Syringe assembly with ion-exchange material

Abstract

A pre-filled syringe is disclosed, comprising a barrel and a plunger, the barrel having an outlet, the barrel containing a pharmaceutically acceptable solution having a non-physiological pH, wherein the syringe further comprises an ion exchange material. The ion exchange material is provided at a position to allow contact with the pharmaceutically acceptable solution upon ejection of the pharmaceutically acceptable solution from the barrel via the outlet. The ion exchange material is capable of adjusting the pH of the solution from a non-physiological pH, at which the pharmaceutically acceptable solution is stored in order to ensure acceptable shelf life, to a more physiological pH at which the discomfort and/or pain experienced during injection may be alleviated.

Claims

1. A syringe comprising a barrel and a plunger, the barrel having an interior volume adapted to contain a liquid pharmaceutical composition having a first, non-physiological pH, wherein the syringe further comprises an ion exchange material provided within the syringe such that it is not in fluid communication with the interior volume of the barrel, and wherein the ion exchange material is provided at a position to, in use, allow contact with the liquid pharmaceutical composition upon ejection of the liquid pharmaceutical composition from the barrel, wherein the ion exchange material is insoluble and/or immiscible in the liquid pharmaceutical composition and is adapted to, upon contact with the liquid pharmaceutical composition, adjust the pH of the liquid pharmaceutical composition from the first, non-physiological pH to a second pH, wherein the first, non-physiological pH is in the range of 3-6.6 and the second pH is in the range of 7.0-8.0, wherein the second pH is higher than the first non-physiological pH.

2. The syringe according to claim 1, further comprising an injection needle mounted in fluid communication with an outlet of the barrel, wherein the ion exchange material is provided within the injection needle.

3. The syringe according to claim 1, wherein the ion exchange material is a solid porous material, configured to allow the liquid pharmaceutical composition to flow through the solid porous material.

4. The syringe according to claim 3, wherein the solid porous material comprises a material selected from a zeolite material loaded with Na.sup.+, H.sup.+ and/or Ca.sup.2+, a polystyrene material, and mesoporous silica.

5. A pre-filled syringe comprising a barrel and a plunger, the barrel having an outlet, the barrel containing a liquid pharmaceutical composition having a first, non-physiological pH, wherein the syringe further comprises an ion exchange material provided such that the liquid pharmaceutical composition, when contained within the barrel, does not contact the ion exchange material, and wherein the ion exchange material is provided at a position to allow contact with the liquid pharmaceutical composition upon ejection of the liquid pharmaceutical composition from the barrel via the outlet, wherein the ion exchange material is insoluble and/or immiscible in the liquid pharmaceutical composition and is adapted to, upon contact with the liquid pharmaceutical composition, adjust the pH of the liquid pharmaceutical composition from the first, non-physiological pH to a second pH, wherein the first, non-physiological pH is in the range of 3-6.6 and the second pH is in the range of 7.0-8.0, wherein the second pH is higher than the first non-physiological pH.

6. The pre-filled syringe according to claim 5, wherein the pre-filled syringe comprises a separator arranged at a position along an ejection path from the barrel, and wherein the liquid pharmaceutical composition is present upstream of said separator along said ejection path, and the ion exchange material is provided downstream of said separator along said ejection path, and the separator is adapted to in a first state prevent the liquid pharmaceutical composition from contacting the ion exchange material, and adapted to in a second state allow fluid communication between the liquid pharmaceutical composition and the ion exchange material.

7. The pre-filled syringe according to claim 5, wherein the syringe comprises an injection needle mounted in fluid communication with said outlet.

8. The pre-filled syringe according to claim 7, wherein the ion exchange material is contained within said needle.

9. The pre-filled syringe according to claim 5, wherein the ion-exchange material comprises a porous solid material.

10. The pre-filled syringe according to any claim 9, wherein the porous solid material comprises a material selected from a zeolite material, a polystyrene material, and mesoporous silica.

11. The pre-filled syringe according to claim 10, wherein the porous solid material comprises a zeolite material, wherein the zeolite is an aluminosilicate zeolite material loaded with Na.sup.+, H.sup.+ and/or Ca.sup.2+ having a SiO.sub.2/Al.sub.2O.sub.3 molar ratio above 1.5; and/or a Na.sub.2O content below 10 wt-% of the total zeolite weight.

12. The pre-filled syringe according to claim 5, wherein the liquid pharmaceutical composition comprises an acidic buffer solution.

13. The pre-filled syringe according to claim 5, wherein the liquid pharmaceutical composition comprises a protein drug or peptide drug.

14. The pre-filled syringe according to claim 13, wherein the protein or peptide drug is an IL-1 receptor antagonist.

15. The pre-filled syringe according to claim 14, wherein the IL-1 receptor antagonist is anakinra.

Description

BRIEF DESCRIPTION OF APPENDED DRAWINGS

(1) The invention will hereinafter be described in detail by reference to exemplary embodiments as illustrated in the following drawings, in which:

(2) FIGS. 1a-1b each schematically shows a pre-filled syringe according to embodiments of the invention.

(3) FIGS. 2a-b each schematically shows an assembly comprising a syringe according to embodiments of the invention.

(4) FIGS. 3a-b each schematically shows an assembly comprising a syringe according to other embodiments of the invention.

