Magnesium alloy bone fracture plate and preparation method thereof

Abstract

The invention relates to the technical field of implantable medical instruments, in particular to a magnesium alloy bone fracture plate and a preparation method thereof.According to the technical scheme, the magnesium alloy bone fracture plate comprises a substrate material, a bone tissue contact face, a bone tissue outer side face and an outer layer protective film, the substrate material is made of magnesium-zinc-calcium-manganese alloy, the zinc content is 1-7%, the calcium content is 0.5-1%, the manganese content is 0.1-0.5%, and the balance is magnesium; and the balance magnesium. The bone tissue contact surface is composed of a micro-arc oxidation layer containing cerium oxide nanoparticles; the bone tissue outer side surface is composed of a hydroxyapatite coating containing a corrosion inhibitor 8-hydroxyquinoline, sodium silicate and sodium dodecyl benzene sulfonate; and the outer-layer protective film is formed by wrapping the surface of the bone fracture plate with a poly (p-xylylene chloride) coating through a chemical vapor deposition method. According to the novel magnesium alloy bone fracture plate and the preparation method thereof, through alloy component design and surface modification, local pitting corrosion is effectively prevented, and the long-term fixing stability of the bone fracture plate is kept.

Description

Technical Field

[0001] The present invention relates to the technical field of implantable medical devices, in particular to a magnesium alloy bone plate and a preparation method thereof. Background Art

[0002] Magnesium alloy is a potential orthopedic implant material due to its good biocompatibility and elastic modulus close to that of bone tissue. Compared with traditional stainless steel or titanium alloy plates, magnesium alloy plates have good biocompatibility and elastic modulus, and their performance is closer to that of bone tissue. They can reduce the stress shielding effect, promote physiological load transfer at the fracture site, and help fracture healing. At the same time, the biodegradability of magnesium alloy enables it to gradually degrade during the healing process, avoiding the long-term existence of traditional metal implants. However, there are still many challenges in the clinical application of magnesium alloy plates, especially problems such as excessively fast degradation rate, premature corrosion caused by local stress concentration, chronic inflammation, and oxidative stress.

[0003] Existing magnesium alloy bone plates primarily improve their mechanical properties by modifying the alloy composition or processing technology, and enhance their corrosion resistance by applying inorganic coatings such as calcium-phosphorus layers and micro-arc oxidation layers. Although these solutions have improved mechanical properties and corrosion resistance, they have not yet effectively addressed the delayed healing and complications caused by rapid degradation and excessive inflammatory responses in clinical applications of magnesium alloy bone plates. Therefore, there is an urgent need for a technical solution that can control the degradation rate of magnesium alloy bone plates, improve biocompatibility, and enhance bone healing.

[0004] The prior art also has the following defects during use:

[0005] Biocompatibility is not a general property of the material itself. Medical safety and clinical success depend on the nature of the interaction between the material and the recipient tissue, as well as the duration of the interaction. Current magnesium alloy bone plates often only consider in vitro physical and chemical properties, but ignore the fundamental process of implant-tissue interface reaction, making it difficult to ensure long-term safety and effectiveness during implantation. Current magnesium alloy bone plates have the following problems:

[0006] (1) After implantation, since the bone plate is often used in conjunction with screws, the bone plate bears a large extrusion force and shear force. The local stress concentration causes the local degradation cycle of the bone plate to be greatly advanced. Although the overall degradation cycle meets the requirements, the stability of the structure is lost in the early stage of degradation due to corrosion of key parts, and the implant loses its effectiveness.

[0007] (2) Excessive degradation will lead to extracellular Mg 2+The concentration increases rapidly, inhibiting the biological behavior of osteoblasts and the crystallization of hydroxyapatite (HA). Medically, this manifests as circulating monocytes secreting pro-inflammatory factors and chemokines, differentiating into M1 macrophages, while the alternately activated M2 macrophages that can produce anti-inflammatory factors, alleviate inflammation and repair damaged tissues differentiate less. Too rapid degradation brings long-term chronic inflammation, oxidative stress and reactive oxygen species (ROS) production to patients, leading to poor bone repair and delayed healing. In severe cases, bone dissolution may even occur, leading to surgical failure.

