Freeze-dried pharmaceutical composition of copper histidinate

Abstract

The present invention relates to a freeze-dried pharmaceutical composition of copper histidinate and one or more pharmaceutically acceptable excipients. It also relates to a process for preparing such a composition.

Description

Technical Field

[0001] Field of the Invention The present invention relates to a freeze-dried pharmaceutical composition of copper histidinate. The present invention also relates to a process for preparing such a composition.

Background Art

[0002] Background of the Invention Copper is an essential nutrient for the body. Together with iron, it enables the body to form red blood cells. It helps to maintain healthy bones, blood vessels, nerves, and immune function, and contributes to iron absorption. Copper deficiency is rare and can cause both blood and nerve diseases. Copper deficiency can also result from a rare genetic disorder called Menkes disease. Researchers have tried to develop various copper-containing formulations to treat copper deficiency.

[0003] Sherwood et al., Journal of Inherited Metabolic Disease, 12 Suppl., 2, 393-396 (1989) discloses a liquid formulation of copper histidinate. Chapter 14, entitled "Small copper complexes for treatment of acquired and inherited copper deficiency syndromes" (pages 202-212, Stephen G. Kaler) of the book "Small molecule therapy for genetic disease" (ISBN 978-0-521-51781-2) by Cambridge University press discloses a freeze-dried product of copper histidinate.

[0004] Basak et al. (Journal of Inorganic Biochemistry, 51 (1-2), page no. 415 (1993)) disclose that copper-histidine was formulated in lyophilized form to avoid stability problems in solution. They also disclose that the presence of sodium chloride causes aggregation during lyophilization and results in a turbid solution when reconstituted with sterile water. They further disclose that lyophilized copper-histidine without additives is much superior, as reflected in stability studies under various storage conditions. Sarkar et al., The Journal of Pediatrics, 123 (5), 828-30 (1993) cite Basak et al. and repeat the same thing.

[0005] Kaler et al., Biochemical and Molecular Medicine, 57, 37-46 (1996) disclose copper histidine prepared as a lyophilized product for Menkes disease. They also disclose that sterile water was used to dissolve copper histidine before lyophilization and that 0.9% saline was used to resuspend the lyophilized product.

[0006] International (PCT) Publication No. WO / 2010 / 042102 discloses the preparation and administration of copper histidine. It also discloses a process for preparing a solution by dissolving copper chloride dihydrate, L-histidine, and sodium hydroxide in water and lyophilizing the solution to obtain a lyophilized product. Reconstitution of the lyophilized product by injection of 0.9% sodium chloride is also disclosed. There is still a need for alternative lyophilized pharmaceutical compositions of copper histidinate that have improved stability and meet other requirements as set forth in the following description. SUMMARY OF THE INVENTION

[0007] SUMMARY OF THE INVENTION In one general aspect, the present invention provides a lyophilized pharmaceutical composition comprising copper histidinate, wherein the lyophilized pharmaceutical composition, for example, a lyophilized powder or cake, has improved parameters such as a good aesthetic appearance.

[0008] Aspects of the lyophilized pharmaceutical composition may include one or more of the following features. The composition may further comprise one or more pharmaceutically acceptable excipients, for example, one or more cryoprotectants, one or more pH adjusters, optionally one or more antioxidants, optionally one or more buffers, and optionally one or more preservatives.

[0009] The cryoprotectant may be mixed with the copper histidinate solution to provide a solution prior to lyophilization, and then the solution may be lyophilized to provide a lyophilized composition comprising copper histidinate and the cryoprotectant. The copper histidinate present in the solution prior to lyophilization may be formed in situ when a solution of copper(II) chloride dihydrate and a histidine solution are mixed.

[0010] In another general aspect, the present invention provides a process for preparing a lyophilized pharmaceutical composition of copper histidinate, wherein the process comprises the following steps: (a) preparing a solution of copper(II) chloride dihydrate, (b) preparing a histidine solution, (c) mixing the solutions obtained in steps (a) and (b), (d) adding one or more cryoprotectants to the solution obtained in step (c), (e) adding one or more pH adjusters such that the pH of the solution is about 7.0 - 7.5, and (f) performing lyophilization (freeze-drying) of the solution obtained in step (e).