DETAILED DESCRIPTION

(5) The present invention will now be described more fully hereinafter with reference to the accompanying drawings, in which currently preferred embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided for thoroughness and completeness, and fully convey the scope of the invention to the skilled person. As illustrated in the figures, the sizes of layers and regions may be exaggerated for illustrative purposes and, thus, are provided to illustrate the general structures of embodiments of the present invention. Like elements are numbered alike.

(6) FIGS. 1a to 1b are schematic illustrations of different conceivable embodiments of a pre-filled syringe 101 according to embodiments of the invention. In FIG. 1a the pre-filled syringe 101 is depicted as having a substantially cylindrical barrel 103 and a plunger 105. The pre-filled syringe of this embodiment is further provided with an injection needle 107 fixed to an outlet 109 of the barrel 103. In this embodiment, an ion exchange material 111 is contained within the barrel 103, provided in an outlet path between the plunger 105 and the outlet 109 of the barrel 103. In this embodiment the ion exchange material 111 has the shape of a porous cylinder. A pharmaceutically acceptable solution 113 is contained within the barrel 103. A separator 115, e.g. a pressure-responsive separator, is also contained within the barrel 103 between the pharmaceutically acceptable solution 113 and the ion exchange material 111 to prevent the pharmaceutically acceptable solution 113 from contacting the ion exchange material 111 before the plunger 105 is pushed down the barrel 103 to eject the pharmaceutically acceptable solution 111 from the syringe 101. The ion exchange material 111 is arranged to be retained within the syringe upon ejection of the pharmaceutically acceptable solution.

(7) The ion exchange material 111 is typically provided downstream the separator 115 within the barrel. The ion exchange material 111 and the separator 115 may be adjacent to each other. The ion exchange material 111 may have a larger mass than the separator 115. The separator 115 may be of any shape and form, provided that it prevents contact between the pharmaceutically acceptable solution and the ion exchange material prematurely, e.g. until the plunger 105 is being pressed down the barrel 103 and/or the separator is deactivated, at which point it allows the pharmaceutically acceptable solution 113 to contact the ion exchange material 111.

(8) In embodiments, the pre-filled syringe 101 may not comprise an injection needle 107. Instead, the pre-filled syringe 101 may be adapted to be connected to an injection needle provided separately. The connection is preferably provided at the outlet 109, and could be any connection known to a person skilled in the art, such as a bayonet mount or a thread screw mount.

(9) The pharmaceutically acceptable solution 113 contained within the barrel 103 is generally intended for parenteral administration and may have a non-physiological pH, in particular an acidic pH. The solution 113 may have a low pH in order to increase the shelf-life of the solution 113, including any drug or active compound such as a protein drug or peptide drug, contained therein. In use, an operator, which may be a medically trained person or the patient himself/herself, presses the plunger 105 down the barrel 103 to push the pharmaceutically acceptable solution 113 along an ejection path from the barrel 103 to contact the ion exchange material 111. The ion exchange material 111 is chosen by a manufacturer and is capable of to exchange ions with the pharmaceutically acceptable solution 113 to provide an increase or decrease of the pH of the solution, as desired, to adjust the pH of the pharmaceutically acceptable solution 113 to a more physiological pH (i.e. about pH 7). Hence, upon contact with the ion exchange material 111, the non-physiological pH of the pharmaceutically acceptable solution 113 is adjusted towards a more physiological pH, such that upon ejection from the syringe 101 and injection into the patient, the pH of the solution is closer to a physiological pH.

(10) FIG. 1b illustrates an alternative embodiment of the pre-filled syringe 101 depicted as having a substantially cylindrical barrel 103 and plunger 105. The pre-filled syringe 101 is in this embodiment is further provided with an injection needle 107 fixed to an outlet 109 of the barrel 103. In this embodiment, an ion exchange material 111 is contained within the injection needle 107. The ion exchange material may be provided as a material arranged to be retained within the needle upon ejection of the pharmaceutically acceptable solution. The syringe is furthermore provided with a pharmaceutically acceptable solution 113 contained within the barrel 103. The pharmaceutically acceptable solution 113 is hindered from prematurely contacting the ion exchange material 111 in the needle 107 by a separator 115. In this embodiment, it may also be possible to omit the separator.

(11) Syringes comprising a barrel and a plunger are well known to a person skilled in the art. Any type of syringe capable of containing an ion exchange material may be contemplated within the scope of the present invention.

(12) In embodiments, the pharmaceutically acceptable solution does not contact the ion exchange material before the plunger is being pressed downstream in the direction of the ejection path. In order to accomplish this, the syringe may comprise a separator. The separator may have a first state in which it prevents the pharmaceutically acceptable solution from contacting the ion exchange material, and a second, pressurized state where it allows the pharmaceutically acceptable solution to flow through or past the separator and into contact with the ion exchange material. The second, pressurized state can be introduced when the plunger is being pressed downstream to push the pharmaceutically acceptable solution along the ejection path of the barrel. The separator prevents the ion exchange material from adjusting the pH of the pharmaceutically acceptable solution prematurely.