[0008] Therefore, magnesium alloy bone plates should not only consider their in vitro physicochemical properties and in vivo safety, but also maintain long-term effectiveness and support the natural healing process of living tissue. To address the poor corrosion resistance and insufficient biocompatibility of magnesium alloy bone plates, the present invention provides a novel magnesium alloy bone plate with controlled degradation, excellent bone tissue healing properties, and a method for its preparation.

[0009] In view of this, we propose a magnesium alloy bone plate and a preparation method thereof to solve the existing problems. Summary of the Invention

[0010] The object of the present invention is to provide a magnesium alloy bone plate and a preparation method thereof to solve the problems raised in the above background technology.

[0011] To achieve the above-mentioned object, the present invention provides the following technical solutions: a magnesium alloy bone plate and a preparation method thereof, comprising a base material, a bone tissue contact surface, a bone tissue outer surface, and an outer protective film:

[0012] Base material: Made of magnesium-zinc-calcium-manganese alloy, in which the zinc content is 1-7%, the calcium content is 0.5-1%, the manganese content is 0.1-0.5%, and the rest is magnesium;

[0013] Bone tissue contact surface: composed of a micro-arc oxidation layer containing cerium oxide nanoparticles;

[0014] The outer side of the bone tissue: composed of a hydroxyapatite coating containing corrosion inhibitors 8-hydroxyquinoline, sodium silicate and sodium dodecylbenzene sulfonate;

[0015] Outer protective film: A layer of poly(p-xylene chloride) coating is wrapped on the surface of the bone plate by chemical vapor deposition.

[0016] Preferably, a method for preparing a magnesium alloy bone plate is based on the magnesium alloy bone plate according to claim 1, and is characterized in that it comprises the following steps:

[0017] S1. Alloy Composition Design and Forming: A magnesium-zinc-calcium-manganese alloy is selected and processed into thin sheets through thermomechanical treatment and vacuum annealing, and then machined into shape.

[0018] S2. Pretreatment of magnesium alloy bone plates: Surface polishing, cleaning, and activation of magnesium alloy bone plates;

[0019] S3. Micro-arc oxidation treatment of the bone tissue contact surface: Preparation of a micro-arc oxidation layer containing cerium oxide nanoparticles on the bone tissue contact surface;

[0020] S4. Preparation of hydroxyapatite coating on the outer surface of bone tissue: A hydroxyapatite coating was prepared on the outer surface of bone tissue by microwave hydration.

[0021] S5. Preparation of poly(p-xylene chloride) protective film: A poly(p-xylene chloride) protective film is prepared on the surface of the bone plate by vapor deposition.

[0022] Preferably, the micro-arc oxidation layer on the bone tissue contact surface contains cerium oxide nanoparticles, which have the functions of scavenging free radicals and alleviating oxidative stress, while enhancing the conductivity of bone tissue and promoting cell adhesion. The coating thickness is 13-22 μm and its surface porosity is 15-30%.

[0023] Preferably, the hydroxyapatite coating on the outer surface of the bone tissue contains corrosion inhibitors 8-hydroxyquinoline, sodium silicate and sodium dodecylbenzenesulfonate, has good coating uniformity, biocompatibility and corrosion resistance, and helps to maintain the structural stability of the bone plate during long-term use. The coating thickness is 11-20 μm, and its surface roughness Ra is less than 0.3 μm.

[0024] Preferably, the poly(p-xylene chloride) coating on the outer protective film can reduce the contact between the magnesium alloy and body fluids, effectively control the degradation rate of the magnesium alloy, and provide biologically inert protection. The thickness of the poly(p-xylene chloride) coating is preferably 1-5 μm, its surface roughness Ra is 3-4 μm, and the sample surface adhesion is above 20 MPa.

[0025] Preferably, in the electrolyte treated by micro-arc oxidation, the dissolution order is sodium hydroxide, sodium silicate nonahydrate and sodium tetraborate decahydrate, with concentrations of 20-40 mg / mL, 90-180 mg / mL and 90-190 mg / mL, respectively. Finally, cerium oxide nanoparticles are added with a particle size of <25 nm and a final concentration of 0.6-1.0 mg / mL. Ultrasonic dispersion for 10-15 minutes is required before addition to avoid agglomeration.

