Ammonium sulfate treated syringes to enhance the stability of pharmaceutical compositions

Abstract

Ammonium sulfate-treated pre-filled syringes and kits containing ammonium sulfate-treated pre-filled syringes and pharmaceutical compositions containing aluminum-sensitive active agents are described. Treating the interior surface of a glass syringe barrel with ammonium sulfate prior to filling the syringe with a desired aqueous diluent, such as water for injection, can limit the amount of aluminum that leaches into the aqueous diluent during storage.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 304,451, filed January 28, 2022, the disclosure of which is incorporated by reference in its entirety herein.

[0002] FIELD OF THEINVENTION Described herein are ammonium sulfate-treated syringes and kits containing the ammonium sulfate-treated syringes, as well as pharmaceutical compositions containing aluminum-sensitive active agents. Also described are methods of making and using the ammonium sulfate-treated syringes. [Background technology]

[0003] background A pre-filled diluent syringe is often provided with the lyophilized pharmaceutical composition to facilitate preparation of the drug for administration. The pre-filled syringe can contain water for injection or other suitable aqueous diluent (e.g., saline solution or buffer) in an amount such that when the contents of the pre-filled syringe are mixed with the lyophilized pharmaceutical composition, the resulting mixture (i.e., pharmaceutical solution) is suitable for injection containing suitable concentrations of active agent and excipients. Summary of the Invention [Problem to be solved by the invention]

[0004] Storage of a prefilled diluent syringe affects the quality of the diluent contained therein. Thus, after storing a kit including a prefilled syringe and a drug, the kit may become stale due to poor quality of the diluent in the syringe, but not the quality of the drug. [Means for solving the problem]

[0005] Summary of the Invention It has been discovered that treating the glass barrel of a syringe with ammonium sulfate can substantially reduce the amount of aluminum that leaches from the glass barrel into the water contained by the syringe, thereby increasing the shelf life of a kit including a pre-filled ammonium sulfate-treated syringe and a pharmaceutical composition including an aluminum-sensitive active drug.

[0006] A kit is described herein that includes a pre-filled syringe that includes an ammonium sulfate-treated glass barrel that contains water for injection or other aqueous diluent; and a container that contains a pharmaceutical composition that includes an aluminum-sensitive active agent. In some embodiments, the aqueous diluent contained by the glass barrel is water for injection. For example, the glass barrel may leach less than 100 ppb of aluminum into the aqueous diluent when stored for about 18 weeks at about 40°C and about 75% relative humidity. The kit may be suitable for long-term storage due to limited aluminum leaching. For example, the glass barrel may leach less than 100 ppb of aluminum into the aqueous diluent when stored for about 12 months at about 25°C and about 75% relative humidity. The ammonium sulfate-treated glass barrel may have a silicone-treated inner surface.

[0007] The aluminum-sensitive active agent may be a bioactive polypeptide. For example, the aluminum-sensitive active agent may include an antihemophilic factor or a functional variant thereof. In some embodiments, the aluminum-sensitive active agent is a full-length antihemophilic factor. In some embodiments, the aluminum-sensitive active agent is a B-domain deleted antihemophilic factor. In some embodiments, the antihemophilic factor or a functional variant thereof is a recombinant antihemophilic factor or a functional recombinant antihemophilic factor variant. In some embodiments, the antihemophilic factor or a functional variant thereof is PEGylated.

[0008] In some embodiments, the pharmaceutical composition comprises one or more pharma- ceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises one or more salts, such as sodium chloride (e.g., about 5 mm to about 60 mm sodium chloride) and / or calcium chloride (e.g., about 0.5 mM to about 10 mM calcium chloride). In some embodiments, the pharmaceutical composition comprises glycine (e.g., about 5 mg / mL to about 50 mg / mL glycine). In some embodiments, the pharmaceutical composition comprises sucrose (e.g., about 0.1% (w / v) to about 10% (w / v) sucrose). In some embodiments, the pharmaceutical composition comprises histidine (e.g., about 5 mM to about 50 mM histidine). In some embodiments, the pharmaceutical composition comprises a polysorbate, such as polysorbate 80 (e.g., about 20 ppm to about 200 ppm polysorbate).

[0009] In some embodiments, the pharmaceutical composition comprises sodium chloride, calcium chloride, glycine, histidine, sucrose, and polysorbate 80. For example, in some embodiments, the pharmaceutical solution produced by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe comprises about 5 mM to about 60 mM sodium chloride, about 0.5 mM to about 10 mM calcium chloride, about 5 mg / mL to about 50 mg / mL glycine, about 0.1% (w / v) to about 10% (w / v) sucrose, about 5 mM to about 50 mM histidine, and about 20 ppm to about 200 ppm polysorbate 80. In some embodiments, the pharmaceutical solution produced by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe has a pH of about 6 to about 8.

[0010] In some embodiments, the container is a vial.

[0011] In some embodiments, the pharmaceutical composition is a lyophilized composition.

[0012] In some embodiments, the glass of the glass barrel is a borosilicate glass. For example, the borosilicate glass can be Type 1, Class B borosilicate glass.

[0013] In some embodiments, the aqueous diluent in the glass barrel of the syringe is sterile.

[0014] In some embodiments, the syringe is sterile.

[0015] The kit may further include instructions for mixing the pharmaceutical composition with an aqueous diluent contained in the glass barrel of the syringe.

[0016] A method of preparing a medicament for administration can include obtaining the above kit and mixing the pharmaceutical composition with an aqueous diluent, thereby forming a pharmaceutical solution. In some embodiments, mixing includes injecting the aqueous diluent into a container that contains the pharmaceutical composition. In some embodiments, the method further includes drawing the pharmaceutical solution into a syringe. [Brief description of the drawings]

[0017] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1A] FIG. 1A shows the pH changes over 18 weeks for water contained in an untreated glass tube (filled circles), an exemplary ammonium sulfate treated 3 mL borosilicate glass barrel syringe (open squares), and an exemplary untreated 3 mL borosilicate glass barrel syringe (filled squares) stored horizontally in a 40° C. / 75% RH incubator, where the 3 mL borosilicate glass barrel syringe and tubes were provided by Glass Supplier A.

