolactone, δ-valerolactone, trimethylene carbonate, 1,4-dioxane-2-one or combinations thereof.

26 . The stable pharmaceutically acceptable formulation of any one of claims 10 - 25 , wherein the pre-polymer (B) segment comprises poly(glycolide-co- L lactide).

27 . The stable pharmaceutically acceptable formulation of any one of claims 10 - 26 , wherein the pre-polymer (B) segment comprises poly(glycolide-co- L lactide) with a M n of about 1000 g/mol or more.

28 . The stable pharmaceutically acceptable formulation of claim 27 , wherein the pre-polymer (B) segment comprises poly(glycolide-co- L lactide) with a M n of about 4000 g/mol.

29 . The stable pharmaceutically acceptable formulation of any one of claims 26 - 28 , wherein the pre-polymer (B) segment comprises a molar amount of about 5% to about 25% of glycolide relative to combined molar amount of glycolide and L -lactide.

30 . The stable pharmaceutically acceptable formulation of claim 29 , wherein the pre-polymer (B) segment comprises a molar amount of about 15% of glycolide relative to the combined molar amount of glycolide and L -lactide.

31 . The stable pharmaceutically acceptable formulation of any one of claims 10 - 30 , wherein the multi-block copolymer comprises from about 10% to about 99% of the pre-polymer (B) segment relative to the total weight of the multi-block copolymer.

32 . The stable pharmaceutically acceptable formulation of any one of claims 10 - 31 , wherein the multifunctional chain extender is a difunctional aliphatic chain extender.

33 . The stable pharmaceutically acceptable formulation of claim 32 , wherein the difunctional aliphatic chain extender is a diisocyanate.

34 . The stable pharmaceutically acceptable formulation of claim 33 , wherein the diisocyanate is 1,4-butane diisocyanate.

35 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 9 , wherein the first biodegradable polymer is selected from the group consisting of: a polylactide, a polyglycolide, and a poly(lactide-co-glycolide) copolymer.

36 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 9 , wherein the first biodegradable polymer is a poly(lactide-co-glycolide) copolymer, wherein the content of polymerized lactic acid units is at least 50 mol % based on the total amount of polymerized units or blends of poly(lactide-co-glycolide) copolymers with different relative amounts of glycolic acid and lactic acid, wherein the content of polymerized lactic acid units is at least 50 mol % based on the total amount of polymerized units.

37 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 36 , wherein the first biodegradable polymer is substantially enclosed by a second biodegradable polymer.

38 . The stable pharmaceutically acceptable formulation of claim 37 , wherein the first biodegradable polymer is not substantially identical in composition to the second biodegradable polymer.

39 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 38 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 30% to about 70% w/w.

40 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 39 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 50% to about 60% w/w.

41 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 39 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 40% to about 50% w/w.

42 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 37 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 30% to about 40% w/w.

43 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 37 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 40% w/w.

44 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 37 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 50% w/w.

45 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 44 , wherein the stable pharmaceutically acceptable formulation is substantially sterile.

46 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 45 , wherein the stable pharmaceutically acceptable formulation comprises less than 5 wt % of an apomorphine-derived impurity after sealed storage for 24 months at a temperature of 25° C.

47 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 46 , wherein the stable pharmaceutically acceptable formulation comprises less than 2% wt/wt of an apomorphine-derived impurity after sealed storage for 24 months at a temperature of 25° C.

48 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 47 , wherein the stable pharmaceutically acceptable formulation comprises less than 1% wt/wt of an apomorphine-derived impurity after sealed storage for 24 months at a temperature of 25° C.

49 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 48 , wherein the stable pharmaceutically acceptable formulation is substantially free of an apomorphine-derived impurity after sealed storage for 24 months at a temperature of 25° C.

50 . The stable pharmaceutically acceptable formulation any one of claims 46 - 49 , wherein the apomorphine-derived impurity is an apomorphine oxidation product.

51 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 50 , wherein the stable pharmaceutically acceptable formulation has a shelf life of about 14 days at 25° C. following refrigeration.

52 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 51 , wherein the stable pharmaceutically acceptable formulation has a shelf life of about 24 months at 25° C.

53 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 52 , wherein the stable pharmaceutically acceptable formulation is stored in a sterile container of about 3.0 mL capacity.

54 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 53 , wherein the stable pharmaceutically acceptable formulation is provided in an injector.

55 . The stable pharmaceutically acceptable formulation of claim 54 , wherein the injector is a disposable pen injector.

