Multi-dose injection pen for leuprolide

Abstract

The present technology relates to multi-dose injection pens, pharmaceutical compositions of leuprolide and combinations thereof. The multi-dose injection pens may be configured to contain multiple doses of leuprolide and to administer a single dose of leuprolide.

Description

PATENT Attorney Docket No. 137249.8003. WOOOMULTI-DOSE INJECTION PEN FOR LEUPROLIDECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 699,099, titled “MULTI-DOSE INJECTION PEN FOR LEUPROLIDE,” filed on September 25, 2024, which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] Injection pens for at-home administration of medications have become increasingly available and are widely used for various different indications. Injection pens are configured to deliver a specific dose of a medication, and as such, are safe and effective for self-administration. However, many injection pens only contain a single-dose of medication due to the attenuated shelf-life of the formulation contained within.

[0003] Accordingly, despite recent advances in injection pens, there exists a need for multi-dose injection pens containing shelf-stable formulations of pharmaceutical agents.SUMMARY

[0004] Provided herein are multi-dose injection pens comprising aqueous pharmaceutical compositions of leuprolide.

[0005] In some aspects, the present technology relates to a multi-dose injection pen comprising a cartridge containing an aqueous pharmaceutical composition comprising leuprolide at a concentration of about 2.5 mg / mL to about 7.5 mg / mL, benzyl alcohol at a concentration of about 8 mg / mL to about 11 mg / mL, a tonicity agent at a concentration sufficient to adjust the osmolarity of the composition to about 250 mOsm / kg to about 600 mOsm / kg, and one or more pH adjusting agents at a concentration sufficient to adjust the pH of the composition to about 4.0 to about 7.0; a housing; a dose setting component at least partially disposed within the housing and configured to set a dose of the aqueous pharmaceutical composition to be dispensed from the cartridge; and a dispensing-1- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO component at least partially disposed within the housing and configured to dispense the dose of the aqueous pharmaceutical composition from the cartridge.

[0006] In some aspects, the present technology relates to a multi-dose injection pen comprising a cartridge containing an aqueous pharmaceutical composition comprising leuprolide in an amount of about 10 mg to about 20 mg, benzyl alcohol in an amount of about 25 mg to about 35 mg, and a tonicity agent at a concentration sufficient to adjust the osmolarity of the composition to about 250 mOsm / kg to about 600 mOsm / kg, and one or more pH adjusting agents at a concentration sufficient to adjust the pH of the composition to about 4.0 to about 7.0; a housing; a dose setting component at least partially disposed within the housing and configured to set a dose of the aqueous pharmaceutical composition to be dispensed from the cartridge; and a dispensing component at least partially disposed within the housing and configured to dispense the dose of the aqueous pharmaceutical composition from the cartridge.

[0007] In other aspects, the present technology relates to a multi-dose injection pen comprising a cartridge containing an aqueous pharmaceutical composition comprising: leuprolide at a concentration of about 2.5 mg / mL to about 7.5 mg / mL, benzyl alcohol at a concentration of about 6 mg / mL to about 12 mg / mL, and atonicity agent at a concentration of about 4.5 mg / mL to about 9 mg / mL; a housing; a dose setting component at least partially disposed within the housing and configured to set a dose of the aqueous pharmaceutical composition to be dispensed from the cartridge; and a dispensing component at least partially disposed within the housing and configured to dispense the dose of the aqueous pharmaceutical composition from the cartridge.

[0008] In other aspects, the present technology relates to a multi-dose injection pen comprising a cartridge containing an aqueous pharmaceutical composition comprising: leuprolide in an amount of about 10 mg to about 20 mg, benzyl alcohol in an amount of about 25 mg to about 35 mg, and a tonicity agent in an amount of about 15 mg to about 25 mg; a housing; a dose setting component at least partially disposed within the housing and configured to set a dose of the aqueous pharmaceutical composition to be dispensed from the cartridge; and a dispensing component at least partially disposed within the housing and-2- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO configured to dispense the dose of the aqueous pharmaceutical composition from the cartridge.

[0009] In other aspects, the present technology relates to a multi-dose injection pen comprising a cartridge with a volume of at least 3 mL and containing an aqueous pharmaceutical composition comprising leuprolide in an amount of about 10 mg to about 20 mg; a housing; a dose setting component partially disposed within the housing and threaded with the housing along first threads, the dose setting component rotatable along the first threads to axially displace the dose setting component axially away from the cartridge when rotating in a first direction and axially toward the cartridge when rotating in a second direction opposite the first direction; a first threaded annular component attached at an interior of the dose setting component and configured to rotate and axially displace with the dose setting component; a second annular component: attached at an interior of the first threaded annular component through a circumferential connection to axially displace at least a first portion of the second annular component with the first threaded annular component, and attached to the dose setting component to cause the second annular component to rotate in the second direction with the dose setting component when the dose setting component is rotated in the second direction; a third annular component attached to the second annular component such that the third annular component is configured to rotate in the second direction with the second annular component, the third annular component having second threads at an interior of the third annular component; and a piston attached to the third annular component at the second threads and configured to displace axially toward the cartridge to dispense the aqueous pharmaceutical composition from the cartridge when the third annular component is rotated in the second direction.

[0010] In still other aspects, the present technology relates to a multi-dose injection pen comprising a cartridge containing an aqueous pharmaceutical composition comprising leuprolide at a concentration of about 2.5 mg / mL to about 7.5 mg / mL; a housing comprising a window exposing at least a portion of a dose setting component; the dose setting component: partially disposed within the housing and threaded with the housing along first threads, rotatable along the first threads to axially displace the dose setting component axially away from the cartridge when rotating in a first direction and axially toward the -3- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO cartridge when rotating in a second direction opposite the first direction, and having dose amount markings disposed around the dose setting component in an arrangement that corresponds to a helix angle of the first threads, respective ones of the dose amount markings visible through the window of the housing when the dose setting component is rotated along the first threads, each respective one of the dose amount markings visible through the window of the housing when the dose setting component is in a respective position along the first threads and corresponding to a respective amount of the aqueous pharmaceutical composition dispensed from the cartridge by returning the dose setting component from the respective position along the first threads to an unset position in which the dose setting component cannot be rotated along the first threads in the second direction; an annular component disposed at least partially within the dose setting component and having: a first portion configured to displace axially away from the cartridge with the dose setting component when the dose setting component is rotated in the first direction and rotate in the second direction with the dose setting component due to friction between the first portion of the annular component and the dose setting component, and a second portion attached to the first portion of the annular component through an axial connection to enable relative axial movement between the first portion of the annular component and the second portion of the annular component and cause the second portion of the annular component to rotate in the second direction with the first portion of the annular component; and a piston configured to displace axially toward the cartridge to dispense the aqueous pharmaceutical composition from the cartridge when the dose setting component is rotated in the second direction.

[0011] In still other aspects, the present technology relates to a multi-dose injection pen comprising a cartridge with a volume of at least about 3 mL and containing an aqueous pharmaceutical composition comprising leuprolide at a concentration of about 2.5 mg / mL to about 7.5 mg / mL; a housing; a dose setting component: partially disposed within the housing and threaded with the housing along first threads, rotatable along the first threads to axially displace the dose setting component axially away from the cartridge when rotating in a first direction and axially toward the cartridge when rotating in a second direction opposite the first direction, and having a protruding portion at an interior of the dose setting component;-4- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO a lipped annular component disposed at least partially within the dose setting component and having: a first portion with a protruding portion at an exterior of the first portion of the lipped annular component, the protruding portion at least partially overlapping with the protruding portion of the dose setting component on an axis along which the dose setting component moves when rotating in the first direction or the second direction along the first threads, and a second portion attached to the first portion of the lipped annular component through an axial connection to enable relative axial movement between the first portion of the lipped annular component and the second portion of the lipped annular component and cause the second portion of the lipped annular component to rotate in the second direction with the first portion of the lipped annular component; a cap coupled with the dose setting component opposite the cartridge and displaceable toward the cartridge, the cap, when displaced toward the cartridge, causing displacement of the first portion of the lipped annular component toward the cartridge such that overlap between the protruding portion of the dose setting component and the protruding portion of the first portion of the lipped annular component cause the first portion of the lipped annular component to rotate in the second direction when the dose setting component rotates in the second direction; and a piston configured to displace axially toward the cartridge to dispense the aqueous pharmaceutical composition from the cartridge when the second portion of the lipped annular component is rotated in the second direction.

[0012] In still other aspects, the present technology relates to a multi-dose injection pen comprising a cartridge with a volume of at least about 3 mL and containing an aqueous pharmaceutical composition comprising leuprolide in an amount of about 10 mg to about 20 mg; a housing; a dose setting component partially disposed within the housing and threaded with the housing along first threads, the dose setting component rotatable along the first threads to axially displace the dose setting component axially away from the cartridge when rotating in a first direction and axially toward the cartridge when rotating in a second direction opposite the first direction; a first annular component interior to the dose setting component and configured to rotate in the second direction and axially displace with the dose setting component; a second annular component attached to the first annular component through an axial connection such that the second annular component is configured to rotate in the-5- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO second direction with the first annular component, the second annular component having second threads at an interior of the second annular component, the second annular component configured to generate an audible noise in response to rotating by a set amount; and a piston attached to the second annular component at the second threads and configured to displace axially toward the cartridge to dispense the aqueous pharmaceutical composition from the cartridge when the second annular component is rotated in the second direction.

[0013] In yet other aspects, the present technology relates to a multi-dose injection pen comprising a cartridge containing an aqueous pharmaceutical composition comprising leuprolide at a concentration of about 2.5 mg / mL to about 7.5 mg / mL; a housing; a dose setting component partially disposed within the housing and threaded with the housing along first threads, the dose setting component rotatable along the first threads to axially displace the dose setting component axially away from the cartridge when rotating in a first direction and axially toward the cartridge when rotating in a second direction opposite the first direction; a first threaded annular component attached at an interior of the dose setting component and configured to rotate and axially displace with the dose setting component; a second annular component: attached at a first end at an interior of the first threaded annular component through a circumferential connection to axially displace at least a portion of the second annular component with the first threaded annular component, attached to the dose setting component to cause the second annular component to rotate in the second direction with the dose setting component, and having a protruding portion at an interior of the second annular component; and a piston configured to displace axially toward the cartridge to dispense the aqueous pharmaceutical composition from the cartridge when the second annular component is rotated in the second direction, the piston having a protruding portion at an exterior of the piston at a distal end opposite the cartridge, wherein the protruding portion at the exterior of the piston contacts the protruding portion at the interior of the second annular component to prevent the second annular component from displacing axially away from the cartridge and prevent the dose setting component from displacing axially away from the cartridge and rotating in the first direction when an amount of the aqueous pharmaceutical composition to be dispensed by returning the dose setting component from-6- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO a current position to an unset position in which the dose setting component cannot be rotated along the first threads in the second direction is equal to an amount of the aqueous pharmaceutical composition remaining in the cartridge.

[0014] Also provided herein are methods of using the multi-dose injection pens comprising aqueous pharmaceutical compositions of leuprolide described herein.