[0018] [Figure 1B]FIG. 1B shows the pH changes over 18 weeks for water contained in an untreated glass tube (filled circles), an exemplary ammonium sulfate-treated 5 mL borosilicate glass barrel syringe (open squares), and an exemplary untreated 5 mL borosilicate glass barrel syringe (filled squares) stored horizontally in a 40° C. / 75% RH incubator, where the 5 mL borosilicate glass barrel syringe and tubes were provided by Glass Supplier A.

[0019] [Figure 1C] FIG. 1C shows the pH change over 18 weeks of water in an untreated glass tube (filled circles), an exemplary ammonium sulfate-treated 5 mL borosilicate glass barrel syringe (open squares), and an exemplary untreated 5 mL borosilicate glass barrel syringe (filled squares) stored horizontally in a 40° C. / 75% RH incubator, where the 5 mL borosilicate glass barrel syringe and tube were provided by Glass Supplier C.

[0020] [Diagram 2] FIG. 2 shows aluminum and sodium leaching over 18 weeks for water contained in exemplary ammonium sulfate treated (AST) 3 mL or 5 mL borosilicate glass barrel syringes (open squares), exemplary untreated 3 mL or 5 mL borosilicate glass barrel syringes (closed squares), and exemplary 5 mL borosilicate glass tubes (closed circles) stored horizontally in a 40° C. / 75% RH incubator, where the 5 mL borosilicate glass barrel syringes and tubes were provided by Glass Supplier A or Glass Supplier B, as indicated.

[0021] [Diagram 3]FIG. 3 shows aluminum and sodium leaching into sterile water for injection over a 26-week period for exemplary ammonium sulfate treated (AST) syringes (open squares) and untreated syringes (closed squares) in an experimental test run on a commercial manufacturing line. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] Detailed Description of the Invention Described herein is a pre-filled, ammonium sulfate-treated syringe that includes a glass barrel (e.g., borosilicate glass, such as type 1, class B glass). The syringe may be included in a kit that further includes a container (e.g., a vial) that holds a pharmaceutical composition that includes an aluminum-sensitive active agent. The aluminum-sensitive active agent may be a bioactive polypeptide, such as an antihemophilic factor (AHF), which may be a recombinant antihemophilic factor (rAHF) or a functional variant thereof (e.g., PEGylated and / or truncated (e.g., B domain deleted)). In some embodiments, the aluminum-sensitive active agent is rAHF or PEGylated rAHF. The pre-filled syringe may be filled with a suitable liquid, such as saline, buffer, or water for injection. In some embodiments, the pre-filled syringe contains water for injection. In some embodiments, the pre-filled syringe contains water for injection and the pharmaceutical composition includes rAHF or PEGylated rAHF.

[0023] Certain active ingredients, such as AHF, are sensitive to aluminum. For example, they may aggregate in the presence of aluminum. Although certain pharmaceutical excipients may limit or prevent aggregation, it is not always possible to formulate the active agent at the excipient concentration desired for administration. It is possible to formulate the initial pharmaceutical composition with a minimal amount of aluminum; however, without ammonium sulfate treatment, aluminum may leach from borosilicate glass into the water or other suitable aqueous diluent held by the pre-filled syringe provided with the pharmaceutical composition. Thus, when the aqueous diluent contaminated with leached aluminum is mixed with the pharmaceutical composition, the aluminum-sensitive active agent may aggregate. As further described herein, it has been found that treating the inner surface of the glass barrel of the syringe with ammonium sulfate can substantially reduce the amount of aluminum leaching into the liquid contained in the glass barrel, thereby limiting or avoiding aggregation of the aluminum-sensitive active agent.

[0024] The advantage of using ammonium sulfate treated syringes is at least an increased shelf life of the syringes and kits containing the syringes. In untreated syringes, aluminum may leach from the glass barrel into the liquid contained by the syringe over time. This leaching can be limited by storing the prefilled syringes and / or kits containing the syringes below room temperature. By treating the glass barrel with ammonium sulfate, aluminum leaching is prevented or limited to extend the shelf life of the prefilled syringes and assembled kits, and further, the need to store the syringes or kits below room temperature can be limited or avoided.

[0025] In an exemplary embodiment, the kit comprises a pre-filled ammonium sulfate treated syringe comprising a borosilicate glass barrel (e.g., a Type 1, Class B borosilicate glass barrel) containing water for injection, and a vial containing a pharmaceutical composition, optionally comprising a lyophilized pharmaceutical composition comprising a PEGylated and / or truncated (e.g., B domain deleted) AHF. The pharmaceutical composition may further comprise a pharma- ceutical acceptable excipient, such as sodium chloride, calcium chloride, glycine, sucrose, histidine, and / or polysorbate.

[0026] The medicament can be prepared for administration using a kit that includes a pre-filled ammonium sulfate-treated syringe that includes a glass barrel containing water for injection or other aqueous diluent, and a container that contains a pharmaceutical composition that includes an aluminum-sensitive active agent. The water or other suitable aqueous diluent in the pre-filled syringe is mixed with the pharmaceutical composition. The resulting mixture contains a concentration of the active agent (and pharma- ceutically acceptable excipients, if present in the pharmaceutical composition or aqueous diluent) suitable for administration.

[0027] definition As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0028] Any reference to "or" herein is intended to include "and / or" unless expressly stated otherwise.

[0029] As used herein, a "pharmaceutical composition comprising an aluminum-sensitive active agent" is a pharmaceutical composition comprising an active agent that exhibits at least a two-fold increase in aggregation after two hours of incubation at 25°C when the pharmaceutical composition, excluding any excipients that inhibit or reverse aluminum-induced aggregation, is dissolved in water containing at least 500 ppb aluminum compared to when the pharmaceutical composition, excluding any excipients that inhibit or reverse aluminum-induced aggregation, is dissolved in water containing less than 1 ppb aluminum, as determined by high performance liquid chromatography size exclusion chromatography (HPLC-SEC).

[0030] As used herein, the terms "comprising" (and any form or variation of "comprising", such as "comprise" and "comprises"), "having" (and any form or variation of "having", such as "have" and "has"), "including" (and any form or variation of "containing", such as "includes" and "include"), and "containing" (and any form or variation of "containing", such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited additives, components, integers, elements, or method steps.

[0031] As used herein, the term "about" of a number refers to a number that is plus or minus 10% of that number. When the term "about" is used in a range, it refers to a range from minus 10% of the lowest value to plus 10% of the highest value.