56 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 55 , wherein the stable pharmaceutically acceptable formulation is suitable for parenteral administration.

57 . The stable pharmaceutically acceptable formulation of claim 56 , wherein the stable pharmaceutically acceptable formulation is suitable for subcutaneous or intramuscular administration.

58 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 57 , wherein the amount of apomorphine or a pharmaceutically acceptable salt thereof per dose is about 40 mg to about 200 mg.

59 . The stable pharmaceutically acceptable formulation of any one of claims 1 - 58 , wherein the amount of apomorphine or a pharmaceutically acceptable salt thereof per dose is about 80 mg to about 100 mg.

60 . A method of producing a stable pharmaceutically acceptable formulation comprising a microsphere, the method comprising:

providing a first phase comprising:

a first biodegradable polymer; and

an active drug load of apomorphine or a pharmaceutically acceptable salt thereof;

adding a second phase comprising an aqueous surfactant continuously into the first phase to form an emulsion;

adding a quench solution to the emulsion to produce a volume comprising a microsphere; and

washing, filtering, and drying the microsphere to reduce solvent content.

61 . A method of producing a stable pharmaceutically acceptable formulation comprising a microsphere, the method comprising:

providing a first phase comprising:

a first biodegradable polymer;

an active drug load of apomorphine or a pharmaceutically acceptable salt thereof; and

a solvent system suitable to dissolve the polymer and apomorphine;

emulsifying the first phase with a second phase, thereby forming an emulsion;

wherein the second phase comprises an aqueous solution which comprises a surfactant; and

removing a substantial portion of the solvent system from the emulsion, thereby obtaining a microsphere.

62 . The method of claim 61 , further comprising collecting and drying the microspheres.

63 . The method of claim 61 or claim 62 , wherein the step of emulsifying the first phase with the second phase comprises membrane emulsification using a membrane through which the first phase is introduced into the second phase.

64 . The method of any one of claims 61 - 63 , wherein the step of removing the substantial portion of the solvent system from the emulsion comprises extraction of the solvent system by the aqueous solution, wherein the aqueous solution comprises a surfactant.

65 . The method of claim 64 , wherein the step of removing the substantial portion of the solvent system from the emulsion by extraction is followed by evaporation of the solvent system.

66 . The method of any one of claims 61 - 65 , further comprising washing and/or filtering the microspheres.

67 . The method of any one of claims 61 - 66 , further comprising drying the microspheres.

68 . The method of claim 67 , wherein the step of drying comprises one or more of lyophilization, vacuum-drying, and freeze-vacuum drying.

69 . The method of any one of claims 60 - 68 , wherein the pharmaceutically acceptable salt is an acid addition salt of apomorphine.

70 . The method of any one of claims 60 - 69 , wherein the pharmaceutically acceptable salt is apomorphine hydrochloride.

71 . The method of any one of claims 60 - 70 , wherein the first phase comprises a solvent system in which apomorphine or a pharmaceutically acceptable salt thereof has a solubility of about 25 mg/mL or more.

72 . The method of any one of claims 60 - 71 , wherein the first phase comprises one or more solvents selected from the group consisting of: dichloromethane, ethyl acetate, chloroform, methanol, benzyl alcohol, dimethyl formamide, dimethyl sulfoxide, N-methyl pyrrolidone and dimethyl acetamide.

73 . The method of any one of claims 60 - 72 , wherein the first phase comprises dichloromethane in combination with one or more additional solvents.

74 . The method of claim 73 , wherein the one or more additional solvents are selected from the group consisting of: dimethyl formamide, dimethyl sulfoxide, and N-methyl pyrrolidone.

75 . The method of any one of claims 60 - 74 , wherein the first phase comprises dichloromethane and dimethyl sulfoxide.

76 . The method of claim 75 , wherein dimethyl sulfoxide is present in an amount of about 5% to about 50% relative to the combined volume of dimethyl sulfoxide and dichloromethane in the first phase.

77 . The method of any one of claims 60 - 76 , wherein the first phase comprises about 2% to about 25% by weight of the combined mass of the first biodegradable polymer and the one or more additional biodegradable polymers.

78 . The method of any one of claims 60 - 77 , wherein the first phase comprises about 2% to about 25% by weight of apomorphine or a pharmaceutically acceptable salt thereof.

79 . The method of any one of claims 60 - 78 , wherein the first phase comprises one or more antioxidants.