[0015] In some aspects, the present technology relates to a method for injecting a dose of an aqueous pharmaceutical composition using a multi-dose injection pen, the method comprising displacing, relative to a housing with which a dose setting component is threaded along first threads, the dose setting component axially away from a cartridge containing the aqueous pharmaceutical composition and in a first rotational direction until a dose amount marking on the dose setting component visible through a window of the housing indicates 1 mg, wherein the dose amount marking corresponds to an amount of the aqueous pharmaceutical composition dispensed from the cartridge by returning the dose setting component from a current position along the first threads to an unset position in which the dose setting component cannot be rotated along the first threads in a second rotational direction opposite the first rotational direction, the aqueous pharmaceutical composition comprising leuprolide at a concentration of about 2.5 mg / mL to about 7.5 mg / mL, benzyl alcohol at a concentration of about 8 mg / mL to about 11 mg / mL, sodium chloride at a concentration of about 4.5 mg / mL to about 9 mg / mL, and one or more pH adjusting agents at a concentration sufficient to adjust the pH of the composition to 4.0 to 7.0; displacing a cap coupled with the dose setting component axially toward the cartridge to increase a pressure between an annular component configured to rotate in the second rotational direction to dispense the aqueous pharmaceutical composition from the cartridge and the dose setting component; and concurrent with displacing the cap axially toward the cartridge, displacing the dose setting component along the first threads, in the second rotational direction, and axially toward the cartridge to cause the annular component to rotate in the second rotational direction due to the pressure with the dose setting component to dispense the amount of the aqueous pharmaceutical composition from the cartridge.-7- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO

[0016] In other aspects, the present technology relates to method for injecting a dose of an aqueous pharmaceutical composition using a multi-dose injection pen, the method comprising displacing, relative to a housing with which a dose setting component is threaded along first threads, the dose setting component axially away from a cartridge containing the aqueous pharmaceutical composition and in a first rotational direction until a dose amount marking on the dose setting component visible through a window of the housing indicates 1 mg, wherein the dose amount marking corresponds to an amount of the aqueous pharmaceutical composition dispensed from the cartridge by returning the dose setting component from a current position along the first threads to an unset position in which the dose setting component cannot be rotated along the first threads in a second rotational direction opposite the first rotational direction, the aqueous pharmaceutical composition comprising leuprolide at a concentration of about 2.5 mg / mL to about 7.5 mg / mL, benzyl alcohol at a concentration of about 8 mg / mL to about 11 mg / mL, sodium chloride at a concentration of about 4.5 mg / mL to about 9 mg / mL, and one or more pH adjusting agents at a concentration sufficient to adjust the pH of the composition to 4.0 to 7.0; displacing a cap coupled with the dose setting component axially toward the cartridge to increase a pressure between an annular component configured to rotate in the second rotational direction to dispense the aqueous pharmaceutical composition from the cartridge and the dose setting component; and concurrent with displacing the cap axially toward the cartridge, displacing the dose setting component along the first threads, in the second rotational direction, and axially toward the cartridge until an additional dose amount marking on the dose setting component indicating 0 mg is visible through the window of the housing.

[0017] Further provided herein are pharmaceutical compositions comprising leuprolide and multi-dose injection pens comprising a cartridge, a housing, a dose setting component, and a dispensing component.BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Detailed descriptions of implementations of the present technology will be described and explained through the use of the accompanying drawings.-8- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO

[0019] Figure 1 illustrates a cross-sectional view of a multi-dose injection pen for leuprolide in accordance with one or more aspects of the present technology.

[0020] Figure 2 illustrates the multi-dose injection pen for leuprolide deconstructed into components in accordance with one or more aspects of the present technology.

[0021] Figure 3 illustrates a cross-sectional view of a multi-dose injection pen for leuprolide in a set position in accordance with one or more aspects of the present technology.

[0022] Figure 4 illustrates a cross-sectional view of a multi-dose injection pen for leuprolide in an unset position in accordance with one or more aspects of the present technology.

[0023] Figure 5 illustrates an external view of a multi-dose injection pen for leuprolide in accordance with one or more aspects of the present technology.

[0024] Figure 6 illustrates a cartridge of a multi-dose injection pen for leuprolide in accordance with one or more aspects of the present technology.

[0025] Figure 7 illustrates a dose setting component of a multi-dose injection pen for leuprolide in accordance with one or more aspects of the present technology.

[0026] The technologies described herein will become more apparent to those skilled in the art from studying the Detailed Description in conjunction with the drawings. Embodiments or implementations describing aspects of the present technology are illustrated byway of example, and the same references can indicate similar elements. While the drawings depict various implementations for the purpose of illustration, those skilled in the art will recognize that alternative implementations can be employed without departing from the principles of the present technologies. Accordingly, while specific implementations are shown in the drawings, the technology is amenable to various modifications.DETAILED DESCRIPTION

[0027] The present technology provides stable aqueous pharmaceutical compositions of leuprolide and multi-dose injection pens comprising the same. Pharmaceutical-9- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO compositions described herein may be formulated with multiple doses of leuprolide, such as, for example, three or more, five or more, ten or more, or fifteen or more doses of leuprolide. The pharmaceutical compositions may be stable for an extended period of time, and therefore, suitable to contain multiple doses of leuprolide, due to the presence of a preservative.

[0028] Pharmaceutical compositions of the present technology may be administered to a subject in need thereof to treat and / or prevent the progression of prostate cancer, an in particular, advanced prostate cancer. To achieve the desired therapeutic outcome, the pharmaceutical compositions may be formulated for specific routes of administration, such as parenteral delivery, including, but not limited to, subcutaneous delivery. In particular, the pharmaceutical compositions may be formulated for administration via a multi-dose injection pen. Accordingly, the present technology further provides a multi-dose injection pen for administering the pharmaceutical compositions described herein. The multi-dose injection pen may be configured to deliver multiple consistent doses of leuprolide via at-home administration, thereby providing an easy-to-use administration technique to subjects in need thereof.

[0029] While the present technology is capable of being embodied in various forms, the description below of several embodiments is made with the understanding that the present technology is to be considered as an exemplification of the present technology and is not intended to limit the present technology to the specific embodiments illustrated. The description and associated drawings are illustrative examples and are not to be construed as limiting. This disclosure provides certain details for a thorough understanding and enabling description of these examples. One skilled in the relevant technology will understand, however, that the present technology can be practiced without many of these details. Likewise, one skilled in the relevant technology will understand that the present technology can include well-known structures or features that are not shown or described in detail to avoid unnecessarily obscuring the descriptions of examples. Headings are provided for convenience only and are not to be construed to limit the present technology in any manner. Embodiments illustrated under any heading can be combined with embodiments illustrated under any other heading.-10- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO Definitions

[0030] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present technology belongs. For the purposes of the present technology, the following terms are defined below.

[0031] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) ofthe grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0032] The term “about” means a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies by acceptable levels in the art. Typically, such variation may be as much 10% above and below a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length and such variation may be influenced by standard applicable measurement practices. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth.

[0033] As used herein, a “composition” or a “pharmaceutical composition” refers to a mixture of the active ingredient with other chemical components, such as pharmaceutically acceptable carriers and / or excipients.

[0034] As used herein, a “pharmaceutically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to an organism, does not abrogate the biological activity and properties of the administered active ingredient, and / or does not interact in a deleterious manner with the other components of the composition in which it is contained.

[0035] Throughout the specification, reference to “leuprolide” is meant to encompass all common forms of leuprolide including leuprolide in the free base form and salt forms of leuprolide, such as leuprolide acetate.

[0036] The formulations of the present technology are injected parenterally, such as subcutaneously. The terms “administering” or “administer” include delivery of the-11- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO formulations of the present technology to a subject by parenteral administration, such as subcutaneous administration.

[0037] As used herein, the term “isotonic” refers to fluids such as a solution having the same effective osmotic pressure as another solution, especially one in a cell or a body fluid. In some instances, an isotonic solution has the same concentration of solutes as the blood, such as an isotonic saline solution.

[0038] The terms “treat,” “treatment,” and “treating” refer to a manner of providing a pharmaceutical composition and / or melanocortin analog to alleviate disease outcomes. This includes utilizing administration techniques as described in the context of the present technology.

[0039] As used herein, the term “prevent,” “preventing,” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.

[0040] The terms “subject” and “patient” refer to anyone being evaluated for disease or being administered a therapeutic or pharmaceutical composition. This includes people without a diagnosed or confirmed disease or condition. This also includes people with a diagnosed or confirmed disease or condition, such as deep vein thrombosis.Selected Embodiments of Multi-Dose Injection Pens Configured in Accordance with Embodiments of the Present TechnologyMulti-Dose Pens and Associated Features

[0041] The present technology provides a multi-dose injection pen for leuprolide. The multi-dose injection pen, while containing multiple doses of leuprolide, may be configured to administer a single dose of leuprolide to a subject in need thereof per use.

[0042] Figure 1 illustrates a cross-sectional view of a multi-dose injection pen 100 for leuprolide in accordance with one or more aspects of the present technology. The injection-12- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO pen 100 can inject multiple doses of leuprolide without replacing the cartridge through repeated dose setting and dose injection using the injection pen 100. The multi-dose injection pen 100 includes a housing having a first part 102 and a second part 104. The first part 102 can at least partially enclose the mechanical components of the injection pen 100. The first part 102 can be a generally cylindrical component. The second part 104 can retain a cartridge used to hold a pharmaceutical composition for injection using the injection pen 100. The cartridge retaining portion can be generally cylindrical (e.g., with a radius roughly equivalent to that of the first part 102). The second part 104 can further extend into the first part 102 to at least partially enclose one or more of the mechanical components of the injection pen 100. This extension can similarly have a generally cylindrical shape and have a lesser radius than the first part 102 to enable the second part 104 to fit within the first part 102. The first part 102 and the second part 104 can couple with one another (e.g., through one or more connections) to form a single housing of the multi-dose injection pen 100. The first part 102 and the second part 104 can be separate components or a single component.

[0043] A dose setting component 106 can be used to specify a dose to be administered from the cartridge using the injection pen 100. The dose setting component 106 can be at least partially enclosed within the first part 102. The dose setting component 106 can be set through rotation with respect to the housing. For example, the first part 102 of the housing can include threads along which the dose setting component 106 can rotate, and the dose setting component 106 can have threads that accept the threads of the first part 102. The threads of the first part 102 can be internal such that the dose setting component 106 couples to the interior of the first part 102. In this way, the dose setting component 106 can be at least partially surrounded by the first part 102. The dose setting component 106 can sit outside of the extending portion of the second part 104 of the housing such that at least a portion of the dose setting component sits between the first part 102 and the second part 104 of the housing.

[0044] The dose to be administered using the injection pen 100 can be set by rotating the dose setting component 106 in a first direction into a set position, and the dose can be administered by rotating the dose setting component 106 in the opposite direction into an unset position. The dose setting component 106 can be rotated by grabbing a portion of the -13- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO dose setting component 106 exposed beyond the first part 102 of the housing. This exposed portion can be generally cylindrical and have a radius roughly equal to that of the first part 102 of the housing, thereby allowing the exposed portion to rest on the first part 102 in the unset position.

[0045] To set the dose to be administered by the injection pen 100, mechanical components are driven both rotationally and axially. The injection pen 100 includes an axial driver 108 that displaces rotationally and axially with the dose setting component 106. In this way, the axial driver 108 can be fixedly attached to the dose setting component 106 (e.g., through a knob or notch that prevents relative rotational or axial displacement). The axial driver 108 can be a generally annular component. The axial driver 108 can be located at least partially within and threaded with the extending portion of the second part 104 of the housing. In this way, the axial driver 108 can rotate and axially displace along the second part 104 of the housing with the dose setting component 106. The axial driver 108 can cause axial displacement of a rotational driver 110 when the axial driver 108 is axially displaced. The axial driver 108 can drive axial displacement of the rotational driver 110 without rotating the rotational driver 110. For example, the axial driver 108 can be connected to the rotational driver 110 through a circumferential connection that allows relative rotation but not relative axial displacement.