[0011] In another general aspect, the present invention provides a glass vial / SiO containing a lyophilized pharmaceutical composition comprising copper histidinate and one or more cryoprotectants 2Provide a vial / quartz vial, glass ampoule, glass bottle, plastic bottle, plastic bag, glass / plastic prefilled syringe, or glass / plastic single / dual chamber cartridge.

[0012] In another general aspect, the present invention provides a method of treating Menkes disease in a patient in need thereof, which comprises administering to the patient a solution comprising copper histidinate, one or more pharmaceutically acceptable excipients, and a vehicle, wherein the administration is made through a subcutaneous route.

[0013] Details of one or more aspects of the present invention are set forth in the following description. Other features, objects, and advantages of the present invention will be apparent from the description.

Brief Description of the Drawings

[0014] Brief Description of the Drawings

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0015] Detailed Description of the Present Invention The inventors of the present invention have found that when a cryoprotectant, such as sodium chloride, is used in the preparation of a lyophilized pharmaceutical composition of copper histidinate, a composition with improved parameters can be obtained. A lyophilized pharmaceutical composition having improved parameters such as a good aesthetic appearance (essentially no aggregates, lumps, and / or defects in the lyophilized powder or cake, i.e., no meltback, collapsed cake, shrinkage of the cake, tilted cake, etc.), for example, a lyophilized powder or cake, can be obtained.

[0016] Furthermore, the inventors have found that when the lyophilized pharmaceutical composition is mixed with sterile water for injection, a clear solution with improved (reconstituted) physical parameters can be obtained. This enables the use of sterile water for injection as a reconstitution vehicle and avoids dependence on physiological saline as a reconstitution vehicle. A reconstituted solution with improved physical parameters such as the solution being clear (hazy-free / without any visible particles / without any particles) can be obtained. Such a clear solution essentially free of any particulate matter is suitable for administration via the parenteral route to a human in need thereof, for example, a patient in need thereof.

[0017] In one aspect, the present invention provides a lyophilized pharmaceutical composition comprising copper histidinate and one or more pharmaceutically acceptable excipients (additives). The lyophilized pharmaceutical composition of the present invention is a lyophilized powder or cake for reconstitution that is essentially free of lyophilization defects such as meltback, collapsed cake, cake shrinkage, and tilted cake. The lyophilized powder or cake is essentially free of aggregates, lumps, and / or any lyophilization defects.

[0018] Examples of pharmaceutically acceptable excipients may include, but are not limited to, cryoprotectants, pH adjusters, antioxidants, buffers, and preservatives.

[0019] Examples of suitable cryoprotectants include, but are not limited to, sodium chloride, mannitol, sucrose, dextrose, lactose, and cyclodextrin derivatives (such as hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, etc.), or any combination thereof. For example, sodium chloride is a suitable cryoprotectant. The lyophilized pharmaceutical composition of the present invention provides a clear solution when mixed with sterile water for injection, where sodium chloride is at a concentration between about 1 mg / mL and about 18 mg / mL. The cryoprotectant may be mixed with the copper histidinate solution to provide a solution before lyophilization, and then the solution is lyophilized to provide a lyophilized composition containing copper histidinate and the cryoprotectant. The copper histidinate present in the solution before lyophilization may be formed in situ when a copper(II) chloride dihydrate solution and an L-histidine solution are mixed. The lyophilized powder or cake of the present invention containing a cryoprotectant is essentially free of any of the following: good aesthetic appearance, such as aggregates, lumps, and / or defects of lyophilization, namely, meltback, collapsed cake, shrinkage of the cake, inclined cake, etc. The presence of the cryoprotectant lowers the collapse temperature. For example, the presence of sodium chloride lowers the collapse temperature from about -70 °C to about -27 °C, enabling efficient lyophilization. Further, when reconstituted with a suitable reconstitution vehicle, such as sterile water for injection, the lyophilized powder or cake of the present invention containing sodium chloride provides a clear solution (without haze or turbidity / visible particles / particles), remaining clear even after being stored at 100 °C for 24 hours. The lyophilized powder or cake of the present invention containing a pharmaceutically acceptable excipient / cryoprotectant / sodium chloride may have a large surface area compared to the surface area of a lyophilized powder or cake that does not contain such excipient / cryoprotectant / sodium chloride.