80 . The method of claim 79 , wherein the one or more antioxidants comprises sodium metabisulfite or sodium ascorbate.

81 . The method of claim 79 or claim 80 , wherein the one or more antioxidants comprises sodium metabisulfite or sodium ascorbate in an amount from about 0.01% to about 5% w/v relative to the first phase.

82 . The method of any one of claims 60 - 81 , wherein the second phase comprises polyvinyl alcohol.

83 . The method of any one of claims 60 - 82 , wherein the second phase comprises sodium chloride.

84 . The method of any one of claims 60 - 83 , wherein the second phase comprises one or more antioxidants.

85 . The method of claim 84 , wherein the one or more antioxidants comprises sodium metabisulfite.

86 . The method of claim 84 or claim 85 , wherein the one or more antioxidants comprises sodium metabisulfite in an amount of about 0.1% to about 1% w/v in the second phase.

87 . The method of any one of claims 84 - 86 , wherein the one or more antioxidants comprises sodium metabisulfite in an amount of about 0.15% w/v in the second phase.

88 . The method of any one of claims 84 - 87 , wherein the one or more antioxidants comprises sodium ascorbate.

89 . The method of any one of claims 84 - 88 , wherein the one or more antioxidants comprises sodium ascorbate in an amount of about 0.1% to about 1% w/v in the second phase.

90 . The method of any one of claims 84 - 89 , wherein the one or more antioxidants comprises sodium ascorbate in an amount of about 0.15% w/v in the second phase.

91 . The method of any one of claims 60 - 90 , wherein the first biodegradable polymer is selected from the group consisting of: a polylactide, a polyglycolide, and a poly(lactide-co-glycolide) copolymer.

92 . The method of any one of claims 60 - 91 , wherein the first biodegradable polymer is a poly(lactide-co-glycolide) copolymer, wherein the content of polymerized lactic acid units is at least 50 mol % based on the total amount of polymerized units or blends of poly(lactide-co-glycolide) copolymers with different relative amounts of glycolic acid and lactic acid, wherein the content of polymerized lactic acid units is at least 50 mol % based on the total amount of polymerized units.

93 . The method of any one of claims 60 - 92 , wherein the aqueous surfactant comprises one or more of a cationic surfactant, an anionic surfactant, or a non-ionic surfactant.

94 . The method of any one of claims 60 - 93 , wherein the second phase further comprises one or more of: a buffer solution, one or more agents for adjusting the viscosity of the aqueous surfactant, and an agent for adjusting the ionic strength of the solution.

95 . The method of any one of claims 60 - 94 , wherein the first phase is stirred prior to and/or during the addition of the second phase.

96 . The method of any one of claims 60 - 95 , wherein the emulsion is stirred prior to and/or during the addition of the quench solution.

97 . The method of any one of claims 60 - 96 , wherein the volume comprising microspheres is stirred prior to and/or during any of the steps of washing, filtering and drying the microspheres.

98 . The method of any one of claims 60 - 97 , wherein the first biodegradable polymer is substantially enclosed by a second biodegradable polymer.

99 . The method of claim 98 , wherein the first biodegradable polymer is not identical in composition to the second biodegradable polymer.

100 . The method of any one of claims 60 - 99 , wherein the first phase is prepared by mixing a solution comprising the first biodegradable polymer with a solution comprising the apomorphine or a pharmaceutically acceptable salt thereof.

101 . The method of any one of claims 60 - 100 , wherein the first biodegradable polymer and/or the second biodegradable polymer is dissolved in a solvent highly or fully miscible with water selected from the group consisting of: dimethyl sulfoxide, N-methyl-2-pyrrolidone, tetrahydrofuran, tetraglycol, acetone, an acetone/methyl ethyl ketone mixture, an acetone/methyl acetate mixture, a tetrahydrofuran/ethyl acetate mixture, and a tetrahydrofuran/ethyl formate mixture.

102 . The method of claim 101 , wherein the solvent highly or fully miscible with water is an acetone/methyl ethyl ketone mixture.

103 . The method of claim 102 , wherein the acetone/methyl ethyl ketone mixture comprises about 70% acetone and about 30% methyl ethyl ketone, by volume.

104 . The method of any one of claims 60 - 103 , wherein the first biodegradable polymer and/or the second biodegradable polymer is dissolved in a solvent having limited water solubility selected from the group consisting of: ethyl acetate, methyl acetate, ethyl formate, propyl formate, isopropyl formate, methyl ethyl ketone, and a mixture of two or more thereof.