[0046] The rotational driver 110 can be rotationally displaced by an additional rotational driver 112 connected therewith. The rotational driver 112 can be axially displaced but not rotationally displaced with respect to the rotational driver 110. Thus, the rotational driver 110 and the rotational driver 112 can be connected through an axial connection. In some cases, the rotational driver 110 can be restricted to rotate only in the dose dispensing direction. This rotation can be restricted through connection with the extending portion of the second part 104 of the housing or another portion of the injection pen 100 restricted to rotate in only the dose dispensing direction. The rotational driver 112 can similarly be restricted to rotate only in the dose dispensing direction (e.g., through the connection with the rotational driver 110). The rotational driver 112 can be driven through connection with the dose setting component 106. Thus, the rotational driver 112 can rotate in the dose dispensing direction with the dose setting component 106 to drive the rotational driver 110.-14- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO

[0047] The rotation of the rotational driver 110 can cause rotation of a piston driver 114 used to drive a piston 116 toward the cartridge to dispense the pharmaceutical composition from the cartridge. The rotational driver 110 can be axially displaced but not rotationally displaced with respect to the piston driver 11 . Thus, the rotational driver 110 and the piston driver 114 can be connected through an axial connection. A portion of the rotational driver 110 can be surrounded by the piston driver 114. The piston driver 114 can be a generally annular component. The piston driver 114 can be restricted to rotate only in the dose dispensing direction (e.g., through connection with the extending portion of the second part 104 of the housing). The piston driver 114 can include threads that mate with threads of the piston 116 to cause the piston 116 to be displaced toward the cartridge to dispense the pharmaceutical composition from the cartridge when the piston driver 114 is rotated in the dose dispensing direction. The piston driver 114 can be restricted from moving axially (e.g., through a connection with the extending portion of the second part 104 of the housing). Thus, the piston 116 can be driven through rotation of the piston driver 114.

[0048] The piston driver 114 can generate auditory feedback when rotated. The auditory feedback can correspond to a set amount of the pharmaceutical composition to be dispensed. For example, the auditory feedback can be generated when the piston driver 114 completes a full rotation, when a fixed amount of the pharmaceutical composition is dispensed, or when the set dose of the pharmaceutical composition is dispensed. In some embodiments, the auditory feedback can be generated when an intended dose of the pharmaceutical is dispensed. Thus, the piston driver 114 can be designed in accordance with the pharmaceutical to emit the auditory feedback at the end of an injection of an expected dose.

[0049] The dose setting component 106 can be rotated in the dose setting direction without rotating the rotational driver 112 through relief of pressure between these components. Then, when the dose setting component 106 is rotated in the dose dispensing direction to inject the pharmaceutical composition, a cap 118 can be pressed to create pressure between the dose setting component 106 and the rotational driver 112 to cause these components to rotate together. For example, the rotational driver 112 can include protruding arms that overlap with protruding portions from the interior of the dose setting -15- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO component 106. Friction between these overlapping portions can cause the rotational driver 112 and the dose setting component 106 to rotate together. A clutch 120 can be disposed between the rotational driver 112 and the dose setting component 106 to increase the friction between these components and cause them to rotate together when the cap 118 is depressed. The clutch 120 can have teeth on either side to increase friction with the dose setting component 106 and the rotational driver 112. The teeth can be angled to create a greater amount of feree when rotating in the dose dispensing direction. The clutch 120 can generate auditory feedback (e.g., clicks) when dose setting component 106 is rotated in either direction (e.g., during dose setting or dispensing). The auditory feedback can be generated by the teeth of the clutch 120.

[0050] The cap 118 can be inserted into a portion of the rotational driver 112 and have peripheral edges that rest within the dose setting component 106. The cap 118 can rest on a spring 122 to relieve pressure between the rotational driver 112 and the dose setting component 106 when the cap 118 is released. Thus, the dose setting component 106 can be rotated in the dose setting direction without causing the rotational driver 112 to be rotated. Moreover, the dose can be unset by rotating the dose setting component 106 in the dose dispensing direction but without pressing the cap 118. In this way, the spring 122 will release pressure between the rotational driver 112 and the dose setting component 106 (e.g., disengaging the clutch 120) and allow the dose setting component 106 to be rotated without rotating the rotational driver 112. Thus, the axial driver 108 can be displaced axially and rotationally, the rotational driver 110 can be displaced axially, and the rotational driver 112 can be displaced axially without displacing the rotational driver 112 rotationally.

[0051] Figure 2 illustrates the multi-dose injection pen 100 for leuprolide deconstructed into components in accordance with one or more aspects of the present technology. In general, components of the injection pen 100 are described as having threads, which can include male or female threads. Similarly, some components are described as being connected through threads, notches, or other protrusions and channels. That is, one component includes a protruding element that fits within a recessed element. It should be appreciated that while described such that a first component includes the protruding element (e.g., the thread, notch, or protrusion) and a second component includes the recessed -16- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO element (e.g., a channel or recession), a similar connection could be implemented such that the first component includes the recessed element and the second component includes the protruding element.

[0052] The injection pen 100 includes a first part 102 of the housing that surrounds various other components. The first part 102 of the housing can include threads 202 that mate with threads 204 of the dose setting component 106. The first part 102 can further include a window 206 through which a current dose amount marking on the dose setting component 106 is displayed. The housing and the dose setting component 106 can be arranged such that the current dose amount marking displayed through the window 206 corresponds to an amount of the pharmaceutical composition to be dispensed through the injection pen 100 by returning the dose setting component 106 to the unset position (e.g., where a dose of “0” is displayed through the window 206 or the dose setting component 106 cannot be further rotated in the dose dispensing direction). Thus, the window 206 can display different dose amount markings as the dose setting component 106 is rotated along the threads 202.

[0053] The second part 104 of the housing can be coupled with the first part 102 of the housing. The second part 104 of the housing can receive a cartridge 208 that holds the pharmaceutical composition. The piston 116 can be driven through the second part 104 of the housing toward the cartridge 208 to move a plunger 210 through the cartridge 208. In doing so, the pharmaceutical composition can be dispensed from the cartridge 208. A portion of the second part 104 can be inserted into the first part 102 of the housing to surround various other components and prevent them from moving axially or rotationally (e.g., in one or more directions) based on the particular component.

[0054] The dose setting component 106 can be threaded into the first part 102 of the housing. The dose setting component 106 can attach to the axial driver 108 through a notch 212 to cause the axial driver 108 to displace axially and rotationally with the dose setting component 106. The axial driver 108 can be threaded to the interior of the second part 104 of the housing along threads 214. The axial driver 108 can be connected to the rotational driver 110 along a circumferential connection. For example, a thread or notch of the axial-17- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO driver 108 can be attached to a circumferential channel 216 on the rotational driver 110. This connection can allow the rotational driver 110 to rotate freely of the axial driver 108 but not axially displace freely of the axial driver 108.

[0055] The rotational driver 110 can be attached to the piston driver 114 through an axial connection that prevents relative rotational movement between the components but allows relative axial movement between the components. For example, the rotational driver 110 can include an axial thread 218 that mates with an axial channel (not shown) of the piston driver 114. The axial thread 218 can be located on a portion of the rotational driver 110 that has a smaller radius than the rest of the rotational driver 110. Thus, the smaller portion can sit within the piston driver 114 and a protrusion between the smaller portion and the larger portion can rest on the piston driver 114 when the dose setting component 106 is in the unset position.

[0056] The piston driver 114 can be prevented from displacing axially. The piston driver 114 can thus attach to the second part 104 of the housing through a circumferential connection that allows rotational displacement but not axial displacement. For example, the second part 104 of the housing can attach to the piston driver 114 at a circumferential channel 222. Thus, the piston driver 114 can drive the piston 116 through rotation along threads 220 of the piston 116. The piston driver 114 can include threads (not shown) that mate with the threads 220 of the piston 116. The piston driver 114 can similarly include a teethed or a ratchet connection with the second part 104 of the housing that prevents the piston driver 114 from rotating in a direction opposite the direction that drives the piston 116 toward the cartridge 208.

[0057] The piston driver 114 can drive the piston 116 toward the cartridge 208. A platform 230 can be coupled with the piston 116 to drive the plunger 210 through the cartridge 208. As the plunger 210 is driven through the cartridge 208, the pharmaceutical composition can be dispensed from the cartridge 208. The piston 116 can include a protrusion 228 at a distal end furthest from the cartridge 208. The protrusion 228 can overlap with the smaller portion of the rotational driver 110 to prevent the internal protrusion between the smaller portion and the larger portion of the rotational driver 110 from displacing past the-18- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO protrusion 228 of the piston 116. This can prevent the axial driver 108, and thus the dose setting component 106, from further displacing away from the cartridge 208. This point at which the protrusion 228 contacts the rotational driver 110 can correspond to a maximum movement of the piston 116 toward the cartridge 208 and thus the maximum amount of pharmaceutical composition that can be dispensed. Accordingly, when a last dose of the cartridge 208 is reached, the protrusion 228 can stop the injection pen 100 from being set to a larger dose than that available to be dispensed through the cartridge 208.

[0058] The rotational driver 110 and thus the piston driver 114 are rotationally displaced by the rotational driver 112. The rotational driver 112 can be at least partially surrounded by the rotational driver 110. The rotational driver 112 can be attached to the rotational driver 110 through an axial connection (e.g., channel and thread) (not shown) that allows relative axial displacement but not relative rotational displacement. The rotational driver 112 can include arms 224 (e.g., a continuous rim or discrete arms extending from multiple sides) that extend from the body of the rotational driver. The arms 224 can create overlap between the rotational driver 112 and an internal protrusion between a smaller portion of the dose setting component 106 on which the threads 204 are located and a grip 226 of the dose setting component 106 exposed beyond the housing. The clutch 120 can be placed between these components to increase the rotational force between them when the dose is dispensed. The clutch 120 can be annular such that it surrounds the body of the rotational component but extends along the arms 224.

[0059] The engagement of the clutch 120 and the connection between the rotational driver 112 and the dose setting component 106 can be controlled through the cap 118. The cap 118 can sit on the spring 122 and be connected to the interior of the dose setting component 106. The cap 118 can be pressed during dispensing to compress the spring 122 to increase the pressure between the rotational driver 112 and the dose setting component 106. In contrast, when the cap 118 is released, the pressure between the dose setting component 106 and the rotational driver 112 can be relieved to disengage the clutch 120 and allow the dose setting component 106 to be rotated (e.g., in either direction) without rotating the rotational driver 112.-19- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO Dose Setting and Associated Features

[0060] Figure 3 illustrates a cross-sectional view of a multi-dose injection pen 100 for leuprolide in a set position in accordance with one or more aspects of the present technology. As illustrated, the dose setting component 106 is axially displaced away from the cartridge 208 by rotating the dose setting component 106 in a dose setting direction along the threads of the housing. The dose setting component 106 can be rotated until a dose amount marking corresponding to the intended dose is visible through the window 206. Thus, the components of the injection pen 100 can be configured to inject a specific amount of the pharmaceutical composition that corresponds to a dose amount marking visible through the window 206. Accordingly, each component of the injection pen 100 can be tuned to the specific arrangement of the dose amount markings, the geometry of the cartridge, the concentration of the pharmaceutical composition, and other factors that relate the displacement of the dose setting component 106 to the amount of the pharmaceutical composition dispensed from the cartridge 208. In some embodiments, leuprolide is injected at a dose of 0.5 mg or 1.0 mg. Accordingly, the injection pen 100 can be set such that 0.5 mg or 1.0 mg is displayed through the window 206. In some embodiments, the pharmaceutical composition is injected at a volume of 0.1 mL or 0.2 mL. Accordingly, the injection pen 100 can be set such that 0.1 mL or 0.2 mL is displayed through the window 206.