[0032] A "functional variant" of a biologically active polypeptide is a variant of a designated biologically active polypeptide that retains the same qualitative biological activity and shares at least 95% amino acid identity with the designated biologically active polypeptide, except for truncated or added terminal regions. Functional variants may include truncations or fusions of the N- or C-terminal regions of the polypeptide, one or more point mutations, or may include non-amino acid modifications (e.g., PEGylation and / or glycosylation).

[0033] It will be understood that the embodiments and variations of the invention described herein include "consisting of" and / or "consisting essentially of" embodiments and variations.

[0034] When a range of values ​​is provided, it is understood that each intervening value between the upper and lower limits of that range, and any other specified or intervening value within that stated range, is encompassed within the scope of the disclosure. When an upper or lower limit is included in the stated range, ranges excluding any of those included limits are also included in the disclosure.

[0035] Some of the analytical methods described herein include mapping a sequence to a reference sequence, determining sequence information, and / or analyzing sequence information. It is well understood in the art that complementary sequences can be easily determined and / or analyzed, and the description provided herein encompasses analytical methods performed with reference to complementary sequences.

[0036] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. The description is presented to enable one skilled in the art to make and use the invention and is provided in a patent application and its requirements. Various modifications to the described embodiments will be readily apparent to those skilled in the art, and the general principles of the present specification may be applied to other embodiments. Thus, the present invention is not intended to be limited to the embodiments shown, but is to be accorded the widest scope consistent with the principles and features described herein.

[0037] The drawings depict processes according to various embodiments. Some blocks are optionally combined in the example processes, the order of some blocks is optionally changed, and some blocks are optionally omitted. In some instances, additional steps may be performed in combination with the example processes. Thus, the operations illustrated (and described in more detail below) are exemplary in nature and, therefore, should not be considered limiting.

[0038] The disclosures of all publications, patents, and patent applications mentioned herein are each incorporated herein by reference in their entirety. To the extent that any reference incorporated by reference conflicts with the present disclosure, the present disclosure shall control.

[0039] Prefilled Syringes The prefilled syringes are treated with ammonium sulfate, which reduces the amount of aluminum and / or sodium that leaches into the aqueous diluent (e.g., water for injection) contained by the syringe barrel, which may occur, for example, during storage of the prefilled syringes and / or during storage of kits that include the prefilled syringes, particularly during storage at or above room temperature (about 25° C.).

[0040] The ammonium sulfate treatment may include the application of an ammonium sulfate solution that is sprayed into the glass barrel of the syringe. The syringe is then heat treated (annealed) to convert the surface alkali (e.g., sodium oxide, sodium borate, etc.) to soluble alkali sulfates. These soluble alkali sulfates can be removed during a subsequent rinsing step that occurs before filling the syringe with the aqueous diluent. The resulting glass therefore has a treated surface that is less likely to leach aluminum into the aqueous diluent contained by the glass barrel.

[0041] One important advantage of treating glass barrels of syringes is the reduction of aluminum leaching during storage. Leaching is temperature dependent and can be increased by increasing the storage temperature. Thus, the aluminum leaching rate can be measured by increasing the storage temperature to more easily quantify the leaching rate. In some embodiments, the ammonium sulfate treated glass barrel leaches less than 100 ppb of aluminum into the aqueous diluent when stored for about 18 weeks at about 40° C. and about 75% relative humidity. In some embodiments, the ammonium sulfate treated glass barrel leaches less than 80 ppb of aluminum into the aqueous diluent when stored for about 18 weeks at about 40° C. and about 75% relative humidity. In some embodiments, the ammonium sulfate treated glass barrel leaches less than 60 ppb of aluminum into the aqueous diluent when stored for about 18 weeks at about 40° C. and about 75% relative humidity. In some embodiments, the ammonium sulfate treated glass barrel leaches less than 50 ppb of aluminum into an aqueous diluent when stored for about 18 weeks at about 40° C. and about 75% relative humidity. In some embodiments, the ammonium sulfate treated glass barrel leaches less than 40 ppb of aluminum into an aqueous diluent when stored for about 18 weeks at about 40° C. and about 75% relative humidity. In some embodiments, the ammonium sulfate treated glass barrel leaches about 1 ppb to about 100 ppb of aluminum (or about 5 ppb to about 80 ppb, about 10 ppb to about 60 ppb, or about 20 ppb to about 50 ppb of aluminum) into an aqueous diluent when stored for about 18 weeks at about 40° C. and about 75% relative humidity.

[0042] More typically, the prefilled syringes are stored at room temperature (about 25° C.). In some embodiments, the glass barrel leaches less than 100 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 12 months. In some embodiments, the glass barrel leaches less than 80 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 12 months. In some embodiments, the glass barrel leaches less than 60 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 12 months. In some embodiments, the glass barrel leaches less than 50 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 12 months. In some embodiments, the glass barrel leaches less than 40 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 12 months. In some embodiments, the ammonium sulfate-treated glass barrel leaches about 1 ppb to about 100 ppb of aluminum (or about 5 ppb to about 80 ppb, about 10 ppb to about 60 ppb, or about 20 ppb to about 50 ppb of aluminum) into an aqueous diluent when stored for about 12 months at about 25° C. and about 75% relative humidity.

[0043] In some embodiments, the glass barrel leaches less than 100 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 18 months. In some embodiments, the glass barrel leaches less than 80 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 18 months. In some embodiments, the glass barrel leaches less than 60 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 18 months. In some embodiments, the glass barrel leaches less than 50 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 18 months. In some embodiments, the glass barrel leaches less than 40 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 18 months. In some embodiments, the ammonium sulfate-treated glass barrel leaches about 1 ppb to about 100 ppb of aluminum (or about 5 ppb to about 80 ppb, about 10 ppb to about 60 ppb, or about 20 ppb to about 50 ppb of aluminum) into an aqueous diluent when stored for about 18 months at about 25° C. and about 75% relative humidity.

[0044] In some embodiments, the glass barrel leaches less than 100 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 24 months. In some embodiments, the glass barrel leaches less than 80 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 24 months. In some embodiments, the glass barrel leaches less than 60 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 24 months. In some embodiments, the glass barrel leaches less than 50 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 24 months. In some embodiments, the glass barrel leaches less than 40 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 24 months. In some embodiments, the ammonium sulfate-treated glass barrel leaches about 1 ppb to about 100 ppb of aluminum (or about 5 ppb to about 80 ppb, about 10 ppb to about 60 ppb, or about 20 ppb to about 50 ppb of aluminum) into an aqueous diluent when stored for about 24 months at about 25° C. and about 75% relative humidity.