[0026] Preferably, the coating solution for the hydroxyapatite coating on the outer surface of bone tissue is added in the following order: sodium dodecylbenzenesulfonate, 8-hydroxyquinoline, sodium silicate, sodium dihydrogen phosphate, and calcium nitrate tetrahydrate, with concentrations of 1.4-4.2 mg / mL, 0.5-0.55 mg / mL, 3-15 mg / mL, 36.0 mg / mL, and 118 mg / mL, respectively. After each addition, the solution is stirred until completely dissolved. Finally, the pH is adjusted to 7.5-9.5.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] 1. The present invention develops a new type of magnesium alloy bone plate and its preparation method, which effectively prevents local pitting corrosion and maintains the long-term fixation stability of the bone plate through alloy composition design and processing.

[0029] 2. The present invention designs a new type of magnesium alloy bone plate coating. The bone tissue contact surface of the bone plate is designed with a dual-functional coating of immunomodulation and bone growth promotion, which can inhibit the polarization of M1 macrophages after implantation, activate M2 macrophages to secrete osteoblast-related cytokines, eliminate reactive oxygen and inflammatory factors, stimulate fibroblasts and promote collagen synthesis, promote bone conduction, and accelerate the bone repair process; the outer surface of the bone tissue is composed of a hydroxyapatite coating containing corrosion inhibitors 8-hydroxyquinoline, sodium silicate and sodium dodecylbenzenesulfonate, which has good biocompatibility and corrosion resistance, as well as good coating adhesion and uniformity; the outermost layer of the bone plate is designed with a smooth and dense waterproof polymer coating. On the outer surface that is in more contact with body fluids, this smooth and dense coating design can well protect the magnesium alloy bone plate from early corrosion, especially avoiding the stress corrosion problem caused by stress load at the connection between the pressurized locking screw and the bone plate. This design can not only prevent the overall degradation rate of the bone plate from being accelerated due to local corrosion, but also avoid the risk of decreased fixation stability and loss of functionality;

[0030] Through the dual optimization of material innovation and coating design, the present invention significantly improves the corrosion resistance, biocompatibility and bone repair efficiency of magnesium alloy bone plates, and has important clinical application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 Schematic diagram of the hydroxyapatite coating on the outer side of the bone tissue of the magnesium alloy bone plate;

[0032] Figure 2 Schematic diagram of the micro-arc oxidation layer on the bone tissue contact surface of the magnesium alloy bone plate;

[0033] Figure 3 This is a schematic diagram of the outermost poly(p-xylene chloride) protective film of the magnesium alloy bone plate;

[0034] Figure 4 Polarization curves of different samples in SBF solution;

[0035] Figure 5 is the expression level of osteogenesis-related gene COL1A1 (*P<0.05). DETAILED DESCRIPTION

[0036] The technical solution of the present invention is further described below with reference to the accompanying drawings and specific embodiments.

[0037] Example 1

[0038] A medical magnesium alloy bone plate, such as Figure 1-Figure 3 As stated, Figure 1-Figure 3 All are schematic diagrams of the structure of magnesium alloy bone plates;

[0039] Base material: Made of magnesium-zinc-calcium-manganese alloy, in which the zinc content is 1-7%, the calcium content is 0.5-1%, the manganese content is 0.1-0.5%, and the rest is magnesium;

[0040] Bone tissue contact surface: composed of a micro-arc oxidation layer containing cerium oxide nanoparticles;

[0041] The outer side of the bone tissue: composed of a hydroxyapatite coating containing corrosion inhibitors 8-hydroxyquinoline, sodium silicate and sodium dodecylbenzene sulfonate;

[0042] Outer protective film: A layer of poly(p-xylene chloride) coating is wrapped on the surface of the bone plate by chemical vapor deposition.

[0043] A method for preparing a medical magnesium alloy bone plate comprises the following steps:

[0044] S1. Alloy composition design and forming

[0045] Alloy Composition: A magnesium-zinc-calcium-manganese alloy is selected, containing 1% zinc, 1% calcium, 0.5% manganese, and the remainder magnesium. The magnesium alloy is processed into thin plates through thermomechanical treatment and vacuum annealing, and then machined according to the design drawings of the screw-type metal locking bone plate.

[0046] S2. Pretreatment of magnesium alloy bone plates

[0047] Surface treatment: The magnesium alloy bone plate was polished with 400# to 2000# silicon carbide sandpaper in sequence until the surface was smooth, and then ultrasonically cleaned with deionized water and ethanol three times, each time for 15 minutes, to remove surface oil and impurities, and finally dried with nitrogen.