[0061] As the dose setting component 106 is rotated, the axial driver 108 rotates and axially displaces with the dose setting component 106. The axial displacement of the axial driver 108 can cause the rotational driver 110 to axially displace away from the cartridge 208. In aspects, this displacement can correspond to the amount of displacement that the piston 116 will undergo by returning the dose setting component 106 to the unset position from the current position. Thus, the axial displacement of the rotational driver 110 can ensure that no dose is set that is greater than a possible dose to be expelled from the cartridge 208 based on how far the piston 116 has progressed. Specifically, the internal protrusion of the rotational driver 110 can contact the protrusion 228 to stop a greater dose from being set when the current dose corresponds to a maximum dose capable of being expelled from the cartridge 208 given the current position of the piston 116.-20- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO

[0062] The rotational driver 112 is similarly displaced away from the cartridge 208. This displacement, however, can be independent of the axial driver 108 and instead based on the dose setting component 106 itself being axially displaced. This displacement can include relative displacement between the rotational driver 110 and the rotational driver 112. In aspects, this axial displacement can take place without any rotational displacement of the rotational driver 112 with the dose setting component 106.Dose Injection or Dose Callback and Associate Features

[0063] Figure 4 illustrates a cross-sectional view of a multi-dose injection pen 100 for leuprolide in an unset position in accordance with one or more aspects of the present technology. The injection pen 100 can be returned to the unset position by injecting a dose or by recalling a dose previously set. To inject the dose, the cap 118 can be pressed to create pressure between the arms 224 of the rotational driver 112 and the dose setting component 106. The cap 118 can engage the clutch 120 to increase the rotational force between these components. With the cap 118 pressed, the dose setting component 106 can be rotated along the threads in a dispensing direction until it is returned to the unset position (e.g., where “0” is the dose amount marking shown through the window 206, where the dose setting component 106 can no longer be rotated in the dispensing direction, or where the dose setting component 106 contacts an overlapping portion of the first part 102 of the housing). The unset position can similarly correspond to a position in which a protruding portion of the rotational driver 110 rests against the piston driver 114.

[0064] The displacement of the dose setting component 106 can cause rotational and axial displacement of the axial driver 108. This can cause axial displacement of the rotational driver 110. The rotation of the dose setting component 106 can similarly cause rotation of the rotational driver 112 due to the engagement of the clutch 120. This rotation can in turn cause rotation of the rotational driver 110. As the rotational driver 110 is rotated, the piston driver 114 can be rotated to drive the piston 116 toward the cartridge. As the piston driver 114 is rotated, it can emit an audible noise. This noise can correspond to a predetermined amount of angular displacement of the piston driver 114. For example, the noise can be emitted when the piston driver 114 rotates enough to drive the piston 116 to dispense an-21- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO intended dose of leuprolide (e.g., 0.25-1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 0.05-0.2 mL, 0.05 mL, 0.1 mL, 0.15 mL, and 0.2 mL).

[0065] Alternatively, a set dose can be retracted without dispensing the pharmaceutical composition from the cartridge 208 by rotating the dose setting component 106 in the dispensing direction without pressing the cap 118. In this case, the axial displacement of the axial driver 108 and the rotational driver 110 can occur as described above. In contrast, however, the rotational driver 112, and thus the rotational driver 110, and the piston driver 114, will not rotate. Instead, by having the cap 118 released, the clutch 120 can be disengaged, and the pressure between the arms 224 of the rotational driver 112 and the dose setting component 106 can be insufficient to rotate the rotational driver 112 with the dose setting component 106. Thus, the injection pen 100 can be returned to the unset position without dispensing the dose from the cartridge 208.External View

[0066] Figure 5 illustrates an external view of a multi-dose injection pen 100 for leuprolide in accordance with one or more aspects of the present technology. The injection pen 100 can include a housing 502 that encloses one or more components. A cartridge 208 can be attached to and extend from the housing 502 (e.g., at least partially within the housing). The cartridge 208 can include one or more capacity markings 504 indicating an amount of pharmaceutical composition within the cartridge 208 when the pharmaceutical composition is filled to respective points. The dose setting component 106 can be exposed beyond the housing 502 to enable dose setting. The cap 118 can similarly be exposed to enable a set dose to be injected. The housing 502 can include a window 206 through which dose amount markings 506 are exposed. A displayed one of the dose amount markings 506 can correspond to a dose of the pharmaceutical composition to be dispensed from the cartridge 208 by returning the dose setting component 106 from the current position to the unset position with the cap 118 depressed. When the injection pen 100 is not in use, the cartridge 208 can be covered with a cap 118 that connects with the housing 502.-22- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO Dose Setting Component and Associated Features

[0067] Figure 7 illustrates a dose setting component 106 of a multi-dose injection pen for leuprolide in accordance with one or more aspects of the present technology. The dose setting component 106 can be used in conjunction with the cartridge 208 of Figure 6. The dose setting component 106 can be rotated along threads 204 to set a dose to be injected through the injection pen. The dose setting component 106 can include dose amount markings 506 that can be displayed through the window of the housing to indicate a current dose set to be dispensed by returning the dose setting component 106 to the unset position. The dose amount markings 506 can be disposed around the threads 204 so that a different dose amount marking is displayed when the dose setting component 106 is rotated along the threads 204. The dose amount markings 506 can correspond to the intended dose of leuprolide to be injected using the injection pen. For example, the dose amount markings 506 can range from 0 mg to 1 mg. The dose amount markings 506 can include a markings every 0.25 mg. Alternatively or additionally, the dose amount markings 506 can correspond to a volume of the pharmaceutical to be injected using the injection pen. For example, the dose amount markings 506 can range from 0 mL to 0.2 mL. The dose amount markings 506 can include a marking every 0.05 mL.Selected Embodiments of Leuprolide Cartridges for Multi-Dose Injection Pens Configured in Accordance with Embodiments of the Present Technology

[0068] Multi-dose injection pens of the present technology are configured to carry a cartridge having a pharmaceutical composition comprising leuprolide disposed therein. Figure 6 illustrates a cartridge 208 of a multi-dose injection pen for leuprolide in accordance with one or more aspects of the present technology. The cartridge 208 can hold a pharmaceutical composition that includes leuprolide. The cartridge 208 can have a volume of at least 3 mL. For example, the cartridge 208 can have a volume of about 3.3 mL. The cartridge 208 can include capacity markings 504 that indicate an amount of leuprolide stored in the cartridge 208 when the pharmaceutical composition fills to a specific location. For example, the capacity markings 504 can range from 3 mg to 12 mg. The capacity markings 504 can include markings indicating 3, 6, 9, and 12 mg.-23- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO Pharmaceutical Compositions Configured in Accordance with Embodiments of the Present Technology

[0069] The present technology also provides pharmaceutical compositions of leuprolide. In some embodiments, the leuprolide is leuprolide acetate. In some embodiments, the pharmaceutical composition includes one or more pharmaceutically acceptable carriers and / or excipients. The pharmaceutical compositions of leuprolide can be carried in a cartridge configured for positioning within the multi-dose pen.

[0070] Leuprolide may be used to treat and / or prevent the progression of prostate cancer. Accordingly, the pharmaceutical compositions described herein may comprise leuprolide in an amount sufficient to elicit a therapeutic effect, i.e. , an amount sufficient to treat or prevent the progression of prostate cancer. For example, the leuprolide may be present in the pharmaceutical composition in an amount sufficient to deliver at least one therapeutic dose of leuprolide to a subject. In some embodiments, the pharmaceutical composition comprises three or more doses of leuprolide. In some embodiments, the pharmaceutical composition comprises five or more, ten or more, or fifteen or more doses of leuprolide. In some embodiments, the pharmaceutical composition comprises six doses of leuprolide.

[0071] The leuprolide may be present in the pharmaceutical composition at a concentration of about 1.0 mg / mL to about 10.0 mg / mL. In some embodiments, the leuprolide is present in the pharmaceutical composition at a concentration of about 2.5 mg / mL to about 7.5 mg / mL, about 3.0 mg / mL to about 7.0 mg / mL, about 3.5 mg / mL to about 6.5 mg / mL, about 4.0 mg / mL to about 6.0 mg / mL, or about 4.5 mg / mL to about 5.5 mg / mL. In some embodiments, the leuprolide is present in the pharmaceutical composition at a concentration of about 4.5 mg / mL, about 4.6 mg / mL, about 4.7 mg / mL, about 4.8 mg / mL, about 4.9 mg / mL, about 5.0 mg / mL, about 5.1 mg / mL, about 5.2 mg / mL, about 5.3 mg / mL, about 5.4 m / mL, or about 5.5 mg / mL. In some embodiments, the leuprolide is present in the pharmaceutical composition at a concentration of about 5.0 mg / mL.

[0072] As described above, the pharmaceutical composition comprises multiple doses of leuprolide. A dose of leuprolide may comprise about 0.1 mg to about 2.0 mg leuprolide.-24- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO In some embodiments, a dose of leuprolide comprises about 0.1 mg to about 1.8 mg, about 0.2 mg to about 1.6 mg, about 0.3 mg to about 1.4 mg, about 0.4 mg to about 1.2 mg, or about 0.5 mg to about 1.0 mg of leuprolide. In some embodiments, a dose of leuprolide comprises about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, or about 1.2 mg leuprolide. In some embodiments, a dose of leuprolide comprises about 0.5 mg of leuprolide. In other embodiments, a dose of leuprolide comprises about 1.0 mg of leuprolide.

[0073] Accordingly, the leuprolide may be present in the pharmaceutical composition in an amount equal to at least two, at least three, at least five, at least ten, at least fifteen, at least twenty, or at least twenty-five doses of leuprolide. In particular, the leuprolide may be present in the pharmaceutical composition in an amount of about 5 mg to about 25 mg. In some embodiments, the leuprolide is present in the pharmaceutical composition in an amount of about 10 mg to about 20 mg, 12 mg to about 20 mg, about 14 mg to about 20 mg, about 16 mg to about 20 mg, about 12 mg to about 18 mg, about 14 mg to about 18 mg, or about 16 mg to about 18 mg. In some embodiments, the leuprolide is present in the pharmaceutical composition in an amount of about 16.5 mg.

[0074] Pharmaceutical compositions of the present technology further comprise one or more pharmaceutically acceptable carriers and / or excipients. Pharmaceutically acceptable carriers and / or excipients included in the pharmaceutical composition may be selected based on the carrier or excipient’s ability to confer desirable properties, such as reduced or lack of delivery site reactions, solubility, stability, pH, buffering, pharmacokinetics, bioavailability, and the like, to the pharmaceutical composition. For example, the one or more pharmaceutically acceptable carriers and / or excipients of the pharmaceutical compositions described herein may include a preservative, a tonicity agent, one or more pH adjusting agents.

[0075] In some embodiments, the pharmaceutical composition includes a preservative. In some embodiments, the pharmaceutical composition includes one preservative. In other embodiments, the pharmaceutical composition includes more than one preservative. Nonlimiting examples of preservatives that may be included in the pharmaceutical composition-25- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO of the present technology include benzyl alcohol, phenol, and m-cresol. In some embodiments, the preservative is benzyl alcohol. In other embodiments, the preservative or preservatives include m-cresol, phenol, or both m-cresol and phenol.

[0076] The preservative may be present in the pharmaceutical composition at a concentration of about 5.0 mg / mL to about 15.0 mg / mL. In some embodiments, the preservative is present in the pharmaceutical composition at a concentration of about 8.0 mg / mL to about 11.0 mg / mL, about 8.0 mg / mL to about 10.5 mg / mL, about 8.5 mg / mL to about 10.0 mg / mL, about 8.5 mg / mL to about 9.5 mg / mL, about 9.0 mg / mL to about 9.5 mg / mL, or about 8.5 mg / mL to about 9.0 mg / mL. In some embodiments, the preservative is present in the pharmaceutical composition at a concentration of about 8.0 mg / mL to about 9.5 mg / mL, about 8.0 mg / mL to about 9.0 mg / mL, about 9.0 mg / mL to about 10.0 mg / mL, about 9.0 mg / mL to about 10.5 mg / mL, or about 9.0 mg / mL to about 11.0 mg / mL. In some embodiments, the preservative is present in the pharmaceutical composition at a concentration of about 9.0 mg / mL.

[0077] In some embodiments, the preservative is benzyl alcohol, and the benzyl alcohol is present in the pharmaceutical composition at a concentration of about 5.0 mg / mL to about 15.0 mg / mL. In some embodiments, the benzyl alcohol is present in the pharmaceutical composition at a concentration of about 8.0 mg / mL to about 11.0 mg / mL, about 8.0 mg / mL to about 10.5 mg / mL, about 8.5 mg / mL to about 10.0 mg / mL, about 8.5 mg / mL to about 9.5 mg / mL, about 9.0 mg / mL to about 9.5 mg / mL, or about 8.5 mg / mL to about 9.0 mg / mL. In some embodiments, the benzyl alcohol is present in the pharmaceutical composition at a concentration of about 8.0 mg / mL to about 9.5 mg / mL, about 8.0 mg / mL to about 9.0 mg / mL, about 9.0 mg / mL to about 10.0 mg / mL, about 9.0 mg / mL to about 10.5 mg / mL, or about 9.0 mg / mL to about 11.0 mg / mL. In some embodiments, the benzyl alcohol is present in the pharmaceutical composition at a concentration of about 9.0 mg / mL.