(13) In embodiments, the separator may be a liquid impermeable membrane or a super-hydrophobic membrane, which allows the pharmaceutically acceptable solution to pass through the membrane only after a certain pressure threshold value is exceeded. This state can be introduced by a collapse of the membrane. Other pressure-responsive separator working after the same general principle may also be contemplated, such as an air pocket. An air pocket may be a bag or balloon filled with air. The bag or balloon may conform to the inner shape and fill a cross-sectional area of the barrel and fill a cross-sectional area. After a certain pressure threshold value is obtained, the bag or balloon breaks, allowing the solution to flow past and into contact with the ion exchange material. Also contemplated is a solution where the ion exchange material is coated with a separator material, such as a hydrophobic material, which is impermeable to fluid until a certain pressure threshold value has been obtained. The pressure threshold value is obtained when the plunger is being pressed down the barrel. The separator may also a valve or a damper, which may be controlled from the outside of the syringe.

(14) The ion exchange material should preferably be permeable to the pharmaceutically acceptable solution. The ion exchange material should furthermore be capable of, upon contact, adjusting the pH of the pharmaceutically adjustable solution. The ion exchange material should preferably be capable of adjusting the pH of the pharmaceutically acceptable solution from a first, acidic pH to a second pH, wherein the second pH is higher than the first pH. In embodiments, the second pH is at least 6.6. The first acidic pH may be in the range of 3-6.6 and the second pH is at least 6.6, or at least 7.0, such as in the range of 7.0-8.0, or 7.1-8.0.

(15) In order to achieve the pH adjustment, the ion exchange material may be loaded with positive ions, such as Na.sup.+, H.sup.+, and/or Ca.sup.2+, preferably Na.sup.+ and/or Ca.sup.2+. Other positive ions may also be contemplated. Preferably, the positive ions have a valence of +1 or +2. The mechanism for the pH adjustment may typically be ion exchange, which mechanism is known to persons skilled in the art. In brief, ion exchange is based on the principle that H.sup.+ ions present in a solution may be exchanged by the ion exchange material for another cation, such as Na.sup.+ and/or Ca.sup.2+, or other ions present in the ion exchange material. Thus, the pH of the solution can be increased. In particular, the present inventor found that zeolite materials having Ca.sup.2+, Na.sup.+ or H.sup.+ as counter-ions could produce a desirable pH shift of a pharmaceutically acceptable solution.

(16) The duration of the contact between the pharmaceutically acceptable solution and the ion exchange material may correspond to the time it takes, during normal use, to eject the solution from the syringe using the plunger. Such a contact may be sufficient for adjusting the pH. The duration of a typical injection of Kineret® is in the range of 10-100 seconds such as in the range of 10-80 seconds, preferably 20-60 seconds.

(17) The ion exchange material may be a porous material, such as an inorganic porous material. In some embodiments the ion exchange material may be an aluminosilicate material such as a zeolite.

(18) The zeolite material may typically have a silica/alumina ratio of above 1, such as above 1.5, preferably in the range of 1.5-1000. It may also be in the range of 1.5-800, such as in the range of 1.5-500.

(19) Preferably, the zeolite material has a sodium content below 20 wt-% of the total zeolite weight, such as below 15 wt-%, preferably below 10 wt-%.

(20) The zeolite material may in embodiments of the invention be a microporous zeolite. The term microporous is supposed to indicate that the pore diameters in the zeolite material is less than 2 nm. Other pore systems may also be contemplated, such as mesoporous (pore diameter between 2 nm and 50 nm) and macroporous (pore diameter larger than 50 nm).

(21) A number of different zeolites may be contemplated, such as the zeolites marketed under the names Zeoflair, faujasite and Zeolite Y.

(22) Other ion exchange materials may also be contemplated, such as mesoporous silica. The mesoporous silica may optionally be functionalized to improve the ion exchange properties.

(23) The ion exchange material may comprise a polymer, such as a polystyrene material. The polystyrene material may be acidic, such as strongly acidic typically comprising sulfonic acid groups, e.g. sodium polystyrene sulfonate or polyAMPS. The polystyrene material may also be weakly acidic, typically comprising carboxylic acid groups.

(24) In some examples, basic polystyrenes may also be contemplated. The basic polystyrenes may be strongly basic polystyrenes such as polystyrenes comprising quaternary amino groups, for example, trimethylammonium groups, e.g. polyAPTAC). The polystyrenes may also be weakly basic, typically comprising featuring primary, secondary, and/or tertiary amino groups, e.g. polyethylene amine groups.

(25) In embodiments where the ion exchange material is contained in the barrel of the syringe, the ion exchange material may have the shape of a cylinder, such as in the shape of a plug. The diameter of the cylinder is typically chosen so that the plug conforms to inner periphery of the barrel, and fills a cross-sectional area of the barrel. Preferably, the dimensions, including diameter, of the cylinder may be chosen such that substantially all of the pharmaceutically acceptable solution passes through the ion exchange material during ejection of the pharmaceutically acceptable solution from the syringe. The height of the cylinder may be less than 15 mm, such as less than 10 mm, such as in the range of 3-10 mm. The height of the cylinder is preferably roughly proportional to the volume of the pharmaceutically acceptable solution in the syringe. A larger volume of pharmaceutically acceptable solution may require a cylinder having a greater height.

(26) The ion exchange material cylinder may be manufactured by for example sintering, such as spark plasma sintering. Other sintering techniques known to a skilled person in the art are also contemplated.

(27) The ion exchange material may be contained in a porous polymer matrix such polyvinylidene fluoride (PVDF).