105 . A pre-filled injector comprising:

a stable pharmaceutically acceptable formulation comprising:

a microsphere comprising:

a first biodegradable polymer; and

an active drug load of apomorphine or a pharmaceutically acceptable salt thereof.

106 . The pre-filled injector of claim 105 , wherein the pharmaceutically acceptable salt is an acid addition salt of apomorphine.

107 . The pre-filled injector of claim 105 or claim 106 , wherein the pharmaceutically acceptable salt is apomorphine hydrochloride.

108 . The pre-filled injector of any one of claims 105 - 107 , wherein the first biodegradable polymer is selected from the group consisting of: a polylactide, a polyglycolide, and a poly(lactide-co-glycolide) copolymer.

109 . The pre-filled injector of any one of claims 105 - 108 , wherein the first biodegradable polymer is a poly(lactide-co-glycolide) copolymer, wherein the content of polymerized lactic acid units is at least 50 mol % based on the total amount of polymerized units or blends of poly(lactide-co-glycolide) copolymers with different relative amounts of glycolic acid and lactic acid, wherein the content of polymerized lactic acid units is at least 50 mol % based on the total amount of polymerized units.

110 . The pre-filled injector of any one of claims 105 - 109 , wherein the first biodegradable polymer is substantially enclosed by a second biodegradable polymer.

111 . The pre-filled injector of claim 110 , wherein the first biodegradable polymer is not identical in composition to the second biodegradable polymer.

112 . The pre-filled injector of any one of claims 105 - 111 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 30% to about 70% w/w.

113 . The pre-filled injector of any one of claims 105 - 112 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 50% to about 60% w/w.

114 . The pre-filled injector of any one of claims 105 - 113 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 40% to about 50% w/w.

115 . The pre-filled injector of any one of claims 105 - 114 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 30% to about 40% w/w.

116 . The pre-filled injector of any one of claims 105 - 111 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 40% w/w.

117 . The pre-filled injector of any one of claims 105 - 111 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 45% w/w.

118 . The pre-filled injector of any one of claims 105 - 117 , wherein the stable pharmaceutical formulation is substantially sterile.

119 . The pre-filled injector of any one of claims 105 - 118 , wherein the stable pharmaceutical formulation has a shelf life of about 14 days at 25° C. following refrigeration.

120 . The pre-filled injector of any one of claims 105 - 119 , wherein the stable pharmaceutical formulation has a shelf life of about 24 months at 25° C.

121 . The pre-filled injector of any one of claims 105 - 120 , wherein the pre-filled injector is a pen injector or an autoinjector.

122 . The pre-filled injector of any one of claims 105 - 121 , wherein the pre-filled injector is disposable.

123 . The pre-filled injector of any one of claims 105 - 122 , wherein the pre-filled injector is a disposable pen injector.

124 . The pre-filled injector of any one of claims 105 - 123 , wherein the pre-filled injector comprises a cartridge comprising the stable pharmaceutically acceptable formulation.

125 . The pre-filled injector of claim 124 , wherein the cartridge is a dual chamber cartridge.

126 . The pre-filled injector of claim 125 , wherein the dual chamber cartridge comprises, in a first chamber, a first volume comprising:

a microsphere comprising an active drug load of apomorphine or a pharmaceutically acceptable salt thereof.

127 . The pre-filled injector of claim 125 or claim 126 , wherein the dual chamber cartridge comprises, in a second chamber, a second volume comprising:

a dilution medium.

128 . The pre-filled injector of claim 127 , wherein the first volume and the second volume can be combined to produce the pharmaceutically acceptable formulation of any one of claims 1 - 59 .

129 . The pre-filled injector of claim 127 or claim 128 , wherein the pre-filled injector is configurable to combine the first volume and the second volume prior to injection.

130 . The pre-filled injector of any one of claims 127 - 129 , wherein the pre-filled injector is configurable to combine the first volume and the second volume during injection.

131 . The pre-filled injector of any one of claims 127 - 130 , wherein the pre-filled injector is configurable to dispense the first volume and the second volume in about equal amounts by volume.

132 . The pre-filled injector of any one of claims 127 - 131 , wherein the pre-filled injector is configurable to dispense the first volume and the second volume in amounts that are not equal by volume.

133 . The pre-filled injector of any one of claims 105 - 132 , wherein the pre-filled injector comprises a 18 G to 30 G needle.