[0045] In some embodiments, the glass barrel leaches less than 100 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 36 months. In some embodiments, the glass barrel leaches less than 80 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 36 months. In some embodiments, the glass barrel leaches less than 60 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 36 months. In some embodiments, the glass barrel leaches less than 50 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 36 months. In some embodiments, the glass barrel leaches less than 40 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 36 months. In some embodiments, the ammonium sulfate-treated glass barrel leaches about 1 ppb to about 100 ppb of aluminum (or about 5 ppb to about 80 ppb, about 10 ppb to about 60 ppb, or about 20 ppb to about 50 ppb of aluminum) into an aqueous diluent when stored for about 36 months at about 25° C. and about 75% relative humidity.

[0046] In some embodiments, the glass barrel leaches less than 100 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 48 months. In some embodiments, the glass barrel leaches less than 80 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 48 months. In some embodiments, the glass barrel leaches less than 60 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 48 months. In some embodiments, the glass barrel leaches less than 50 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 48 months. In some embodiments, the glass barrel leaches less than 40 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 48 months. In some embodiments, the ammonium sulfate-treated glass barrel leaches about 1 ppb to about 100 ppb of aluminum (or about 5 ppb to about 80 ppb, about 10 ppb to about 60 ppb, or about 20 ppb to about 50 ppb of aluminum) into an aqueous diluent when stored for about 48 months at about 25° C. and about 75% relative humidity.

[0047] In some embodiments, the glass barrel leaches less than 100 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 60 months. In some embodiments, the glass barrel leaches less than 80 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 60 months. In some embodiments, the glass barrel leaches less than 60 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 60 months. In some embodiments, the glass barrel leaches less than 50 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 60 months. In some embodiments, the glass barrel leaches less than 40 ppb of aluminum into the aqueous diluent when stored at about 25° C. and about 75% relative humidity for about 60 months. In some embodiments, the ammonium sulfate-treated glass barrel leaches about 1 ppb to about 100 ppb of aluminum (or about 5 ppb to about 80 ppb, about 10 ppb to about 60 ppb, or about 20 ppb to about 50 ppb of aluminum) into an aqueous diluent when stored for about 60 months at about 25° C. and about 75% relative humidity.

[0048] The syringe comprises a glass barrel. The glass may be borosilicate glass. In some embodiments, the glass of the glass barrel is Type 1, Class B borosilicate glass.

[0049] The size of the syringe can be selected based on the desired volume of the aqueous diluent to be contained in the barrel. For example, in some embodiments, the syringe has a capacity (i.e., barrel size) of about 0.5 mL to about 100 mL, such as about 0.5 mL to about 1 mL, about 1 mL to about 3 mL, about 3 mL to about 5 mL, about 5 mL to about 10 mL, about 10 mL to about 25 mL, about 25 mL to about 50 mL, or about 50 mL to about 100 mL.

[0050] In some embodiments, the syringe is sterile. In some embodiments, the aqueous diluent contained in the glass barrel is sterile. The syringe and / or the aqueous diluent can be sterilized by any suitable method, such as heat, steam, radiation, or chemical sterilization. In some embodiments, the syringe is sterilized before filling the syringe barrel with the aqueous diluent. In some embodiments, the syringe is sterilized after filling the syringe barrel with the aqueous diluent.

[0051] Ammonium sulfate-treated syringes can be made by applying an ammonium sulfate solution to the inner surface of a glass barrel and then heating the glass barrel. For example, an ammonium sulfate solution (e.g., about 0.5% to about 4%, or about 1% to about 3% ammonium sulfate in water) can be sprayed onto the inner surface of the glass barrel. Optionally, the syringe is preheated before applying the ammonium sulfate, which can allow for a more uniform distribution of the ammonium sulfate on the barrel surface. Once the inner surface of the glass barrel of the syringe is coated with ammonium sulfate, the syringe is heated. At high temperatures, ammonium sulfate decomposes to produce ammonia and sulfur dioxide. The ammonia evaporates, while the sulfur dioxide reacts with available alkali species on the inner surface of the glass barrel to form soluble alkali sulfates. The alkali sulfates leave a visible, cloudy residue on the inner barrel surface after annealing. The barrel is washed (e.g., using an aqueous diluent such as water for injection) to remove the alkali sulfates. After washing, the barrel can be sterilized, for example, using dry heat sterilization or irradiation. The interior surface of the barrel may be siliconized after the ammonium sulfate treatment, for example, by spraying the interior surface of the barrel with a silicone oil or silicone oil emulsion. The silicone oil or emulsion may be applied to the interior surface of the barrel prior to sterilization. The completed syringe barrel is filled with the desired aqueous diluent. The syringe tip may be capped and a plunger or stopper may be inserted into the barrel to seal the aqueous diluent within the syringe barrel. The aqueous diluent used to fill the syringe barrel may be sterile or may be sterilized prior to filling the syringe. The syringe may alternatively or additionally be sterilized after being filled with the aqueous diluent.

[0052] The aqueous diluent of the pre-filled syringe may be any suitable aqueous liquid. When included in a kit, the aqueous diluent should be suitable for the pharmaceutical composition included in the kit. The aqueous diluent may be a buffered diluent or a non-buffered diluent. Aluminum leaching may be associated with an increase in the pH of the diluent held by the glass barrel. Thus, ammonium sulfate treated syringes are particularly beneficial when unbuffered aqueous diluents are contained. Unbuffered aqueous diluents may include, for example, saline (e.g., sodium chloride solution, e.g., 0.9% sodium chloride solution) or water. In some embodiments, the aqueous diluent is water. In some embodiments, the aqueous diluent is water for injection. In some embodiments, the aqueous diluent is sterile water for injection.

[0053] Pharmaceutical Compositions The pharmaceutical composition can include an aluminum-sensitive active agent.The pharmaceutical composition can further include one or more pharma-ceutically acceptable excipients.An aqueous diluent, such as water for injection, contained in a pre-filled syringe, can be mixed with the pharmaceutical composition to provide a drug suitable for administration by injection.In some embodiments, the pharmaceutical composition is contained in a suitable container, such as a vial.