(28) The pharmaceutically acceptable solution of the present invention may comprise an acidic buffer, such as a citrate buffer. A reason for using an acidic buffer is that an acidic pH may improve stability of the solution, in particular of a pharmaceutically active agent contained in the solution, which is useful in that it increases the shelf-life. During administration, and in particular subcutaneous administration, pharmaceutically acceptable solutions comprising an acidic buffer may cause irritation and pain. By adjusting the pH of the solution just prior to injection, the pain and/or irritation experienced by patient can be drastically reduced. However, since the stability of the solution is often dependent on that it is provided in a buffered solution with a non-physiological pH, it is important that the pH of the solution is not adjusted prematurely. FIGS. 1a and 1b show two examples of how the solution can be prevented from prematurely contacting the ion exchange material.

(29) The pharmaceutically acceptable solution may comprise a biological drug, such as a protein drug or a peptide drug. In some embodiments, the protein drug may be an IL-1 receptor antagonist (IL-1ra), such as anakinra. Anakinra is a drug used in the treatment of rheumatoid arthritis and requires daily subcutaneous administration. Anakinra may be provided in an acidic buffer in order to increase the stability of the solution so that the shelf-life may be increased. However, it is also contemplated that the drug contained in the pharmaceutically acceptable solution according to embodiments of the present invention may be a non-protein drug, such as a small organic molecule, such as a steroid. Hence, the type of drug or pharmaceutically active agent intended for use with the syringe described herein is not particularly limited, except in that it can be formulated as a liquid composition suitable for parenteral administration and that it benefits (e.g. with regard to stability of shelf life) from a non-physiological pH in solution.

(30) Accordingly, the syringe of the invention may be intended to be used with any injectable pharmaceutical solution having a non-physiological pH.

(31) A pre-filled syringe according to the invention may be manufactured by providing a syringe having a barrel and a plunger with an ion exchange material at a position in the barrel and placing a pharmaceutically acceptable solution within said barrel. The ion exchange material is preferably placed in the syringe before the ion exchange material. Preferably, the ion exchange material is placed in the syringe, followed by a sterilization of the syringe before the barrel is filled with the pharmaceutically acceptable solution. The ion exchange material should be placed downstream from the pharmaceutically acceptable solution.

(32) Arranging the ion exchange material within the injection needle is also contemplated. The ion exchange material may be provided in the syringe an any manner such that the pharmaceutically acceptable solution contacts the ion exchange material before the solution is ejected from the syringe. Preferably, the ion exchange material is sintered to a shape which conforms to the inner shape of the needle.

(33) FIG. 2a is a schematic illustration of a kit according to the invention. The kit 200 comprises a pre-filled syringe 201 and a needle unit 212 (also referred to as “injection needle unit”). The pre-filled syringe 201 comprises a barrel 203 and a plunger 205. In the barrel 203, a pharmaceutically acceptable solution 213 is contained. Downstream of the pharmaceutically acceptable solution there is provided an ion exchange material. The barrel 203 further comprises an outlet 209 adapted to allow ejection of the pharmaceutically acceptable solution 213. The outlet 209 is preferably provided with a connection which allows mounting of the needle unit 212 to the outlet 209. The barrel 203 furthermore contains a separator 215 between pharmaceutically acceptable solution 213 and the ion exchange material 211.

(34) The needle unit 212 comprises an injection needle 207. The needle unit 212 is adapted to be mounted on the pre-filled syringe 201, preferably to a connection at the outlet 209 of the barrel. Such connections are known to a person skilled in the art, and comprises thread-screw mounts and bayonet mounts. The connection should allow for fluid connection between the barrel 203 and the needle unit 212.

(35) FIG. 2b is a schematic illustration of a kit according to the invention. The kit 200′ comprises a pre-filled syringe 201 and a needle unit 222, (also referred to as “injection needle unit”). The pre-filled syringe comprises a barrel 203 and a plunger 205. In the barrel 203, a pharmaceutically acceptable solution 213 is contained. The barrel 203 further comprises an outlet 209 adapted to allow ejection of the pharmaceutically acceptable solution 213. The outlet 209 is preferably provided with a connection which allows mounting of the needle unit 222 to the outlet 209. The barrel 203 furthermore contains a separator 215 between the outlet 209 and the pharmaceutically acceptable solution 213.

(36) The needle unit 222 of FIG. 2b comprises an injection needle 207 and an ion exchange material 221. The needle unit 222 is adapted to be mounted on the pre-filled syringe 201, preferably to a connection at the outlet of the barrel. Such connections are known to a person skilled in the art, and comprises thread-screw mounts and bayonet mounts. The connection should allow for fluid connection between the barrel 203 and the needle unit 222. The ion exchange material 221 is preferably contained within the needle 207 to provide contact between the pharmaceutically acceptable solution 213 and the ion exchange material 221 upon ejection of the pharmaceutically acceptable solution 213 upon ejection via the needle 207. The ion exchange material 221 should be capable of adjusting the pH of a pharmaceutically acceptable solution 213 from a non-physiological pH to physiological pH upon contact between the ion exchange material 221 and the pharmaceutically acceptable solution 213.

(37) The pre-filled syringe and injection needle unit may optionally comprise the elements discussed in relation to FIGS. 1a and 1 b.

(38) FIG. 3a schematically shows yet another kit according to embodiments of the invention. The kit 300 comprises a syringe 301 and an injection needle unit 312. The syringe comprises a barrel 303 comprising an interior volume 314 adapted to contain a pharmaceutically acceptable solution and a plunger 305. In the barrel, there is provided a ion exchange material 311. The barrel 303 further comprises an outlet 309 adapted to allow ejection of the pharmaceutically acceptable solution. The outlet 309 is preferably provided with a connection which allows mounting of the needle unit 312 to the outlet 309.