134 . The pre-filled injector of any one of claims 105 - 133 , wherein the pre-filled injector comprises a 21 G needle.

135 . The pre-filled injector of any one of claims 105 - 134 , wherein the amount of the stable pharmaceutically acceptable formulation dispensed in a single injection contains about 40 mg to about 200 mg of apomorphine or a pharmaceutically acceptable salt thereof.

136 . The pre-filled injector of any one of claims 105 - 135 , wherein the amount of the stable pharmaceutical formulation dispensed in a single injection contains about 80 mg to about 100 mg of apomorphine or a pharmaceutically acceptable salt thereof.

137 . The pre-filled injector of any one of claims 105 - 136 , wherein the amount of the stable pharmaceutical formulation dispensed in a single injection contains about 90 mg of apomorphine or a pharmaceutically acceptable salt thereof.

138 . A method of manufacturing a pre-filled injector comprising a stable pharmaceutically acceptable formulation, the method comprising:

preparing a stable pharmaceutically acceptable formulation comprising:

a microsphere comprising:

a first biodegradable polymer; and

an active drug load of apomorphine or a pharmaceutically acceptable salt thereof.

loading a sterile cartridge with the stable pharmaceutically acceptable formulation; and

attaching the sterile cartridge operably to an injector.

139 . The method of claim 138 , wherein the pharmaceutically acceptable salt is an acid addition salt of apomorphine.

140 . The method of claim 138 or claim 139 , wherein the pharmaceutically acceptable salt is apomorphine hydrochloride.

141 . The method of any one of claims 138 - 140 , wherein the first biodegradable polymer is selected from the group consisting of: a polylactide, a polyglycolide, and a poly(lactide-co-glycolide) copolymer.

142 . The method of any one of claims 138 - 141 , wherein the first biodegradable polymer is a poly(lactide-co-glycolide) copolymer, wherein the content of polymerized lactic acid units is at least 50 mol % based on the total amount of polymerized units or blends of poly(lactide-co-glycolide) copolymers with different relative amounts of glycolic acid and lactic acid, wherein the content of polymerized lactic acid units is at least 50 mol % based on the total amount of polymerized units.

143 . The method of any one of claims 138 - 142 , wherein the first biodegradable polymer is substantially enclosed by a second biodegradable polymer.

144 . The method of claim 142 , wherein the first biodegradable polymer is not identical in composition to the second biodegradable polymer.

145 . The method of any one of claims 138 - 144 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 30% to about 70% w/w.

146 . The method of any one of claims 138 - 145 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 50% to about 60% w/w.

147 . The method of any one of claims 138 - 145 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 40% to about 50% w/w.

148 . The method of any one of claims 138 - 145 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 30% to about 40% w/w.

149 . The method of any one of claims 138 - 148 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 40% w/w.

150 . The method of any one of claims 138 - 149 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 45% w/w.

151 . The method of any one of claims 138 - 150 , wherein the stable pharmaceutical formulation is substantially sterile.

152 . The method of any one of claims 138 - 151 , wherein the stable pharmaceutical formulation has a shelf life of about 14 days at 25° C. following refrigeration.

153 . The method of any one of claims 138 - 152 , wherein the stable pharmaceutical formulation has a shelf life of about 24 months at 25° C.

154 . The method of any one of claims 138 - 153 , wherein the pre-filled injector is a pen injector or an autoinjector.

155 . The method of any one of claims 138 - 154 , wherein the pre-filled injector is disposable.

156 . The method of any one of claims 138 - 155 , wherein the pre-filled injector is a disposable pen injector.

157 . The method of any one of claims 138 - 156 , wherein the pre-filled injector comprises a cartridge comprising the stable pharmaceutically acceptable formulation.

158 . The method of claim 157 , wherein the cartridge is a dual chamber cartridge.

159 . The method of any one of claims 138 - 158 , wherein the pre-filled injector comprises a 18 G to 30 G needle.

160 . The method of any one of claims 138 - 159 , wherein the pre-filled injector comprises a 21 G needle.

161 . The method of any one of claims 138 - 160 , wherein the amount of the stable pharmaceutically acceptable formulation dispensed in a single injection contains about 40 mg to about 200 mg of apomorphine or a pharmaceutically acceptable salt thereof.

162 . The method of any one of claims 138 - 161 , wherein the amount of the stable pharmaceutically acceptable formulation dispensed in a single injection contains about 80 mg to about 100 mg of apomorphine or a pharmaceutically acceptable salt thereof.