[0020] As used herein, the term "about" refers to encompassing + / −20%, 15%, 10%, 5%, 2%, 1%, 0.5%, or 0.25% of the numerical value in which it is used.

[0021] Examples of suitable pH adjusters may include, but are not limited to, sodium hydroxide, potassium hydroxide, hydrochloric acid, and phosphoric acid, or any combination thereof. The sodium hydroxide present in the lyophilized pharmaceutical composition is in an amount sufficient to produce a clear solution having a pH value of about 6.0 to about 8.0, for example, a pH value of about 7.0 to about 7.5 when mixed with sterile water for injection.

[0022] Examples of suitable antioxidants may include, but are not limited to, monothioglycerol, ascorbic acid, l-cysteine, sodium sulfite, sodium bisulfite, disodium edetate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, sodium ascorbate, erythorbic acid, potassium metabisulfite, propionic acid, sodium formaldehyde sulfoxylate, reduced glutathione, thiourea, n-acetylcysteine, methionine, alkyl gallates including propyl gallate, vitamin E, or other tocopherol analogs including tocopheryl acetate or TPGS, or any combination thereof.

[0023] Examples of suitable buffers may include, but are not limited to, acetate buffers (such as sodium acetate and acetic acid), phosphate buffers (such as sodium monophosphate, disodium phosphate, etc.), citrate buffers (such as anhydrous citric acid and trisodium citrate dihydrate, etc.), carbonate buffers, lactate buffers, glycine buffers, borate buffers (boric acid / potassium chloride), tris buffers, tromethamine buffers, or any combination thereof.

[0024] Examples of suitable preservatives include, but are not limited to, chlorobutanol, benzalkonium chloride, methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, thimerosal, merthiolate, chlorhexidine, phenylethyl alcohol, quaternary ammonium chloride, sodium benzoate, sodium propionate, or any combination thereof.

[0025] In one aspect, the present invention provides a lyophilized pharmaceutical composition comprising copper histidinate, one or more cryoprotectants, and one or more pH adjusters. The lyophilized pharmaceutical composition may comprise copper histidinate, sodium chloride, and sodium hydroxide. The lyophilized pharmaceutical composition in each vial may comprise copper histidinate in an amount of about 0.500 mg to about 10.000 mg, such as about 0.725 mg to about 6.100 mg, sodium chloride in an amount of about 1 mg to about 18 mg, and sodium hydroxide in an amount sufficient to adjust the pH to about 7.0 to about 7.5.

[0026] In another aspect, the lyophilized pharmaceutical composition comprises copper histidinate, sodium chloride, and sodium hydroxide, wherein the composition contains sodium chloride in an amount of about 1 mg to about 18 mg, such as 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, or 17 mg.

[0027] In another aspect, a lyophilized pharmaceutical composition comprising copper histidinate, sodium chloride, and sodium hydroxide provides a weight ratio of copper histidinate to sodium chloride between about 1:0.1 and about 1:7.0, for example, between about 1:0.3 and about 1:6.3. The lyophilized pharmaceutical composition retains at least 90% of the titer (% assay) of copper histidinate in the pharmaceutical composition, as determined by ultraviolet-visible spectroscopy, after storage at 50 °C and 80% RH, at 40 °C and 75% RH, at controlled room temperature (about 20 °C to about 25 °C) and 60% RH, at 2 °C to 8 °C, or at -15 °C to -20 °C for 1 month or more, for example, 6 months, 12 months, 18 months, 24 months, or 36 months. The lyophilized pharmaceutical composition can be supplied under storage conditions either at 2 °C to 8 °C or at controlled room temperature.