[0054] The pharmaceutical composition may be solid before being mixed with the aqueous diluent. For example, the pharmaceutical composition may be a powder, such as a lyophilized powder. Mixing the aqueous diluent with the pharmaceutical composition preferably dissolves the pharmaceutical composition in the aqueous diluent (i.e., no visible aggregates are present). Vibration, shaking, or stirring can be used to dissolve the pharmaceutical composition in the aqueous diluent.

[0055] The active agent may be an aluminum-sensitive active agent.For example, the active agent may tend to aggregate in the presence of aluminum.Some pharma-ceutically acceptable excipients may be included in the pharmaceutical composition to reverse or limit the aggregation caused by aluminum, but the concentration of such excipients may not be suitable or preferred for administration.Therefore, sensitivity to aluminum is considered when there is no excipient that reverses or limits the aggregation caused by aluminum.

[0056] The active agent may be a bioactive polypeptide, possibly a recombinant bioactive polypeptide. For example, the active agent may be an antihemophilic factor (AHF) or a functional variant thereof (e.g., PEGylated and / or truncated antihemophilic factor). Antihemophilic factor may be used to treat factor VIII deficiency in patients. Factor VIII is a blood clotting protein, and defects in the protein or protein expression may result in hemophilia A. AHF is sensitive to aluminum in that it aggregates at sufficiently high aluminum concentrations. Certain pharmacologic acceptable excipients (such as sodium chloride or glycine) may be used to help limit the aggregation of AHF or its functional variants in the presence of aluminum, but it is not always preferable to include such excipients at the concentrations required to prevent aggregation by aluminum.

[0057] In some embodiments, the active agent is an antihemophilic factor. In some embodiments, the active agent is a human antihemophilic factor. In some embodiments, the active agent is a recombinant antihemophilic factor (rAHF). In some embodiments, the active agent is a recombinant human antihemophilic factor. In some embodiments, the active agent is a PEGylated antihemophilic factor. In some embodiments, the active agent is a PEGylated human antihemophilic factor. In some embodiments, the active agent is a PEGylated recombinant antihemophilic factor. In some embodiments, the active agent is a PEGylated recombinant human antihemophilic factor.

[0058] In some embodiments, the antihemophilic factor remains functional but is truncated. For example, in some embodiments, the antihemophilic factor has a B domain deletion. In some embodiments, the active agent is a B domain deleted antihemophilic factor. In some embodiments, the active agent is a B domain deleted human antihemophilic factor. In some embodiments, the active agent is a B domain deleted recombinant antihemophilic factor. In some embodiments, the active agent is a B domain deleted recombinant human antihemophilic factor. In some embodiments, the active agent is a PEGylated B domain deleted antihemophilic factor. In some embodiments, the active agent is a PEGylated B domain deleted human antihemophilic factor. In some embodiments, the active agent is a PEGylated recombinant B domain deleted antihemophilic factor. In some embodiments, the active agent is a PEGylated recombinant B domain deleted antihemophilic factor. In some embodiments, the active agent is a PEGylated recombinant B domain deleted human antihemophilic factor.

[0059] In some embodiments, the antihemophilic factor is a full length antihemophilic factor. In some embodiments, the active agent is a full length antihemophilic factor. In some embodiments, the active agent is a full length human antihemophilic factor. In some embodiments, the active agent is a full length recombinant antihemophilic factor. In some embodiments, the active agent is a full length recombinant human antihemophilic factor. In some embodiments, the active agent is a PEGylated full length antihemophilic factor. In some embodiments, the active agent is a PEGylated full length human antihemophilic factor. In some embodiments, the active agent is a PEGylated recombinant full length antihemophilic factor. In some embodiments, the active agent is a PEGylated recombinant full length human antihemophilic factor.

[0060] Optionally, the antihemophilic factor may be fused to an additional polypeptide sequence, such as a purification tag or a second bioactive polypeptide.

[0061] Pharmaceutical compositions (e.g., lyophilized pharmaceutical compositions) may contain one or more pharma- ceutically acceptable excipients. Pharmaceutical excipients and additives useful in the pharmaceutical formulations of the present invention include, but are not limited to, amino acids, peptides, proteins, non-biological polymers, biological polymers, carbohydrates such as sugars, derivatized sugars such as alditols, aldonic acids, esterified sugars, and sugar polymers, which may be present alone or in combination.

[0062] Suitable amino acid excipients that can also function in buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, tyrosine, tryptophan, etc. Amino acids and polypeptides that function as dispersing agents are preferred. Amino acids that fall into this category include hydrophobic amino acids such as leucine, valine, isoleucine, tryptophan, alanine, methionine, phenylalanine, tyrosine, histidine, and proline.

[0063] Carbohydrate excipients suitable for use in the present invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, etc.; disaccharides such as lactose, sucrose, trehalose, cellobiose, etc.; polysaccharides such as raffinose, melezitose, maltodextrin, dextran, starch, etc.; and alditols such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), pyranosyl sorbitol, myo-inositol, etc.

[0064] Pharmaceutical formulations may also include buffers or pH adjusters, such as salts prepared from organic acids or bases. Representative buffers include organic acid salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, Tris, tromethamine hydrochloride, or phosphate buffers.

[0065] Pharmaceutical formulations may also include polymeric excipients / additives, such as polyvinylpyrrolidone, celluloses and derivatized celluloses, such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose, Ficolls (polymeric sugars), hydroxyethyl starch, dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin), polyethylene glycol, and pectin.

[0066] Pharmaceutical formulations may further include flavoring agents, taste masking agents, inorganic salts (e.g., sodium chloride), antimicrobial agents (e.g., benzalkonium chloride), sweeteners, antioxidants, antistatic agents, surface active agents (e.g., polysorbates such as polysorbate 20 and polysorbate 80), sorbitan esters, lipids (e.g., lecithin and other phospholipids such as phosphatidylcholines, phosphatidylethanolamines), fatty acids and fatty acid esters, steroids (e.g., cholesterol), and chelating agents (e.g., EDTA). Other pharmaceutical excipients and / or additives suitable for use in the compositions according to the present invention are listed in "Remington: The Science & Practice of Pharmacy", 19th Edition, Williams & Williams, (1995), and "Physician's Desk Reference", 52nd Edition, Medical Economics, Montvale, NJ (1998), both of which are incorporated herein by reference in their entirety.