[0048] Surface activation: Immerse the sample in a 40 mg / mL sodium hydroxide solution at 60°C for 1 hour for surface activation. Rinse thoroughly with distilled water and dry at 60°C for later use.

[0049] S3. Micro-arc oxidation treatment of bone tissue contact surface

[0050] Sample preparation: The lower surface of the magnesium alloy bone plate was exposed, and the remaining surfaces were sealed with epoxy resin.

[0051] Prepare the electrolyte: first dissolve sodium hydroxide, then add sodium silicate nonahydrate and sodium tetraborate decahydrate in sequence at concentrations of 20 mg / mL, 90 mg / mL, and 90 mg / mL, respectively. Finally, add cerium oxide nanoparticles (particle size <25 nm, final concentration 0.6 mg / mL, ultrasonically disperse for 10 minutes before addition to avoid agglomeration).

[0052] Micro-arc oxidation treatment: Micro-arc oxidation treatment is performed on the bone tissue contact surface with a current density of 20mA / cm 2 , the pulse frequency is 400 Hz, the duty cycle is 20%, the temperature is 20 ° C, and the processing time is 15 minutes.

[0053] Sealing treatment: The samples were sealed with a sodium silicate solution (25 mg / mL) for 15 minutes at 20°C. After sealing, the sample surface was rinsed with distilled water and dried at 50°C for 4 hours to ensure that the sealed film layer was uniform and dry.

[0054] S4. Preparation of Hydroxyapatite Coating on the External Surface of Bone Tissue

[0055] Solution Preparation: Add sodium dodecylbenzenesulfonate, 8-hydroxyquinoline, sodium silicate, sodium dihydrogen phosphate, and calcium nitrate tetrahydrate to water in the order specified, to concentrations of 1.4 mg / mL, 0.5 mg / mL, 3 mg / mL, 36.0 mg / mL, and 118 mg / mL, respectively. Stir each time until completely dissolved to ensure a homogeneous solution. Finally, adjust the pH to 7.5.

[0056] Microwave hydration: The epoxy resin on the surface of the magnesium alloy plate was removed, and the outer surface of the bone tissue sample was immersed in the coating solution. The sample was placed in a microwave chemical reactor, with an initial heating rate of 30°C / min, a microwave power of 2000W, and a heating time of 5 minutes. After heating, the sample was removed, rinsed with distilled water, and dried in an oven at 60°C for 2 hours.

[0057] S5. Preparation of poly(p-xylene chloride) protective film

[0058] Vapor deposition method: The vapor deposition method was used to prepare a poly(p-xylene chloride) protective film on the outermost layer of the magnesium alloy bone plate specimen, with a film thickness of 1 μm.

[0059] Example 2

[0060] A medical magnesium alloy bone plate and a preparation method thereof, comprising the following steps:

[0061] S1. Alloy composition design and forming

[0062] Alloy Composition: A magnesium-zinc-calcium-manganese alloy is selected, containing 7% zinc, 0.5% calcium, 0.1% manganese, and the remainder magnesium. The magnesium alloy is processed into thin sheets through thermomechanical treatment and vacuum annealing, and then machined according to the design drawings of the screw-type metal locking bone plate.

[0063] S2. Pretreatment of magnesium alloy bone plates

[0064] Surface treatment: The magnesium alloy bone plate was polished with 400# to 2000# silicon carbide sandpaper in sequence until the surface was smooth, and then ultrasonically cleaned with deionized water and ethanol three times, each time for 20 minutes to remove surface oil and impurities, and finally dried with nitrogen.

[0065] Surface activation: Immerse the sample in a 60 mg / mL sodium hydroxide solution and treat at 80°C for 1 hour for surface activation. Rinse thoroughly with distilled water and dry at 60°C for later use.

[0066] S3. Micro-arc oxidation treatment of bone tissue contact surface

[0067] Sample preparation: The lower surface of the magnesium alloy bone plate was exposed, and the remaining surfaces were sealed with epoxy resin.