[0028] In another aspect, a lyophilized pharmaceutical composition comprising copper histidinate, sodium chloride, and sodium hydroxide has a water content percentage (% by weight of the composition) of 4% or less immediately after its manufacture (initial) and during its storage under various conditions. For example, after storing the lyophilized pharmaceutical composition at 40 °C and 75% RH, at 25 °C and 60% RH, or at 2 °C to 8 °C for 1 month or more, for example, 6 months, 12 months, 18 months, 24 months, or 36 months, the water content percentage (% by weight of the composition) is about 4% or less, for example 3% or less. The water content percentage (% by weight of the composition) of the lyophilized pharmaceutical composition after storage at 25 °C and 60% RH for 6 months does not change / increase by more than 5.0%, for example, 4.0%, 3.0%, or 2.0% compared to that of the composition at the initial level. The water content percentage (% by weight of the composition) of the lyophilized pharmaceutical composition after storage at 2 °C to 8 °C for 6 months does not change / increase by more than 5.0%, for example 4.0%, 3.0%, or 2.0% compared to that of the composition at the initial level. The determination of the water content percentage can be carried out with a Karl Fischer coulometer.

[0029] In one aspect, the present invention provides a clear (reconstituted) solution when a lyophilized pharmaceutical composition containing copper histidinate, sodium chloride, and sodium hydroxide is mixed with sterile water for injection. The clear solution is provided in less than 60 seconds after mixing, for example, 45 seconds, 30 seconds, 15 seconds, or 10 seconds. The clear solution contains copper histidinate at a concentration of about 2.9 mg / mL, sodium chloride at a concentration of about 9 mg / mL, and an amount of sodium hydroxide sufficient to provide a pH of about 7.0 to about 7.5, and can be administered to a human in need thereof without further dilution. The administration can be made via a subcutaneous injection route at a dose of about 0.5 mL of the clear solution (2.9 mg / mL of copper histidinate).

[0030] As used herein, the term "clear solution" means a solution that is essentially free of visible particles / particulate matter observable by visual inspection and complies with the following limitations for subvisible particulate matter: NMT 6000 particles / container of NMT 25 μm size and NMT 600 particles / container of NMT 10 μm size as determined by laser light scattering microscopy. The clear solution may provide a transmittance % of 95% or more, for example, 96% or more, 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, or 99.8% or more when measured at 650 nm. The clear solution may provide an absorbance value of 1 AU or less, for example, 0.75, 0.5, 0.4, 0.3, 0.2, 0.1, or 0.05 or less. The clear solution of the present invention may provide an osmotic pressure value between about 300 mOsmol / kg and about 380 mOsmol / kg.

[0031] The clear solution (reconstituted solution) of the present invention is suitable for administration via various parenteral routes, such as intramuscular routes (intramuscular in the deltoid or intramuscular in the gluteal region), subcutaneous routes, or intravenous routes.

[0032] In one aspect, a lyophilized pharmaceutical composition comprising copper histidinate, sodium chloride, and sodium hydroxide may retain at least 90% of the copper histidinate (% assay) determined by ultraviolet-visible spectroscopy after storage at 40 °C and 75% RH, controlled room temperature and 60% RH, 2 °C to 8 °C, or -15 °C to -20 °C for a period longer than 1 month, for example, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, or 36 months.

[0033] The lyophilized pharmaceutical composition does not contain more than 2.0 wt%, for example 1.5 wt%, 1.0 wt%, or 0.5 wt% of the total impurities of copper histidinate determined by HPLC after storage at 40 °C and 75% RH, controlled room temperature and 60% RH, 2 °C to 8 °C, or -15 °C to -20 °C for 6 months, 12 months, 18 months, 24 months, 30 months, or 36 months. The lyophilized pharmaceutical composition does not contain more than 0.5 wt%, for example 0.2 wt% or 0.1 wt% of 2-oxo-L-histidine determined by HPLC after storage at 40 °C and 75% RH, controlled room temperature and 60% RH, 2 °C to 8 °C, or -15 °C to -20 °C for 6 months, 12 months, 18 months, 24 months, 30 months, or 36 months.