[0067] In one example, a pharmaceutical composition (e.g., a lyophilized pharmaceutical composition) includes one or more salts (e.g., sodium chloride, calcium chloride, or both), one or more amino acids (e.g., glycine, histidine, or both), sucrose, and / or a polysorbate (e.g., polysorbate 80). A pharmaceutical composition can include one, some, or all of these excipients.

[0068] The amount of pharmaceutically acceptable excipient and / or active agent contained in the pharmaceutical composition may depend on the amount of diluent (e.g., aqueous diluent such as water for injection) that is desired to be added to the pharmaceutical composition.For example, as further discussed herein, the amount of pharmaceutically acceptable excipient and / or active agent and the volume of aqueous diluent accommodated by the glass barrel of the syringe included in the kit are selected to obtain the desired concentration of pharmaceutically acceptable excipient and / or active agent when the aqueous diluent is mixed with the pharmaceutical composition.

[0069] kit The pre-filled ammonium sulfate treated syringe may be included with a container housing a pharmaceutical composition comprising an aluminum sensitive active agent. As discussed, treating the glass barrel of the syringe with ammonium sulfate reduces leaching of aluminum into the aqueous diluent held by the syringe barrel, thereby making it particularly beneficial for use in kits that include pharmaceutical compositions having aluminum sensitive active agents.

[0070] The kit may include a kit container (e.g., a box, case, or other suitable container) that holds the pre-filled ammonium sulfate-treated syringes, and a container that holds the pharmaceutical composition. The kit container may include information about the kit contents, such as one or more of the dose of an active agent in the pharmaceutical composition, excipients in the pharmaceutical composition, and prescribing information. Such information may be provided on the outside of the kit container (e.g., printed on the kit container itself or on a label affixed to the container), or may be provided as an insert carried by the kit container, or both.

[0071] Optionally, the kit includes a needle that can be attached to the syringe. For example, the needle can be attached to the syringe using a luer fitting or other suitable adapter. The needle is preferably sterile.

[0072] The kit may include instructions for mixing the pharmaceutical composition with an aqueous diluent contained in the glass barrel of the syringe. For example, the container (e.g., a vial) holding the pharmaceutical composition may be provided with a rubber stopper. The tip of the syringe may be uncapped and a needle (included in the kit or provided separately) may be attached to the syringe tip. The needle may be inserted (e.g., by inserting the needle through the rubber stopper) into the container holding the pharmaceutical composition, and the aqueous diluent may be injected into the pharmaceutical composition container. The pharmaceutical composition and the aqueous diluent may be mixed together to form a pharmaceutical solution, for example, by rocking, shaking or stirring the container contents. The pharmaceutical solution may then be drawn into a syringe (either the same or a different syringe). The pharmaceutical solution may then be administered to the patient by injection using the same or a different needle.

[0073] The amount of pharma- ceutically acceptable excipient and / or active agent and the volume of the aqueous diluent contained by the glass barrel of the syringe included in the kit are selected to obtain a desired concentration of the pharma- ceutically acceptable excipient and / or active agent when the aqueous diluent is mixed with the pharmaceutical composition. For example, it may be desirable to include a concentration of sodium chloride of about 5 mM to about 60 mM in the pharmaceutical solution. Thus, the kit may be configured such that the pharmaceutical solution made by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe contains about 5 mM to about 60 mM sodium chloride. In some embodiments, the kit may be configured such that the pharmaceutical solution made by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe contains about 10 mM to about 50 mM sodium chloride. In some embodiments, the kit may be configured such that the pharmaceutical solution made by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe contains about 20 mM to about 40 mM sodium chloride.

[0074] In some embodiments, it may be desirable to include calcium chloride at a concentration of about 0.5 mM to about 10 mM in the pharmaceutical solution. Thus, the kit may be configured such that the pharmaceutical solution made by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe contains about 0.5 mM to about 10 mM calcium chloride. In some embodiments, the kit may be configured such that the pharmaceutical solution made by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe contains about 1 mM to about 6 mM calcium chloride. In some embodiments, the kit may be configured such that the pharmaceutical solution made by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe contains about 1.5 mM to about 4 mM calcium chloride.

[0075] In some embodiments, it may be desirable to include glycine at a concentration of about 5 mg / mL to about 50 mg / mL in the pharmaceutical solution. Thus, the kit may be configured such that the pharmaceutical solution made by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe contains about 5 mg / mL to about 50 mg / mL of glycine. In some embodiments, the kit may be configured such that the pharmaceutical solution made by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe contains about 10 mg / mL to about 40 mg / mL of glycine. In some embodiments, the kit may be configured such that the pharmaceutical solution made by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe contains about 15 mg / mL to about 30 mg / mL of glycine.

[0076] In some embodiments, it may be desirable to include sucrose in the pharmaceutical solution at a concentration of about 0.1% (w / v) to about 10% (w / v). Thus, the kit may be configured such that the pharmaceutical solution made by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe contains about 0.1% (w / v) to about 10% (w / v) sucrose. In some embodiments, the kit may be configured such that the pharmaceutical solution made by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe contains about 0.5% (w / v) to about 5% (w / v) sucrose. In some embodiments, the kit may be configured such that the pharmaceutical solution made by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe contains about 0.7% (w / v) to about 2% (w / v) sucrose.

[0077] In some embodiments, it may be desirable to include histidine at a concentration of about 5 mM to about 50 mM in the pharmaceutical solution. Thus, the kit may be configured such that the pharmaceutical solution produced by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe contains about 5 mM to about 50 mM histidine. In some embodiments, the kit may be configured such that the pharmaceutical solution produced by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe contains about 10 mM to about 40 mM histidine. In some embodiments, the kit may be configured such that the pharmaceutical solution produced by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe contains about 15 mM to about 30 mM histidine.

[0078] In some embodiments, it may be desirable to include a polysorbate (e.g., polysorbate 80) at a concentration of about 20 ppm to about 200 ppm in the pharmaceutical solution. Thus, the kit may be configured such that the pharmaceutical solution made by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe contains about 20 ppm to about 200 ppm of polysorbate. In some embodiments, the kit may be configured such that the pharmaceutical solution made by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe contains about 40 ppm to about 150 ppm of polysorbate. In some embodiments, the kit may be configured such that the pharmaceutical solution made by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe contains about 60 ppm to about 100 ppm of polysorbate.