(39) The injection needle unit 312 comprises a needle 307. The needle unit 307 is adapted to be mounted on the syringe 301, preferably to a connection at the outlet 309 of the barrel. Such connections are known to a person skilled in the art, and comprises thread-screw mounts and bayonet mounts. The connection should allow for fluid connection between the barrel 303 and the needle unit 307.

(40) The kit is adapted to be assembled, i.e. by connecting the injection needle unit 312 to the syringe 301 and to be provided with a pharmaceutically acceptable solution in the barrel 303 just prior to injection of the pharmaceutically acceptable solution.

(41) FIG. 3b schematically shows another kit according to embodiments of the invention. The kit 300′ comprises a syringe 301 and an injection needle unit 322. The syringe comprises a barrel 303 comprising an interior volume 314 adapted to contain a pharmaceutically acceptable solution and a plunger 305. The barrel 203 further comprises an outlet 309. The outlet 309 is preferably provided with a connection which allows mounting of the needle unit 322 to the outlet 309.

(42) The injection needle unit 322 comprises a needle 307 and an ion exchange material 311. The needle unit 322 is adapted to be mounted on the syringe 301, preferably to a connection at the outlet 309 of the barrel 303. Such connections are known to a person skilled in the art, and comprises thread-screw mounts and bayonet mounts. The connection should allow for fluid connection between the barrel 303 and the needle unit 322. An ion exchange material 321 is preferably contained within the needle 307 to provide contact between a pharmaceutically acceptable solution and the ion exchange material 321 upon ejection of the pharmaceutically acceptable solution via the needle 307. The ion exchange material 321 should be capable of adjusting the pH of a pharmaceutically acceptable solution from a non-physiological pH to physiological pH upon contact between the ion exchange material 311 and the pharmaceutically acceptable solution.

(43) The kit is adapted to be assembled, by connecting the injection needle unit 312 to the syringe 301, and to be provided with a pharmaceutically acceptable solution in the barrel 303 just prior to injection of the pharmaceutically acceptable solution.

(44) While the invention has been described with reference to various exemplary embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof.

(45) Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.

(46) Additionally, variations to the disclosed embodiments can be understood and effected by the skilled person in practicing the claimed invention, from a study of the drawings, the disclosure, and the appended claims. In the claims, the word “comprising” does not exclude other elements or steps, and the indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measured cannot be used to advantage.

EXAMPLES

(47) The invention is illustrated by way of the following, non-limiting examples. Table 1 briefly summarizes the experimental set-up of Examples 1-10, performed to illustrate the invention. The purpose of the experiments was to investigate the pH shift of pharmaceutically acceptable solution when contacted with different ion exchange materials:

(48) TABLE-US-00001 TABLE 1 Overview of the examples performed to illustrate the invention. Example Pharmaceutically acceptable solution used  1 Pharmaceutical acidic buffer  2 Pharmaceutical acidic buffer  3 Pharmaceutical acidic buffer  4 Pharmaceutical acidic buffer  5 Pharmaceutical acidic buffer  6 Anakinra  7 Anakinra  8 Pharmaceutical acidic buffer  9 Glycopressin 10 Somatropin

(49) Table 2 summarizes the different zeolites investigated in the Examples 1-10.

(50) TABLE-US-00002 TABLE 2 Summary of the investigated zeolites. Sodium Trade Counter content Si/Al namn Producer Notation ion (%) ratio Faujasite Merck A Calcium 7.3 2 KGaA 720KOA Tosoh B Potassium 1.3 18 500KOA Tosoh C Potassium 0.25 6.1 340NHA Tosoh D Ammonium 0.15 7 320NAA Tosoh E Sodium 12.5 5.5 642NAA Tosoh F Sodium 5 18 840NHA Tosoh G Ammonium <0.05 40 CBV720 Zeolyst H Hydrogen 1.3 30 CBV901 Zeolyst I Hydrogen 0.03 80 CP814E Zeolyst J Ammonium 0.05 25 ZEOflair110 Zeochem K Sodium 1.1 400 CBV100 Zeolyst L Sodium 13 5.1 CP811-300 Zeolyst M Hydrogen 0.05 300 ZEOflair800 Zeochem N Hydrogen 4.3 800 CPV10A Zeolyst O Sodium 6.5 13 CBV400 Zeolyst P Hydrogen 2.8 5.1 ZEOflair100 Zeochem Q Sodium 1.1 10

Example 1: Measurement of pH Shift

(51) An aqueous buffer solution consisting of 10 mM sodium citrate, 125 mM sodium chloride, 0.1% (w/v) EDTA was used as test solution. The solution was aliquoted in a portion of 10 mL in a glass beaker at room temperature. The pH of the buffer solution was measured with a pH-meter to 6.50. A dry zeolite (aluminum silicate) powder was weighed and added to the aliquoted buffer and mixed by gentle stirring. The zeolite were added in an amount equal 0.1 gram/1 mL buffer. The resulting pH was measured after 5 minutes to be 8.63 and the positive shift in pH was recorded to 2.13.

(52) CONCLUSION: The pH of a buffered aqueous solution can be increased by mixing with a zeolite powder.