[0068] Prepare the electrolyte: First dissolve sodium hydroxide, then add sodium silicate nonahydrate and sodium tetraborate decahydrate in sequence at concentrations of 40 mg / mL, 180 mg / mL, and 190 mg / mL, respectively. Finally, add cerium oxide nanoparticles (particle size <25 nm, final concentration 1.0 mg / mL, ultrasonically disperse for 15 minutes before addition to avoid agglomeration).

[0069] Micro-arc oxidation treatment: The bone tissue contact surface is subjected to micro-arc oxidation treatment with a current density of 40mA / cm 2 , the pulse frequency is 1000 Hz, the duty cycle is 20%, the temperature is 25 ° C, and the processing time is 10 minutes.

[0070] Sealing treatment: The samples were sealed with a sodium silicate solution (30 mg / mL) for 30 minutes at 40°C. After sealing, the sample surface was rinsed with distilled water and dried at 60°C for 2 hours to ensure that the sealed film layer was uniform and dry.

[0071] S4. Preparation of Hydroxyapatite Coating on the External Surface of Bone Tissue

[0072] Solution Preparation: Add sodium dodecylbenzenesulfonate, 8-hydroxyquinoline, sodium silicate, sodium dihydrogen phosphate, and calcium nitrate tetrahydrate to water in the order specified, to concentrations of 4.2 mg / mL, 0.55 mg / mL, 15 mg / mL, 36.0 mg / mL, and 118 mg / mL, respectively. Stir each time until completely dissolved to ensure a homogeneous solution. Finally, adjust the pH to 9.5.

[0073] Microwave hydration: The epoxy resin on the surface of the magnesium alloy plate was removed, and the outer surface of the bone tissue sample was immersed in the coating solution. The sample was placed in a microwave chemical reactor, with an initial heating rate of 30°C / min, a microwave power of 2000W, and a heating time of 10 minutes. After heating, the sample was removed, rinsed with distilled water, and dried in an oven at 60°C for 2 hours.

[0074] S5. Preparation of poly(p-xylene chloride) protective film

[0075] Vapor deposition method: The vapor deposition method was used to prepare a poly(p-xylene chloride) protective film on the outermost layer of the magnesium alloy bone plate specimen, with a film thickness of 5 μm.

[0076] Comparative Example 1

[0077] A medical magnesium alloy bone plate and a preparation method thereof, comprising the following steps:

[0078] A magnesium-zinc-calcium-manganese alloy containing 4% zinc, 1% calcium, 0.5% manganese, and the remainder magnesium is selected. The magnesium alloy is processed into a thin plate through thermomechanical treatment and vacuum annealing, and then machined according to the design of a screw-type metal locking bone plate to produce a magnesium alloy bone plate.

[0079] Performance characterization:

[0080] Figure 4 Polarization curves of the embodiment and the comparative example in SBF solution are shown. The embodiment has a higher corrosion potential and better corrosion resistance than the comparative example. The potential of Example 2 is higher than that of Example 1 and Comparative Example 1 in the later stage, indicating that it has better corrosion resistance; Example 1 has a higher initial potential, but is slightly inferior to Example 2 in the later stage. The overall potential of Comparative Example 1 is lower and the corrosion resistance is poor. The results show that the samples of the present invention have excellent corrosion resistance and can ensure the stability and functionality of the magnesium alloy bone plate after implantation.

[0081] Figure 5 The expression of the adhesion gene (COL1A1) in the extracts of bone marrow mesenchymal stem cells cultured on the surfaces of the comparative and example samples was demonstrated. The results showed that the expression level of the COL1A1 gene in the example was significantly higher than that in the comparative example, indicating that the coating of the example is more conducive to promoting osteoblast differentiation. This result further demonstrates the excellent performance of the coating of the present invention in enhancing cell adhesion and promoting bone repair, providing strong support for the clinical application of orthopedic implant materials.

[0082] In summary, the present invention provides a medical magnesium alloy bone plate and a preparation method thereof. The prepared magnesium alloy bone plate has excellent corrosion resistance and biocompatibility, can effectively meet the long-term fixation requirements after implantation, and ensure the stable healing of bone tissue. At the same time, its surface coating significantly promotes the differentiation and adhesion of osteoblasts, further enhancing the bone repair effect. The present invention has good clinical application prospects and can provide a safe and reliable new solution for the field of orthopedic implants. The above specific embodiments are only several preferred embodiments of the present invention. Based on the technical solutions of the present invention and the relevant inspiration of the above embodiments, those skilled in the art can make a variety of alternative improvements and combinations to the above specific embodiments.