[0034] In one aspect, the reconstituted solution of the present invention remains clear immediately after its preparation and after storage at 25 °C and 60% RH for 1 month and / or after storage at 2 °C to 8 °C for 2 months.

[0035] In one aspect, the present invention provides a process for preparing a lyophilized pharmaceutical composition comprising copper histidinate, sodium chloride, and sodium hydroxide, the process comprising the following steps: (a) Dissolving copper(II) chloride dihydrate in water, for example, sterile water for injection, to obtain a solution of copper(II) chloride dihydrate; (b) Dissolving L-histidine in sterile water for injection to obtain a histidine solution; (c) Mixing the solutions obtained in steps (a) and (b); (d) Adding a cryoprotectant to the solution obtained in step (c), (e) Adding a pH adjuster to have a solution with a pH of 7.0 to 7.5, (f) Filtering the solution obtained in step (e) using sterile filtration, (g) Filling the vial with the solution obtained in step (f), and (h) Performing lyophilization of the vial obtained in step (g).

[0036] In another aspect, the present invention provides a process for preparing a lyophilized pharmaceutical composition comprising copper histidinate, sodium chloride, and sodium hydroxide, the process comprising the following steps: (a) Dissolving lyophilized copper histidinate in sterile water for injection, (b) Adding a cryoprotectant to the solution obtained in step (a), (c) Adding a pH adjuster to have a solution with a pH of 7.0 to 7.5, (d) Filtering the solution obtained in step (c) using sterile filtration, (e) Filling the vial with the solution obtained in step (d), and (f) Performing lyophilization of the vial obtained in step (e).

[0037] The lyophilized copper histidinate may be obtained by a method comprising the following steps: (a) Dissolving copper(II) chloride dihydrate in water, for example, sterile water for injection, to obtain a solution of copper(II) chloride dihydrate, (b) Dissolving L-histidine in water, for example, sterile water for injection, to obtain a histidine solution, (c) Mixing the solutions obtained in steps (a) and (b), and (d) Performing lyophilization of the solution obtained in step (c).

[0038] The lyophilized pharmaceutical composition may be suitable for undergoing a sterilization process to provide a sterilized composition. Examples of suitable sterilization processes may include, but are not limited to, sterile membrane filtration sterilization.

[0039] In one aspect, the lyophilized pharmaceutical composition of the present invention is provided in a suitable container (primary packaging material), for example, a glass vial / SiO 2 vial / quartz vial, glass ampoule, glass bottle, plastic bottle, glass / plastic prefilled syringe, or glass / plastic single / dual chamber cartridge.

[0040] In another aspect, the lyophilized pharmaceutical composition of the present invention is provided in a dual chamber injection device, where the first chamber contains a copper histidinate lyophilized powder and the second chamber contains sterile water for injection. Mixing the contents of both chambers upon administration of the drug to a human in need thereof, for example, a patient in need thereof, provides a clear solution. The dual chamber injection device may contain various components, for example, a barrel made of glass or plastic, a plunger, one or more rubber stoppers, a needle, and a cap.

[0041] In one aspect, the present invention provides a method for treating Menkes disease, comprising administering to a patient in need thereof a solution comprising copper histidinate, one or more pharmaceutically acceptable excipients, and a vehicle, wherein the administration is made through a subcutaneous route. Subcutaneous administration provides a 2.9 mg / mL copper histidinate solution (1.45 mg of copper histidinate) in a dose of 0.5 mL. The solution is a reconstituted solution provided by reconstituting a lyophilized pharmaceutical composition containing copper histidinate and one or more pharmaceutically acceptable excipients (such as cryoprotectants) in a vehicle (such as sterile water for injection). The administration is made through a parenteral route, for example, a subcutaneous route, an intravenous route, or an intramuscular route.