Example 2: Measurements of pH Shift Using Different Zeolites

(53) An aqueous buffer solution consisting of 10 mM sodium citrate, 125 mM sodium chloride, 0.1% (w/v) EDTA was used as test solution. The solution was aliquoted in portions of 10 or 4 mL in glass beakers at room temperature. The pH of the buffer solution was measured with a pH meter to be 6.25. Dry zeolite powders with different properties were weighed and added to the aliquoted buffer and mixed by gentle stirring. The zeolites were added in equal amounts: 0.1 gram/1 mL buffer. The resulting pH was measured after 5 minutes and the shift in pH was recorded. The results are shown in Table 3.

(54) TABLE-US-00003 TABLE 3 pH shift for different zeolites. Na.sub.2O Counter content Si/Al pH Zeolite ion (%) ratio shift A Calcium 7.3 2 2.13 B Potassium 1.3 18 0.36 C Potassium 0.25 6.1 0.25 D Ammonium 0.15 7 −0.91 E Sodium 12.5 5.5 0.04 F Sodium 5 18 0.83 G Ammonium <0.05 40 −0.3 H Hydrogen 1.3 30 −2.47 I Hydrogen 0.03 80 −0.97 J Ammonium 0.05 25 −1.42 K Sodium 1.1 400 2.42 L Sodium 13 5.1 0.27 M Hydrogen 0.05 300 −0.82 N Sodium 4.3 800 1.17 O Sodium 6.5 13 3.21 P Hydrogen 2.8 5.1 −0.76 Q Sodium 1.1 10 3.02

Example 3. pH Shift Over Time and Different Concentration of Ion Exchange Material

(55) An aqueous buffer solution consisting of 10 mM sodium citrate, 125 mM sodium chloride, 0.1% (w/v) EDTA was used as test solution. The solution was aliquoted in portions of 1 mL in glass beakers at room temperature. The pH of the buffer solution was measured with a pH-meter to be 6.25.

(56) Dry zeolite powders with different properties were weighed and added to the aliquoted buffer and mixed by gentle stirring. The zeolites were added in varying amounts as shown in Table 2. The resulting pH was measured after 5 and 60 minutes, respectively and the shift in pH was recorded. The results are shown in Table 4.

(57) TABLE-US-00004 TABLE 4 pH shift for different zeolites after 5 and 60 minutes, respectively. Na.sub.2O Counter content Si/Al pH shift 5 pH shift 60 Zeolite ion (%) ratio Amount minutes minutes A Calcium 7.3 2 10 mg 0.04 0.04 A Calcium 7.3 2 20 mg 0.1 0.1 A Calcium 7.3 2 30 mg 0.17 0.17 B Potassium 1.3 18 20 mg 0.02 0.02 F Sodium 5 18 20 mg 0.21 0.21

(58) It was concluded that the pH shift correlates with the amount of zeolite material. It was also seen that the pH shift is fast, occurring within 5 minutes.

Example 5. pH Shift of Solution Comprising Anakinra Over Time and Different Concentration of Ion Exchange Material

(59) An aqueous protein solution consisting of 150 mg/ml anakinra, 10 mM sodium citrate, 125 mM sodium chloride, 0.1% (w/v) EDTA was used as test solution.

(60) The solution was aliquoted in portions of 0.7 mL in glass beakers at room temperature. The pH of the protein solution was determined using a pH-meter to 6.30.

(61) Dry powder of zeolite A was weighed to 70 mg and added to the aliquoted protein solution and mixed by gentle stirring. The resulting pH was measured after 0.5, 1, 2, 3, 4 and 5 minutes and the shift in pH was recorded for each time point. The results are shown in Table 5.

(62) TABLE-US-00005 TABLE 5 pH shift over time for anakinra. Na.sub.2O Counter content Si/Al Time Zeolite ion (%) ratio (minutes) pH-shift A Calcium 7.3 2 0.5 0.15 A Calcium 7.3 3 1 0.15 A Calcium 7.3 4 2 0.37 A Calcium 7.3 5 3 0.63 A Calcium 7.3 6 4 0.73 A Calcium 7.3 7 5 0.95

(63) It was concluded that the positive pH shift for the protein solution is similar to the pH shift observed with pure buffer in Example 2, and that the positive pH-shift is fast but correlates with time.

Example 6. Protein Quality Measurement

(64) An aqueous protein solution consisting of 150 mg/ml anakinra, 10 mM sodium citrate, 125 mM sodium chloride, 0.1% (w/v) EDTA was used as test solution. The solution was aliquoted in portions of 0.7 mL in polypropylene test tube at room temperature. The pH of the protein solution was measured with a pH-meter to 6.25.

(65) Dry powders of zeolites with different properties were added to aliquoted protein solutions to a concentration of 50 mg/0.7 mL and incubated at 25 C for 2 hours. One aliquot of the protein solution was incubated without zeolite as control.

(66) The protein quality and protein concentration of anakinra was determined by Size Exclusion Chromatography (SEC) HPLC and absorbance at 280 nm. The SEC-HPLC method was set up according to in-house standard protocol. A TSK-Gel G2000 SWXL 7.8 mm×30 cm column was used. The mobile phase was CSE Buffer, the injection volume/concentration was 100 μL/5 mg/mL, the wavelength was 280 nm, and the flow rate was 0.5 mL/min. The remaining monomer content of anakinra are presented in percentages. The results are presented in Table 6.