163 . The method of any one of claims 138 - 162 , wherein the amount of the stable pharmaceutically acceptable formulation dispensed in a single injection contains about 90 mg of apomorphine or a pharmaceutically acceptable salt thereof.

164 . A method of treating motor symptoms associated with Parkinson's disease comprising:

administering to a subject in need thereof a stable pharmaceutically acceptable formulation comprising:

a microsphere comprising:

a first biodegradable polymer; and

an active drug load of apomorphine or a pharmaceutically acceptable salt thereof.

165 . The method of claim 164 , wherein the pharmaceutically acceptable salt is an acid addition salt of apomorphine.

166 . The method of claim 164 or claim 165 , wherein the pharmaceutically acceptable salt is apomorphine hydrochloride.

167 . The method of any one of claims 164 - 166 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 30% to about 70% w/w.

168 . The method of any one of claims 164 - 167 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 50% to about 60% w/w.

169 . The method of any one of claims 164 - 168 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 40% to about 50% w/w.

170 . The method of any one of claims 164 - 169 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 30% to about 40% w/w.

171 . The method of any one of claims 164 - 170 , wherein the amount of the stable pharmaceutically acceptable formulation administered to the subject contains an amount of apomorphine or a pharmaceutically acceptable salt thereof of about 40 mg to about 200 mg.

172 . The method of any one of claims 164 - 171 , wherein the amount of the stable pharmaceutically acceptable formulation administered to the subject contains an amount of apomorphine or a pharmaceutically acceptable salt thereof of about 80 mg to about 100 mg.

173 . The method of any one of claims 164 - 172 , wherein the amount of the stable pharmaceutically acceptable formulation administered to the subject contains an amount of apomorphine or a pharmaceutically acceptable salt thereof of about 90 mg.

174 . The method of any one of claims 164 - 173 , wherein the stable pharmaceutically acceptable formulation is administered with an injector.

175 . The method of any one of claims 164 - 174 , wherein the stable pharmaceutically acceptable formulation is administered parenterally.

176 . The method of claim 175 , wherein the stable pharmaceutically acceptable formulation is administered subcutaneously or intramuscularly.

177 . The method of any one of claims 164 - 176 , wherein administration of the stable pharmaceutically acceptable formulation effects a steady-state plasma concentration of apomorphine following an initial burst of apomorphine in the plasma.

178 . The long-acting dosage form of any one of claims 164 - 177 , wherein the steady-state plasma concentration is about 35 μg/L.

179 . The long-acting dosage form of any one of claims 164 - 178 , wherein the steady-state plasma concentration is maintained for about 7 days.

180 . The method of any one of claims 164 - 179 , wherein the initial burst of apomorphine or a pharmaceutically acceptable salt thereof is about 5% of the total dose of apomorphine or a pharmaceutically acceptable salt thereof.

181 . The method of any one of claims 164 - 180 , wherein the initial burst of apomorphine is completed about 0.5 to about 24 hours after injection.

182 . The method of any one of claims 164 - 181 , wherein the stable pharmaceutically acceptable formulation is administered once per week.

183 . The method of any one of claims 164 - 182 , wherein administration of the stable pharmaceutically acceptable formulation results in less hypotension relative to administration with immediate release subcutaneous apomorphine hydrochloride injection.

184 . The method of any one of claims 164 - 183 , wherein administration of the stable pharmaceutically acceptable formulation results in less nausea relative to administration with immediate release subcutaneous apomorphine hydrochloride injection.

185 . The method of any one of claims 164 - 184 , wherein administration of the stable pharmaceutically acceptable formulation results in less adverse injection site reactions relative to administration with immediate release subcutaneous apomorphine hydrochloride injection.

186 . The method of any one of claims 164 - 185 , wherein the subject in need suffers from Parkinson's disease.

187 . The method of claim 186 , wherein administration of the stable pharmaceutically acceptable formulation is effective in reducing the occurrence, duration, or severity of intermittent episodes of muscle stiffness and/or loss of muscle control associated with Parkinson's disease.

188 . The method of any one of claims 164 - 187 , wherein administration of the stable pharmaceutically acceptable formulation is effective at minimizing hypotension or nausea, or reducing hypotension or nausea by at least 50% when compared to parenteral administration of immediate release apomorphine hydrochloride.

189 . The method of any one of claims 164 - 188 , wherein injection site reactions are substantially reduced relative to injection site reactions characteristic of injection with immediate release apomorphine hydrochloride.