[0042] In one aspect, when the lyophilized pharmaceutical composition of the present invention is mixed with water, for example, sterile water for injection, it provides a clear solution for administration via a parenteral route, where upon administration to a human in need thereof, for example, a patient in need thereof, the administration may provide a very mild pain intensity. The Visual Analog Scale score (VAS score) is a tool for determining the intensity of perceived pain. After administration, for example, a human / patient one minute after administration may indicate the intensity of perceived pain along a 100 mm horizontal line, where 0 means "no pain" and 100 means "intolerable pain". Administration according to the present invention may provide a VAS score value of less than 80, for example, less than 50, less than 30, less than 16, less than 10, or 0.

[0043] In another aspect, the present invention provides a method for treating low copper levels (copper deficiency) in a human, for example, a patient's plasma, the method comprising administering to a human in need thereof, for example, a patient in need thereof, a solution comprising copper histidinate, one or more pharmaceutically acceptable excipients, and a vehicle, where the administration is made via a parenteral route. The solution is a reconstituted solution provided by reconstituting a lyophilized pharmaceutical composition comprising copper histidinate and one or more pharmaceutically acceptable excipients (e.g., cryoprotectant) in a vehicle (e.g., sterile water for injection).

[0044] Abbreviations: μm: micrometer mg: milligram mL: milliliter RH: relative humidity ℃: Degree Centigrade / Celsius NMT: not more than q.s.: quantity sufficient AU: absorbance unit mOsm / kg: milliosmole per kilogram HPLC: high performance liquid chromatography 1M: 1 month 2M: 2 months

[0045] The present invention is further illustrated by the following examples, which are provided for illustrative purposes of the present invention and do not limit the scope of the present invention. The present invention is described from the perspective of its specific embodiments, but specific modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

[0046] Example 1: Table 1: [Table 1]

[0047] Process: Solution of copper(II) chloride dihydrate: 1. Copper(II) chloride dihydrate was added to water for injection. Solution of histidine: 2. L-Histidine was added to water for injection. Freeze-dried powder / cake of copper(II) histidinate: 3. The solution of copper(II) chloride dihydrate and the solution of histidine were mixed. 4. Sodium chloride was added to the solution obtained in Step 3. 5. The pH was adjusted to 7.0 - 7.5 using sodium hydroxide. 6. The solution obtained in Step 5 was filtered using sterile membrane filtration. 7. The solution obtained in Step 6 was filled into glass vials. 8. The vials obtained in Step 7 were freeze-dried to obtain a freeze-dried powder / cake.

[0048] Comparative Example: Table 2: [Table 2]

[0049] Process: Solution of copper(II) chloride dihydrate: 1. Copper(II) chloride dihydrate was added to water for injection. Solution of histidine: 2. L-Histidine was added to water for injection. Lyophilization: 3. The copper(II) chloride dihydrate solution and the histidine solution were mixed. 4. The pH was adjusted to 7.0 - 7.5 using sodium hydroxide. 5. The solution obtained in Step 4 was filtered using sterile membrane filtration. 6. The solution obtained in Step 5 was filled into glass vials. 7. The vials obtained in Step 6 were lyophilized.

[0050] The lyophilized composition of Example 1 (Step 8) and the lyophilized composition of the comparative example (Step 7) were tested for their physical stability, and the results are reported in Table 3A below. Table 3A:

Table 3A

[0051] The lyophilized composition of Example 1 (Step 8) was tested for its chemical stability, and the results are reported in Table 3B below. Table 3B:

Table 3B

[0052] The lyophilized compositions of Example 1 (Step 8) and the lyophilized compositions of the comparative examples (Step 7) were tested for water content % (by weight of the composition), and the results are reported in Table 3C below as determined by a Karl Fischer coulometer (equipment: Metrohm 831 KF coulometer). Table 3C:

Table 3C

[0053] The lyophilized compositions of Example 1 (Step 8) and the lyophilized compositions of the comparative examples (Step 7) were separately mixed with a sufficient amount of sterile water for injection to prepare two separate reconstituted solutions having a concentration of copper histidinate of about 2.9 mg / mL, and such reconstituted solutions were tested for physical and chemical parameters, and the results are reported in Table 3D below. Table 3D: Results of Reconstituted Solutions (Reconstitution Vehicle: Sterile Water for Injection)

Table 3D

Claims

1. A lyophilized pharmaceutical composition comprising copper histidine and one or more pharmaceutically acceptable excipients.