(67) TABLE-US-00006 TABLE 6 Protein quality after zeolite treatment. Na.sub.2O Protein Counter content Si/Al % conc Zeolite ion (%) ratio Monomer (mg/mL) NA NA NA NA 96.55 155 F Sodium 5 18 96.52 157 O Sodium 6.5 13 96.4 156 Q Sodium 1.1 10 96.32 153 A Calcium 7.3 2 96.3 156

(68) It was concluded that the quality and concentration of the drug anakinra is not affected by the zeolite.

Example 7. pH Adjustment in a Syringe Comprising Ion Exchange Material

(69) An aqueous protein solution consisting of 150 mg/ml anakinra, 10 mM sodium citrate, 125 mM sodium chloride, 0.1% (w/v) EDTA was used as test solution. The solution was aliquoted in portions of 0.7 mL in siliconized glass 1 mL prefillable syringe with an attached stainless steel needle. The syringe was closed by mounting a butyl rubber plunger at the open end of the syringe. The assembling was performed at room temperature. The pH of the protein solution was measured with a pH-meter to 6.34.

(70) Dry Zeolite F powder was weighed added to aliquoted protein solutions to a concentration of 70 mg/0.7 mL and incubated at 25° C. for 3 minutes. The pH of the ejected protein solution from the syringe was recorded and the pH-shift noted, see table 7.

(71) TABLE-US-00007 TABLE 7 pH measurements after pH adjustment in a syringe comprising an ion exchange material. Na.sub.2O Counter content Si/Al pH Zeolite ion (%) ratio shift F Sodium 5 18 0.12

(72) Hence, ejecting a protein solution from a syringe containing a zeolite increases the pH of the protein solution.

Example 8. pH Adjustment in a Syringe Comprising Sintered Ion Exchange Material

(73) An aqueous buffer solution consisting of 10 mM sodium citrate, 125 mM sodium chloride, 0.1% (w/v) EDTA was used as test solution. The pH of the buffer solution was measured with a pH meter to 6.59.

(74) Dry zeolite powder (Q in Table 8) was weighed in a portion of 100 mg, placed between two stainless steel plugs. The powder was then sintered by increasing the pressure on the powder to 6 MPa and heating to 730° C. The resulting sintered zeolite powder cylinder had a diameter of 20 mm. The zeolite plug was pressed into the barrel of a polypropylene syringe barrel all the way to the front of the barrel. The buffer solution described above was filled with 5 mL from the rear end of the syringe. A rubber plunger was mounted in to the syringe. Pressure was applied on the rubber plunger and the buffer solution was forced to pass through the powder plug. The pH of the ejected solution from the syringe was recorded and the pH-shift was calculated as shown in table 8.

(75) TABLE-US-00008 TABLE 8 pH measurements after pH adjustment in a syringe comprising a zeolite as ion exchange material. Na.sub.2O Counter content Si/Al Zeolite ion (%) ratio pH-shift Q Sodium 1.1 10 2.8

(76) Hence, ejecting a buffered solution through a sintered zeolite cylinder in a syringe increases the pH.

Example 9. pH Adjustment of Glycopressin

(77) 1 mL of Glycopressin (1 mg/8.5 mL manufactured by Ferring) was aliquoted in a test tube. The pH of the solution was measured with a pH-meter to 3.74. Dry zeolite powder (Q) was weighed in a portion of 70 mg and added to the Glycopressin solution. The pH of the sample solution was then determined to be 5.92.

(78) A new portion of the Glycopressin was aliquoted with 1 mL in a new test tube. The pH of the solution was measured with a pH-meter to 3.75. Dry Zeolite powder (Q) was weighed in a portion of 100 mg and added to the Glycopressin solution The pH of the sample solution was then determined to be 6.88.

(79) Conclusion: The pH of the Glycopressin solution was increased by zeolite in a concentration dependent way.

Example 10. pH Adjustment of Somatatropin

(80) 0.5 mL of Somatatropin (Norditropin Simplex 10 mg/1.5 mL) manufactured by NovoNordisk was aliquoted in a test tube. The pH of the solution was measured with a pH-meter to 6.15. Dry zeolite powder (Q) was weighed in a portion of 50 mg and added to the somatropin solution The pH of the sample solution was determined to be 9.07

(81) A new portion of the Somatropin was aliquoted with 0.5 mL in a new test tube. The pH of the solution was measured with a pH-meter to 6.22. Dry Zeolite powder (Q) was weighed in a portion of 19 mg and added to the somatropin solution The pH of the sample solution was then determined to be 7.28.

(82) Conclusion: The pH of the Somatatropin solution was increased by zeolite in a concentration dependent way.

(83) In the following, prophetic examples 11-18 are discussed.

Example 11. Sintered Zeolite Material in Needle

(84) Zeolite material K is compressed into a porous plug using Spark Plug Sintering (SPS) technology. The zeolite powder is weighed into a cylindrical cavity with two open ends. The zeolite is compressed into a compact plug at a predefined pressure (100 to 1000 MPa) and sintered with pre-defined heat (500 to 1000° C.) into a porous mechanically stable plug. The cylindrical cavity may contain spikes parallel to the plug geometry to create channels of controlled diameters. The resulting plug is cooled and mounted into a female luer cone cannula hub with a stainless steel needle attached to the hub.