[0079] In some embodiments, in a pharmaceutical solution (e.g., a pharmaceutical composition containing as an active agent an antihemophilic factor or a PEGylated antihemophilic factor, either full length or B domain deleted), about 5 mM to about 60 mM sodium chloride (e.g., about 10 mM to about 50 mM, or about 20 mM to about 40 mM sodium chloride), about 0.5 mM to about 10 mM calcium chloride (e.g., about 1 mM to about 6 mM, or about 1.5 mM to about 4 mM calcium chloride), about 5 mg / mL to about 50 mg / mL glycine (e.g., about 10 mg / mL to about 40 mg / mL, or about 15 mg / mL to about 20 mg / mL to about 20 mM). It may be desirable to include about 100 mg / mL to about 30 mg / mL glycine), about 0.1% (w / v) to about 10% (w / v) sucrose (e.g., about 0.5% (w / v) to about 5% (w / v), or about 0.7% (w / v) to about 2% (w / v) sucrose), about 5 mM to about 50 mM histidine (e.g., about 10 mM to about 40 mM histidine, or about 15 mM to about 30 mM histidine), and about 20 ppm to about 200 ppm polysorbate 80 (e.g., about 60 ppm to about 100 ppm, or about 60 ppm to about 100 ppm polysorbate).

[0080] The pharmaceutical composition may include one or more buffers so that when the aqueous diluent contained by the syringe is mixed with the pharmaceutical composition, the resulting pH is within a desired pH range. For example, in some embodiments, the pharmaceutical solution produced by mixing the pharmaceutical composition with the aqueous diluent contained by the glass barrel of the syringe has a pH of about 6 to about 8. EXAMPLES

[0081] Working Example Example 1 Borosilicate glass syringes from two different syringe manufacturers (Manufacturer A and Manufacturer B) manufactured using one of two glass sources (Glass 1 and Glass 2) and pre-filled with 2.5 mL, 3 mL, or 5 mL of water for injection were stored at 5° C., room temperature, 30° C., or 40° C., as shown in Table 1.

[0082] [Table 1]

[0083] Prefilled syringes (PFS) for a given sample ID were pooled in a metal-free tube (4 PFS for 2.5 mL or 3 mL fills, 2 PFS for 5 mL fills). 5 mL of each pooled sample was transferred to a new metal-free tube, spiked with 1 / 100 volume of concentrated HNO3, and analyzed by inductively coupled plasma mass spectrometry (ICP-MS) to measure sodium and aluminum. The remaining volume was used to measure pH. ICP-MS data were obtained in two runs in no gas and He mode, triplicate runs were performed for each water sample, and an internal standard was combined with each sample and standard via a T-junction before the peristaltic pump. The results are shown in Table 2.

[0084] [Table 2]

[0085] Example 2 Borosilicate glass syringes prefilled with 5 mL water for injection (WFI) were stored for 6 months at 30 °C / 75% RH, 40 °C / 75% RH, or 5 °C / 75% RH. 250 IU of lyophilized rAHF (formulated with glycine, sucrose, histidine, sodium chloride, calcium chloride, and polysorbate 80) was reconstituted with 2.8 mL of WFI from a prefilled syringe (PFS). A control sample was reconstituted with 2.8 mL of purified water. Reconstituted samples were analyzed by HPLC-SEC and the aluminum content of the WFI was determined by ICP-MS.

[0086] The amount of aggregation was determined by HPLC-SEC. The aluminum content and aggregation percentage measured for each sample are reported in Table 3.

[0087] [Table 3]

[0088] Example 3 Fifty-four filled glass syringes (filled with WFI) from each of the five batches were stored horizontally in a 40°C / 75%RH chamber (three batches of 3 mL syringes, one batch of 2.8 mL syringes, and one batch of 5 mL syringes). At each time point (0 weeks, 2 weeks, 5 weeks, 7 weeks, 9 weeks, 11 weeks, 15 weeks, and 20 weeks), six syringes from each batch were removed from the chamber and ICP-MS analysis was performed in He mode to determine the aluminum content of the water. Results from the 20 week time point are shown in Table 4.

[0089] [Table 4]

[0090] Example 4 Two prefilled glass syringes (prefilled with 5 mL of WFI) were stored at 5° C. for 6 months. The syringe contents were pooled and 2.5 mL of the pooled syringe water was used to reconstitute a vial of 250 IU of PEGylated recombinant antihemophilic factor (rAHF) (formulated with glycine, sucrose, histidine, sodium chloride, calcium chloride, and polysorbate 80). A vial of 250 IU of PEGylated rAHF was reconstituted as a control using purified water. The reconstituted composition was incubated at room temperature for 2 hours. Samples were analyzed by HPLC-SEC. The pooled syringe water and purified water were analyzed by ICP-MS and determined to have an aluminum content of 433.4 ppb and 0.1 ppb aluminum, respectively. Reconstitution of 250 IU of PEGylated rAHF with 2.5 mL of pooled syringe water resulted in aggregation.

[0091] Example 5 Pre-syringe formed borosilicate glass syringe barrels or glass tubes were obtained as described in Table 5, some of which were treated with ammonium sulfate and some of which were untreated. The syringes and tubes, syringe tips, and plungers were rinsed and air-dried. The 3 mL syringes and tubes were filled with 3 mL of purified water, and the 5 mL syringes and tubes were filled with 5 mL of purified water. To fill the tubes, a plunger was inserted into one end of the tube and purified water was added to the open end, after which a second plunger was used to seal the open end and ventilated by piercing it with a 21-gauge needle while pressing down on the second plunger. To fill the syringes, a piece of parafilm was pressed against the tip opening of the syringe before adding 3 mL or 5 mL of purified water. The plunger was then placed on the open barrel end and a tip cap was placed on the syringe tip before removing the parafilm. All samples were stored horizontally in a 40°C / 75% RH incubator. At each time point (2 weeks, 4 weeks, 6 weeks, 9 weeks, 12 weeks, 16 weeks, and 18 weeks), water from five syringes was pooled for each sample. The pH of the pooled syringe water was measured, as shown in Table 6 and Figure 1A (glass tubes and 3 mL syringes from glass supplier A), Figure 1B (glass tubes and 5 mL syringes from glass supplier A), and Figure 1C (glass tubes and 5 mL syringes from glass supplier B), and the aluminum and sodium content of the pooled syringe water was measured by ICP-MS, as shown in Figure 2.