[0078] In some embodiments, the preservative is m-cresol, and the m-cresol is present in the pharmaceutical composition at a concentration of about 0.02 mg / mL to about 10.0 mg / mL. In some embodiments, the m-cresol is present in the pharmaceutical composition at a concentration of about 0.05 mg / mL to about 9.0 mg / mL, about 0.1 mg / mL to about 8.0-26- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO mg / mL, about 0.2 mg / mL to about 7.5 mg / mL, about 0.4 mg / mL to about 7.0 mg / mL, about 0.8 mg / mL to about 6.5 mg / mL, , about 1.0 mg / mL to about 6.0 mg / mL, about 1.2 mg / mL to about 5.5 mg / mL, about 1.4 mg / mL to about 5.0 mg / mL, or about 1.8 mg / mL to about 4.5 mg / mL. In some embodiments, the m-cresol is present in the pharmaceutical composition at a concentration of about 1.0 mg / mL to about 5.0 mg / mL, about 1.0 mg / mL to about 1.5 mg / mL, about 1.5 mg / mL to about 4.5 mg / mL, about 2.0 mg / mL to about 4.0 mg / mL, about 2.5 mg / mL to about 3.8 mg / mL, or about 2.8 mg / mL to about 3.5 mg / mL. In some embodiments, the m-cresol is present in the pharmaceutical composition at a concentration of about 3.0 mg / mL.

[0079]

[0081] In some embodiments, the preservative or preservatives used in the pharmaceutical composition includes phenol, and the phenol is present in the pharmaceutical composition in an amount of about 0.5 mg / mL to about 5.0 mg / mL, 1.0 mg / mL to about 5.0 mg / mL, 1.5 mg / mL to about 5.0 mg / mL, 2.0 mg / mL to about 5.0 mg / mL, 2.5 mg / mL to about 5.0 mg / mL, 3.5 mg / mL to about 5.0 mg / mL, 4.0 mg / mL to about 5.0 mg / mL, about 4.5 mg / mL to about 5.0 mg / mL, about 1.0 mg / mL to about 4.0 mg / mL, about 1.0 mg / mL to about 3.0 mg / mL, about 1.0 mg / mL to about 2.0 mg / mL, about 1.5 mg / mL to about 4.0 mg / mL, about 1.5 mg / mL to about 3.0 mg / mL, or about 1.5 mg / mL to about 2.0 mg / mL. In some embodiments, the phenol is present in the pharmaceutical composition in an amount of about 1.5 mg / mL to about 3.0 mg / mL. In some embodiments, the preservative or preservatives used in the pharmaceutical composition includes phenol and m-cresol in a combined concentration of about 1.0 mg / mL to about 5.0 mg / mL. In some embodiments, the preservatives used in the pharmaceutical composition includes m-cresol at a concentration of about 1.0 to about 1.5 mg / mL and phenol at a concentration of about 1.5 mg / mL to about 3 mg / mL).

[0080] The preservative may be present in the pharmaceutical composition in an amount of about 10 mg to about 50 mg. In some embodiments, the preservative is present in the pharmaceutical composition in an amount of about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 25 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 26 mg to about 30 mg, about 27 mg to about 30 mg, about 28 mg to about 30 mg, or about 29 m to about 30 mg. In some -27- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO embodiments, the preservative is present in the pharmaceutical composition in an amount of about 29.0 mg, 29.1 mg, about 29.2 mg, about 29.3 mg, about 29.4 mg, about 29.5 mg, about 29.6 mg, about 29.7 mg, about 29.8 mg, about 29.9 mg, or about 30.0 mg. In some embodiments, the preservative is present in the pharmaceutical composition in an amount of about 29.7 mg.

[0081] In some embodiments, the preservative is benzyl alcohol, and the benzyl alcohol is present in the pharmaceutical composition in an amount of about 10 mg to about 50 mg. In some embodiments, the benzyl alcohol is present in the pharmaceutical composition in an amount of about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 25 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 26 mg to about 30 mg, about 27 mg to about 30 mg, about 28 mg to about 30 mg, or about 29 m to about 30 mg. In some embodiments, the benzyl alcohol is present in the pharmaceutical composition in an amount of about 29.0 mg, 29.1 mg, about 29.2 mg, about 29.3 mg, about 29.4 mg, about 29.5 mg, about 29.6 mg, about 29.7 mg, about 29.8 mg, about 29.9 mg, or about 30.0 mg. In some embodiments, the benzyl alcohol is present in the pharmaceutical composition in an amount of about 29.7 mg.

[0082] In some embodiments, the preservative is m-cresol, and the m-cresol is present in the pharmaceutical composition in an amount of about 2.0 mg to about 15 mg. In some embodiments, the m-cresol is present in the pharmaceutical composition at a concentration of about 5.0 mg to about 13.5 mg, about 5.5 mg to about 13.0 mg, about 6.0 mg to about 12.5 mg, about 6.5 mg to about 12.0 mg, about 7.0 mg to about 11.5 mg, about 7.5 mg to about 11.0 mg, about 8.0 mg to about 10.5 mg, about 8.5 mg to about 10.0 mg, or about 9.0 mg to about 10.0 mg. In some embodiments, the m-cresol is present in the pharmaceutical composition in an amount of about 9.0 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, or about 10.0 mg. In some embodiments, the m-cresol is present in the pharmaceutical composition in an amount of about 9.0 mg. In some embodiments, the m-cresol is present in the pharmaceutical composition in an amount of about 9.9 mg.-28- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO

[0083] In some embodiments, the pharmaceutical composition includes a tonicity agent. In some embodiments, the pharmaceutical composition includes one tonicity agent. In other embodiments, the pharmaceutical composition includes more than one tonicity agent. The one or more tonicity agent may be a sugar or derivative thereof, glycerol, glycerin, a gelatin, a propylene glycol, a propylparaben, PVP, PLGA, PEG, or sodium chloride. In some embodiments, the tonicity agent is sodium chloride.

[0084] The tonicity agent may be present in the pharmaceutical composition at a concentration of about 2.5 mg / mL to about 10.0 mg / mL. In some embodiments, the tonicity agent is present in the pharmaceutical composition at a concentration of about 2.5 mg / mL to about 10 mg / mL, about 3.0 mg / mL to about 9.0 mg / mL, about 3.5 mg / mL to about 8.0 mg / mL, about 4.0 mg / mL to about 7.0 mg / mL, about 4.5 mg / mL to about 6.5 mg / mL, about 5.0 mg / mL to about 6.5 mg / mL, or about 6.0 mg / mL to about 6.5 mg / mL. In some embodiments, the tonicity agent is present in the pharmaceutical composition at a concentration of about 4.5 mg / mL to about 10.0 mg / mL, about 4.5 mg / mL to about 8.0 mg / mL, about 4.5 mg / mL to about 6.0 mg / mL, about 4.5 mg / mL to about 4.0 mg / mL, or about 4.5 mg / mL to about 0 mg / mL. In some embodiments, the tonicity agent is present in the pharmaceutical composition at a concentration of about 6.3 mg / mL.

[0085] In some embodiments, the tonicity agent is sodium chloride, and the sodium chloride is present in the pharmaceutical composition at a concentration of about 2.5 mg / mL to about 10.0 mg / mL. In some embodiments, the sodium chloride is present in the pharmaceutical composition at a concentration of about 2.5 mg / mL to about 10 mg / mL, about 3.0 mg / mL to about 9.0 mg / mL, about 3.5 mg / mL to about 8.0 mg / mL, about 4.0 mg / mL to about 7.0 mg / mL, about 4.5 mg / mL to about 6.5 mg / mL, about 5.0 mg / mL to about 6.5 mg / mL, or about 6.0 mg / mL to about 6.5 mg / mL. In some embodiments, the sodium chloride is present in the pharmaceutical composition at a concentration of about 4.5 mg / mL to about 10.0 mg / mL, about 4.5 mg / mL to about 8.0 mg / mL, about 4.5 mg / mL to about 6.0 mg / mL, about 4.5 mg / mL to about 4.0 mg / mL, or about 4.5 mg / mL to about 0 mg / mL. In some embodiments, the sodium chloride is present in the pharmaceutical composition at a concentration of about 6.3 mg / mL.-29- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO

[0086] The tonicity agent may be present in the pharmaceutical composition in an amount of about 10 mg to about 30 mg. In some embodiments, the tonicity agent is present in the pharmaceutical composition in an amount of about 15 mg to about 25 mg, about 16 mg to about 24 mg, about 17 mg to about 23 mg, about 18 mg to about 22 mg, about 19 mg to about 21 mg, or about 20 mg to about 21 mg. In some embodiments, the tonicity agent is present in the pharmaceutical composition in an amount of about 20.0 mg, about 20.1 mg, about 20.2 mg, about 20.3 mg, about 20.4 mg, about 20.5 mg, about 20.6 mg, about 20.7 mg, about 20.8 mg, about 20.9 mg, or about 21.0 mg. In some embodiments, the tonicity agent is present in the pharmaceutical composition in an amount of about 20.8 mg.

[0087] In some embodiments, the tonicity agent is sodium chloride, and the sodium chloride is present in the pharmaceutical composition in an amount of about 10 mg to about 30 mg. In some embodiments, the sodium chloride is present in the pharmaceutical composition in an amount of about 15 mg to about 25 mg, about 16 mg to about 24 mg, about 17 mg to about 23 mg, about 18 mg to about 22 mg, about 19 mg to about 21 mg, or about 20 mg to about 21 mg. In some embodiments, the sodium chloride is present in the pharmaceutical composition in an amount of about 20.0 mg, about 20.1 mg, about 20.2 mg, about 20.3 mg, about 20.4 mg, about 20.5 mg, about 20.6 mg, about 20.7 mg, about 20.8 mg, about 20.9 mg, or about 21.0 mg. In some embodiments, the sodium chloride is present in the pharmaceutical composition in an amount of about 20.8 mg.

[0088] A tonicity agent may be included in the pharmaceutical composition to achieve a certain osmolality. For example, the pharmaceutical compositions of the present technology may include a tonicity agent to achieve an isotonic or hypertonic solution to minimize injection site pain and cellular damage. An isotonic solution may have an osmolality of about 250 mOsm / kg to about 350 mOsm / kg and a hypertonic solution may have an osmolality of about 350 mOsm / kg to about 600 mOsm / kg. Accordingly, in some embodiments, the tonicity agent is included in the pharmaceutical composition to achieve an osmolality of about 250 mOsm / kg to about 600 mOsm / kg. In some embodiments, the osmolyte is included in the pharmaceutical composition to achieve an osmolality of about 280 mOsm / kg to about 560 mOsm / kg, about 280 mOsm / kg to about 520 mOsm / kg, about 280 mOsm / kg to about 500 mOsm / kg, about 280 mOsm / kg to about 460 mOsm / kg, about -30- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO 280 mOsm / kg to about 420 mOsm / kg, about 280 mOsm / kg to about 400 mOsm / kg, about 280 mOsm / kg to about 360 mOsm / kg, or about 280 mOsm / kg to about 320 mOsm / kg.