Claims

1. A magnesium alloy bone plate comprising a base material, a bone tissue contact surface, a bone tissue outer surface, and an outer protective film, characterized in that: Base material: Made of magnesium-zinc-calcium-manganese alloy, in which the zinc content is 1-7%, the calcium content is 0.5-1%, the manganese content is 0.1-0.5%, and the rest is magnesium; Bone tissue contact surface: composed of a micro-arc oxidation layer containing cerium oxide nanoparticles; The outer side of the bone tissue: composed of a hydroxyapatite coating containing corrosion inhibitors 8-hydroxyquinoline, sodium silicate and sodium dodecylbenzene sulfonate; Outer protective film: A layer of poly(p-xylene chloride) coating is wrapped on the surface of the bone plate by chemical vapor deposition.

2. A method for preparing a magnesium alloy bone plate, based on the magnesium alloy bone plate according to claim 1, characterized in that: The following steps are involved: S1. Alloy Composition Design and Forming: A magnesium-zinc-calcium-manganese alloy is selected and processed into thin sheets through thermomechanical treatment and vacuum annealing, and then machined into shape. S2. Pretreatment of magnesium alloy bone plates: Surface polishing, cleaning, and activation of magnesium alloy bone plates; S3. Micro-arc oxidation treatment of the bone tissue contact surface: Preparation of a micro-arc oxidation layer containing cerium oxide nanoparticles on the bone tissue contact surface; S4. Preparation of hydroxyapatite coating on the outer surface of bone tissue: A hydroxyapatite coating was prepared on the outer surface of bone tissue by microwave hydration. S5. Preparation of poly(p-xylene chloride) protective film: A poly(p-xylene chloride) protective film is prepared on the surface of the bone plate by vapor deposition.

3. The magnesium alloy bone plate according to claim 1, characterized in that: The micro-arc oxidation layer on the bone tissue contact surface contains cerium oxide nanoparticles, which can scavenge free radicals and relieve oxidative stress, while enhancing the conductivity of bone tissue and promoting cell adhesion. The coating thickness is 13-22 μm and its surface porosity is 15-30%.

4. The magnesium alloy bone plate according to claim 1, characterized in that: The hydroxyapatite coating on the outer surface of the bone tissue contains corrosion inhibitors 8-hydroxyquinoline, sodium silicate and sodium dodecylbenzenesulfonate, has good coating uniformity, biocompatibility and corrosion resistance, and helps maintain the structural stability of the bone plate during long-term use. The coating thickness is 11-20 μm and its surface roughness Ra is less than 0.3 μm.

5. The magnesium alloy bone plate according to claim 1, characterized in that: The poly(p-xylene chloride) coating on the outer protective film can reduce the contact between the magnesium alloy and body fluids, effectively control the degradation rate of the magnesium alloy, and provide biological inert protection. The thickness of the poly(p-xylene chloride) coating is preferably 1-5 μm, its surface roughness Ra is 3-4 μm, and the sample surface adhesion is above 20 MPa.

6. The method for preparing a magnesium alloy bone plate according to claim 2, wherein: In the electrolyte of micro-arc oxidation treatment, the dissolution order is sodium hydroxide, sodium silicate nonahydrate and sodium tetraborate decahydrate, with concentrations of 20-40 mg / mL, 90-180 mg / mL and 90-190 mg / mL, respectively. Finally, cerium oxide nanoparticles are added with a particle size of <25 nm and a final concentration of 0.6-1.0 mg / mL. Ultrasonic dispersion for 10-15 minutes is required before addition to avoid agglomeration.

7. The method for preparing a magnesium alloy bone plate according to claim 2, wherein: To coat the hydroxyapatite coating on the outer surface of bone tissue, the coating solution is added in the following order: sodium dodecylbenzenesulfonate, 8-hydroxyquinoline, sodium silicate, sodium dihydrogen phosphate, and calcium nitrate tetrahydrate, with concentrations of 1.4-4.2 mg / mL, 0.5-0.55 mg / mL, 3-15 mg / mL, 36.0 mg / mL, and 118 mg / mL, respectively. After each addition, stir until completely dissolved. Finally, adjust the pH to 7.5-9.5.

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