2. The freeze-dried pharmaceutical composition according to claim 1, wherein the excipient is a cryoprotectant.

3. The freeze-dried pharmaceutical composition according to claim 2, wherein the cryoprotectant is sodium chloride.

4. The freeze-dried pharmaceutical composition according to claim 1, wherein the excipient is a pH adjuster.

5. The freeze-dried pharmaceutical composition according to claim 4, wherein the pH adjuster is sodium hydroxide.

6. The lyophilized pharmaceutical composition according to claim 1, comprising approximately 0.500 mg to approximately 10.000 mg of copper histidine.

7. The freeze-dried pharmaceutical composition according to claim 3, wherein sodium chloride is present in an amount ranging from about 1 mg to about 18 mg.

8. The freeze-dried pharmaceutical composition according to claim 1, which is a freeze-dried powder or cake.

9. The lyophilized pharmaceutical composition according to claim 8, wherein the lyophilized powder or cake is essentially free from aggregates, lumps, and / or lyophilization defects.

10. The lyophilized pharmaceutical composition according to claim 8, wherein the lyophilized powder or cake retains at least about 90% of the potency (% assay) of copper histidate in the pharmaceutical composition, as determined by ultraviolet-visible spectroscopy, after being stored at 2°C to 8°C for 6 months.

11. The lyophilized pharmaceutical composition according to claim 8, wherein the lyophilized powder or cake does not contain more than 2.0% by weight of total copper histidine impurities as determined by HPLC.

12. A lyophilized pharmaceutical composition comprising copper histidine and one or more pharmaceutically acceptable excipients, wherein the lyophilized pharmaceutical composition provides a clear solution when mixed with sterile water.

13. The freeze-dried pharmaceutical composition according to claim 12, wherein the solution remains clear even after being stored at 100°C for 24 hours.

14. The lyophilized pharmaceutical composition according to claim 12, wherein the solution remains clear even after being stored at 25°C and 60% RH for one month.

15. The lyophilized pharmaceutical composition according to claim 12, wherein the solution has a pH of about 7.0 to about 7.

5.

16. The lyophilized pharmaceutical composition according to claim 12, wherein the solution contains approximately 2.9 mg / mL of copper histidate.

17. The lyophilized pharmaceutical composition according to claim 16, wherein the solution is intended for administration via a subcutaneous route in a dose of approximately 0.5 mL of solution.

18. A lyophilized pharmaceutical composition comprising copper histidate and one or more pharmaceutically acceptable excipients, wherein the lyophilized pharmaceutical composition provides a clear solution when mixed with water, and the solution has an osmotic pressure value ranging from about 300 mOsm / kg to about 380 mOsm / kg.

19. A process for preparing a lyophilized pharmaceutical composition comprising copper histidine, sodium chloride, and one or more pH adjusters, comprising the following steps: (a) Dissolve copper(II) chloride dihydrate in water to obtain a solution of copper(II) chloride dihydrate. (b) Dissolve L-histidine in water to obtain a histidine solution. (c) Mix the solutions obtained in steps (a) and (b), (d) Add sodium chloride to the solution obtained in step (c), (e) Add a pH adjuster to achieve a pH of approximately 7.0 to 7.

5. (f) Fill the container with the solution obtained in step (e), and (g) Freeze-dry the container obtained in step (f). The process including the process described above.

20. A freeze-dried pharmaceutical composition according to claim 12 for treating Menkes disease.

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