[0089] In some embodiments, the pharmaceutical composition is isotonic. In further embodiments, the osmolality of the pharmaceutical composition is about 250 mOsm / kg to about 350 mOsm / kg. In some embodiments, the osmolality of the pharmaceutical composition is about 260 mOsm / kg to about 340 mOsm / kg, about 270 mOsm / kg to about 330 mOsm / kg, about 275 mOsm / kg to about 325 mOsm / kg, about 280 mOsm / kg to about 320 mOsm / kg, about 285 mOsm / kg to about 315 mOsm / kg, or about 290 mOsm / kg to about 310 mOsm / kg. In some embodiments, the osmolality of the pharmaceutical composition is about 290 mOsm / kg, 292 mOsm / kg, 294 mOsm / kg, 296 mOsm / kg, 298 mOsm / kg, 300 mOsm / kg, 302 mOsm / kg, 304 mOsm / kg, 306 mOsm / kg, 3808 mOsm / kg, or 310 mOsm / kg. In some embodiments, the osmolality of the pharmaceutical composition is about 300 mOsm / kg.

[0090] In some embodiments, the pharmaceutical composition is hypertonic. In further embodiments, the osmolality of the pharmaceutical composition is about 350 mOsm / kg to about 600 mOsm / kg. In some embodiments, the osmolality of the pharmaceutical composition is about 360 mOsm / kg to about 550 mOsm / kg, about 365 mOsm / kg to about 530 mOsm / kg, about 370 mOsm / kg to about 510 mOsm / kg, about 375 mOsm / kg to about 500 mOsm / kg, about 380 mOsm / kg to about 490 mOsm / kg, about 385 mOsm / kg to about 470 mOsm / kg, or about 390 mOsm / kg to about 450 mOsm / kg. In some embodiments, the osmolality of the pharmaceutical composition is about 400 mOsm / kg to about 600 mOsm / kg, about 420 mOsm / kg to about 580 mOsm / kg, about 440 mOsm / kg to about 560 mOsm / kg, about 460 mOsm / kg to about 540 mOsm / kg, or about 480 mOsm / kg to about 520 mOsm / kg.

[0091] In some embodiments, the pharmaceutical composition includes one or more pH adjusting agents. The one or more pH adjusting agents comprise be an acid and / or a base. Non-limiting examples of acids that may be included in the pharmaceutical compositions as a pH adjusting agent include acetic acid, citric acid, fumaric acid, hydrochloric acid, and nitric acid. In some embodiments, the acid is acetic acid. Non-limiting examples of bases that may be included in the pharmaceutical composition as a pH-31- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO adjusting agent include sodium hydroxide, potassium hydroxide, ammonium carbonate, sodium bicarbonate, sodium carbonate, and sodium borate. In some embodiments, the base is sodium hydroxide.

[0092] The one or more pH adjusting agents may be included in the pharmaceutical composition in ana amount sufficient to achieve a certain pH. For example, the pharmaceutical compositions of the present technology may include one or more pH adjusting agents to achieve a pH that is acceptable for physiological use. Such pH range may be from about 4.0 to about 7.0. Accordingly, the pharmaceutical composition or formulation has a pH of about 4.0 to about 7.0. In some embodiments, the pharmaceutical composition or formulation has a pH of about 4.0 to about 6.5. In some embodiments, the pharmaceutical composition or formulation has a pH of about 4.0 to about 6.0. In some embodiments, pharmaceutical composition or formulation has a pH of about 4.0 to about 5.5. In some embodiments, the pharmaceutical composition or formulation has a pH of about 4.0 to about 5.0. In some embodiments, the pharmaceutical composition or formulation has a pH of about 4.5 to about 7.0. In some embodiments, the pharmaceutical composition or formulation has a pH of about 4.5 to about 6.5. In some embodiments, the pharmaceutical composition or formulation has a pH of about 4.5 to about 6.0. In some embodiments, the pharmaceutical composition or formulation has a pH of about 4.5 to about 5.5. In some embodiments, the pharmaceutical composition or formulation has a pH of about 5.0 to about 7.0. In some embodiments, the pharmaceutical composition or formulation has a pH of about 5.0 to about 6.5. In some embodiments, the pharmaceutical composition or formulation has a pH of about 5.5 to about 6.5. In some embodiments, the pharmaceutical composition or formulation has a pH of about 6.0 to about 6.5. In some embodiments, the pharmaceutical composition or formulation has a pH of about 5.5 to about 6.0. In some embodiments, the pharmaceutical composition or formulation has a pH of about 6.0.

[0093] Pharmaceutical compositions of the present technology further comprise water. The water may be sterile water for injection (SWFI), sterile water, bacteriostatic water for injection (BWFI), distilled water, bidistilled water, deionized water, deionized distilled water, and reverse osmosis water. The water may be present in amount sufficient to fill the container comprising the pharmaceutical composition, such as the cartridge of the multi- -32- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO dose injection pen described herein. In some embodiments, water is present in the pharmaceutical composition in an amount of less than 4.0 mL. In some embodiments, water is present in the pharmaceutical composition in an amount of at least about 3.0 mL. In some embodiments, water is present in the pharmaceutical composition in an amount of about 3.0 mL to about 4.0 mL. In some embodiments, water is present in the pharmaceutical composition in an amount of not greater than 3.3 mL. In some embodiments, water is present in the pharmaceutical composition in an amount of less than 3.3 mL.

[0094] Pharmaceutical compositions of the present technology may have a viscosity suitable for parenteral administration, and in particular, for subcutaneous administration. In some embodiments, the pharmaceutical composition has a viscosity of about 1.0 mm2 / s to 3.0 mm2 / s.Example 1: Stability Data for Leuprolide Injection Pen

[0095] Samples of pharmaceutical compositions including leuprolide in the amount of 5 mg / mL in a 3.3 mL fill cartridge (16.5 mg / pen) were placed in stability chambers under various storage conditions for six months and the following parameters were tested at monthly intervals: benzyl alcohol (% of label claim), assay (% of label claim), related compound RRT~0.06, related compound RRT~0.18, related compound RRT~0.45, related compound RRT~0.76, related compound RRT~0.91, total impurities, pH, and hunter color. Results below show stable compositions within the acceptance criteria.

[0096] Table 1 below shows results from lot tests containing leuprolide (5 mg / mL), sodium chloride (6.3 mg / mL), benzyl alcohol (9 mg / mL), and water (q.s. to 3.3 mL / pen) at 0, 3, and 6 months for each parameter as indicated under the following storage conditions: 25°C ± 2°C, 60% RH ± 5% RH, Horizontal storage (RH = relative humidity).

[0097] Table 1-33- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO<< <<<< <<<< <<< <<< <-34- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO< <<< <<<<

[0098] Table 2 below shows results from lot tests containing leuprolide (5 mg / mL), sodium chloride (6.3 mg / mL), benzyl alcohol (9 mg / mL), and water (q.s. to 3.3 mL / pen) at 0, 3, and 6 months for each parameter as indicated under the following storage conditions: 30°C ± 2°C, 75% RH ± 5% RH, Horizontal (RH = relative humidity).-35- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO

[0099] Table 2<< <<<<-36- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO<< <<<<<<<<-37- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO

[0100] Table 3 below shows results from lot tests containing leuprolide (5 mg / mL), sodium chloride (6.3 mg / mL), benzyl alcohol (9 mg / mL), and water (q.s. to 3.3 mL / pen) at 0, 1 , 2, 3, and 6 months for each parameter as indicated under the following storage conditions: 40°C ± 2°C, 75% RH ± 5% RH, Horizontal (RH = relative humidity).

[0101] Table 3<< <<-38- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO<<<<<<-39- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO<Remarks

[0102] The terms “example,” “embodiment,” and “implementation” are used interchangeably. For example, references to “one example” or “an example” in the disclosure can be, but not necessarily are, references to the same implementation; and such references mean at least one of the implementations. The appearances of the phrase “in one example” are not necessarily all referring to the same example, nor are separate or alternative examples mutually exclusive of other examples. A feature, structure, or characteristic described in connection with an example can be included in another example of the disclosure. Moreover, various features are described that can be exhibited by some examples and not by others. Similarly, various requirements are described that can be requirements for some examples but not for other examples.

[0103] The terminology used herein should be interpreted in its broadest reasonable manner, even though it is being used in conjunction with certain specific examples of the present technology. The terms used in the disclosure generally have their ordinary meanings in the relevant technical art, within the context of the disclosure, and in the specific context where each term is used. A recital of alternative language or synonyms does not exclude-40- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO the use of other synonyms. Special significance should not be placed upon whether or not a term is elaborated or discussed herein. The use of highlighting has no influence on the scope and meaning of a term. Further, it will be appreciated that the same thing can be said in more than one way.

[0104] Details of the disclosed implementations can vary considerably in specific implementations while still being encompassed by the disclosed teachings. As noted above, particular terminology used when describing features or aspects of the present technology should not be taken to imply that the terminology is being redefined herein to be restricted to any specific characteristics, features, or aspects of the present technology with which that terminology is associated. In general, the terms used in the following claims should not be construed to limit the present technology to the specific examples disclosed herein unless the Detailed Description above explicitly defines such terms. Accordingly, the actual scope of the present technology encompasses not only the disclosed examples but also all equivalent ways of practicing or implementing the present technology under the claims. Some alternative implementations can include additional elements to those implementations described above or include fewer elements.

[0105] Any patents and applications and other references noted above, and any that may be listed in accompanying filing papers, are incorporated herein by reference in their entireties, except for any subject matter disclaimers or disavowals, and except to the extent that the incorporated material is inconsistent with the express disclosure herein, in which case the language in this disclosure controls. Aspects of the present technology can be modified to employ the systems, functions, and concepts of the various references described above to provide yet further implementations of the present technology.-41- 183840252.2

Claims

PATENT Attorney Docket No. 137249.8003. WOOO CLAIMSWe claim:

1. A multi-dose injection pen comprising:a cartridge containing an aqueous pharmaceutical composition comprising:leuprolide at a concentration of about 2.5 mg / mL to about 7.5 mg / mL, benzyl alcohol at a concentration of about 8 mg / mL to about 11 mg / mL, a tonicity agent at a concentration sufficient to adjust the osmolarity of the composition to about 250 mOsm / kg to about 600 mOsm / kg, and one or more pH adjusting agents at a concentration sufficient to adjust the pH of the composition to about 4.0 to about 7.0;a housing;a dose setting component at least partially disposed within the housing and configured to set a dose of the aqueous pharmaceutical composition to be dispensed from the cartridge; anda dispensing component at least partially disposed within the housing and configured to dispense the dose of the aqueous pharmaceutical composition from the cartridge.

2. A multi-dose injection pen comprising:a cartridge containing an aqueous pharmaceutical composition comprising:leuprolide in an amount of about 10 mg to about 20 mg,benzyl alcohol in an amount of about 25 mg to about 35 mg, and a tonicity agent at a concentration sufficient to adjust the osmolarity of the composition to about 250 mOsm / kg to about 600 mOsm / kg, and one or more pH adjusting agents at a concentration sufficient to adjust the pH of the composition to about 4.0 to about 7.0;a housing;-42- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO a dose setting component at least partially disposed within the housing and configured to set a dose of the aqueous pharmaceutical composition to be dispensed from the cartridge; anda dispensing component at least partially disposed within the housing and configured to dispense the dose of the aqueous pharmaceutical composition from the cartridge.

3. A multi-dose injection pen comprising:a cartridge containing an aqueous pharmaceutical composition comprising:leuprolide at a concentration of about 2.5 mg / mL to about 7.5 mg / mL, benzyl alcohol at a concentration of about 6 mg / mL to about 12 mg / mL, and atonicity agent at a concentration of about 4.5 mg / mL to about 9 mg / mL; a housing;a dose setting component at least partially disposed within the housing and configured to set a dose of the aqueous pharmaceutical composition to be dispensed from the cartridge; anda dispensing component at least partially disposed within the housing and configured to dispense the dose of the aqueous pharmaceutical composition from the cartridge.

4. A multi-dose injection pen comprising:a cartridge containing an aqueous pharmaceutical composition comprising:leuprolide in an amount of about 10 mg to about 20 mg,benzyl alcohol in an amount of about 25 mg to about 35 mg, and a tonicity agent in an amount of about 15 mg to about 25 mg;a housing;a dose setting component at least partially disposed within the housing and configured to set a dose of the aqueous pharmaceutical composition to be dispensed from the cartridge; and-43- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO a dispensing component at least partially disposed within the housing and configured to dispense the dose of the aqueous pharmaceutical composition from the cartridge.