190 . A long-acting dosage form comprising:

a microsphere comprising:

a first biodegradable polymer; and

about 40 mg to about 200 mg of an active drug load of apomorphine or a pharmaceutically acceptable salt thereof;

wherein administration of a single dose of the long-acting dosage form to a subject results in at least one of the pharmacokinetic parameters selected from the group consisting of:

a steady state plasma profile of apomorphine from day 1 to day 7 following administration exhibiting a mean C max value no greater than the steady state plasma level of apomorphine provided by 2 mg of immediate release subcutaneous injection of apomorphine hydrochloride;

an apomorphine elimination half-life of about 40 minutes to about 60 minutes; and

a zero-order release profile corresponding to about 12% to about 14% release of the total administered dose of apomorphine or a pharmaceutically acceptable salt thereof per day.

191 . The long-acting dosage form of claim 190 , wherein the pharmaceutically acceptable salt is an acid addition salt of apomorphine.

192 . The long-acting dosage form of claim 190 or claim 191 , wherein the pharmaceutically acceptable salt is apomorphine hydrochloride.

193 . The long-acting dosage form of any one of claims 190 - 192 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 30% to about 70% w/w.

194 . The long-acting dosage form of any one of claims 190 - 193 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 50% to about 60% w/w.

195 . The long-acting dosage form of any one of claims 190 - 194 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 40% to about 50% w/w.

196 . The long-acting dosage form of any one of claims 190 - 195 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 30% to about 40% w/w.

197 . The long-acting dosage form of any one of claims 190 - 196 , wherein the amount of the stable pharmaceutically acceptable formulation administered to the subject contains an amount of apomorphine or a pharmaceutically acceptable salt thereof of about 80 mg to about 100 mg.

198 . The long-acting dosage form of any one of claims 190 - 197 , wherein the amount of the stable pharmaceutically acceptable formulation administered to the subject contains an amount of apomorphine or a pharmaceutically acceptable salt thereof of about 90 mg.

199 . The long-acting dosage form of any one of claims 190 - 198 , wherein the first biodegradable polymer is selected from the group consisting of: a polylactide, a polyglycolide, and a poly(lactide-co-glycolide) copolymer.

200 . The long-acting dosage form of any one of claims 190 - 199 , wherein the first biodegradable polymer is a poly(lactide-co-glycolide) copolymer, wherein the content of polymerized lactic acid units is at least 50 mol % based on the total amount of polymerized units or blends of poly(lactide-co-glycolide) copolymers with different relative amounts of glycolic acid and lactic acid, wherein the content of polymerized lactic acid units is at least 50 mol % based on the total amount of polymerized units.

201 . The long-acting dosage form of any one of claims 190 - 200 , wherein the first biodegradable polymer is substantially enclosed by a second biodegradable polymer.

202 . The long-acting dosage form of claim 201 , wherein the first biodegradable polymer is not identical in composition to the second biodegradable polymer.

203 . The long-acting dosage form of any one of claims 190 - 202 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 50% w/w.

204 . The long-acting dosage form of any one of claims 190 - 203 , wherein the active drug load of apomorphine or a pharmaceutically acceptable salt thereof in the microsphere is about 40% w/w.

205 . The long-acting dosage form of any one of claims 190 - 204 , wherein the stable pharmaceutical formulation is substantially sterile.

206 . The long-acting dosage form of any one of claims 190 - 205 , wherein the stable pharmaceutical formulation has a shelf life of about 14 days at 25° C. following refrigeration.

207 . The long-acting dosage form of any one of claims 190 - 206 , wherein the stable pharmaceutical formulation has a shelf life of about 24 months at 25° C.

208 . The long-acting dosage form of any one of claims 190 - 207 , wherein the stable pharmaceutically acceptable formulation is administered from an injector.

209 . The long-acting dosage form of claim 208 , wherein the injector is a pen injector or an autoinjector.

210 . The long-acting dosage form of claim 208 or claim 209 , wherein the injector is disposable.

211 . The long-acting dosage form of any one of claims 208 - 210 , wherein the injector is a disposable pen injector.

212 . The long-acting dosage form of any one of claims 190 - 211 , wherein the injector comprises a cartridge comprising the stable pharmaceutically acceptable formulation.

213 . The long-acting dosage form of any one of claims 190 - 212 , wherein the cartridge is a dual chamber cartridge.

214 . The long-acting dosage form of any one of claims 190 - 213 , wherein the injector comprises a 18 G to 30 G needle.