(85) The cannula is mounted at the male luer part of a syringe. The syringe is filled with a pharmaceutical solution having a solution pH of 6.0. The open part of the syringe is closed with a rubber plunger. The rubber plunger is pushed forward and the pharmaceutical solution is transferred through the zeolite matrix in the hub and out through the needle. The pH of the ejected solution from the needle is 7.0.

(86) Conclusion: The pH of the pharmaceutical solution is raised upon contact with the sintered zeolite material.

Example 12 Sintered Zeolite Material in Barrel

(87) The porous zeolite plug of Example 11 is mounted at the front end of a glass or plastic syringe. A stainless steel needle is attached into the syringe end. The syringe is filled with a pharmaceutical solution having a solution pH of 6.0. The open part of the syringe is closed with a rubber plunger. The rubber plunger is pushed forward and the pharmaceutical solution is transferred through the zeolite matrix in the syringe and out through the needle. The pH of the ejected solution from the needle is 7.0.

(88) Conclusion: The pH of the pharmaceutical solution is raised upon contact with the sintered zeolite material.

Example 13. Zeolite Material Immobilized on Support in Needle

(89) Zeolite material K is immobilized on a porous titanium oxide, aluminum or mullite support or similar. The immobilization is performed by making a suspension of the zeolites in distilled water and having it nucleate on the support creating a porous membrane.

(90) The resulting membrane is mounted into a female luer cone cannula hub with a stainless steel needle attached to the hub. The cannula is mounted at the male luer part of a syringe. The syringe is filled with a pharmaceutical solution having a solution pH of 6.0. The open part of the syringe is closed with a rubber plunger. The rubber plunger is pushed forward and the pharmaceutical solution is transferred through the zeolite matrix in the hub and out through the needle. The pH of the ejected solution from the needle is 7.0.

(91) Conclusion: The pH of the pharmaceutical solution is raised upon contact with the immobilized zeolite material.

Example 14. Zeolite Material Immobilized on Support in Barrel

(92) The porous zeolite membrane of Example 13 is mounted at the front end of a glass or plastic syringe. A stainless needle is attached into the syringe end.

(93) The syringe is filled with a pharmaceutical solution having a solution pH of 6.0. The open part of the syringe is closed with a rubber plunger. The rubber plunger is pushed forward and the pharmaceutical solution is transferred through the zeolite matrix in the syringe and out through the needle. The pH of the ejected solution from the needle is 7.0.

(94) Conclusion: The pH of the pharmaceutical solution is raised upon contact with the immobilized zeolite material.

Example 15. Zeolite/Polymer Membrane in Needle

(95) PVDF (polyvinylidene difluoride) is dissolved in NMP (N-Methyl-2-pyrrolidone) solvent to a solution. Zeolite material K is suspended in the PVDF/NMP solution by mixing for 5 hours at room temperature. The resulting suspension is distributed over a glass plate. The glass plate is immersed in distilled water to solidify into a membrane. The resulting membrane is mounted into a female luer cone cannula hub with a stainless steel needle attached to the hub.

(96) The cannula is mounted on a the male luer part of a syringe. The syringe is filled with a pharmaceutical solution having a solution pH of 6.0. The open part of the syringe is closed with a rubber plunger. The rubber plunger is pushed forward and the pharmaceutical solution is transferred through the zeolite matrix in the hub and out through the needle. The pH of the ejected solution from the needle is 7.0.

(97) Conclusion: The pH of the pharmaceutical solution is raised upon contact with the zeolite/polymer material.

Example 16. Zeolite/Polymer Membrane in Barrel

(98) The porous zeolite membrane of Example 15 is mounted at the front end of a glass or plastic syringe. A stainless steel needle is attached into the syringe end. The syringe is filled with a pharmaceutical solution having a solution pH of 6.0. The open part of the syringe is closed with a rubber plunger. The rubber plunger is pushed forward and the pharmaceutical solution is transferred through the zeolite matrix in the syringe and out through the needle.

(99) Conclusion: The pH of the pharmaceutical solution is raised upon contact with the zeolite/polymer material.

Example 17. Zeolite Powder in Needle

(100) Powder of zeolite K is contained in a cylindrical container. The container is made from polymer or metallic materials where the base and top of the cylinder is permeable to water. The container with the zeolite powder is mounted into a female luer cone cannula hub with a stainless steel needle attached to the hub.

(101) The cannula is mounted at the male luer part of a syringe. The syringe is filled with a pharmaceutical solution having a solution pH of 6.0. The open part of the syringe is closed with a rubber plunger. The rubber plunger is pushed forward and the pharmaceutical solution is transferred through the cylindrical with the zeolite in the hub and out through the needle. The pH of the ejected solution from the needle is 7.0.

(102) Conclusion: The pH of the pharmaceutical solution is raised upon contact with the powder zeolite material.

Example 18. Zeolite Powder in Needle

(103) The cylindrical container with zeolite powder is mounted at the front end of a glass or plastic syringe. A stainless steel needle is attached. The syringe is filled with a pharmaceutical solution having a solution pH of 6.0. The open part of the syringe is closed with a rubber plunger. The rubber plunger is pushed forward and the pharmaceutical solution is transferred through the cylindrical container in the syringe and out through the needle. The pH of the ejected solution from the needle is 7.0.

(104) Conclusion: The pH of the pharmaceutical solution is raised upon contact with the powder zeolite material.