5. A multi-dose injection pen comprising:a cartridge with a volume of at least 3 mL and containing an aqueous pharmaceutical composition comprising leuprolide in an amount of about 10 mg to about 20 mg;a housing;a dose setting component partially disposed within the housing and threaded with the housing along first threads, the dose setting component rotatable along the first threads to axially displace the dose setting component axially away from the cartridge when rotating in a first direction and axially toward the cartridge when rotating in a second direction opposite the first direction;a first threaded annular component attached at an interior of the dose setting component and configured to rotate and axially displace with the dose setting component;a second annular component:attached at an interior of the first threaded annular component through a circumferential connection to axially displace at least a first portion of the second annular component with the first threaded annular component, andattached to the dose setting component to cause the second annular component to rotate in the second direction with the dose setting component when the dose setting component is rotated in the second direction;a third annular component attached to the second annular component such that the third annular component is configured to rotate in the second direction with the second annular component, the third annular component having second threads at an interior of the third annular component; and-44- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO a piston attached to the third annular component at the second threads and configured to displace axially toward the cartridge to dispense the aqueous pharmaceutical composition from the cartridge when the third annular component is rotated in the second direction.

6. The multi-dose injection pen of claim 5, wherein the second annular component comprises:the first portion of the second annular component attached at the interior of the first threaded annular component through the circumferential connection to cause the first portion of the second annular component to displace axially with the first threaded annular component and attached to the third annular component; anda second portion of the second annular component:attached to the dose setting component to cause the second portion of the second annular component to rotate in the second direction with the dose setting component, andattached to the first portion of the second annular component through an axial connection to cause the first portion of the second annular component to rotate in the second direction with the second portion of the second annular component.

7. The multi-dose injection pen of claim 6, wherein the second portion of the second annular component can be axially displaced relative to the first portion of the second annular component.

8. The multi-dose injection pen of claim 5-7, wherein the second annular component and the third annular component are prevented from rotating in the first direction.-45- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO 9. The multi-dose injection pen of claim 5-8, wherein the second annular component and the third annular component are attached through an axial groove connection.

10. The multi-dose injection pen of claim 5-9, further comprising a clutch element coupling the second annular component with the dose setting component, the clutch element configured to apply a first rotational force on the second annular component when the dose setting component is rotated in the second direction, the first rotational force greater than a second rotational force applied by the clutch element on the second annular component when the dose setting component is rotated in the first direction.

11. A multi-dose injection pen comprising:a cartridge containing an aqueous pharmaceutical composition comprising leuprolide at a concentration of about 2.5 mg / mL to about 7.5 mg / mL;a housing comprising a window exposing at least a portion of a dose setting component;the dose setting component:partially disposed within the housing and threaded with the housing along first threads,rotatable along the first threads to axially displace the dose setting component axially away from the cartridge when rotating in a first direction and axially toward the cartridge when rotating in a second direction opposite the first direction, andhaving dose amount markings disposed around the dose setting component in an arrangement that corresponds to a helix angle of the first threads, respective ones of the dose amount markings visible through the window of the housing when the dose setting component is rotated along the first threads, each respective one of the dose amount markings visible through the window of the housing when the dose setting component is in a respective position along the first threads and-46- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO corresponding to a respective amount of the aqueous pharmaceutical composition dispensed from the cartridge by returning the dose setting component from the respective position along the first threads to an unset position in which the dose setting component cannot be rotated along the first threads in the second direction;an annular component disposed at least partially within the dose setting component and having:a first portion configured to displace axially away from the cartridge with the dose setting component when the dose setting component is rotated in the first direction and rotate in the second direction with the dose setting component due to friction between the first portion of the annular component and the dose setting component, anda second portion attached to the first portion of the annular component through an axial connection to enable relative axial movement between the first portion of the annular component and the second portion of the annular component and cause the second portion of the annular component to rotate in the second direction with the first portion of the annular component; anda piston configured to displace axially toward the cartridge to dispense the aqueous pharmaceutical composition from the cartridge when the dose setting component is rotated in the second direction.

12. The multi-dose injection pen of claim 11 , wherein the dose amount markings comprise dose volume markings, each respective volume markings visible through the window of the housing when the dose setting component is in the respective position and corresponding to a volume of the respective amount of the aqueous pharmaceutical composition dispensed from the cartridge by returning the dose setting component from the respective position along the first threads to the unset position.-47- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO 13. The multi-dose injection pen of claim 12, wherein the dose volume markings range between 0 and 0.2 mL.

14. The multi-dose injection pen of claim 12, wherein the dose volume markings consist of a first marking of 0 mg, a second marking of 0.25 mg, a third marking of 0.5 mg, a fourth marking of 0.75 mg, and a fifth marking of 1 mg.

15. The multi-dose injection pen of claim 11-14, wherein the dose amount markings range between 0 and 1 mg.

16. The multi-dose injection pen of claim 11-15, wherein the dose amount markings consist of a first marking of 0 mL, a second marking of 0.05 mL, a third marking of 0.1 mL, a fourth marking of 0.15 mL, and a fifth marking of 0.2 mL.

17. The multi-dose injection pen of claim 11-16, wherein the cartridge comprises capacity markings ranging from 3 mg to 12 mg, each respective capacity marking corresponding to a respective capacity of the cartridge at a respective location corresponding to the respective capacity marking.

18. The multi-dose injection pen of claim 17, wherein the capacity markings consist of a first marking of 3 mg, a second marking of 6 mg, a third marking of 9 mg, and a fourth marking of 12 mg.

19. The multi-dose injection pen of claim 11-18, wherein a first marking of the dose amount markings indicating 0 mg is exposed through the window of the housing when the dose setting component is in the unset position.-48- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO 20. A multi-dose injection pen comprising:a cartridge with a volume of at least about 3 mL and containing an aqueous pharmaceutical composition comprising leuprolide at a concentration of about 2.5 mg / mL to about 7.5 mg / mL;a housing;a dose setting component:partially disposed within the housing and threaded with the housing along first threads,rotatable along the first threads to axially displace the dose setting component axially away from the cartridge when rotating in a first direction and axially toward the cartridge when rotating in a second direction opposite the first direction, andhaving a protruding portion at an interior of the dose setting component; a lipped annular component disposed at least partially within the dose setting component and having:a first portion with a protruding portion at an exterior of the first portion of the lipped annular component, the protruding portion at least partially overlapping with the protruding portion of the dose setting component on an axis along which the dose setting component moves when rotating in the first direction or the second direction along the first threads, anda second portion attached to the first portion of the lipped annular component through an axial connection to enable relative axial movement between the first portion of the lipped annular component and the second portion of the lipped annular component and cause the second portion of the lipped annular component to rotate in the second direction with the first portion of the lipped annular component;a cap coupled with the dose setting component opposite the cartridge and displaceable toward the cartridge, the cap, when displaced toward the cartridge, causing displacement of the first portion of the lipped annular-49- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO component toward the cartridge such that overlap between the protruding portion of the dose setting component and the protruding portion of the first portion of the lipped annular component cause the first portion of the lipped annular component to rotate in the second direction when the dose setting component rotates in the second direction; anda piston configured to displace axially toward the cartridge to dispense the aqueous pharmaceutical composition from the cartridge when the second portion of the lipped annular component is rotated in the second direction.

21. The multi-dose injection pen of claim 20, wherein lipped annular component is prevented from rotating in the first direction.

22. The multi-dose injection pen of claim 20 or 21, further comprising a clutch element coupling the lipped annular component with the dose setting component to cause the lipped annular component to rotate in the second direction when the dose setting component rotates in the second direction and the cap is displaced toward the cartridge.

23. The multi-dose injection pen of claim 22, wherein the clutch element is configured to apply a first rotational force on the lipped annular component when the dose setting component is rotated in the second direction, the first rotational force greater than a second rotational force applied by the clutch element on the lipped annular component when the dose setting component is rotated in the first direction.

24. The multi-dose injection pen of claim 22, wherein the clutch element comprises angled teeth exert a rotational force on the clutch element by the dose setting component when the dose setting component is rotated in the second direction.

25. The multi-dose injection pen of claim 22, wherein the clutch element comprises angled teeth to exert a rotational force by the clutch element on the lipped annular-50- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO component when the dose setting component is rotated in the second direction and the cap is displaced toward the cartridge.

26. The multi-dose injection pen of claim 20-25, further comprising a spring separating the cap and the lipped annular component, the spring configured to create a pressure between the dose setting component and the lipped annular component when the spring is in a compressed position due to the cap being displaced toward the cartridge.

27. The multi-dose injection pen of claim 26, wherein the dose setting component can be rotated in the second direction and displaced axially toward the cartridge without rotating the lipped annular component when the spring is in an extended position due to the cap not being displaced toward the cartridge.

28. A multi-dose injection pen comprising:a cartridge with a volume of at least about 3 mL and containing an aqueous pharmaceutical composition comprising leuprolide in an amount of about 10 mg to about 20 mg;a housing;a dose setting component partially disposed within the housing and threaded with the housing along first threads, the dose setting component rotatable along the first threads to axially displace the dose setting component axially away from the cartridge when rotating in a first direction and axially toward the cartridge when rotating in a second direction opposite the first direction;a first annular component interior to the dose setting component and configured to rotate in the second direction and axially displace with the dose setting component;a second annular component attached to the first annular component through an axial connection such that the second annular component is configured to rotate in the second direction with the first annular component, the second annular component having second threads at an interior of the second annular-51- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO component, the second annular component configured to generate an audible noise in response to rotating by a set amount; anda piston attached to the second annular component at the second threads and configured to displace axially toward the cartridge to dispense the aqueous pharmaceutical composition from the cartridge when the second annular component is rotated in the second direction.

29. The multi-dose injection pen of claim 28, wherein the set amount comprises a complete rotation of the second annular component.

30. The multi-dose injection pen of claim 28 or 29, wherein the set amount comprises an amount of rotation effective to dispense about 1 mg of the aqueous pharmaceutical composition from the cartridge.

31. A multi-dose injection pen comprising:a cartridge containing an aqueous pharmaceutical composition comprising leuprolide at a concentration of about 2.5 mg / mL to about 7.5 mg / mL;a housing;a dose setting component partially disposed within the housing and threaded with the housing along first threads, the dose setting component rotatable along the first threads to axially displace the dose setting component axially away from the cartridge when rotating in a first direction and axially toward the cartridge when rotating in a second direction opposite the first direction;a first threaded annular component attached at an interior of the dose setting component and configured to rotate and axially displace with the dose setting component;a second annular component:attached at a first end at an interior of the first threaded annular component through a circumferential connection to axially displace at least a-52- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO portion of the second annular component with the first threaded annular component,attached to the dose setting component to cause the second annular component to rotate in the second direction with the dose setting component, andhaving a protruding portion at an interior of the second annular component;anda piston configured to displace axially toward the cartridge to dispense the aqueous pharmaceutical composition from the cartridge when the second annular component is rotated in the second direction, the piston having a protruding portion at an exterior of the piston at a distal end opposite the cartridge, wherein the protruding portion at the exterior of the piston contacts the protruding portion at the interior of the second annular component to prevent the second annular component from displacing axially away from the cartridge and prevent the dose setting component from displacing axially away from the cartridge and rotating in the first direction when an amount of the aqueous pharmaceutical composition to be dispensed by returning the dose setting component from a current position to an unset position in which the dose setting component cannot be rotated along the first threads in the second direction is equal to an amount of the aqueous pharmaceutical composition remaining in the cartridge.

32. The multi-dose injection pen of claim 31, wherein second annular component is prevented from rotating in the first direction.

33. The multi-dose injection pen of claim 31 , wherein the dose setting component is displaceable to dispense doses of the aqueous pharmaceutical composition from the cartridge in amounts ranging between 0 mg and 1 mg.-53- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO 34. The multi-dose injection pen of any one of claims 1-33, wherein the cartridge has a volume of at least about 3 mL.