215 . The long-acting dosage form of any one of claims 190 - 214 , wherein the injector comprises a 21 G needle.

216 . The long-acting dosage form of any one of claims 190 - 215 , wherein the injector is a pre-filled injector comprising the stable pharmaceutically acceptable formulation.

217 . The long-acting dosage form of any one of claims 190 - 216 , wherein the stable pharmaceutically acceptable formulation is administered parenterally.

218 . The long-acting dosage form of claim 217 , wherein the stable pharmaceutically acceptable formulation is administered subcutaneously or intramuscularly.

219 . The long-acting dosage form of any one of claims 190 - 218 , wherein administration of the stable pharmaceutically acceptable formulation effects a steady-state plasma concentration of apomorphine following an initial burst of apomorphine in the plasma.

220 . The long-acting dosage form of any one of claims 190 - 219 , wherein the steady-state plasma concentration is about 35 μg/L.

221 . The long-acting dosage form of any one of claims 190 - 220 , wherein the steady-state plasma concentration is maintained for about 7 days.

222 . The long-acting dosage form of any one of claims 190 - 221 , wherein the initial burst of apomorphine or a pharmaceutically acceptable salt thereof is about 5% of the total dose of apomorphine or a pharmaceutically acceptable salt thereof.

223 . The long-acting dosage form of any one of claims 190 - 222 , wherein following the initial burst of apomorphine or a pharmaceutically acceptable salt thereof, there is an extended release of apomorphine for about 7 days.

224 . The long-acting dosage form of any one of claims 190 - 223 , wherein the extended release corresponds to a release of about 5% to about 25% release of the total administered dose of apomorphine or a pharmaceutically acceptable salt thereof per day.

225 . The long-acting dosage form of any one of claims 190 - 224 , wherein the extended release corresponds to a release of about 10% to about 15% release of the total administered dose of apomorphine or a pharmaceutically acceptable salt thereof per day.

226 . The long-acting dosage form of any one of claims 190 - 225 , wherein following the initial burst of apomorphine or a pharmaceutically acceptable salt thereof, there is a zero-order release profile for about 7 days.

227 . The long-acting dosage form of any one of claims 190 - 226 , wherein the zero-order release profile corresponds to a release of about 5% to about 14% release of the total administered dose of apomorphine or a pharmaceutically acceptable salt thereof per day.

228 . The long-acting dosage form of any one of claims 190 - 227 , wherein the zero-order release profile corresponds to a release of about 12% to about 14% release of the total administered dose of apomorphine or a pharmaceutically acceptable salt thereof per day.

229 . The long-acting dosage form of any one of claims claim 190 - 228 , wherein the elimination half-life of apomorphine is about 40 minutes to about 60 minutes.

230 . The long-acting dosage form of any one of claims 190 - 229 , wherein the steady state plasma profile of apomorphine from day 1 to day 7 following administration exhibits a mean C max value no greater than the steady state plasma level of apomorphine provided by 2 mg of immediate release subcutaneous injection of apomorphine hydrochloride.

231 . The long-acting dosage form of any one of claims 190 - 230 , wherein administration of the stable pharmaceutically acceptable formulation results in less hypotension relative to administration with immediate release subcutaneous apomorphine hydrochloride injection.

232 . The long-acting dosage form of any one of claims 190 - 231 , wherein administration of the stable pharmaceutically acceptable formulation results in less nausea relative to administration with immediate release subcutaneous apomorphine hydrochloride injection.

233 . The long-acting dosage form of any one of claims 190 - 232 , wherein administration of the stable pharmaceutically acceptable formulation results in less adverse injection site reactions relative to administration with immediate release subcutaneous apomorphine hydrochloride injection.

234 . A kit comprising:

a first vial comprising a concentrated form of the stable pharmaceutically acceptable formulation of any one of claims 1 - 59 or of the long-acting dosage form of any one of claims 190 - 233 ;

a second vial comprising a pharmaceutically acceptable diluent;

a first syringe suitable for withdrawing the pharmaceutically acceptable diluent from the second vial;

an adapter which can operably attach to the first syringe and is suitable for dispensing the pharmaceutically acceptable diluent into the first vial;

a second syringe suitable for withdrawing a liquid from the second vial and for injecting the liquid into a subject; and

instructions for diluting the concentrated form and for administering the stable pharmaceutically acceptable formulation or the long-acting dosage form to a patient in need thereof.