[0092] [Table 5]

[0093] [Table 6]

[0094] Example 6 Diluent pre-filled syringes were prepared on a commercial manufacturing line where barrels (either ammonium sulfate treated (AST) or untreated) were cleaned, siliconized, and dry heat sterilized. The barrels were capped, filled with water for injection, and stoppered. The filled syringes were then terminally sterilized using steam sterilization. In contrast to the untreated barrel samples, sWFI PFS prepared in AST barrels showed minimal release of aluminum and sodium during 26 weeks of storage at 40°C / 75% RH. Aluminum and sodium content was measured as shown in Figure 3.

[0095] The foregoing description has been described with reference to specific embodiments for purposes of illustration. However, the above exemplary discussion is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in light of the above teachings. The embodiments have been chosen and described in order to best explain the principles of the technology and their practical application. This will enable those skilled in the art to best utilize the technology and various embodiments with various modifications as suited to the particular use contemplated.

Claims

1. a prefilled syringe comprising an ammonium sulfate treated glass barrel containing an aqueous diluent; and Container containing a pharmaceutical composition containing an aluminum-sensitive active drug Including the kit.

2. 10. The kit of claim 1, wherein the glass barrel leaches less than 100 ppb of aluminum into an aqueous diluent when stored at about 40° C. and about 75% relative humidity for about 18 weeks.

3. 3. The kit of claim 1 or 2, wherein the glass barrel leaches less than 100 ppb of aluminum into an aqueous diluent when stored for about 12 months at about 25° C. and about 75% relative humidity.

4. 10. The kit of claim 1, wherein the ammonium sulfate treated glass barrel comprises a siliconized interior surface.

5. The kit of claim 1 , wherein the aluminum-sensitive active agent is a bioactive polypeptide.

6. The kit of claim 1 , wherein the aluminum-sensitive active agent comprises an antihemophilic factor or a functional variant thereof.

7. 2. The kit of claim 1, wherein the aluminum-sensitive active agent is a full-length antihemophilic factor.

8. 2. The kit of claim 1, wherein the aluminum-sensitive active agent is a B-domain deleted antihemophilic factor.

9. The kit of claim 6, wherein the antihemophilic factor or functional variant thereof is a recombinant antihemophilic factor or a functional recombinant antihemophilic factor variant.

10. The kit of claim 6 , wherein the antihemophilic factor or functional variant thereof is PEGylated.

11. 2. The kit of claim 1, wherein the aqueous diluent is water for injection.

12. The kit of claim 1 , wherein the pharmaceutical composition comprises one or more pharma- ceutically acceptable excipients.

13. The kit of claim 1 , wherein the pharmaceutical composition comprises one or more salts.

14. The kit of claim 1 , wherein the pharmaceutical composition comprises sodium chloride.

15. 10. The kit of claim 1, wherein the pharmaceutical solution made by mixing the pharmaceutical composition with an aqueous diluent contained by the glass barrel of the syringe comprises about 5 mM to about 60 mM sodium chloride.

16. The kit of claim 1 , wherein the pharmaceutical composition comprises calcium chloride.

17. 10. The kit of claim 1, wherein the pharmaceutical solution made by mixing the pharmaceutical composition with an aqueous diluent contained by the glass barrel of the syringe comprises about 0.5 mM to about 10 mM calcium chloride.

18. The kit of claim 1 , wherein the pharmaceutical composition comprises glycine.

19. 10. The kit of claim 1, wherein the pharmaceutical solution made by mixing the pharmaceutical composition with an aqueous diluent contained by the glass barrel of the syringe comprises from about 5 mg / mL to about 50 mg / mL of glycine.

20. The kit of claim 1 , wherein the pharmaceutical composition comprises sucrose.

21. 10. The kit of claim 1, wherein the pharmaceutical solution made by mixing the pharmaceutical composition with an aqueous diluent contained by the glass barrel of the syringe comprises about 0.1% (w / v) to about 10% (w / v) sucrose.

22. The kit of claim 1 , wherein the pharmaceutical composition comprises histidine.

23. 10. The kit of claim 1, wherein the pharmaceutical solution made by mixing the pharmaceutical composition with an aqueous diluent contained by the glass barrel of the syringe comprises about 5 mM to about 50 mM histidine.

24. The kit of claim 1 , wherein the pharmaceutical composition comprises a polysorbate.

25. 10. The kit of claim 1, wherein the pharmaceutical solution made by mixing the pharmaceutical composition with an aqueous diluent contained by the glass barrel of the syringe comprises from about 20 ppm to about 200 ppm of polysorbate.

26. 26. The kit of claim 24 or 25, wherein the polysorbate is polysorbate 80.

27. 2. The kit of claim 1, wherein the pharmaceutical composition comprises sodium chloride, calcium chloride, glycine, histidine, sucrose, and polysorbate 80.

28. 2. The kit of claim 1, wherein the pharmaceutical solution made by mixing the pharmaceutical composition with an aqueous diluent contained by the glass barrel of the syringe comprises about 5 mM to about 60 mM sodium chloride, about 0.5 mM to about 10 mM calcium chloride, about 5 mg / mL to about 50 mg / mL glycine, about 0.1% (w / v) to about 10% (w / v) sucrose, about 5 mM to about 50 mM histidine, and about 20 ppm to about 200 ppm polysorbate 80.

29. 10. The kit of claim 1, wherein the pharmaceutical solution made by mixing the pharmaceutical composition with an aqueous diluent contained by the glass barrel of the syringe has a pH of about 6 to about 8.

30. The kit of claim 1 , wherein the container is a vial.

31. The kit of claim 1 , wherein the pharmaceutical composition is a lyophilized composition.

32. 2. The kit of claim 1, wherein the glass of the glass barrel is borosilicate glass.

33. 33. The kit of claim 32, wherein the borosilicate glass is Type 1, Class B borosilicate glass.

34. 10. The kit of claim 1, wherein the aqueous diluent in the glass barrel of the syringe is sterile.

35. 1. A method of preparing a medicament for administration comprising: Obtaining the kit of claim 1; Mixing the pharmaceutical composition with an aqueous diluent, thereby forming a pharmaceutical solution. The method comprising:

36. 36. The method of claim 35, wherein the mixing comprises injecting the aqueous diluent into a container containing the pharmaceutical composition.

37. 37. The method of claim 36, further comprising drawing the pharmaceutical solution into a syringe.

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