35. The multi-dose injection pen of any one of claims 1-34, wherein the cartridge has a volume of about 3.3 mL.

36. The multi-dose injection pen of any one of claims 1-35, wherein the cartridge comprises three or more doses of the aqueous pharmaceutical composition.

37. The multi-dose injection pen of any one of claims 1-36, wherein the cartridge comprises five or more, ten or more, fifteen or more, twenty or more, or twenty-five or more doses of the aqueous pharmaceutical composition.

38. The multi-dose injection pen of any one of claims 1-37, wherein the cartridge comprises twenty-eight doses of the aqueous pharmaceutical composition.

39. The multi-dose injection pen of any one of claims 1-37, wherein the cartridge comprises fourteen doses of the aqueous pharmaceutical composition.

40. The multi-dose injection pen of any one of claims 1 -39, configured to dispense a single dose of the aqueous pharmaceutical composition per injection.

41. The multi-dose injection pen of claim 40, wherein the single dose is 0.1 mL of the aqueous pharmaceutical composition.

42. The multi-dose injection pen of claim 40, wherein the single dose is 0.2 mL of the aqueous pharmaceutical composition.

43. The multi-dose injection pen of any one of claims 1-42, wherein a headspace in the cartridge comprises nitrogen gas.-54- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO 44. The multi-dose injection pen of any one of claims 2, 4-10, 28-30, and 34-43, wherein the leuprolide is present in the aqueous pharmaceutical composition at a concentration of 2.5 mg / mL to about 7.5 mg / mL.

45. The multi-dose injection pen of any one of claims 1 -44, wherein the leuprolide is present in the aqueous pharmaceutical composition at a concentration of about 5 mg / mL.

46. The multi-dose injection pen of any one of claims 1, 3, 11-27, and 31-45, wherein the leuprolide is present in the aqueous pharmaceutical composition in an amount of about 10 mg to about 20 mg.

47. The multi-dose injection pen of any one of claims 1 -46, wherein the leuprolide is present in the aqueous pharmaceutical composition in an amount of about 16.5 mg.

48. The multi-dose injection pen of any one of claims 5-33, wherein the aqueous pharmaceutical composition further comprises benzyl alcohol.

49. The multi-dose injection pen of any one of claims 2, 4, and 34-48, wherein the benzyl alcohol is present at a concentration of about 8 mg / mL to about 11 mg / mL.

50. The multi-dose injection pen of any one of claims 1-4 and 34-49, wherein the benzyl alcohol is present at a concentration of about 9 mg / mL.

51. The multi-dose injection pen of any one of claims 1, 3, and 34-50, wherein benzyl alcohol is present in the aqueous pharmaceutical composition in an amount of about 25 mg to about 35 mg.

52. The multi-dose injection pen of any one of claims 1-4 and 34-51, wherein the benzyl alcohol is present in the aqueous pharmaceutical composition in an amount of about 29.7 mg.-55- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO 53. The multi-dose injection pen of any one of claims 5-33, wherein the aqueous pharmaceutical composition further comprises a tonicity agent.

54. The multi-dose injection pen of claim 3, 4, and 34-53, wherein the tonicity agent is present in the aqueous pharmaceutical composition at a concentration sufficient to adjust the osmolarity of the composition to about 250 mOsm / kg to about 600 mOsm / kg.

55. The multi-dose injection pen of any one of claims 1, 2, 4, and 34-54, wherein the tonicity agent is present in the aqueous pharmaceutical composition at a concentration of about 4.5 mg / mL to about 9.0 mg / mL.

56. The multi-dose injection pen of any one of claims 1-4 and 34-55, wherein the tonicity agent is present in the aqueous pharmaceutical composition at a concentration of about 6.3 mg / mL.

57. The multi-dose injection pen of any one of claims 1-3 and 34-56, wherein the tonicity agent is present in the aqueous pharmaceutical composition in an amount of about 15 mg to about 25 mg.

58. The multi-dose injection pen of any one of claims 1-4 and 34-57, wherein the tonicity agent is present in the aqueous pharmaceutical composition in an amount of about 20.8 mg.

59. The multi-dose injection pen of any one of claims 1-58, wherein the tonicity agent is sodium chloride.

60. The multi-dose injection pen of any one of claims 3-33, wherein the aqueous pharmaceutical composition further comprises one or more pH adjusting agents.-56- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO 61. The multi-dose injection pen of any one of claims 1 , 2, and 34-60, wherein the one or more pH adjusting agents are present in the aqueous pharmaceutical composition in an amount sufficient to adjust the pH of the composition to about 4.0 to about 7.0.

62. The multi-dose injection pen of any one of claims 1 , 2, and 34-61 , wherein the one or more pH adjusting agents comprise acetic acid and sodium hydroxide.

63. The multi-dose injection pen of any one of claims 1-62, wherein the aqueous pharmaceutical composition further comprises water.

64. The multi-dose injection pen of claim 63, wherein the water is present in an amount less than 3.3 mL.

65. The multi-dose injection pen of any one of claims 3-64, wherein the aqueous pharmaceutical composition has a pH of about 4.0 to about 7.0.

66. The multi-dose injection pen of any one of claims 1-65, wherein the aqueous pharmaceutical composition has a pH of about 5.0.

67. The multi-dose injection pen of any one of claims 3-66, wherein the aqueous pharmaceutical composition has an osmolarity of about 250 mOsm / kg to about 350 mOsm / kg.

68. The multi-dose injection pen of any one of claims 1-67, wherein the aqueous pharmaceutical composition has an osmolarity of about 300 mOsm / kg.

69. The multi-dose injection pen of any one of claims 1-68, wherein the aqueous pharmaceutical composition comprises:leuprolide in an amount of about 16.5 mg,sodium chloride in an amount of about 20.8 mg,-57- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO benzyl alcohol in an amount of about 29.7 mg, andwater in an amount of not more than 3.3 mL.

70. The multi-dose injection pen of any one of claims 1-68, wherein the aqueous pharmaceutical composition comprises:leuprolide at a concentration of about 5 mg / mL,sodium chloride at a concentration of about 6.3 mg / mL,benzyl alcohol at a concentration of about 9 mg / mL, andwater in an amount of not more than 3.3 mL.

71. A method for injecting a dose of an aqueous pharmaceutical composition using a multi-dose injection pen, the method comprising:displacing, relative to a housing with which a dose setting component is threaded along first threads, the dose setting component axially away from a cartridge containing the aqueous pharmaceutical composition and in a first rotational direction until a dose amount marking on the dose setting component visible through a window of the housing indicates 1 mg, wherein the dose amount marking corresponds to an amount of the aqueous pharmaceutical composition dispensed from the cartridge by returning the dose setting component from a current position along the first threads to an unset position in which the dose setting component cannot be rotated along the first threads in a second rotational direction opposite the first rotational direction, the aqueous pharmaceutical composition comprising:leuprolide at a concentration of about 2.5 mg / mL to about 7.5 mg / mL, benzyl alcohol at a concentration of about 8 mg / mL to about 11 mg / mL, sodium chloride at a concentration of about 4.5 mg / mL to about 9 mg / mL, and one or more pH adjusting agents at a concentration sufficient to adjust the pH of the composition to 4.0 to 7.0;displacing a cap coupled with the dose setting component axially toward the cartridge to increase a pressure between an annular component configured to rotate in-58- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO the second rotational direction to dispense the aqueous pharmaceutical composition from the cartridge and the dose setting component; and concurrent with displacing the cap axially toward the cartridge, displacing the dose setting component along the first threads, in the second rotational direction, and axially toward the cartridge to cause the annular component to rotate in the second rotational direction due to the pressure with the dose setting component to dispense the amount of the aqueous pharmaceutical composition from the cartridge.

72. The method of claim 71, further comprising, after displacing the dose setting component until the dose amount marking is visible through the window of the housing and without displacing the cap axially toward the cartridge, displacing the dose setting component along the first threads, in the second rotational direction, and axially toward the cartridge without causing the annular component to rotate in the second rotational direction to dispense the amount of the aqueous pharmaceutical composition from the cartridge.

73. A method for injecting a dose of an aqueous pharmaceutical composition using a multi-dose injection pen, the method comprising:displacing, relative to a housing with which a dose setting component is threaded along first threads, the dose setting component axially away from a cartridge containing the aqueous pharmaceutical composition and in a first rotational direction until a dose amount marking on the dose setting component visible through a window of the housing indicates 1 mg, wherein the dose amount marking corresponds to an amount of the aqueous pharmaceutical composition dispensed from the cartridge by returning the dose setting component from a current position along the first threads to an unset position in which the dose setting component cannot be rotated along the first threads in a second rotational direction opposite the first rotational direction, the aqueous pharmaceutical composition comprising:leuprolide at a concentration of about 2.5 mg / mL to about 7.5 mg / mL,-59- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO benzyl alcohol at a concentration of about 8 mg / mL to about 11 mg / mL, sodium chloride at a concentration of about 4.5 mg / mL to about 9 mg / mL, and one or more pH adjusting agents at a concentration sufficient to adjust the pH of the composition to 4.0 to 7.0;displacing a cap coupled with the dose setting component axially toward the cartridge to increase a pressure between an annular component configured to rotate in the second rotational direction to dispense the aqueous pharmaceutical composition from the cartridge and the dose setting component; and concurrent with displacing the cap axially toward the cartridge, displacing the dose setting component along the first threads, in the second rotational direction, and axially toward the cartridge until an additional dose amount marking on the dose setting component indicating 0 mg is visible through the window of the housing.

74. The method of claim 73, further comprising, after displacing the dose setting component until the dose amount marking is visible through the window of the housing and without displacing the cap axially toward the cartridge, displacing the dose setting component along the first threads, in the second rotational direction, and axially toward the cartridge without causing the annular component to rotate in the second rotational direction to dispense the amount of the aqueous pharmaceutical composition from the cartridge.

75. The method of any one of claims 71-74, wherein the multi-dose injection pen has a cartridge with a volume of about 3 mL.

76. The method of any one of claims 71-75, wherein leuprolide is present in the aqueous pharmaceutical composition at a concentration of about 5 mg / mL.

77. The method of any one of claims 71-76, wherein leuprolide is present in the aqueous pharmaceutical composition in an amount of about 16.5 mg.-60- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO 78. The method of any one of claims 71-77, wherein the benzyl alcohol is present in the aqueous pharmaceutical composition at a concentration of about 9 mg / mL.

79. The method of any one of claims 71-78, wherein the benzyl alcohol is present in the aqueous pharmaceutical composition in an amount of about 25 mg to about 35 mg.

80. The method of any one of claims 71-79, wherein the benzyl alcohol is present in the aqueous pharmaceutical composition in an amount of about 29.7 mg.

81. The method of any one of claims 71 -80, wherein the sodium chloride is present in the aqueous pharmaceutical composition at a concentration of about 6.3 mg / mL.

82. The method of any one of claims 71 -81 , wherein the sodium chloride is present in the aqueous pharmaceutical composition in an amount of about 20.8 mg.

83. The method of any one of claims 71 -82, wherein the sodium chloride is present in the aqueous pharmaceutical composition in an amount sufficient to adjust the osmolarity of the composition to about 250 mOsm / kg to about 600 mOsm / kg.

84. The method of any one of claims 71-83, wherein one or more pH adjusters comprise acetic acid and sodium hydroxide.

85. The method of any one of claims 71 -84, wherein the one or more pH adjusting agents are present in the aqueous pharmaceutical composition in an amount sufficient to adjust the pH of the composition to about 5.0.

86. The method of any one of claims 71 -85, wherein the aqueous pharmaceutical composition further comprises water.-61- 183840252.2PATENT Attorney Docket No. 137249.8003. WOOO 87. The method of claim 86, wherein the water is present in the aqueous pharmaceutical composition an amount less than 3.3 mL.-62- 183840252.2

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